Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel.

PubMed

Kretsinger, Katrina; Broder, Karen R; Cortese, Margaret M; Joyce, M Patricia; Ortega-Sanchez, Ismael; Lee, Grace M; Tiwari, Tejpratap; Cohn, Amanda C; Slade, Barbara A; Iskander, John K; Mijalski, Christina M; Brown, Kristin H; Murphy, Trudy V

2006-12-15

On June 10, 2005, a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) formulated for use in adults and adolescents was licensed in the United States for persons aged 11-64 years (ADACEL, manufactured by sanofi pasteur, Toronto, Ontario, Canada). Prelicensure studies demonstrated safety and efficacy, inferred through immunogenicity, against tetanus, diphtheria, and pertussis when Tdap was administered as a single booster dose to adults. To reduce pertussis morbidity among adults and maintain the standard of care for tetanus and diphtheria prevention and to reduce the transmission of pertussis to infants and in health-care settings, the Advisory Committee on Immunization Practices (ACIP) recommends that: 1) adults aged 19-64 years should receive a single dose of Tdap to replace tetanus and diphtheria toxoids vaccine (Td) for booster immunization against tetanus, diphtheria, and pertussis if they received their last dose of Td >or=10 years earlier and they have not previously received Tdap; 2) intervals shorter than 10 years since the last Td may be used for booster protection against pertussis; 3) adults who have or who anticipate having close contact with an infant aged <12 months (e.g., parents, grandparents aged <65 years, child-care providers, and health-care personnel) should receive a single dose of Tdap to reduce the risk for transmitting pertussis. An interval as short as 2 years from the last Td is suggested; shorter intervals can be used. When possible, women should receive Tdap before becoming pregnant. Women who have not previously received Tdap should receive a dose of Tdap in the immediate postpartum period; 4) health-care personnel who work in hospitals or ambulatory care settings and have direct patient contact should receive a single dose of Tdap as soon as feasible if they have not previously received Tdap. An interval as short as 2 years from the last dose of Td is recommended; shorter intervals may be used. These

Transcutaneous immunization with cross-reacting material CRM(197) of diphtheria toxin boosts functional antibody levels in mice primed parenterally with adsorbed diphtheria toxoid vaccine.

PubMed

Stickings, Paul; Peyre, Marisa; Coombes, Laura; Muller, Sylviane; Rappuoli, Rino; Del Giudice, Giuseppe; Partidos, Charalambos D; Sesardic, Dorothea

2008-04-01

Transcutaneous immunization (TCI) capitalizes on the accessibility and immunocompetence of the skin, elicits protective immunity, simplifies vaccine delivery, and may be particularly advantageous when frequent boosting is required. In this study we examined the potential of TCI to boost preexisting immune responses to diphtheria in mice. The cross-reacting material (CRM(197)) of diphtheria toxin was used as the boosting antigen and was administered alone or together with either one of two commonly used mucosal adjuvants, cholera toxin (CT) and a partially detoxified mutant of heat-labile enterotoxin of Escherichia coli (LTR72). We report that TCI with CRM(197) significantly boosted preexisting immune responses elicited after parenteral priming with aluminum hydroxide-adsorbed diphtheria toxoid (DTxd) vaccine. In the presence of LTR72 as an adjuvant, toxin-neutralizing antibody titers were significantly higher than those elicited by CRM(197) alone and were comparable to the functional antibody levels induced after parenteral booster immunization with the adsorbed DTxd vaccine. Time course study showed that high levels of toxin-neutralizing antibodies persisted for at least 14 weeks after the transcutaneous boost. In addition, TCI resulted in a vigorous antigen-specific proliferative response in all groups of mice boosted with the CRM(197) protein. These findings highlight the promising prospect of using booster administrations of CRM(197) via the transcutaneous route to establish good herd immunity against diphtheria.

Comparison of CRM197, diphtheria toxoid and tetanus toxoid as protein carriers for meningococcal glycoconjugate vaccines.

PubMed

Tontini, M; Berti, F; Romano, M R; Proietti, D; Zambonelli, C; Bottomley, M J; De Gregorio, E; Del Giudice, G; Rappuoli, R; Costantino, P; Brogioni, G; Balocchi, C; Biancucci, M; Malito, E

2013-10-01

Glycoconjugate vaccines are among the most effective and safest vaccines ever developed. Diphtheria toxoid (DT), tetanus toxoid (TT) and CRM197 have been mostly used as protein carriers in licensed vaccines. We evaluated the immunogenicity of serogroup A, C, W-135 and Y meningococcal oligosaccharides conjugated to CRM197, DT and TT in naïve mice. The three carriers were equally efficient in inducing an immune response against the carbohydrate moiety in immunologically naïve mice. The effect of previous exposure to different dosages of the carrier protein on the anti-carbohydrate response was studied using serogroup A meningococcal (MenA) saccharide conjugates as a model. CRM197 showed a strong propensity to positively prime the anti-carbohydrate response elicited by its conjugates or those with the antigenically related carrier DT. Conversely in any of the tested conditions TT priming did not result in enhancement of the anti-carbohydrate response elicited by the corresponding conjugates. Repeated exposure of mice to TT or to CRM197 before immunization with the respective MenA conjugates resulted in a drastic suppression of the anti-carbohydrate response in the case of TT conjugate and only in a slight reduction in the case of CRM197. The effect of carrier priming on the anti-MenA response of DT-based conjugates varied depending on their carbohydrate to protein ratio. These data may have implications for human vaccination since conjugate vaccines are widely used in individuals previously immunized with DT and TT carrier proteins. Copyright © 2013 Elsevier Ltd. All rights reserved.

Diphtheria in the United States, 1971-81.

PubMed Central

Chen, R T; Broome, C V; Weinstein, R A; Weaver, R; Tsai, T F

1985-01-01

After a decade-long resurgence, including a large cutaneous diphtheria outbreak in Washington State, the diphtheria incidence rate in the United States reached its lowest recorded level ever in 1980--two patients (0.01 case per million). Mortality paralleled the decline in incidence rate. Only 143 of the 3,141 US counties reported noncutaneous diphtheria patients during 1971-81; most were located in the West. The highest attack rates were experienced by children less than 15 years old (0.8 case per million) and by American Indians (22.6 cases per million). Persons immunized with three or more doses of diphtheria toxoid had a lower death-to-case ratio (1.3 per cent) than totally unimmunized persons (13.4 per cent). The reasons for the dramatic decline in diphtheria incidence rates are unclear, although it has been postulated that the gene for producing diphtheria toxin may be lost from organisms in highly immunized populations. Significant proportions of the adult and elderly populations are susceptible to diphtheria. Continuation of primary immunization with increased emphasis on the routine use of tetanus and diphtheria toxoids (Td) boosters in adults should ensure that diphtheria will remain largely a scourge of the past. PMID:4061710

Postbooster Antibodies from Humans as Source of Diphtheria Antitoxin

PubMed Central

Avila-Alonso, Ana; González-Rivera, Milagros; Tamayo, Eduardo; Eiros, Jose María; Almansa, Raquel

2016-01-01

Diphtheria antitoxin for therapeutic use is in limited supply. A potential source might be affinity-purified antibodies originally derived from plasma of adults who received a booster dose of a vaccine containing diphtheria toxoid. These antibodies might be useful for treating even severe cases of diphtheria. PMID:27314309

Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older - Advisory Committee on Immunization Practices (ACIP), 2012.

PubMed

2012-06-29

Since 2005, the Advisory Committee on Immunization Practices (ACIP) has recommended a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine booster dose for all adolescents aged 11 through 18 years (preferred at 11 through 12 years) and for those adults aged 19 through 64 years who have not yet received a dose. In October 2010, despite the lack of an approved Tdap vaccine for adults aged 65 years and older, ACIP recommended that unvaccinated adults aged 65 years and older be vaccinated with Tdap if in close contact with an infant, and that other adults aged 65 years and older may receive Tdap. In July 2011, the Food and Drug Administration (FDA) approved expanding the age indication for Boostrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) to aged 65 years and older. In February 2012, ACIP recommended Tdap for all adults aged 65 years and older. This recommendation supersedes previous Tdap recommendations regarding adults aged 65 years and older.

Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women--Advisory Committee on Immunization Practices (ACIP), 2012.

PubMed

2013-02-22

In October 2011, in an effort to reduce the burden of pertussis in infants, the Advisory Committee on Immunization Practices (ACIP) recommended that unvaccinated pregnant women receive a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap). Vaccination of women with Tdap during pregnancy is expected to provide some protection to infants from pertussis until they are old enough to be vaccinated themselves. Tdap given to pregnant women will stimulate the development of maternal antipertussis antibodies, which will pass through the placenta, likely providing the newborn with protection against pertussis in early life, and will protect the mother from pertussis around the time of delivery, making her less likely to become infected and transmit pertussis to her infant. The 2011 Tdap recommendation did not call for vaccinating pregnant women previously vaccinated with Tdap. On October 24, 2012, ACIP voted to recommend use of Tdap during every pregnancy. This report summarizes data considered and conclusions made by ACIP and provides guidance for implementing its recommendations. These updated recommendations on use of Tdap in pregnant women aim to optimize strategies for preventing pertussis morbidity and mortality in infants.

Cost-benefit analysis of hospital based postpartum vaccination with combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap).

PubMed

Ding, Yao; Yeh, Sylvia H; Mink, Chris Anna M; Zangwill, Kenneth M; Allred, Norma J; Hay, Joel W

2013-05-24

To assess the economic benefits associated with hospital-based postpartum Tdap (combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccination. A decision tree model was constructed to calculate the potential cost-benefit of this strategy from both a health care system and a societal perspective. Probabilities and costs were derived from published literature, data reported to Centers for Disease Control and Prevention, and recommendations from expert panels. The maternal vaccination protection period for infants was defined as 7 months, and 10 years of waning immunity following Tdap for birth mothers was estimated in the model. All cost estimates were inflated to year 2012 US dollars and discounted at a 3% annual discount rate. In the base case from a societal perspective, the expected costs per vaccinated and unvaccinated mother were estimated at $129.27 and $187.97, respectively, suggesting an expected net benefit of $58.70 per vaccinated mother. The overall societal benefits in the cohort of 3.6 million U.S. birth mothers ranged from $52.8-126.8 million, depending on the vaccination coverage level. If including direct medical costs only, the strategy would not generate net savings from a health care system perspective. Annual incidence of pertussis in birth mothers and Tdap efficacy exhibited substantial impact on the model as shown in one-way and two-way sensitivity analyses. Although postpartum Tdap vaccination is not cost-beneficial from a health care system perspective in the base case, this strategy is likely to generate net benefits from a societal perspective. Copyright © 2013 Elsevier Ltd. All rights reserved.

Outbreak of pyogenic abscesses after diphtheria and tetanus toxoids and pertussis vaccination.

PubMed

Simon, P A; Chen, R T; Elliott, J A; Schwartz, B

1993-05-01

Nine children who received diphtheria and tetanus toxoids and pertussis vaccine from the same vial at a clinic in Colorado developed pyogenic abscesses at the site of injection. Eight abscesses required surgical drainage and five children were hospitalized. Group A Streptococcus (GAS) was cultured from eight wounds and Staphylococcus aureus was also isolated from four. Epidemiologic investigation revealed that within the hour of the first child's vaccination, three children had been diagnosed in the clinic with GAS pharyngitis. GAS recovered from repeat throat swabs from two of these children and the eight case-isolates were all serotype M-12, T-12 and had identical immunoblot patterns on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Laboratory simulation studies demonstrated that GAS can survive for at least 4 days on the external surface of a vaccine vial rubber stopper and contaminate needles inserted through the stopper. Swabbing the stopper with 70% isopropyl alcohol resulted in effective disinfection. To prevent potential contamination meticulous attention to sterile technique is important when withdrawing vaccine from multidose vaccine vials.

In vitro pyrogenicity of the diphtheria, tetanus and acellular pertussis components of a trivalent vaccine.

PubMed

Carlin, Gunnar; Viitanen, Eila

2005-05-25

We have earlier found that a trivalent vaccine, containing antigenic components from both Gram-positive and Gram-negative bacteria, induced secretion of the endogenous pyrogen interleukin 6 (IL-6) when added to fresh human blood in vitro. The results of the present study showed that the IL-6 secretion was induced by toxoids derived from the Gram-positive bacterium Corynebacterium diphtheriae. However, fresh whole blood from different donors reacted differently to the stimulation. The blood from some donors induced secretion of large concentrations of IL-6, while the blood from other donors induced essentially no IL-6 secretion as a response to stimulation with diphtheria toxoid or a mixture of diphtheria and tetanus toxoids. Repeated testing over several years using blood from the same donor confirmed a donor-dependency of the reaction. This donor-dependency was only found for the toxoid, since blood from all donors reacted with approximately similar IL-6 production to stimulation by endotoxin from the Gram-negative bacterium Escherichia coli, known to be mediated via the toll-like receptor (TLR) 4. Also, no donor-dependecy was found to highly purified lipoteichoic acid from the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus, known to be mediated via TLR-2 and TLR-6. The receptors involved in stimulation by diphtheria toxoid are not known, but may differ from those used by endotoxin and lipoteichoic acid.

Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP)

PubMed Central

Tiwari, Tejpratap; Moro, Pedro; Messonnier, Nancy E.; Reingold, Arthur; Sawyer, Mark; Clark, Thomas A.

2018-01-01

Summary This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of tetanus, diphtheria, and pertussis in the United States. As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations and replaces all previously published reports and policy notes; it is intended for use by clinicians and public health providers as a resource. ACIP recommends routine vaccination for tetanus, diphtheria, and pertussis. Infants and young children are recommended to receive a 5-dose series of diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, with one adolescent booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Adults who have never received Tdap also are recommended to receive a booster dose of Tdap. Women are recommended to receive a dose of Tdap during each pregnancy, which should be administered from 27 through 36 weeks’ gestation, regardless of previous receipt of Tdap. After receipt of Tdap, adolescents and adults are recommended to receive a booster tetanus and diphtheria toxoids (Td) vaccine every 10 years to assure ongoing protection against tetanus and diphtheria. PMID:29702631

Meningococcal Conjugate and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccination Among HIV-infected Youth.

PubMed

Setse, Rosanna W; Siberry, George K; Moss, William J; Wheeling, John; Bohannon, Beverly A; Dominguez, Kenneth L

2016-05-01

The meningococcal conjugate vaccine (MCV4) and the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) were first recommended for adolescents in the US in 2005. The goal of our study was to determine MCV4 and Tdap vaccines coverage among perinatally and behaviorally HIV-infected adolescents in 2006 and to compare coverage estimates in our study population to similarly aged healthy youth in 2006. Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) is a retrospective cohort study of HIV-infected youth in 22 HIV specialty clinics across the US. Among LEGACY participants ≥11 years of age in 2006, we conducted a cross-sectional analysis to determine MCV4, Tdap and MCV4/Tdap vaccine coverage. We compared vaccine coverage among our study population to coverage among similarly aged youth in the 2006 National Immunization Survey for Teens (NIS-Teen Survey). Multivariable mixed effects logistic regression modeling was used to examine associations between MCV4/Tdap vaccination and mode of HIV transmission. MCV4 and Tdap coverage rates among 326 eligible participants were 31.6% and 28.8%, respectively. Among adolescents 13-17 years of age, MCV4 and Tdap coverage was significantly higher among HIV-infected youth than among youth in the 2006 NIS-Teen Survey (P <0.01). In multivariable analysis, perinatally HIV-infected youth were significantly more likely to have received MCV4/Tdap vaccination compared with their behaviorally infected counterparts (adjusted odds ratio: 5.1; 95% confidence interval: 2.0, 12.7). HIV-infected youth with CD4 cell counts of 200-499 cells/μL were more likely to have had MCV4/Tdap vaccination compared with those with CD4 counts ≥500 cells/μL (adjusted odds ratio: 2.2; 95% confidence interval: 1.2, 4.3). Participants with plasma HIV RNA viral loads of >400 copies/mL were significantly less likely to have received MCV4/Tdap vaccination (P < 0.05). MCV4 and Tdap coverage among

[Diphtheria in the military forces: lessons and current status of prophylaxis, prospects of epidemiological control process].

PubMed

Belov, A B; Ogarkov, P I

2014-01-01

We analyzed the epidemiological situation of diphtheria in the world and in Russia and experience of mass vaccination of military personnel and civil population with diphtheria toxoid for the last 50 years. Early diagnosis of diphtheria in military personnel has a prognostic value. Authors described the peculiarities of epidemiological process of diphtheria in military personnel in 80-90 years of 20th century and organizational aspects of mass vaccination with diphtheria toxoid. Authors analyzed current problems of epidemiology and prophylaxis of diphtheria in military personnel and civil population and possible developments. According to long-term prognosis authors mentioned the increase of morbidity and came to conclusion that it is necessary enhance the epidemiological surveillance. Authors presented prospect ways of improvement of vaccination and rational approaches to immunization of military personnel under positive long-term epidemiological situation.

Association of a Best-Practice Alert and Prenatal Administration With Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccination Rates.

PubMed

Morgan, Jamie L; Baggari, Sangameshwar R; Chung, Wendy; Ritch, Julia; McIntire, Donald D; Sheffield, Jeanne S

2015-08-01

To evaluate how implementation of a best-practice alert, a reminder of clinical guidelines within the electronic medical record, in combination with the recommended change in immunization timing from postpartum to antepartum, affected tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) rates, and to examine the association of vaccination with local pertussis attack rates. A Tdap best-practice alert was introduced into the electronic prenatal charting system in June 2013. The best-practice alert was designed to appear starting at 32 weeks of gestation and to reappear at every subsequent encounter until vaccine acceptance was recorded or delivery occurred. The overall acceptance rate was then compared with postpartum vaccination rates at our institution from the previous year. Records of pertussis cases in children younger than 2 years of age diagnosed since 2012 in Dallas County were also reviewed to correlate local trends with vaccination efforts. Of the 10,201 women offered Tdap during prenatal care, 9,879 (96.8%) ultimately accepted. This is compared with a 48% (5,064 of 10,600) Tdap postpartum immunization rate in the year prior, before introduction of the best-practice alert. The incidence of pertussis among neonates born to mothers who received prenatal care at Parkland Hospital showed a nonsignificant decline from 13 cases per 10,000 deliveries (19 of 14,834, 95% confidence interval [CI] 7-19) between January 2012 and May 2013 to seven per 10,000 deliveries during the study period (eight of 11,788, 95% CI 2-11, P=.174). The use of a best-practice alert, in concert with the recommended change in timing of maternal vaccination from postpartum to antepartum, was associated with an increase in the Tdap immunization rate to 97%. II.

Infant pertussis epidemiology and implications for tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination: King County, Washington, 2002 through 2007.

PubMed

Hanson, Matthew P; Kwan-Gett, Tao S; Baer, Atar; Rietberg, Krista; Ohrt, Mara; Duchin, Jeffrey S

2011-07-01

To describe the epidemiology of infant pertussis in King County, Washington, and to better understand the implications for tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination among older children, adolescents, and adults. Retrospective analysis of reported pertussis cases among infants younger than 1 year, January 1, 2002, through December 31, 2007. King County, Washington. Reported pertussis cases among infants younger than 1 year between 2002 and 2007. Bordetella pertussis from a household member or close contact was the primary exposure. The main outcome measures were age and vaccination status, incidence by race/ethnicity, suspected exposure, and Tdap eligibility of household members and close contacts. Among 176 confirmed cases of infants with pertussis, the median age was 3 months (age range, 0-11 months); 80.1% were younger than 6 months. Seventy-seven percent were age-appropriately vaccinated. Between 2002 and 2007, the overall mean annual incidence was 136 cases per 100,000 infant population. Compared with a mean annual incidence of 73 cases per 100,000 infant population among whites, the incidence was 246 cases per 100,000 infant population among blacks (rate ratio [RR], 3.37; 95% confidence interval [CI], 2.59-4.44) and 194 cases per 100,000 infant population among Hispanics (RR, 2.66; 95% CI, 2.02-3.53). Households were the suspected exposure location for 70.0% of cases. Case households had a median of 3 (range, 1-15) Tdap-eligible persons. The burden of infant pertussis in King County, Washington, was high between 2002 and 2007, especially among racial/ethnic minorities. Tdap vaccination of eligible household members and close contacts should be promoted as an additional means of protecting infants from pertussis.

Microbe Profile: Corynebacterium diphtheriae - an old foe always ready to seize opportunity.

PubMed

Hoskisson, Paul A

2018-02-21

Corynebacterium diphtheriae is a globally important Gram-positive aerobic Actinobacterium capable of causing the toxin-mediated disease, diphtheria. Diphtheria was a major cause of childhood mortality prior to the introduction of the toxoid vaccine, yet it is capable of rapid resurgence following the breakdown of healthcare provision, vaccination or displacement of people. The mechanism and treatment of toxin-mediated disease is well understood, however there are key gaps in our knowledge on the basic biology of C. diphtheriae particularly relating to host colonisation, the nature of asymptomatic carriage, population genomics and host adaptation.

Diphtheria toxoid loaded poly-(epsilon-caprolactone) nanoparticles as mucosal vaccine delivery systems.

PubMed

Singh, Jasvinder; Pandit, Sreenivas; Bramwell, Vincent W; Alpar, H Oya

2006-02-01

Poly-(epsilon-caprolactone) (PCL), a poly(lactide-co-glycolide) (PLGA)-PCL blend and co-polymer nanoparticles encapsulating diphtheria toxoid (DT) were investigated for their potential as a mucosal vaccine delivery system. The nanoparticles, prepared using a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation method, demonstrated release profiles which were dependent on the properties of the polymers. An in vitro experiment using Caco-2 cells showed significantly higher uptake of PCL nanoparticles in comparison to polymeric PLGA, the PLGA-PCL blend and co-polymer nanoparticles. The highest uptake mediated by the most hydrophobic nanoparticles using Caco-2 cells was mirrored in the in vivo studies following nasal administration. PCL nanoparticles induced DT serum specific IgG antibody responses significantly higher than PLGA. A significant positive correlation between hydrophobicity of the nanoparticles and the immune response was observed following intramuscular administration. The positive correlation between hydrophobicity of the nanoparticles and serum DT specific IgG antibody response was also observed after intranasal administration of the nanoparticles. The cytokine assays showed that the serum IgG antibody response induced is different according to the route of administration, indicated by the differential levels of IL-6 and IFN-gamma. The nanoparticles eliciting the highest IgG antibody response did not necessarily elicit the highest levels of the cytokines IL-6 and IFN-gamma.

The diphtheria vaccine debacle of 1940 that ushered in comprehensive childhood immunization in the United Kingdom.

PubMed

Mortimer, P P

2011-04-01

In January 1940 British Ministry of Health circular 1307 proposed the introduction of mass childhood diphtheria immunization. This was a policy reversal after a decade during which opportunities for diphtheria prophylaxis were ignored, or resisted on grounds of cost. Diphtheria toxoid was to be the first of many centrally funded childhood immunizations in the UK and it set a pattern that has now held good for over 70 years. The circumstances in 1940 were particularly fortuitous, and diphtheria toxoid has since given successive generations of children a lifetime's protection from the disease; but difficulties have been experienced in introducing and evaluating some of the more recent immunizations, and in maintaining and justifying them in the face of parental scepticism and academic or pressure-group opposition, however ill-founded this may have been. The task of decision-making with regard to new candidate vaccines demands a careful balancing against the costs of the expected benefits during the recipient's lifespan.

Adjuvant action of melittin following intranasal immunisation with tetanus and diphtheria toxoids.

PubMed

Bramwell, V W; Somavarapu, S; Outschoorn, I; Alpar, H O

2003-01-01

Melittin, a 26-amino acid peptide and the major active component of the venom of the honey bee--Apis mellifera--has recently been shown to have absorption enhancing properties in Caco-2 cells at levels well below the level required for the generation of cytotoxicity. Given the potential of absorption enhancing agents to act as adjuvants when administered nasally [Alpar, H.O., Eyles, J.E., Williamson, E.D. and Somavarapu, S. (2001) "Intranasal vaccination against plague, tetanus and diphtheria", Adv. Drug Delivery Rev. 51, 173-201] we hypothesized that melittin may have potential as a mucosal adjuvant. Following our initial studies reported here, it was found that the co-administration of 4 microg of melittin in conjunction with tetanus toxoid in BALB/c mice was effective in eliciting markedly enhanced antibody titres in comparison to control groups and groups receiving free antigen administered intranasally. Lower concentrations of melittin were less effective and mice receiving 4 microg of melittin plus antigen exhibited antibody titres significantly higher (i.e. P<0.05) than any of the other groups tested. The observed IgG2a titres were shown to be dependent upon the dose of melittin co-administered with the immunising antigen in a similar fashion to the observed total IgG responses. In summary, melittin has been shown here to have potential as a novel mucosal adjuvant for antigens administered via the nasal route.

Multiple Diphtheria Antigen-Antibody Systems Investigated by Passive Haemagglutination Techniques and Other Methods

PubMed Central

Fulthorpe, A. J.

1962-01-01

A fair degree of correlation has been found between the in vivo antitoxin content of sera from horses immunized with crude Corynebacterium diphtheriae culture filtrates and the direct agglutinin titre of the sera when tested with sheep cells sensitized with diphtheria toxoid. Haemagglutination inhibition tests at the LA level of test with the same sera showed some rather large discrepancies from the in vivo and further tests with special agglutinin inhibiting toxins suggested that specific antitoxin free from other accessory antibodies might be non-agglutinating, and therefore not titratable by haemagglutination inhibition. The phosphate-stable, pepsin-stable and trypsin-stable antigens isolated from culture filtrates of C. diphtheriae were found to contain extremely small quantities of specific toxoid, and cross titration of each of the three antigen preparations showed that there was very little contamination by other antigens within the group. Absorption of diphtheria antiserum with red cells sensitized with each of the three accessory antigens individually, showed that the antibodies were highly specific and distinct. Absorption of diphtheria antiserum with a mixture of red cells sensitized with the three different antigens removed all demonstrable accessory antibodies, and the absorbed serum would no longer agglutinate cells sensitized with complete diphtheria toxoid. The absorbed serum, however, retained a large proportion of its neutralizing capacity for diphtheria toxin, when titrated in vivo. Titration of each of the accessory antibodies in a number of horse sera by haemagglutination inhibition demonstrated a correlation between the values for the accessory antibodies to the phosphate-stable and pepsin-stable antigens, but no correlation with the values for the antibody to the trypsin-stable antigen, when compared with results of the flocculation test. The relative proportions of diphtheria toxin and of the phosphate-stable and pepsin-stable antigens

Impact and cost-effectiveness of a second tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine dose to prevent pertussis in the United States.

PubMed

Kamiya, Hajime; Cho, Bo-Hyun; Messonnier, Mark L; Clark, Thomas A; Liang, Jennifer L

2016-04-04

The United States experienced a substantial increase in reported pertussis cases over the last decade. Since 2005, persons 11 years and older have been routinely recommended to receive a single dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine. The objective of this analysis was to evaluate the potential impact and cost-effectiveness of recommending a second dose of Tdap. A static cohort model was used to calculate the epidemiologic and economic impact of adding a second dose of Tdap at age 16 or 21 years. Projected costs and outcomes were examined from a societal perspective over a 20-year period. Quality-adjusted Life Years (QALY) saved were calculated. Using baseline pertussis incidence from the National Notifiable Diseases Surveillance System, Tdap revaccination at either age 16 or 21 years would reduce outpatient visits by 433 (5%) and 285 (4%), and hospitalization cases by 7 (7%) and 5 (5%), respectively. The costs per QALY saved with a second dose of Tdap were approximately US $19.7 million (16 years) and $26.2 million (21 years). In sensitivity analyses, incidence most influenced the model; as incidence increased, the costs per QALY decreased. To a lesser degree, initial vaccine effectiveness and waning of effectiveness also affected cost outcomes. Multivariate sensitivity analyses showed that under a set of optimistic assumptions, the cost per QALY saved would be approximately $163,361 (16 years) and $204,556 (21 years). A second dose of Tdap resulted in a slight decrease in the number of cases and other outcomes, and that trend is more apparent when revaccinating at age 16 years than at age 21 years. Both revaccination strategies had high dollar per QALY saved even under optimistic assumptions in a multivariate sensitivity analysis. Published by Elsevier Ltd.

Predictors of Low Uptake of Prenatal Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Immunization in Privately Insured Women in the United States.

PubMed

Butler, Anne M; Layton, J Bradley; Li, Dongmei; Hudgens, Michael G; Boggess, Kim A; McGrath, Leah J; Weber, David J; Becker-Dreps, Sylvia

2017-04-01

To examine the uptake of prenatal tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) immunization among pregnant women in the United States. Using MarketScan data, we conducted a historical cohort study among pregnant women with employer-based commercial insurance in the United States who delivered between January 1, 2010, and December 31, 2014. We examined temporal trends of uptake, predictors of uptake, and timing of Tdap immunization. Among 1,222,384 eligible pregnancies in 1,147,711 women, receipt of prenatal Tdap immunization increased from 0.0% of women who delivered in January 2010 to 9.8% who delivered in October 2012 (the date of the recommendation by the Advisory Committee on Immunization Practices for Tdap during every pregnancy) to 44.4% who delivered in December 2014. Among women who received Tdap during pregnancy, the majority were immunized between 27 weeks and 36 6/7 weeks of gestation per the Advisory Committee on Immunization Practices recommendation. In multivariable analyses among women who delivered between November 2012 and December 2014, rates of prenatal Tdap immunization were lower for women younger than 25 years of age (eg, 20-24 compared with 30-34 years rate ratio [RR] 0.83, 95% confidence interval [CI] 0.85-0.88), with other children (eg, three compared with zero children: RR 0.86, 95% CI 0.84-0.88), residing in the South compared with the Midwest (RR 0.81, 95% CI 0.80-0.82), or with emergency department visits in early pregnancy (RR 0.93, 95% CI 0.92-0.95). The proportion of pregnant women who received prenatal Tdap increased with increasing gestational age at birth. By the end of 2014, fewer than half of pregnant women in the United States were receiving prenatal Tdap immunization. Implementation and dissemination strategies are needed to increase Tdap coverage among pregnant women, especially those who are young, have other children, or reside in the South.

Identification of a Human Monoclonal Antibody To Replace Equine Diphtheria Antitoxin for Treatment of Diphtheria Intoxication

PubMed Central

Sevigny, Leila M.; Booth, Brian J.; Rowley, Kirk J.; Leav, Brett A.; Cheslock, Peter S.; Garrity, Kerry A.; Sloan, Susan E.; Thomas, William; Babcock, Gregory J.

2013-01-01

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic. PMID:23940209

Carrier priming with CRM 197 or diphtheria toxoid has a different impact on the immunogenicity of the respective glycoconjugates: biophysical and immunochemical interpretation.

PubMed

Pecetta, S; Lo Surdo, P; Tontini, M; Proietti, D; Zambonelli, C; Bottomley, M J; Biagini, M; Berti, F; Costantino, P; Romano, M R

2015-01-03

Glycoconjugate vaccines play an enormous role in preventing infectious diseases. The main carrier proteins used in commercial conjugate vaccines are the non-toxic mutant of diphtheria toxin (CRM197), diphtheria toxoid (DT) and tetanus toxoid (TT). Modern childhood routine vaccination schedules include the administration of several vaccines simultaneously or in close sequence, increasing the concern that the repeated exposure to conjugates based on these carrier proteins might interfere with the anti-polysaccharide response. Extending previous observations we show here that priming mice with CRM197 or DT does not suppress the response to the carbohydrate moiety of CRM197 meningococcal serogroup A (MenA) conjugates, while priming with DT can suppress the response to DT-MenA conjugates. To explain these findings we made use of biophysical and immunochemical techniques applied mainly to MenA conjugates. Differential scanning calorimetry and circular dichroism data revealed that the CRM197 structure was altered by the chemical conjugation, while DT and the formaldehyde-treated form of CRM197 were less impacted, depending on the degree of glycosylation. Investigating the binding and avidity properties of IgGs induced in mice by non-conjugated carriers, we found that CRM197 induced low levels of anti-carrier antibodies, with decreased avidity for its MenA conjugates and poor binding to DT and respective MenA conjugates. In contrast, DT induced high antibody titers able to bind with comparable avidity both the protein and its conjugates but showing very low avidity for CRM197 and related conjugates. The low intrinsic immunogenicity of CRM197 as compared to DT, the structural modifications induced by glycoconjugation and detoxification processes, resulting in conformational changes in CRM197 and DT epitopes with consequent alteration of the antibody recognition and avidity, might explain the different behavior of CRM197 and DT in a carrier priming context. Copyright © 2014

Enhanced surveillance of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines in pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 2011-2015.

PubMed

Moro, Pedro L; Cragan, Janet; Tepper, Naomi; Zheteyeva, Yenlik; Museru, Oidda; Lewis, Paige; Broder, Karen

2016-04-29

In October 2011, the Advisory Committee on Immunization Practices (ACIP) issued updated recommendations that all pregnant women routinely receive a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS) in pregnant women who received Tdap after this updated recommendation (2011-2015) and compared the pattern of adverse events (AEs) with the period before the updated recommendation (2005-2010). We searched the VAERS database for reports of AEs in pregnant women who received Tdap vaccine after the routine recommendation (11/01/2011-6/30/2015) and compared it to published data before the routine Tdap recommendation (01/01/2005-06/30/2010). We conducted clinical review of reports and available medical records. The clinical pattern of reports in the post-recommendation period was compared with the pattern before the routine Tdap recommendation. We found 392 reports of Tdap vaccination after the routine recommendation. One neonatal death but no maternal deaths were reported. No maternal or neonatal deaths were reported before the recommendation. We observed an increase in proportion of reports for stillbirths (1.5-2.8%) and injection site reactions/arm pain (4.5-11.9%) after the recommendation compared to the period before the routine recommendation for Tdap during pregnancy. We noted a decrease in reports of spontaneous abortion (16.7-1%). After the 2011 Tdap recommendation, in most reports, vaccination (79%) occurred during the third trimester compared to 4% before the 2011 Tdap recommendation. Twenty-six reports of repeat Tdap were received in VAERS; 13 did not report an AE. One medical facility accounted for 27% of all submitted reports. No new or unexpected vaccine AEs were noted among pregnant women who received Tdap after routine recommendations for maternal Tdap vaccination. Changes in reporting patterns would be expected, given the broader use of

Dot immunoassay for the simultaneous determination of postvaccination immunity against pertussis, diphtheria, and tetanus.

PubMed

Khramtsov, Pavel; Bochkova, Maria; Timganova, Valeria; Zamorina, Svetlana; Rayev, Mikhail

2017-06-01

A dot immunoassay for simultaneous semiquantitative detection of IgG against tetanus toxoid (Ttx) and diphtheria toxoid (Dtx) and qualitative detection of anti-Bordetella pertussis IgGs in human blood serum using carbon nanoparticles functionalized with streptococcal protein G was developed. Inactivated B. pertussis cells in suspension form were used as an antigen in the immunoassay. Pertussis, tetanus, and diphtheria antigens were separately spotted onto nitrocellulose strips, and then the immunostrips were successively incubated with blood sera and a suspension of carbon nanoparticles. The immunostrips were then scanned with a flatbed scanner, and the images obtained were processed with ImageJ. One hundred fifty-five venous blood serum samples from children vaccinated with diphtheria, tetanus, and whole-cell pertussis (DTwP) vaccine were tested in comparison with a conventional ELISA and agglutination test. The total time required for analysis of 32 serum samples was less than 3 h. Comparison between the results of the dot immunoassay and the corresponding ELISA/agglutination test revealed a high level of agreement (Cohen's kappa between 0.765 and 0.813). The lower limit of quantification was 0.06 IU/ml for anti-Ttx and anti-Dtx. The intra-assay coefficients of variation were less than 15% for anti-Ttx and anti-Dtx and less than 10% for anti-pertussis. The diagnostic sensitivity of detection of the antibody protection level was 93.5% for anti-Ttx [95% confidence interval (CI) 83.5-97.9%], 92.4% for anti-Dtx (95% CI 80.9297.5%), and 90.2% for anti-pertussis (95% CI 75.9-96.8%). The diagnostic specificity was 90.9% for anti-Ttx (95% CI 57.1-99.5%), 85% for anti-Dtx (95% CI 61.1-96.0%), and 89.3% for anti-pertussis (95%CI 80.8-94.5%). The dot immunoassay developed does not require expensive reading equipment, and allows detection of antibodies against three antigens in a single analysis. The immunostrips can be stored for a long time without changes in the

Licensure of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine and Guidance for Use as a Booster Dose.

PubMed

Liang, Jennifer; Wallace, Greg; Mootrey, Gina

2015-09-04

On March 24, 2015, the Food and Drug Administration licensed an additional combined diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP) and inactivated poliovirus (IPV) vaccine (DTaP-IPV) (Quadracel, Sanofi Pasteur Inc.). Quadracel is the second DTaP-IPV vaccine to be licensed for use among children aged 4 through 6 years in the United States (1). Quadracel is approved for administration as a fifth dose in the DTaP series and as a fourth or fifth dose in the IPV series in children aged 4 through 6 years who have received 4 doses of DTaP-IPV-Hib (Pentacel, Sanofi Pasteur) and/or DTaP (Daptacel, Sanofi Pasteur) vaccine (2,3). This report summarizes the indications for Quadracel vaccine and provides guidance from the Advisory Committee on Immunization Practices (ACIP) for its use.

Quadracel: Vaccination Against Diphtheria, Tetanus, Pertussis, and Poliomyelitis in Children.

PubMed

Mosley, Juan F; Smith, Lillian L; Parke, Crystal K; Brown, Jamal A; LaFrance, Justin M; Clark, Patricia K

2016-04-01

Vaccinations in school-aged children are required by state and local law to maintain high vaccination coverage rates, as well as low rates of vaccine-preventable diseases. Diphtheria, tetanus, and pertussis are childhood diseases that can be life threatening; poliomyelitis, another childhood disease, can be disabling. In turn, vaccinations were developed to provide protection against these diseases. Today, several vaccinations are recommended for children, including but not limited to diphtheria, tetanus, and pertussis (DTaP) and poliomyelitis (IPV). DTaP requires five doses, and IPV requires four. Quadracel (diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine, Sanofi Pasteur Inc.) is a new vaccination developed to condense the last dose of both DTaP and IPV so they do not have to be given separately, thus reducing the total number of vaccinations required. The Quadracel vaccine is an option for use in children who are completing the DTaP and IPV series. In a randomized, controlled, phase 3, pivotal trial, Quadracel proved to be as efficacious and safe as Daptacel (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed, Sanofi Pasteur Inc.) and IPOL (poliovirus vaccine inactivated, Sanofi Pasteur Inc.), given separately, to children between the ages of 4 and 6 years. Quadracel should be recommended to parents who have children between the ages of 4 and 6 years who meet the necessary administration criteria and need to finalize their DTaP and IPV series. Quadracel's administration in the vaccination series replaces one additional injection, which may benefit children who are afraid of receiving shots and parents who need to schedule one less doctor's appointment.

Anti-idiotypic antibodies that protect cells against the action of diphtheria toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rolf, J.M.; Gaudin, H.M.; Tirrell, S.M.

1989-03-01

An anti-idiotypic serum prepared against the combining site (idiotype) of specific anti-diphtheria toxoid antibodies was characterized with respect to its interaction with highly diphtheria toxin-sensitive Vero cells. Although the anti-idiotypic serum protected Vero cells against the cytotoxic action of diphtheria toxin, it did not prevent the binding of /sup 125/I-labeled diphtheria toxin to the cells but did inhibit the internalization and degradation of /sup 125/I-labeled toxin. This anti-idiotypic serum immunoprecipitated a cell-surface protein from radiolabeled Vero cells with an apparent Mr of approximately 15,000. These results are consistent with the hypothesis that the anti-idiotypic serum contains antibodies that carry anmore » internal image of an internalization site on the toxin and that a cell-surface protein involved in toxin internalization possesses a complementary site recognized by both the toxin and the anti-idiotypic antibodies.« less

Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months --- Advisory Committee on Immunization Practices (ACIP), 2011.

PubMed

2011-10-21

Compared with older children and adults, infants aged <12 months have substantially higher rates of pertussis and the largest burden of pertussis-related deaths. Since 2004, a mean of 3,055 infant pertussis cases with more than 19 deaths has been reported each year through the National Notifiable Diseases Surveillance System (CDC, unpublished data, 2011). The majority of pertussis cases, hospitalizations, and deaths occur in infants aged ≤2 months, who are too young to be vaccinated; therefore, other strategies are required for prevention of pertussis in this age group. Since 2005, the Advisory Committee on Immunization Practices (ACIP) has recommended tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) booster vaccines to unvaccinated postpartum mothers and other family members of newborn infants to protect infants from pertussis, a strategy referred to as cocooning. Over the past 5 years, cocooning programs have proven difficult to implement widely. Cocooning programs might achieve moderate vaccination coverage among postpartum mothers but have had limited success in vaccinating fathers or other family members. On June 22, 2011, ACIP made recommendations for use of Tdap in unvaccinated pregnant women and updated recommendations on cocooning and special situations. This report summarizes data considered and conclusions made by ACIP and provides guidance for implementing its recommendations.

Hib antibody responses in infants following diphtheria, tetanus, acellular pertussis, and conjugated Haemophilus influenzae type b (Hib) combination vaccines with decreasing amounts of tetanus toxoid.

PubMed

Bernstein, Henry H; Seyferth, Elisabeth R

2017-12-04

While combination vaccines have contributed to improved vaccine uptake rates in children, studies have documented varied immunogenicity to specific vaccine components. We studied whether varying the amount of tetanus toxoid (TT) in a DTaP and Hib combination vaccine would result in immunogenicity comparable with separate, concurrent administration. We evaluated the immunogenicity of Massachusetts Biologic Laboratories (MBL) diphtheria, tetanus, and acellular pertussis (mDTaP) vaccine combined with tetanus-conjugated MBL Haemophilus influenzae type b vaccine (mHib) in a single injection (DTaPH). We compared four DTaPH vaccines containing varying concentrations of TT. We also evaluated the immune response to the DTaP vaccine manufactured by Connaught Laboratories (now known as Sanofi Pasteur) given with mHib and with Wyeth Hib-CRM 197 (HbOC) as separate injections. Vaccines were administered to 240 healthy infants at 2, 4, and 6 months of age, and blood specimens for antibody determination were obtained before each immunization and one month after the third immunization. We found no significant differences in immune response to the vaccines between the four DTaPH groups. Hib antibody responses were similar in the mHib and the HbOC groups but significantly lower in the DTaPH groups, as measured by Chinese Hamster Ovary (CHO) cell neutralization titers and filamentous hemagglutinin antigen (FHA) geometric mean concentrations (GMC) of anti-Hib antibodies. There were no significant differences between the groups in pertussis or tetanus toxoid antibody levels. Reducing tetanus toxoid amounts did not produce comparable immunogenicity for Hib. The nature of the interaction between immune responses to DTaPH components should be explored further to enable the development of better Hib-containing combination vaccines. Copyright © 2017 Elsevier Ltd. All rights reserved.

A randomized controlled trial [corrected] administration of tetanus toxoid (TT) versus tetanus and reduced diphtheria (Td) in pregnant women.

PubMed

Salama, Maha M; Hady, Osama A W; Ashour, Wael; Mostafa, Amal; El Alkamy, Sahar; El Sayed, Nehad; El Yazeed, Remon Abu

2009-07-01

The present study was designed as a randomized clinical trial to compare the immunogenicity, reactogenicity, and efficacy of tetanus toxoid (TT) and the combined tetanus and reduced diphtheria (Td) in pregnant women in four rural communities in Egypt. The pregnant women in each four villages received either TT or Td randomly. Both TT and Td vaccines are manufactured by the Egyptian Company for Biological Products & Vaccines (VACSERA) in Egypt. A total of 131 pregnant women were enrolled during the time of antenatal care visit (at 20 weeks gestational age of pregnancy) in one of four health units in Abu Homos district, Beheira Governorate, Egypt. Unimmunized women received two random doses of either TT or Td 8 weeks apart during their pregnancy. Outpatient follow-up for adverse reactions occurred at the third day after each vaccine dose as either local effects such as pain, redness, and swelling or systematic effects such as fever, malaise, and headache or body aches which was served as primary safety endpoint. Blood was collected three times from each woman for determination of antibody titer against tetanus and diphtheria by using enzyme-linked immunosorbent assay technique. The first sample was collected immediately before the first dose, the second before the second dose, and the third sample 1 week after delivery. Active surveillance home visits to all study participants were done twice: the first home visit during the first week after delivery and the second 1 month after labor to report the health status of the mother and the baby. A total of 122 pregnant women received two ordinary doses with interdose intervals within the allowable range and three blood samples were collected in each protocol analysis (62 in the TT group and 60 in the Td group). There was no statistically significant difference between groups in the percentage of reporting a primary safety endpoint (fever, malaise, body ache, headache) or local reactions at the site of injection as redness

Adverse events after tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine administered to adults 65 years of age and older reported to the Vaccine Adverse Event Reporting System (VAERS), 2005-2010.

PubMed

Moro, Pedro L; Yue, Xin; Lewis, Paige; Haber, Penina; Broder, Karen

2011-11-21

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine was not licensed for use in adults aged ≥65 years due to lack of sufficient efficacy and safety data. To characterize reports to the Vaccine Adverse Event Reporting System (VAERS) among adults aged ≥65 years who received Tdap vaccine 'off-label' to assess for potential vaccine safety concerns. We searched VAERS for US reports of adverse events (AEs) in subjects aged ≥65 years who received Tdap vaccine from 9/1/2005 to 9/08/2010. Medical records were requested for all reports coded as serious (death, hospitalization, prolonged hospitalization, permanent disability, life-threatening-illness). Proportional reporting ratio (PRR) was used to assess for higher proportionate reporting for AEs after Tdap compared with Td reports in subjects aged ≥65 years. VAERS received 243 reports following Tdap administered to persons aged ≥65 years. Eleven (4.5%) reports were serious, including two deaths. Most common AEs were local reactions in 100 (41.2%) reports. Seventy-eight (32.1%) reports contained coding terms that denoted inappropriate administration of vaccine. 'Cough' was the only term associated with disproportionately higher reporting after Tdap compared with Td. Six of seven Tdap reports containing the term 'Cough' were non-serious. Clinical review of serious reports identified no unusual patterns of AEs. Our VAERS review of the 'off-label' use of Tdap vaccine in adults ≥65 years did not find any safety concerns that warrant further study. These data will provide useful baseline information to assist CDC and FDA with monitoring efforts as permissive recommendations for Tdap in older persons are adopted. Published by Elsevier Ltd.

Safety and immunogenicity of two inactivated poliovirus vaccines in combination with an acellular pertussis vaccine and diphtheria and tetanus toxoids in seventeen- to nineteen-month-old infants.

PubMed

Halperin, S A; Davies, H D; Barreto, L; Guasparini, R; Meekison, W; Humphreys, G; Eastwood, B J

1997-04-01

To compare the safety and immunity of an acellular pertussis vaccine containing pertussis toxoid, filamentous hemagglutinin, 69 kd protein, fimbriae 2 and 3 combined with diphtheria and tetanus toxoids given as single or separate injection with inactivated poliovirus vaccine (MRC-5-or Vero cell-derived) or live attenuated polio vaccine. A total of 425 healthy children between 17 and 19 months of age who were receiving the fourth dose of their routine immunization series were randomly allocated to receive either the acellular pertussis vaccine and oral poliovirus vaccine or one of two inactivated poliovirus vaccines as a combined injection or separate injections. Although minor adverse events were commonly reported, differences between the groups were few. Fever and decreased feeding were less common in recipients of live attenuated poliovirus vaccine than the combination vaccine containing MRC-5 cell-derived inactivated poliovirus vaccine. A significant antibody response was demonstrated in all groups against all the antigens contained in the vaccines. Antibodies against poliovirus were higher in the groups immunized with the inactivated poliovirus vaccine than the live attenuated vaccine. Anti-69 kd protein antibodies were higher in the group given the MRC-5 cell-derived inactivated poliovirus vaccine as a combined injection than in the group given the separate injection or the group immunized with the live attenuated poliovirus vaccine. The five-component acellular pertussis vaccine combined with diphtherid and tetanus toxoids is safe and immunogenic when combined with either MRC-5- or Vero cell-derived inactivated poliovirus vaccine. This will facilitate the implementation of acellular pertussis vaccine and the movement to inactivated poliovirus vaccine programs.

Immune memory in children previously vaccinated with an experimental quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine.

PubMed

Pichichero, Michael; Papa, Thomas; Blatter, Mark; Mitchell, Douglas; Kratz, Richard; Sneed, Jane; Bassily, Ehab; Casey, Janet; Gilmet, Gregory

2006-11-01

In a previous study, a meningococcal diphtheria toxoid conjugate vaccine (MCV-4) triggered robust bactericidal antibody responses against serogroups A, C, Y, and W-135 in 2- to 10-year-old children. A subset of participants, 2 to 3 years of age at the initial vaccination, was evaluated for persistence of antibody, immune memory, and antibody avidity. Participants were healthy children vaccinated 23 to 36 months earlier with MCV-4 (primed) or newly recruited meningococcal vaccine-naive 4-year-olds. Participants in both groups were alternately allocated to provide sera 8 or 28 days after administration of one tenth of the recommended dose of a meningococcal polysaccharide vaccine (PSV-4). Immune responses were assessed in sera obtained at baseline and either 8 or 28 days after reduced-dose PSV-4 administration. Safety was monitored. Before PSV-4 challenge, serum bactericidal antibody geometric mean titers (SBA GMTs) were higher for all 4 serogroups in the MCV-4-primed group than in the vaccine-naive group. SBA GMTs, geometric mean concentrations of immunoglobulin G (IgG) and geometric mean avidity indices for all 4 serogroups were significantly higher among MCV-4-primed versus vaccine-naive participants in the cohorts evaluated at 8 or 28 days after PSV-4 challenge. Adverse events were generally mild, self-limited, and comparable in all groups of children. Persistence of bactericidal antibody was seen for 23 to 36 months after a primary dose of MCV-4 in young children. Booster responses and avidity maturation were evident after a challenge with reduced-dose polysaccharide vaccine.

Collaborative study for establishment of the European Pharmacopoeia BRP batch 1 for diphtheria toxin.

PubMed

Sesardic, D; Prior, C; Daas, A; Buchheit, K H

2003-07-01

A stable liquid candidate Biological Reference Preparation (BRP) for diphtheria toxin was prepared in peptone buffer (nominal content of diphtheria toxin: 1 Lf/ml, 0.4 micro g/ml), filled in ampoules (filling volume: 1 ml) and characterised in a collaborative study. The toxin is to be used in the test "Absence of toxin and irreversibility of toxoid" as described in the current European Pharmacopoeia (Ph. Eur.) monograph Diphtheria Vaccine (Adsorbed) (2002:0443). Eleven laboratories assessed the specific activity of the preparation by in vivo and in vitro assays. The material is assumed to have satisfactory stability with a calculated predicted loss of activity of <1% per year at 4-8 degrees C. From the collaborative study, the specific activity was calculated as 77.6 (45-113) LD( 50)/ml (lethal challenge) and >75 000 Lr/Lf (intradermal challenge). The candidate BRP was successfully used in nine laboratories and confirmed suitable for use in the Vero cell test for "Absence of toxin and irreversibility of toxoid" as described in the Ph. Eur. monograph 2002:0443; i.e., concentrations of 5 x 10( -5) Lf/ml and below caused cytotoxic effects in the Vero cell test. Due to its liquid nature, the stability of the material will be monitored at regular intervals and preparation of a stable freeze-dried formulation will be considered for long-term use. Additional studies will be performed to confirm suitability of this BRP for other applications. The candidate BRP was adopted as the Ph. Eur. reference material for Diphtheria Toxin Batch 1 by the Ph. Eur. Commission at its session in March 2003.

Safety and immunogenicity of a combined Tetanus, Diphtheria, recombinant acellular Pertussis vaccine (TdaP) in healthy Thai adults.

PubMed

Sirivichayakul, Chukiat; Chanthavanich, Pornthep; Limkittikul, Kriengsak; Siegrist, Claire-Anne; Wijagkanalan, Wassana; Chinwangso, Pailinrut; Petre, Jean; Hong Thai, Pham; Chauhan, Mukesh; Viviani, Simonetta

2017-01-02

An acellular Pertussis (aP) vaccine containing recombinant genetically detoxified Pertussis Toxin (PTgen), Filamentous Hemagglutinin (FHA) and Pertactin (PRN) has been developed by BioNet-Asia (BioNet). We present here the results of the first clinical study of this recombinant aP vaccine formulated alone or in combination with tetanus and diphtheria toxoids (TdaP). A phase I/II, observer-blind, randomized controlled trial was conducted at Mahidol University in Bangkok, Thailand in healthy adult volunteers aged 18-35 y. The eligible volunteers were randomized to receive one dose of either BioNet's aP or Tetanus toxoid-reduced Diphtheria toxoid-acellular Pertussis (TdaP) vaccine, or the Tdap Adacel® vaccine in a 1:1:1 ratio. Safety follow-up was performed for one month. Immunogenicity was assessed at baseline, at 7 and 28 d after vaccination. Anti-PT, anti-FHA, anti-PRN, anti-tetanus and anti-diphtheria IgG antibodies were assessed by ELISA. Anti-PT neutralizing antibodies were assessed also by CHO cell assay. A total of 60 subjects (20 per each vaccine group) were enrolled and included in the safety analysis. Safety laboratory parameters, incidence of local and systemic post-immunization reactions during 7 d after vaccination and incidence of adverse events during one month after vaccination were similar in the 3 vaccine groups. One month after vaccination, seroresponse rates of anti-PT, anti-FHA and anti-PRN IgG antibodies exceeded 78% in all vaccine groups. The anti-PT IgG, anti-FHA IgG, and anti-PT neutralizing antibody geometric mean titers (GMTs) were significantly higher following immunization with BioNet's aP and BioNet's TdaP than Adacel® (P< 0.05). The anti-PRN IgG, anti-tetanus and anti-diphtheria GMTs at one month after immunization were comparable in all vaccine groups. All subjects had seroprotective titers of anti-tetanus and anti-diphtheria antibodies at baseline. In this first clinical study, PTgen-based BioNet's aP and TdaP vaccines showed a

Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P-diphtheria toxoid conjugate.

PubMed

Schellenberger, Mario T; Grova, Nathalie; Farinelle, Sophie; Willième, Stéphanie; Schroeder, Henri; Muller, Claude P

2013-09-01

Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P-diphtheria toxoid (B[a]P-DT) conjugate vaccine were sub-acutely exposed to 2mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P-DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P. Copyright © 2013 Elsevier Inc. All rights reserved.

Modulation of Benzo[a]pyrene induced immunotoxicity in mice actively immunized with a B[a]P-diphtheria toxoid conjugate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schellenberger, Mario T.; Grova, Nathalie; Willieme, Stephanie

2009-10-01

Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also toxic for mammalian immune cells. To develop a prophylactic immune strategy against detrimental effects of B[a]P, we have immunized mice with a B[a]P-diphtheria toxoid conjugate vaccine. We showed that high levels of antibodies against B[a]P and its metabolites modulate the redistribution of these PAHs in the blood. After immunization, increased levels of B[a]P and its metabolites were recovered in the blood. B[a]P significantly suppressed the proliferative response of bothmore » T and B cells after a sub-acute administration, an effect that was completely reversed by vaccination. In immunized mice also the immunotoxic effect of B[a]P on IFN-{gamma}, IL-12, TNF-{alpha} production and the reduced B cell activation was restored. Finally, our results showed that specific antibodies inhibited the induction of Cyp1a1 by B[a]P in lymphocytes and Cyp1b1 in the liver, enzymes that are known to convert the procarcinogen B[a]P to the ultimate DNA-adduct forming metabolite, a major risk factor of chemical carcinogenesis. Thus, we demonstrate that vaccination with a B[a]P conjugate vaccine based on a carrier protein used in licensed human vaccines reduces immunotoxicity and possibly other detrimental effects associated with B[a]P.« less

Immunogenicity of MenACWY-CRM in Korean Military Recruits: Influence of Tetanus-Diphtheria Toxoid Vaccination on the Vaccine Response to MenACWY-CRM.

PubMed

Kim, Han Wool; Park, In Ho; You, Sooseong; Yu, Hee Tae; Oh, In Soo; Sung, Pil Soo; Shin, Eui Cheol; Kim, Kyung Hyo

2016-11-01

The quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) has been introduced for military recruits in Korea since 2012. This study was performed to evaluate the immunogenicity of MenACWY-CRM in Korean military recruits. In addition, the influence of tetanus-diphtheria toxoids (Td) vaccination on the vaccine response to MenACWY-CRM was analyzed. A total of 75 military recruits were enrolled. Among them, 18 received a dose of MenACWY-CRM only (group 1), and 57 received Td three days before MenACWY-CRM immunization (group 2). The immunogenicity of MenACWY-CRM was compared between the two groups. The serum bactericidal activity with baby rabbit complement was measured before and three weeks after immunization against serogroups A, C, W-135, and Y. The geometric mean titers (GMTs) against four serogroups were significantly increased in both groups after immunization. Compared to group 2, group 1 exhibited significantly higher vaccine responses in several aspects: post-immune GMTs against serogroup A and C, seroresponse rates against serogroup A, and a fold increases of titers against serogroup A, C, and Y. MenACWY-CRM was immunogenic against all vaccine-serogroups in Korean military recruits. Vaccine response to MenACWY-CRM was influenced by Td administered three days earlier.

Antibody status to poliomyelitis, measles, rubella, diphtheria and tetanus, Ontario, 1969-70: deficiencies discovered and remedies required.

PubMed

MacLeod, D R; Ing, W K; Belcourt, R J; Pearson, E W; Bell, J S

1975-10-04

A serologic survey was made in 15 health unit areas, testing some 5000 individuals in the age groups 4 to 6, 11 to 13, 15 to 17 and 23 to 45 years. Two types of serious deficiency were found. Only 65% of children 4 to 6 years old had antibodies to all three types of poliovirus, the antibodies being due almost entirely to immunization with Salk vaccine. Even in children who had had six or more doses only 74% had antibodies to the three types. The high percentage of students 11 to 13 and 15 to 17 years old with poliovirus antibodies can be attributed largely to natural infection and to Sabin vaccine in the mass campaign of 1962, as well as to Salk vaccine. In children who had received Sabin vaccine as well as Salk vaccine a very high level of immunity was found. The immunity of the school-age population will decline to an insufficient level unless Sabin vaccine is used after immunization with Salk vaccine. Of children 4 to 6 years old 18% had no diphtheria antitoxin and 6% had no tetanus antitoxin. Even in those who had had six or more doses of the antigens 5% had no diphtheria antitoxin and 1 to 2% had no tetanus antitoxin. This apparently refractory state is probably due to the use of unadsorbed toxoids, and it is clear that adsorbed toxoids should be used. In the adults, diphtheria antitoxin was found in only 55% and tetanus antitoxin in only 38%.

The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs

PubMed Central

Yano, Akira; Ito, Kaori; Miwa, Yoshikatsu; Kanazawa, Yoshito; Chiba, Akiko; Iigo, Yutaka; Kashimoto, Yoshinori; Kanda, Akira; Murata, Shinji; Makino, Mitsuhiro

2015-01-01

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer's disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβ antibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ 40, and Aβ 42 compared to Aβ fibrils. The levels of serum anti-Aβ antibodies and plasma Aβ peptides increased in both animals and decreased the brain Aβ 40 level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβ antibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβ peptides and their toxic effects via clearance of Aβ peptides by generated antibodies. PMID:26539559

The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs.

PubMed

Yano, Akira; Ito, Kaori; Miwa, Yoshikatsu; Kanazawa, Yoshito; Chiba, Akiko; Iigo, Yutaka; Kashimoto, Yoshinori; Kanda, Akira; Murata, Shinji; Makino, Mitsuhiro

2015-01-01

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer's disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβ antibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ 40, and Aβ 42 compared to Aβ fibrils. The levels of serum anti-Aβ antibodies and plasma Aβ peptides increased in both animals and decreased the brain Aβ 40 level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβ antibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβ peptides and their toxic effects via clearance of Aβ peptides by generated antibodies.

Reactogenicity of tetanus, diphtheria, 5-component acellular pertussis vaccine administered as a sixth consecutive acellular pertussis vaccine dose to adolescents.

PubMed

Liese, Johannes G; Rieber, Nikolaus; Malzer, Thomas; Ocak, Marion; Johnson, David R; Decker, Michael D

2010-12-01

Safety of a sixth consecutive dose of acellular pertussis vaccine in adolescents was assessed in a 2-armed, randomized study. Adolescents who had received 5 doses of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (6-dose group) received 1 dose of reduced 5-component acellular pertussis vaccine combined with tetanus toxoid and reduced diphtheria toxoid (Tdap). Adolescents who had received a primary series of 3 doses of whole-cell pertussis and 1 acellular or whole-cell pertussis booster received 1 dose of Tdap vaccine (5-dose group). Of 214 participants, 176 (82%) reported an injection-site reaction with pain (80%), erythema (22%), and swelling (19%) most frequently reported. A systemic reaction was reported by 169 of 214 (79%) with myalgia (66%), headache (42%), malaise (39%), and fever (9%) most frequently reported. The overall rate of solicited reactions was lower in the 6-dose group than in the 5-dose group (for injection-site reactions: 76.1% vs. 89.7%; for systemic reactions 72.6% vs. 86.6%). Significant differences were observed for injection-site pain, erythema, and for grade 1 or grade 2 increases in arm circumference. Fever, myalgia, and headache were reported at a significantly lower rate in the 6-dose group. Swelling >10 cm was observed in 5 patients (2%), 4 in the 5-dose group. Tdap vaccine was safe when given to adolescents who had received 5 prior doses of acellular pertussis vaccine.

Immunogenicity of diphtheria toxoid and poly(I:C) loaded cationic liposomes after hollow microneedle-mediated intradermal injection in mice.

PubMed

Du, Guangsheng; Leone, Mara; Romeijn, Stefan; Kersten, Gideon; Jiskoot, Wim; Bouwstra, Joke A

2018-06-02

In this study, we aimed to investigate the immunogenicity of cationic liposomes loaded with diphtheria toxoid (DT) and poly(I:C) after hollow microneedle-mediated intradermal vaccination in mice. The following liposomal formulations were studied: DT loaded liposomes, a mixture of free DT and poly(I:C)-loaded liposomes, a mixture of DT-loaded liposomes and free poly(I:C), and liposomal formulations with DT and poly(I:C) either individually or co-encapsulated in the liposomes. Reference groups were DT solution adjuvanted with or without poly(I:C) (DT/poly(I:C)). The liposomal formulations were characterized in terms of particle size, zeta potential, loading and release of DT and poly(I:C). After intradermal injection of BALB/c mice with the formulations through a hollow microneedle, the immunogenicity was assessed by DT-specific ELISAs. All formulations induced similar total IgG and IgG1 titers. However, all the liposomal groups containing both DT and poly(I:C) showed enhanced IgG2a titers compared to DT/poly(I:C) solution, indicating that the immune response was skewed towards a Th1 direction. This enhancement was similar for all liposomal groups that contain both DT and poly(I:C) in the formulations. Our results reveal that a mixture of DT encapsulated liposomes and poly(I:C) encapsulated liposomes have a similar effect on the antibody responses as DT and poly(I:C) co-encapsulated liposomes. These findings may have implications for future design of liposomal vaccine delivery systems. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Diphtheria

MedlinePlus

Respiratory diphtheria; Pharyngeal diphtheria; Diphtheric cardiomyopathy; Diphtheric polyneuropathy ... The bacteria that cause diphtheria spread through respiratory ... or someone who carries the bacteria but has no symptoms. The ...

Does vaccination ensure protection? Assessing diphtheria and tetanus antibody levels in a population of healthy children

PubMed Central

Gowin, Ewelina; Wysocki, Jacek; Kałużna, Ewelina; Świątek-Kościelna, Bogna; Wysocka-Leszczyńska, Joanna; Michalak, Michał; Januszkiewicz-Lewandowska, Danuta

2016-01-01

Abstract Vaccination effectiveness is proven when the disease does not develop after a patient is exposed to the pathogen. In the case of rare diseases, vaccination effectiveness is assessed by monitoring specific antibody levels in the population. Such recurrent analyses allow the evaluation of vaccination programs. The primary schedule of diphtheria and tetanus vaccinations is similar in various countries, with differences mainly in the number and timing of booster doses. The aim of the study was to assess diphtheria and tetanus antibody concentrations in a population of healthy children. Diphtheria and tetanus antibody levels were analyzed in a group of 324 children aged 18 to 180 months. All children were vaccinated in accordance with the Polish vaccination schedule. Specific antibody concentrations greater than 0.1 IU/mL were considered protective against tetanus or diphtheria. Levels above 1.0 were considered to ensure long-term protection. Protective levels of diphtheria antibodies were found in 229 patients (70.46%), and of tetanus in 306 patients (94.15%). Statistically significant differences were found in tetanus antibody levels in different age groups. Mean concentrations and the percentage of children with high tetanus antibody titers increased with age. No similar correlation was found for diphtheria antibodies. High diphtheria antibody levels co-occurred in 72% of the children with high tetanus antibody levels; 95% of the children with low tetanus antibody levels had low levels of diphtheria antibodies. The percentage of children with protective diphtheria antibody levels is lower than that in the case of tetanus antibodies, both in Poland and abroad, but the high proportion of children without diphtheria protection in Poland is an exception. This is all the more puzzling when taking into account that Polish children are administered a total of 5 doses containing a high concentration of diphtheria toxoid, at intervals shorter than 5 years. The

Public health action following an outbreak of toxigenic cutaneous diphtheria in an Auckland refugee resettlement centre.

PubMed

Reynolds, Gary E; Saunders, Helen; Matson, Angela; O'Kane, Fiona; Roberts, Sally A; Singh, Salvin K; Voss, Lesley M; Kiedrzynski, Tomasz

2016-12-24

Global forced displacement has climbed to unprecedented levels due largely to regional conflict. Degraded public health services leave displaced people vulnerable to multiple environmental and infectious hazards including vaccine preventable disease. While diphtheria is rarely notified in New Zealand, a 2 person outbreak of cutaneous diphtheria occurred in refugees from Afghanistan in February 2015 at the refugee resettlement centre in Auckland. Both cases had uncertain immunisation status. The index case presented with a scalp lesion during routine health screen and toxigenic Corynebacterium diphtheriae was isolated. A secondary case of cutaneous diphtheria and an asymptomatic carrier were identified from skin and throat swabs. The 2 cases and 1 carrier were placed in consented restriction until antibiotic treatment and 2 clearance swabs were available. A total of 164 contacts were identified from within the same hostel accommodation as well as staff working in the refugee centre. All high risk contacts (n=101) were swabbed (throat, nasopharynx and open skin lesions) to assess C. diphtheriae carriage status. Chemoprophylaxis was administered (1 dose of intramuscular benzathine penicillin or 10 days of oral erythromycin) and diphtheria toxoid-containing vaccine offered regardless of immunisation status. Suspected cases were restricted on daily monitoring until swab clearance. A group of 49 low risk contacts were also offered vaccination. Results suggest a significant public health effort was required for a disease rarely seen in New Zealand. In light of increased worldwide forced displacement, similar outbreaks could occur and require a rigorous public health framework for management.

Levels of diphtheria and tetanus specific IgG of Portuguese adult women, before and after vaccination with adult type Td. Duration of immunity following vaccination

PubMed Central

Gonçalves, Guilherme; Santos, Maria Augusta; Frade, João Graça; Cunha, José Saraiva

2007-01-01

Background The need for tetanus toxoid decennial booster doses has been questioned by some experts. Several counter arguments have been presented, supporting the maintenance of decennial adult booster doses with tetanus and diphtheria toxoids (adult formulation of the vaccine: Td). This study aimed to evaluate the use of Td in Portuguese adult women under routine conditions. For that purpose we selected a group of women 30+ years of age to which vaccination was recommended. We intended to know if pre-vaccination antibody concentrations were associated with factors as age at first and last vaccination, number of doses and time since last revaccination. We also intended to assess the serological efficacy of Td booster. Methods Following the Portuguese guidelines 100 women were vaccinated with Td. Antitetanus toxin IgG (ATT IgG) and antidiphtheria toxin IgG (ADT IgG) levels were measured (mIU/ml) in 100 pre-vaccination and 91 post-vaccination sera. Detailed vaccination records were available from 88 participants. Results Twenty-two women (Group A) began vaccination with DPT/DT in their early childhood and their pre-vaccination ATT IgG levels increased with the number of doses received (p = 0.022) and decreased with time since last vaccination (p = 0.016). Among the 66 women who began vaccination in adolescence and adulthood (Group B), with monovalent TT, ATT IgG levels decreased with age at first dose (p < 0.001) and with time since last vaccination (p = 0.041). In Group A, antidiphtheria toxin IgG kinetics was very similar to that observed for ATT IgG. Among women not vaccinated with diphtheria toxoid, ADT IgG levels decreased with age. Serological response to both components of Td was good but more pronounced for ATT IgG. Conclusion Our study suggests that, to protect against tetanus, there is no need to administer decennial boosters to the Portuguese adults who have complied with the childhood/adolescent schedule (6 doses of tetanus toxoid). The adult booster

Impact of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccinations on Reported Pertussis Cases Among Those 11 to 18 Years of Age in an Era of Waning Pertussis Immunity: A Follow-up Analysis.

PubMed

Skoff, Tami H; Martin, Stacey W

2016-05-01

There is accumulating literature on waning acellular pertussis vaccine-induced immunity, confirming the results of studies assessing the duration of protection of pertussis vaccines. To evaluate the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine's effect over time among those 11 to 18 years old, while accounting for the transition from whole-cell to acellular pertussis vaccines for the childhood primary series. Extended, retrospective analysis of reported pertussis cases between January 1, 1990, and December 31, 2014, in the United States. The analysis included all nationally reported pertussis cases. US Tdap vaccination program and the transition from whole-cell to acellular pertussis vaccines. Rate ratios of reported pertussis incidence (defined as incidence among 11- to 18-year-old individuals divided by the combined incidence in all other age groups) modeled with segmented regression analysis and age-specific trends in reported pertussis incidence over time. Between 1990 and 2014, 356 557 pertussis cases were reported in the United States. Of those, 191 914 (53.8%) were female and 240 665 (67.5%) were white. Overall incidence increased from 1.7 in 100 000 to 4.0 in 100 000 between 1990 and 2003, while latter years were dominated by epidemic peaks. Incidence was highest among infants younger than 1 year throughout the analysis period. Pertussis rates were comparable among all other age groups until the late 2000s, when an increased burden of pertussis emerged among children 1 to 10 years old, resulting in the second highest age-specific incidence. By 2014, 11- to 18-year-old individuals once again had the second highest incidence. While slope coefficients from segmented regression analysis showed a positive impact of Tdap immediately following introduction (slope, -0.4959; P < .001), a reversal in trends was observed in 2010 when rates of disease among 11- to 18-year-old individuals increased at a faster rate than

Evaluation of Immunogenicity and Safety of the New Tetanus-Reduced Diphtheria (Td) Vaccines (GC1107) in Healthy Korean Adolescents: A Phase II, Double-Blind, Randomized, Multicenter Clinical Trial

PubMed Central

Rhim, Jung-Woo; Lee, Kyung-Yil; Kim, Sang-Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Kim, Hwang Min; Choi, Young-Youn; Ma, Sang-Hyuk; Kim, Dong-Ho; Ahn, Dong Ho

2013-01-01

This phase II clinical trial was conducted to compare the immunogenicity and safety of a newly developed tetanus-reduced diphtheria (Td) vaccine (GC1107-T5.0 and GC1107-T7.5) and control vaccine. This study was also performed to select the proper dose of tetanus toxoid in the new Td vaccines. Healthy adolescents aged between 11 and 12 yr participated in this study. A total of 130 subjects (44 GC1107-T5.0, 42 GC1107-T7.5 and 44 control vaccine) completed a single dose of vaccination. Blood samples were collected from the subjects before and 4 weeks after the vaccination. In this study, all subjects (100%) in both GC1107-T5.0 and GC1107-T7.5 groups showed seroprotective antibody levels (≥ 0.1 U/mL) against diphtheria or tetanus toxoids. After the vaccination, the geometric mean titer (GMT) against diphtheria was significantly higher in Group GC1107-T5.0 (6.53) and GC1107-T7.5 (6.11) than in the control group (3.96). The GMT against tetanus was 18.6 in Group GC1107-T5.0, 19.94 in GC1107-T7.5 and 19.01 in the control group after the vaccination. In this study, the rates of local adverse reactions were 67.3% and 59.1% in GC1107-T5.0 and GC1107-7.5, respectively. No significant differences in the number of adverse reactions, prevalence and degree of severity of the solicited and unsolicited adverse reactions were observed among the three groups. Thus, both newly developed Td vaccines appear to be safe and show good immunogenicity. GC1107-T5.0, which contains relatively small amounts of tetanus toxoid, has been selected for a phase III clinical trial. PMID:23579367

Augmentation of humoral and cellular immunity in response to Tetanus and Diphtheria toxoids by supercritical carbon dioxide extracts of Hippophae rhamnoides L. leaves.

PubMed

Jayashankar, Bindhya; Singh, Divya; Tanwar, Himanshi; Mishra, K P; Murthy, Swetha; Chanda, Sudipta; Mishra, Jigni; Tulswani, R; Misra, K; Singh, S B; Ganju, Lilly

2017-03-01

Hippophae rhamnoides L. commonly known as Seabuckthorn (SBT), a wild shrub of family Elaegnacea, has extensively used for treating various ailments like skin diseases, jaundice, asthma, lung troubles. SBT leaves have been reported to possess several pharmacological properties including immunomodulatory, antioxidant, anti-inflammatory, antimicrobial and tissue regeneration etc. The present study was undertaken to evaluate the adjuvant property of supercritical carbon dioxide extracts (SCEs 300ET and 350ET) of SBT leaves in balb/c mice immunized with Tetanus and Diphtheria toxoids. The dynamic changes in the immune response were measured in terms of humoral and cell-mediated immune responses. We have seen the effect of SCEs on immunoglobulin subtypes and secondary immune response generation. In addition, the effect of SCEs on antigen specific cellular immunity was evaluated. Our results show that SCEs 300ET and 350ET significantly enhanced antibody titers in response to both TT and DT antigens. The secondary immune response generated was significantly increased in case of TT immunized animals. SCEs also enhanced cytokine levels (IFN-γ, IL-4, TNF-α and IL-1β) and increased lymphoproliferation. Besides, both SCEs did not show any toxic effects. Therefore, the study suggests that SCEs are safe and have potent immunostimulatory activity and hence, seems to be a promising balanced Th1 and Th2 directing immunological adjuvant for various veterinary as well as human vaccines. Copyright © 2017. Published by Elsevier B.V.

Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P–diphtheria toxoid conjugate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schellenberger, Mario T.; Grova, Nathalie; Farinelle, Sophie

Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P–diphtheria toxoid (B[a]P–DT) conjugate vaccine were sub-acutely exposed to 2 mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured inmore » 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P–DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P. - Highlights: • B[a]P-antibodies attenuated B[a]P induced NMDA expression in several brain regions. • B[a]P had measurable consequences on anxiety, short term learning and memory. • B[a]P immunization attenuated the pharmacological and neurotoxic effects of B[a]P. • Vaccination may also provide some protection against chemical carcinogenesis.« less

Oral immunogenicity of tomato-derived sDPT polypeptide containing Corynebacterium diphtheriae, Bordetella pertussis and Clostridium tetani exotoxin epitopes.

PubMed

Soria-Guerra, Ruth E; Rosales-Mendoza, Sergio; Moreno-Fierros, Leticia; López-Revilla, Rubén; Alpuche-Solís, Angel G

2011-03-01

DPT vaccine, designed to immunize against diphtheria, pertussis, and tetanus, has been shown to be effective in humans. Nevertheless, dissatisfaction with the whole-cell preparations is due to the reactogenicity, which has to lead to the development of new safer formulations. Previously, we described the expression in tomato of a plant-optimized synthetic gene encoding the recombinant polypeptide sDPT, containing mainly immunoprotective epitopes of the diphtheria, pertussis and tetanus exotoxins and two adjuvants. In this study, we examined whether the ingestion of tomato-derived sDPT protein induces specific antibodies in mice after three weekly doses scheme. A positive group immunized with DPT toxoids was included. Specific antibody levels were assessed in serum, gut and lung. Sera tested for IgG antibody response to pertussis, tetanus and diphtheria toxin showed responses to the foreign antigens; interestingly, the response to diphtheria epitope was similar to those observed in the positive group. We found higher IgG1 than IgG2a responses in serum. A modest IgG response was observed in the tracheopulmonary fluid. High response of IgA against tetanus toxin was evident in gut, which was statistically comparable to that obtained in the positive group. The levels of response in these groups were higher than those in mice that received wild-type tomato. These findings support the concept of using transgenic tomatoes expressing sDPT polypeptide as model for edible vaccine against diphtheria, pertussis, and tetanus.

Diphtheria Complications

MedlinePlus

... Search Form Controls Cancel Submit Search The CDC Diphtheria Note: Javascript is disabled or is not supported ... message, please visit this page: About CDC.gov . Diphtheria Home About Diphtheria Causes and Transmission Symptoms Complications ...

Does vaccination ensure protection? Assessing diphtheria and tetanus antibody levels in a population of healthy children: A cross-sectional study.

PubMed

Gowin, Ewelina; Wysocki, Jacek; Kałużna, Ewelina; Świątek-Kościelna, Bogna; Wysocka-Leszczyńska, Joanna; Michalak, Michał; Januszkiewicz-Lewandowska, Danuta

2016-12-01

Vaccination effectiveness is proven when the disease does not develop after a patient is exposed to the pathogen. In the case of rare diseases, vaccination effectiveness is assessed by monitoring specific antibody levels in the population. Such recurrent analyses allow the evaluation of vaccination programs. The primary schedule of diphtheria and tetanus vaccinations is similar in various countries, with differences mainly in the number and timing of booster doses. The aim of the study was to assess diphtheria and tetanus antibody concentrations in a population of healthy children.Diphtheria and tetanus antibody levels were analyzed in a group of 324 children aged 18 to 180 months. All children were vaccinated in accordance with the Polish vaccination schedule.Specific antibody concentrations greater than 0.1 IU/mL were considered protective against tetanus or diphtheria. Levels above 1.0 were considered to ensure long-term protection.Protective levels of diphtheria antibodies were found in 229 patients (70.46%), and of tetanus in 306 patients (94.15%). Statistically significant differences were found in tetanus antibody levels in different age groups. Mean concentrations and the percentage of children with high tetanus antibody titers increased with age. No similar correlation was found for diphtheria antibodies. High diphtheria antibody levels co-occurred in 72% of the children with high tetanus antibody levels; 95% of the children with low tetanus antibody levels had low levels of diphtheria antibodies.The percentage of children with protective diphtheria antibody levels is lower than that in the case of tetanus antibodies, both in Poland and abroad, but the high proportion of children without diphtheria protection in Poland is an exception. This is all the more puzzling when taking into account that Polish children are administered a total of 5 doses containing a high concentration of diphtheria toxoid, at intervals shorter than 5 years. The decrease in

Diphtheria

MedlinePlus

Diphtheria is a serious bacterial infection. You can catch it from a person who has the infection ... as a toy, that has bacteria on it. Diphtheria usually affects the nose and throat. Symptoms include ...

A clinical trial examining the effect of increased total CRM(197) carrier protein dose on the antibody response to Haemophilus influenzae type b CRM(197) conjugate vaccine.

PubMed

Usonis, Vytautas; Bakasenas, Vytautas; Lockhart, Stephen; Baker, Sherryl; Gruber, William; Laudat, France

2008-08-18

CRM(197) is a carrier protein in certain conjugate vaccines. When multiple conjugate vaccines with the same carrier protein are administered simultaneously, reduced response to vaccines and/or antigens related to the carrier protein may occur. This study examined responses of infants who, in addition to diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine (DTaP) received either diphtheria CRM(197)-based Haemophilus influenzae type b conjugate vaccine (HbOC) or HbOC and a diphtheria CRM(197)-based combination 9-valent pneumococcal conjugate vaccine/meningococcal group C conjugate vaccine. Administration of conjugate vaccines with CRM(197) carrier protein load >50 microg did not reduce response to CRM(197) conjugate vaccines or immunogenicity to immunologically cross-reactive diphtheria toxoid.

Immunogenicity and safety of the new reduced-dose tetanus-diphtheria vaccine in healthy Korean adolescents: A comparative active control, double-blind, randomized, multicenter phase III study.

PubMed

Han, Seung Beom; Rhim, Jung-Woo; Shin, Hye Jo; Kim, Sang Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Lee, Kyung-Yil; Kim, Hwang Min; Choi, Young Youn; Ma, Sang Hyuk; Kim, Chun Soo; Kim, Dong Ho; Ahn, Dong Ho; Kang, Jin Han

2017-04-01

A new reduced-dose tetanus-diphtheria (Td) vaccine was developed in Korea, and phase I and II clinical trials were successfully undertaken. We conducted this double-blind, randomized, multicenter phase III clinical trial to assess the immunogenicity and safety of the new Td vaccine. Healthy adolescents 11-12 years of age were enrolled and randomized to receive the new Td vaccine (study group) or a commercially available Td vaccine (control group). Blood samples were collected prior to and 4 weeks after the vaccination. Between the study and control groups, seroprotection rate, booster response, and geometric mean titer of antibodies against diphtheria and tetanus toxoids were compared after the vaccination. All solicited and unsolicited adverse events and serious adverse events during the 6-week study period were monitored. A total of 164 adolescents received vaccination, and 156 of them were evaluated to assess immunogenicity. The seroprotection rate and geometric mean titer for antibodies against diphtheria were significantly higher in the study group, whereas those against tetanus were significantly higher in the control group. However, all seroprotection rates against diphtheria and tetanus in the study and control groups were high: 100% against diphtheria and tetanus in the study group, and 98.7% against diphtheria and 100% against tetanus in the control group. No significant differences in the frequency of solicited and unsolicited adverse events were observed between the two vaccine groups. The new Td vaccine is highly immunogenic and safe, and this new Td vaccine can be effectively used for preventing diphtheria and tetanus. Copyright © 2015. Published by Elsevier B.V.

Diphtheria (For Parents)

MedlinePlus

... throat cultures, and booster doses of the diphtheria vaccine. They will also receive antibiotics as a precaution. Immediate hospitalization and early intervention allow most patients to recover from diphtheria. After the antibiotics and anti-toxin have taken effect, someone with diphtheria will ...

Lichen planus following tetanus-diphtheria-acellular pertussis vaccination: A case report and review of the literature.

PubMed

Rosengard, Heather C; Wheat, Chikoti M; Tilson, Matthew P; Cuda, Jonathan D

2018-01-01

Lichen planus is an inflammatory dermatosis with a prevalence of approximately 1%. Recent meta-analyses show that patients with hepatitis C virus have a 2.5- to 4.5-fold increased risk of developing lichen planus. Lichen planus has also followed vaccinations and has specifically been attributed to the hepatitis B vaccine, the influenza vaccine, and the tetanus-diphtheria-acellular pertussis vaccine. We describe a case of lichen planus in a hepatitis C virus-infected African American male occurring in temporal association with the administration of the tetanus-diphtheria-acellular pertussis vaccine. The patient's presentation was clinically consistent with lichen planus and confirmed by biopsy. It is likely that many cases of vaccine-induced lichen planus have gone unpublished or unrecognized. In areas with high prevalence of hepatitis C virus infection, we may expect to see more cases of vaccine-induced lichen planus especially in light of the updated Centers for Disease Control and Prevention tetanus-diphtheria-acellular pertussis vaccination recommendations. This case serves to educate healthcare providers about vaccine-induced lichen planus and, in particular, the need to counsel hepatitis C virus-infected patients about a potential risk of developing lichen planus following vaccination. We also reflect on current theories suggesting the T-cell-mediated pathogenesis of lichen planus and the role that hepatitis C virus and toxoid or protein vaccines may play in initiating the disease.

SIALIDASE (NEURAMINIDASE) OF CORYNEBACTERIUM DIPHTHERIAE.

PubMed

WARREN, L; SPEARING, C W

1963-11-01

Warren, Leonard (National Institute of Arthritis and Metabolic Diseases, Bethesda, Md.) and C. W. Spearing. Sialidase (neuraminidase) of Corynebacterium diphtheriae. J. Bacteriol. 86:950-955. 1963.-The characteristics of a sialidase produced by Corynebacterium diphtheriae were studied. The enzyme was partially purified from preparations of diphtheria toxin on a column of Sephadex G-75. By this means the lethal factor of diphtheria toxin was separated, in part, from the sialidase activity. There appeared to be a close immunological relationship between the sialidases of C. diphtheriae and clostridia, since a preparation of diphtheria antitoxin was as effective an inhibitor of diphtheria sialidase as of the sialidase of three species of clostridia. Conversely, antitoxin to clostridia inhibited diphtheria sialidase. Diphtheria antitoxin was essentially inactive toward influenza virus sialidase, and was completely inactive against purified sialidase of Vibrio cholerae. Removal of sialic acid from the proteins in a preparation of diphtheria antitoxin did not alter the inhibitory activity of the antitoxin against diphtheria sialidase. The enzyme operated optimally at pH 5.5 and did not require calcium ions for activity. The substrate specificity of diphtheria sialidase appears to be the same as that of other previously described sialidases.

SIALIDASE (NEURAMINIDASE) OF CORYNEBACTERIUM DIPHTHERIAE

PubMed Central

Warren, Leonard; Spearing, C. W.

1963-01-01

Warren, Leonard (National Institute of Arthritis and Metabolic Diseases, Bethesda, Md.) and C. W. Spearing. Sialidase (neuraminidase) of Corynebacterium diphtheriae. J. Bacteriol. 86:950–955. 1963.—The characteristics of a sialidase produced by Corynebacterium diphtheriae were studied. The enzyme was partially purified from preparations of diphtheria toxin on a column of Sephadex G-75. By this means the lethal factor of diphtheria toxin was separated, in part, from the sialidase activity. There appeared to be a close immunological relationship between the sialidases of C. diphtheriae and clostridia, since a preparation of diphtheria antitoxin was as effective an inhibitor of diphtheria sialidase as of the sialidase of three species of clostridia. Conversely, antitoxin to clostridia inhibited diphtheria sialidase. Diphtheria antitoxin was essentially inactive toward influenza virus sialidase, and was completely inactive against purified sialidase of Vibrio cholerae. Removal of sialic acid from the proteins in a preparation of diphtheria antitoxin did not alter the inhibitory activity of the antitoxin against diphtheria sialidase. The enzyme operated optimally at pH 5.5 and did not require calcium ions for activity. The substrate specificity of diphtheria sialidase appears to be the same as that of other previously described sialidases. PMID:14080806

Effect of total lymphoid irradiation on levels of serum autoantibodies in systemic lupus erythematosus and in rheumatoid arthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanay, A.; Schiffman, G.; Strober, S.

1986-01-01

The effects of total lymphoid irradiation (TLI) on serum levels of autoantibodies, and of antibodies to diphtheria toxoid, tetanus toxoid, and pneumococcal polysaccharide in patients with lupus nephritis were compared with those previously observed in rheumatoid arthritis (RA) patients. Baseline levels of antibodies to diphtheria toxoid and tetanus toxoid decreased significantly after TLI in patients with lupus and RA, but antibody levels to pneumococcal polysaccharide remained unchanged. After TLI, the levels of antinuclear and anti-DNA antibodies were reduced significantly in lupus, but levels of rheumatoid factor, antinuclear, and antigranulocyte antibodies all tended to increase in RA.

Development and clinical testing of multivalent vaccines based on a diphtheria-tetanus-acellular pertussis vaccine: difficulties encountered and lessons learned.

PubMed

Capiau, Carine; Poolman, Jan; Hoet, Bernard; Bogaerts, Hugues; Andre, Francis

2003-06-02

The widespread use of whole-cell pertussis vaccines in the second half of the 20th century have reduced the incidence of the disease significantly. However, in some countries, concerns about the reactogenicity and potential neurological damage associated with whole-cell vaccines led to a decrease in vaccine acceptance and an increase in morbidity and mortality of pertussis in several countries. This prompted the development of less reactogenic acellular pertussis vaccines combined with diphtheria and tetanus toxoids, initially in Japan and later in other countries. In Europe, the improved diphtheria, tetanus and acellular pertussis (DTPa) vaccine was first introduced in March 1994. The pertussis component of this DTPa vaccine, developed by Glaxo SmithKline, consists of pertussis toxoid, filamentous haemagglutinin and pertactin. The vaccine is well tolerated, with a lower incidence of adverse reactions than after administration of whole-cell vaccines. The long-lasting efficacy and effectiveness of DTPa vaccines have been extensively documented and these are now the cornerstone of a large range of combined vaccines including DTPa-hepatitis B (HBV), DTPa-inactivated polio (IPV) and DTPa-HBV-IPV. A lyophilised Haemophilus influenzae type b (Hib) vaccine can be reconstituted with all of these liquid combinations. The introduction of well-tolerated and efficacious DTPa vaccines and their more polyvalent combinations has improved the acceptance and simplified the implementation of childhood immunisation. This paper is a review of the technical and scientific difficulties encountered and the lessons learned over the 10-year period that it took to develop and introduce six multivalent vaccines using the Glaxo SmithKline DTPa as a building block.

Safety and immunogenicity of a booster dose of meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine.

PubMed

Robertson, Corwin A; Greenberg, David P; Hedrick, James; Pichichero, Michael; Decker, Michael D; Saunders, Martha

2016-10-17

Quadrivalent meningococcal conjugate vaccines (MenACWY) were developed to offer long-term protection against invasive disease caused by serogroups A, C, W, and Y. Reduced MenACWY effectiveness within 5 years after primary vaccination (likely due to declining bactericidal antibody titers) has been described, particularly with respect to C and Y disease in the United States. We evaluated the safety and immunogenicity of a single booster dose of quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) in adolescents and adults who received a previous dose 4-6 years earlier. This phase 2, open-label, multicenter study of 834 persons was conducted in the United States. Participants received a single 0.5-mL booster dose of MenACWY-D. Serogroup-specific bactericidal antibody geometric mean titers (GMTs) were measured with a serum bactericidal antibody assay using human complement (hSBA). Proportions of participants achieving antibody titers of ⩾1:8 for each vaccine serogroup on Days 6 and 28 were determined. Rates of adverse events (AEs), including serious adverse events (SAEs), were also assessed. Before booster vaccination, 38.7-68.5% of participants had an hSBA titer ⩾1:8, depending on vaccine serogroup. By Day 6 post-vaccination, 98.2-99.1% of participants had hSBA titers ⩾1:8. By Day 28, >99% of participants achieved this threshold and the primary hypothesis (lower limit of the one-sided 95% confidence limit ⩾85% for each serogroup) was met. The GMT ratios (post-vaccination divided by pre-vaccination) at Day 28 ranged from 47.2 (serogroup A) to 209.1 (serogroup Y). Rates of AEs, including SAEs, were similar to those observed among adolescents and adults who received a primary dose of MenACWY-D in previous studies. There were no study discontinuations due to an AE and no deaths. Booster vaccination with MenACWY-D was safe and induced robust bactericidal antibody responses, consistent with immune memory, among adolescents and

75 FR 7281 - Pediatric Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-18

... and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine), Pentacel [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b...

Concurrent diphtheria and infectious mononucleosis: difficulties for management, investigation and control of diphtheria in developing countries.

PubMed

Mattos-Guaraldi, A L; Damasco, P V; Gomes, D L R; Melendez, M G; Santos, L S; Marinelli, R S; Napoleão, F; Sabbadini, P S; Santos, C S; Moreira, L O; Hirata, R

2011-11-01

We report a case of concurrent diphtheria and infectious mononucleosis in an 11-year-old Brazilian child. Two days after specific treatment for diphtheria was started the patient was discharged following clinical recovery. This case highlights the difficulties in the clinical diagnosis of diphtheria in partially immunized individuals, and for the management and control of diphtheria in developing countries.

Safety and immunogenicity of a single intramuscular dose of a tetanus-diphtheria toxoid (Td) vaccine (BR-TD-1001) in healthy Korean adult subjects.

PubMed

Hong, Taegon; Chung, Yong-Ju; Kim, Tae-Yeon; Kim, Ik-Hwan; Choe, Yong-Kyung; Lee, Jongtae; Jeon, Sangil; Han, Seunghoon; Yim, Dong-Seok

2015-01-01

BR-TD-1001 was developed as a booster for the immunity maintenance of diphtheria and tetanus. The aim of this study was to evaluate the safety and immunogenicity of BR-TD-1001 (test vaccine) in comparison with placebo and an active comparator in healthy Korean adults. A randomized, double-blind, placebo-controlled, active comparator, phase I clinical trial was conducted. Fifty subjects were randomly assigned to one of 3 treatment groups in a ratio of 2:2:1, and were administered a single intramuscular dose of test vaccine, active comparator, or placebo, respectively. All subjects were monitored for 4 weeks after injection. The antibody titers of the patients 2 and 4 weeks after vaccination were compared with the baseline. The frequencies of all adverse events including adverse drug reactions in the test group were not statistically different from those of the other treatment groups (P = 0.4974, 0.3061). No serious adverse event occurred, and no subject was withdrawn from the study for safety. The seroprotection rates against both tetanus and diphtheria at 4 weeks after vaccination were over 0.95. For anti-tetanus antibody, the geometric mean titer in the test group was significantly higher than those of the other groups (P = 0.0364, 0.0033). The geometric mean titer of anti-diphtheria antibody in the test group was significantly higher than the value of the placebo (P = 0.0347) while it was not for the value of the active comparator (P = 0.8484). In conclusion, BR-TD-1001 was safe, well-tolerated, and showed sufficient immunogenicity as a booster for diphtheria and tetanus.

Immunogenicity and safety after booster vaccination of diphtheria, tetanus, and acellular pertussis in young adults: an open randomized controlled trial in Japan.

PubMed

Hara, Megumi; Okada, Kenji; Yamaguchi, Yuko; Uno, Shingo; Otsuka, Yasuko; Shimanoe, Chisato; Nanri, Hinako; Horita, Mikako; Ozaki, Iwata; Nishida, Yuichiro; Tanaka, Keitaro

2013-12-01

The recent increase of pertussis in young adults in Japan is hypothesized to be due in part to waning protection from the acellular pertussis vaccine. While a booster immunization may prevent an epidemic of pertussis among these young adults, little is known about the safety and immunogenicity of such a booster with the diphtheria, tetanus, and acellular pertussis vaccine (DTaP), which is currently available in Japan. One hundred and eleven medical students with a mean age of 19.4 years were randomly divided into 2 groups of 55 and 56 subjects and received, respectively, 0.2 or 0.5 ml of DTaP. Immunogenicity was assessed by performing the immunoassay using serum, and the geometric mean concentration (GMC), GMC ratio (GMCR), seropositive rate, and booster response rate were calculated. Adverse reactions and adverse events were monitored for 7 days after vaccination. After booster vaccination in the two groups, significant increases were found in the antibodies against pertussis toxin, filamentous hemagglutinin, diphtheria toxoid, and tetanus toxoid, and the booster response rates for all subjects reached 100%. The GMCs and GMCRs against all antigens were significantly higher in the 0.5-ml group than in the 0.2-ml group. No serious adverse events were observed. Frequencies of local reactions were similar in the 2 groups, although the frequency of severe local swelling was significantly higher in the 0.5-ml group. These data support the acceptability of booster immunization using both 0.2 and 0.5 ml of DTaP for young adults for controlling pertussis. (This study was registered at UMIN-CTR under registration number UMIN000010672.).

Immunogenicity and safety of an inactivated hepatitis A vaccine administered concomitantly with diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines to children less than 2 years of age.

PubMed

Nolan, Terry; Bernstein, Henry; Blatter, Mark M; Bromberg, Kenneth; Guerra, Fernando; Kennedy, William; Pichichero, Michael; Senders, Shelly D; Trofa, Andrew; Collard, Alix; Sullivan, Diane C; Descamps, Dominique

2006-09-01

The availability of a hepatitis A virus vaccine for infant and early childhood immunization could reduce the transmission of hepatitis A virus in the United States. This study evaluated the immunogenicity and safety of a hepatitis A virus vaccine (Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) administered concomitantly with diphtheria-tetanus-acellular pertussis and Haemophilus influenzae type b vaccines to children < 2 years. In this open, comparative, multicenter study, 1084 healthy children aged 11 to 25 months were allocated (4:4:3:3:4 ratio) to 5 treatment groups based on age and previous vaccination history. Subjects 11 to 13 months of age received 2 doses of hepatitis A virus vaccine 6 months apart (N = 243). Subjects aged 15 to 18 months received 2 doses of hepatitis A virus vaccine 6 months apart (N = 241); or hepatitis A virus vaccine, diphtheria-tetanus-acellular pertussis, and H influenzae type b at month 0 and the second dose of hepatitis A virus vaccine 6 months later (N = 183); or diphtheria-tetanus-acellular pertussis and H influenzae type b at month 0 and hepatitis A virus vaccine at months 1 and 7 (N = 175). Subjects 23 to 25 months of age received hepatitis A virus vaccine at months 0 and 6 (N = 242). Immune responses were measured at baseline and 30 days after vaccine doses, and solicited and unsolicited adverse events were collected. After 2 doses of hepatitis A virus vaccine, all of the subjects in all of the groups were seropositive. Coadministration of hepatitis A virus vaccine with diphtheria-tetanus-acellular pertussis and H influenzae type b vaccines did not impact the immunogenicity of the 3 vaccines, except for the antipertussis toxoid vaccine response, which was slightly decreased. Hepatitis A virus vaccine was well tolerated in children 11 to 25 months of age. The administration of 2 doses of hepatitis A virus vaccine on a 0- and 6-month schedule starting at 11 to 13 months of age or at 15 to 18 months of age was as

Diphtheria Disease Villain

MedlinePlus

... are now immunized that diphtheria was forced to change its plan of attack. The disease now targets adults who have not had the ... but attacks can happen anytime, especially in warmer climates. Criminal Record Years ago, diphtheria was a common disease among children. And, it was also a common ...

Corynebacterium diphtheriae in a free-roaming red fox: case report and historical review on diphtheria in animals.

PubMed

Sing, Andreas; Konrad, Regina; Meinel, Dominik M; Mauder, Norman; Schwabe, Ingo; Sting, Reinhard

2016-08-01

Corynebacterium diphtheriae, the classical causative agent of diphtheria, is considered to be nearly restricted to humans. Here we report the first finding of a non-toxigenic C. diphtheriae biovar belfanti strain in a free-roaming wild animal. The strain obtained from the subcutis and mammary gland of a dead red fox (Vulpes vulpes) was characterized by biochemical and molecular methods including MALDI-TOF and Multi Locus Sequence Typing. Since C. diphtheriae infections of animals, usually with close contact to humans, are reported only very rarely, an intense review comprising also scientific literature from the beginning of the 20th century was performed. Besides the present case, only 11 previously reported C. diphtheriae animal infections could be verified using current scientific criteria. Our report is the first on the isolation of C. diphtheriae from a wildlife animal without any previous human contact. In contrast, the very few unambiguous publications on C. diphtheriae in animals referred to livestock or pet animals with close human contact. C. diphtheriae carriage in animals has to be considered as an exceptionally rare event.

Seroepidemiology of diphtheria and pertussis in Beijing, China: A cross-sectional study

PubMed Central

Li, Xiaomei; Chen, Meng; Zhang, Tiegang; Li, Juan; Zeng, Yang; Lu, Li

2015-01-01

The aim of this study was to assess the level of humoral immunity against diphtheria and pertussis by measuring IgG to diphtheria toxoid (DT) and pertussis toxin (PT) in general population of Beijing. A total of 2147 subjects aged 0–74 y were selected with a random sample of resident population in Beijing. The information of socio-demographic characteristics, vaccination history, disease history of diphtheria and pertussis were collected for each subject by questionnaire. Serum samples were tested for IgG antibodies to DT and PT by using commercial ELISA kits. The overall positivity rate of anti-DT IgG was 66.28% with the mean concentration of 2.169 IU/ml. Age stratified data showed that the highest positivity rate of 97.63% was observed in 1–4 y and the rates decreased with age. The positivity rates were only around 50% or below since 25 y old. The positivity rate of anti-PT IgG was 12.34% with the mean concentration of 15.163 IU/ml. The highest level of positivity rate (22.23%) and antibody level (23.101 IU/ml) was seen in <1 year old. In subjects older than 10 y old, the anti-PT IgG positivity rate was 10.19%–13.51% and concentration was 13.295 IU/ml −16.353 IU/ml, with no significant differences between these groups (χ2 = 1.664, P = 0.948; F = 0.369, P = 0.899). The subjects with anti-PT IgG ≥100 IU/ml were observed in nearly all the groups older than 5 y except for 10–14 age group. The estimated incidences of pertussis infection were higher than 6000/100000 in these age groups. A sharp increase of immunity level of diphtheria was observed at 1 y and 6 y respectively, which was consistent with the current immunization schedule. But there was no significant increase of immunity to pertussis observed after booster immunization at 18–24 months, but the proportions of undetectable were lowest in <1, 1, 2 years in children <14 years. As shown in the present study, the adult population was generally lack of protective antibody against

Imported Cutaneous Diphtheria, United Kingdom

PubMed Central

de Benoist, Anne-Claire; White, Joanne Margaret; Efstratiou, Androulla; Kelly, Carole; Mann, Ginder; Nazareth, Bernadette; Irish, Charles James; Kumar, Deepti

2004-01-01

Cutaneous diphtheria is endemic in tropical countries but unusual in the United Kingdom. Four cases occurred in the United Kingdom within 2 months in 2002. Because cutaneous diphtheria causes outbreaks of both cutaneous and pharyngeal forms, early diagnosis is essential for implementing control measures; high diphtheria vaccination coverage must also be maintained. PMID:15109425

Molecular epidemiology of C. diphtheriae strains during different phases of the diphtheria epidemic in Belarus

PubMed Central

Kolodkina, Valentina; Titov, Leonid; Sharapa, Tatyana; Grimont, Francine; Grimont, Patrick AD; Efstratiou, Androulla

2006-01-01

Background The reemergence of epidemic diphtheria in Belarus in 1990s has provided us with important information on the biology of the disease and the diversity of the causative agent Corynebacterium diphtheriae. Molecular investigations were conducted with the aim to analyze the genetic variability of C diphtheriae during the post-epidemic period. Methods The biotype and toxigenicity status of 3513 C. diphtheriae strains isolated from all areas in Belarus during a declining period of diphtheria morbidity (1996–2005) was undertaken. Of these, 384 strains were isolated from diphtheria cases, 1968 from tonsillitis patients, 426 from contacts and 735 from healthy carriers. Four hundred and thirty two selected strains were ribotyped. Results The C diphtheriae gravis biotype, which was prevalent during 1996–2000, was "replaced" by the mitis biotype during 2001–2005. The distribution of toxigenic C. diphtheriae strains also decreased from 47.1% (1996) to 5.8% (2005). Changes in the distribution of the epidemic ribotypes Sankt-Peterburg and Rossija were also observed. During 2001–2005 the proportion of the Sankt-Peterburg ribotype decreased from 24.3% to 2.3%, in contrast to the Rossija ribotype, that increased from 25.1% to 49.1%. The circulation of other toxigenic ribotypes (Otchakov, Lyon, Bangladesh), which were prevalent during the period of high diphtheria incidence, also decreased. But at the same time, the proportion of non-toxigenic strains with the Cluj and Rossija ribotypes dramatically increased and accounted for 49.3% and 30.1%, respectively. Conclusion The decrease in morbidity correlated with the dramatic decrease in the isolation of the gravis biotype and Sankt Peterburg ribotype, and the prevalence of the Rossija ribotype along with other rare ribotypes associated with non-toxigenic strains (Cluj and Rossija, in particular). PMID:16911772

Safety and Immunogenicity of Tetanus-Diphtheria-Acellular Pertussis Vaccine Administered to Children 10 or 11 Years of Age

PubMed Central

Pool, Vitali; Greenberg, David P.; Johnson, David R.; Sheng, Xiaohua; Decker, Michael D.

2014-01-01

Boosting immunity to tetanus, diphtheria, and pertussis through the use of Tdap vaccines is routinely recommended at 11 to 12 years of age; some states, however, require Tdap for entry into middle school, which may begin at 10 years of age. This study was conducted to determine whether Tdap5 (Adacel), which is licensed for use in children beginning at 11 years of age, is as safe and immunogenic in 10-year-olds as it is in 11-year-olds. Children who had received 5 previous doses of any diphtheria-tetanus-acellular pertussis (DTaP) vaccine were enrolled in a phase IV clinical trial; 646 10-year-olds and 645 11-year-olds completed the study, which involved a single intramuscular dose of Tdap5 along with pre- and postvaccination serologies. Postvaccination geometric mean concentrations (GMCs) of antibody to pertussis antigens (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbria types 2 and 3) of 10-year-olds were noninferior to those of 11-year-olds, as were booster response rates for all pertussis antibodies, except for those to fimbrial antigens (94% and 97%, respectively). Seroprotection rates among 10-year-olds for tetanus and diphtheria were noninferior to those in 11-year-olds. Rates of injection site reactions, solicited systemic reactions, and unsolicited adverse events, adverse reactions, and serious adverse events were similar in the two groups. These data support the conclusion that Tdap5 is safe and immunogenic in 10-year-olds. (This study has been registered at ClinicalTrials.gov under registration no. NCT01311557.) PMID:25230939

Diphtheria and hearing loss.

PubMed

Schubert, C R; Cruickshanks, K J; Wiley, T L; Klein, R; Klein, B E; Tweed, T S

2001-01-01

To determine if infectious diseases usually experienced in childhood have an effect on hearing ability later in life. The Epidemiology of Hearing Loss Study (N = 3,753) is a population-based study of age-related hearing loss in adults aged 48 to 92 years in Beaver Dam, Wisconsin. As part of this study, infectious disease history was obtained and hearing was tested using pure-tone audiometry. Hearing loss was defined as a pure-tone average of thresholds at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz greater than 25 decibels hearing level in either ear. After adjusting for confounders, only a history of diphtheria (n = 37) was associated with hearing loss (odds ratio [OR] 2.79; 95% confidence interval [CI] 1.05, 7.36). There was no relationship between hearing loss and history of chickenpox, measles, mumps, pertussis, polio, rheumatic fever, rubella, or scarlet fever. Only two participants with a history of diphtheria and hearing loss reported having a hearing loss before age 20. Diphtheria in childhood may have consequences for hearing that do not become apparent until later in life. A possible biological mechanism for a diphtheria effect on hearing ability exists: The toxin produced by the Corynebacterium diphtheriae bacteria can cause damage to cranial nerves and therefore may affect the auditory neural pathway. These data may have important implications for areas facing a resurgence of diphtheria cases.

Effectiveness and acceptance of a health care-based mandatory vaccination program.

PubMed

Leibu, Rachel; Maslow, Joel

2015-01-01

To decrease the risk of transmission of hospital-associated transmission of influenza and pertussis through mandatory vaccination of staff. A mandatory influenza and toxoid-diphtheria toxoid-acellular pertussis program was implemented systemwide. A structured vaccine exemption program was implemented for those requesting a medical and/or religious/moral/ethical exemption. Systemwide influenza vaccination rates increased from 67% historically, 76.2% in the 2012 to 2013 influenza season, to 94.7% in 2013 to 2014 with an overall compliance rate of 97.8%. Toxoid-diphtheria toxoid-acellular pertussis vaccination rates systemwide reached 94.9%, with an overall compliance rate of 98%. Higher rates were experienced at individual hospital facilities compared with the corporate location. Successful vaccination campaign outcomes can be achieved through diligent enforcement of mandatory vaccination, masking, and other infection prevention procedures.

Immunogenicity and protection in small-animal models with controlled-release tetanus toxoid microparticles as a single-dose vaccine.

PubMed Central

Singh, M; Li, X M; Wang, H; McGee, J P; Zamb, T; Koff, W; Wang, C Y; O'Hagan, D T

1997-01-01

Tetanus toxoid (TT) was encapsulated in microparticles prepared from polylactide-co-glycolide polymers by a solvent-evaporation technique. Combinations of small- and large-sized microparticles with controlled-release characteristics were used to immunize Sprague-Dawley rats, and the antibody responses were monitored for 1 year. For comparison, control groups of rats were immunized at 0, 1, and 2 months with TT adsorbed to alum. The antibody responses generated by the TT entrapped in microparticles were comparable to those generated by TT adsorbed to alum in control groups from 32 weeks onwards. Microparticles with a single entrapped antigen (TT) induced better antibody responses than microparticles with two antigens (TT and diphtheria toxoid) entrapped simultaneously. A combination vaccine consisting of TT adsorbed to alum and also entrapped in microparticles gave the best antibody responses. In an inhibition assay designed to determine the relative levels of binding of antisera to the antigens, the sera from the microparticle- and the alum-immunized animals showed comparable levels of binding. In addition, in a passive-challenge study with mice, TT adsorbed to alum and TT entrapped in microparticles provided equal levels of protection against a lethal challenge with tetanus toxin. An intradermal-challenge study was also performed with rabbits, which showed similar levels of protection in sera from alum- and microparticle-immunized animals at 4, 12, and 32 weeks after immunization. PMID:9125552

Vaccine effectiveness of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine during a pertussis outbreak in Maine.

PubMed

Terranella, Andrew; Rea, Vicki; Griffith, Matthew; Manning, Susan; Sears, Steven; Farmer, Ann; Martin, Stacey; Patel, Manisha

2016-05-11

Multiple school-associated pertussis outbreaks were reported in Maine from 2010 to 2011. These outbreaks were associated with an overall increase in pertussis cases statewide. Waning of protection in students recently vaccinated with tetanus, diphtheria, and acellular pertussis (Tdap) has been implicated in the increase in reported rates of pertussis nationally. We conducted a retrospective cohort study to evaluate Tdap vaccine effectiveness (VE) among students aged 11-19 years in two schools reporting outbreaks in 2011. All pertussis cases reported from August through November, 2011 at the two schools were included. Vaccination history was verified using provider information, state vaccine registry data, and parental verification. Attack rates (AR) were calculated. VE and duration of protection was calculated as VE=1-(ARvaccinated/ARunvaccinated)×100% using a log binomial regression model. Of 416 students enrolled, 314 were included in the analyses. Twenty-nine cases collectively in Schools A and B. Tdap coverage was 65% at School A and 42% at School B before the start of the outbreak. Among students enrolled in the study, attack rates were 11.9% and 7.7% at Schools A and B, respectively. Overall VE was 68.5% (95% confidence interval (CI) 37.7-86.2). VE was 70.4% (95% CI 17.5-89.4) for School A and 65.2% (95% CI -19.2 to 89.9) for School B. VE <2 years versus ≥2 years from outbreak onset was not significantly different. Tdap was moderately effective in preventing disease among vaccinated students. Vaccine coverage of 65% or less was suboptimal and might contribute to outbreaks. Waning VE was not demonstrated. Increased vaccination coverage rates as well as further evaluation of the role of acellular vaccine on VE is needed. Published by Elsevier Ltd.

Diphtheria Diagnosis and Treatment

MedlinePlus

... the Alaskan Iditarod Diagnosis and Treatment Recommend on Facebook Tweet Share Compartir Getting treatment quickly for diphtheria is important. Doctors usually decide if a person has diphtheria by looking for common signs and symptoms . They can use a swab from the back of the throat ...

Physicochemical and immunochemical assays for monitoring consistent production of tetanus toxoid.

PubMed

Metz, Bernard; Tilstra, Wichard; van der Put, Robert; Spruit, Nanda; van den Ijssel, Jan; Robert, Jolanda; Hendriksen, Coenraad; Kersten, Gideon

2013-07-01

The detoxification of tetanus toxin by formaldehyde is a crucial step in the production of tetanus toxoid. The inactivation results in chemically modified proteins and it determines largely the ultimate efficacy and safety of the vaccine. Currently, the quality of tetanus toxoid lots is evaluated in potency and safety tests performed in animals. As a possible alternative, this article describes a panel of in vitro methods, which provides detailed information about the quality of tetanus toxoid. Ten experimental lots of tetanus toxoid were prepared using increasing concentrations of formaldehyde and glycine to obtain tetanus toxoids having differences in antigenicity, immunogenicity, residual toxicity and protein structure. The structural properties of each individual toxoid were determined using immunochemical and physicochemical methods, including biosensor analysis, ELISA, circular dichroism, TNBS assay, differential scanning calorimetry, fluorescence and SDS-PAGE. The quality of a tetanus toxoid lot can be assessed by these set of analytical techniques. Based on antigenicity, immunogenicity and residual toxicity data, criteria are formulated that tetanus toxoids lot have to meet in order to have a high quality. The in vitro methods are a valuable selection of techniques for monitoring consistency of production of tetanus toxoid, especially for the detoxification process of tetanus toxin. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Safety and immunogenicity of tetanus-diphtheria-acellular pertussis vaccine administered to children 10 or 11 years of age.

PubMed

Marshall, Gary S; Pool, Vitali; Greenberg, David P; Johnson, David R; Sheng, Xiaohua; Decker, Michael D

2014-11-01

Boosting immunity to tetanus, diphtheria, and pertussis through the use of Tdap vaccines is routinely recommended at 11 to 12 years of age; some states, however, require Tdap for entry into middle school, which may begin at 10 years of age. This study was conducted to determine whether Tdap5 (Adacel), which is licensed for use in children beginning at 11 years of age, is as safe and immunogenic in 10-year-olds as it is in 11-year-olds. Children who had received 5 previous doses of any diphtheria-tetanus-acellular pertussis (DTaP) vaccine were enrolled in a phase IV clinical trial; 646 10-year-olds and 645 11-year-olds completed the study, which involved a single intramuscular dose of Tdap5 along with pre- and postvaccination serologies. Postvaccination geometric mean concentrations (GMCs) of antibody to pertussis antigens (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbria types 2 and 3) of 10-year-olds were noninferior to those of 11-year-olds, as were booster response rates for all pertussis antibodies, except for those to fimbrial antigens (94% and 97%, respectively). Seroprotection rates among 10-year-olds for tetanus and diphtheria were noninferior to those in 11-year-olds. Rates of injection site reactions, solicited systemic reactions, and unsolicited adverse events, adverse reactions, and serious adverse events were similar in the two groups. These data support the conclusion that Tdap5 is safe and immunogenic in 10-year-olds. (This study has been registered at ClinicalTrials.gov under registration no. NCT01311557.). Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Accelerated stability studies for moisture-induced aggregation of tetanus toxoid.

PubMed

Jain, Nishant Kumar; Roy, Ipsita

2011-03-01

The study was carried out to evaluate the effect of exposing solid tetanus toxoid to moisture in two different ways on the structure and function of the toxoid. Tetanus toxoid was exposed to moisture by (i) the addition of an optimized amount of buffer and (ii) incubation under an environment provided by a saturated solution of K(2)CrO(4.) The changes in the conformational, structural and antigenic properties of tetanus toxoid were measured and compared. Results show that even at a similar level of moisture-induced aggregation, the amounts of water absorbed by the two preparations of tetanus toxoid are different. Differences in antigenicity and changes in structure of the toxoid at primary, secondary and tertiary structure levels were seen. Although both conditions are used to mimic accelerated stability conditions in the laboratory, the final products are different in the two cases. Thus, conditions for 'accelerated stability studies' for therapeutic proteins need to be selected with care so that they resemble the fate of the actual product.

44 CFR Appendix 1 to Part 323 - List of Essential Survival Items

Code of Federal Regulations, 2010 CFR

2010-10-01

... of preattack planning to insure the availability of basic essentials for a productive economy in the...: Blood collecting and dispensing containers. Blood donor sets. Blood grouping and typing sera. Blood recipient sets. Blood shipping containers. 3. Biologicals: Diphtheria toxoid. Diphtheria antitoxin...

Production and Characterization of Chemically Inactivated Genetically Engineered Clostridium difficile Toxoids.

PubMed

Vidunas, Eugene; Mathews, Antony; Weaver, Michele; Cai, Ping; Koh, Eun Hee; Patel-Brown, Sujata; Yuan, Hailey; Zheng, Zi-Rong; Carriere, Marjolaine; Johnson, J Erik; Lotvin, Jason; Moran, Justin

2016-07-01

A recombinant Clostridium difficile expression system was used to produce genetically engineered toxoids A and B as immunogens for a prophylactic vaccine against C. difficile-associated disease. Although all known enzymatic activities responsible for cytotoxicity were genetically abrogated, the toxoids exhibited residual cytotoxic activity as measured in an in vitro cell-based cytotoxicity assay. The residual cytotoxicity was eliminated by treating the toxoids with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide. Mass spectrometry and amino acid analysis of the EDC-inactivated toxoids identified crosslinks, glycine adducts, and β-alanine adducts. Surface plasmon resonance analysis demonstrated that modifications resulting from the chemical treatment did not appreciably affect recognition of epitopes by both toxin A- and B-specific neutralizing monoclonal antibodies. Compared to formaldehyde-inactivated toxoids, the EDC/N-hydroxysuccinimide-inactivated toxoids exhibited superior stability in solution with respect to reversion of cytotoxic activity. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Tetanus toxoid purification: chromatographic procedures as an alternative to ammonium-sulphate precipitation.

PubMed

Stojićević, Ivana; Dimitrijević, Ljiljana; Dovezenski, Nebojša; Živković, Irena; Petrušić, Vladimir; Marinković, Emilija; Inić-Kanada, Aleksandra; Stojanović, Marijana

2011-08-01

Given an existing demand to establish a process of tetanus vaccine production in a way that allows its complete validation and standardization, this paper focuses on tetanus toxoid purification step. More precisely, we were looking at a possibility to replace the widely used ammonium-sulphate precipitation by a chromatographic method. Based on the tetanus toxin's biochemical characteristics, we have decided to examine the possibility of tetanus toxoid purification by hydrophobic chromatography, and by chromatographic techniques based on interaction with immobilized metal ions, i.e. chelating chromatography and immobilized metal affinity chromatography. We used samples obtained from differently fragmented crude tetanus toxins by formaldehyde treatment (assigned as TTd-A and TTd-B) as starting material for tetanus toxoid purification. Obtained results imply that purification of tetanus toxoid by hydrophobic chromatography represents a good alternative to ammonium-sulphate precipitation. Tetanus toxoid preparations obtained by hydrophobic chromatography were similar to those obtained by ammonium-sulphate precipitation in respect to yield, purity and immunogenicity. In addition, their immunogenicity was similar to standard tetanus toxoid preparation (NIBSC, Potters Bar, UK). Furthermore, the characteristics of crude tetanus toxin preparations had the lowest impact on the final purification product when hydrophobic chromatography was the applied method of tetanus toxoid purification. On the other hand, purifications of tetanus toxoid by chelating chromatography or immobilized metal affinity chromatography generally resulted in a very low yield due to not satisfactory tetanus toxoid binding to the column, and immunogenicity of the obtained tetanus toxoid-containing preparations was poor. Copyright © 2011 Elsevier B.V. All rights reserved.

Diphtheria in the Republic of Georgia: Use of Molecular Typing Techniques for Characterization of Corynebacterium diphtheriae Strains

PubMed Central

Sulakvelidze, Alexander; Kekelidze, Merab; Gomelauri, Tsaro; Deng, Yingkang; Khetsuriani, Nino; Kobaidze, Ketino; De Zoysa, Aruni; Efstratiou, Androulla; Morris, J. Glenn; Imnadze, Paata

1999-01-01

Sixty-six Corynebacterium diphtheriae strains (62 of the gravis biotype and 4 of the mitis biotype) isolated during the Georgian diphtheria epidemic of 1993 to 1998 and 13 non-Georgian C. diphtheriae strains (10 Russian and 3 reference isolates) were characterized by (i) biotyping, (ii) toxigenicity testing with the Elek assay and PCR, (iii) the randomly amplified polymorphic DNA (RAPD) technique, and (iv) pulsed-field gel electrophoresis (PFGE). Fifteen selected strains were ribotyped. Six RAPD types and 15 PFGE patterns were identified among all strains examined, and 12 ribotypes were found among the 15 strains that were ribotyped. The Georgian epidemic apparently was caused by one major clonal group of C. diphtheriae (PFGE type A, ribotype R1), which was identical to the predominant epidemic strain(s) isolated during the concurrent diphtheria epidemic in Russia. A dendrogram based on the PFGE patterns revealed profound differences between the minor (nonpredominant) epidemic strains found in Georgia and Russia. The methodologies for RAPD typing, ribotyping, and PFGE typing of C. diphtheriae strains were improved to enable rapid and convenient molecular typing of the strains. The RAPD technique was adequate for biotype differentiation; however, PFGE and ribotyping were better (and equal to each other) at discriminating between epidemiologically related and unrelated isolates. PMID:10488190

Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults.

PubMed

Gasparini, Roberto; Conversano, Michele; Bona, Gianni; Gabutti, Giovanni; Anemona, Alessandra; Dull, Peter M; Ceddia, Francesca

2010-04-01

This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults.

Mathematical modeling of diphtheria transmission in Thailand.

PubMed

Sornbundit, Kan; Triampo, Wannapong; Modchang, Charin

2017-08-01

In this work, a mathematical model for describing diphtheria transmission in Thailand is proposed. Based on the course of diphtheria infection, the population is divided into 8 epidemiological classes, namely, susceptible, symptomatic infectious, asymptomatic infectious, carrier with full natural-acquired immunity, carrier with partial natural-acquired immunity, individual with full vaccine-induced immunity, and individual with partial vaccine-induced immunity. Parameter values in the model were either directly obtained from the literature, estimated from available data, or estimated by means of sensitivity analysis. Numerical solutions show that our model can correctly describe the decreasing trend of diphtheria cases in Thailand during the years 1977-2014. Furthermore, despite Thailand having high DTP vaccine coverage, our model predicts that there will be diphtheria outbreaks after the year 2014 due to waning immunity. Our model also suggests that providing booster doses to some susceptible individuals and those with partial immunity every 10 years is a potential way to inhibit future diphtheria outbreaks. Copyright © 2017 Elsevier Ltd. All rights reserved.

[First confirmed case of laryngeal diphtheria in Djibouti].

PubMed

Koeck, J L; Merle, C; Bimet, F; Kiredjian, M; Goullin, B; Teyssou, R

2000-01-01

The first bacteriologically confirmed case of laryngeal diphtheria in Djibouti was reported in 1998. It involved a three-year-old native-born infant who had been vaccinated during the first year of life with three doses of a combined vaccine against diphtheria, tetanus, poliomyelitis, and pertussis. A rapid clinical improvement was observed under erythromycin treatment. Other cases of laryngeal diphtheria have been observed. It is important to reverse decreasing vaccinal coverage in Djibouti and to warn incoming travelers of the need to be adequate immunized against diphtheria. Enhanced epidemiologic surveillance of this disease is also needed.

The changing epidemiology of diphtheria in Jordan*

PubMed Central

Khuri-Bulos, N.; Hamzah, Y.; Sammerrai, S. M.; Shehabi, A.; Hamed, R.; Arnaout, M. A.; Turk, J.; Qubain, H.

1988-01-01

Outbreaks of diphtheria used to occur regularly in Jordan, the last such outbreak being in 1977-78. Since that time, a massive immunization programme targeted at pre-school-age children has been markedly successful. Hence, when an outbreak of diphtheria occurred in 1982-83, it was unexpected. Of the 35 patients who were treated at the Jordan University Hospital, two died and the remaining 33 recovered uneventfully. Contrary to our findings in previous diphtheria epidemics in Jordan, this outbreak largely involved adolescents and young adults. PMID:3260143

Diphtheria in the Postepidemic Period, Europe, 2000–2009

PubMed Central

White, Joanne M.; Lucenko, Irina; Mercer, David; Crowcroft, Natasha S.; Neal, Shona; Efstratiou, Androulla

2012-01-01

Diphtheria incidence has decreased in Europe since its resurgence in the 1990s, but circulation continues in some countries in eastern Europe, and sporadic cases have been reported elsewhere. Surveillance data from Diphtheria Surveillance Network countries and the World Health Organization European Region for 2000–2009 were analyzed. Latvia reported the highest annual incidence in Europe each year, but the Russian Federation and Ukraine accounted for 83% of all cases. Over the past 10 years, diphtheria incidence has decreased by >95% across the region. Although most deaths occurred in disease-endemic countries, case-fatality rates were highest in countries to which diphtheria is not endemic, where unfamiliarity can lead to delays in diagnosis and treatment. In western Europe, toxigenic Corynebacterium ulcerans has increasingly been identified as the etiologic agent. Reduction in diphtheria incidence over the past 10 years is encouraging, but maintaining high vaccination coverage is essential to prevent indigenous C. ulcerans and reemergence of C. diphtheriae infections. PMID:22304732

Impact of tetanus, diphtheria, and acellular pertussis (Tdap) vaccine use in wound management on health care costs and pertussis cases.

PubMed

Talbird, Sandra E; Graham, Jonathan; Mauskopf, Josephine; Masseria, Cristina; Krishnarajah, Girishanthy

2015-01-01

The Advisory Committee on Immunization Practices (ACIP) recommends the use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine for routine wound management in adolescents and adults who require a tetanus toxoid-containing vaccine who were vaccinated ≥ 5 years earlier with tetanus toxoid, reduced diphtheria toxoid (Td) vaccine, and who have not previously received Tdap. To estimate the overall budget and health impact of vaccinating individuals presenting for wound management with Tdap instead of Td vaccine, the current standard of care in practices that do not use Tdap for purposes of wound management. A decision-analytic economic model was developed to estimate the expected increase in direct medical costs and the expected number of cases of pertussis avoided associated with the use of Tdap instead of Td vaccine in the wound management setting. Patients eligible for Tdap were aged 10+ years and required a tetanus-containing vaccine. Age-specific wound incidence data and Td and Tdap vaccination rates were taken from the National Health Interview Survey and the National Immunization Survey for the most recent available year. Age-specific pertussis incidence used in this analysis (151 per 100,000 for adolescents, 366 per 100,000 for those aged 20-64 years, and 176 per 100,000 for those aged 65+ years) used reported incidence rates adjusted by a factor of 10 for adolescents and by a factor of 100 for adults, based on assumptions previously made by ACIP to account for underreporting. Vaccine wholesale acquisition costs without federal excise tax were assumed in the base case. Efficacy of vaccination with Tdap in preventing pertussis was based on clinical trial data. Possible herd immunity effects of vaccination were not included in the model. Costs associated with vaccination and treatment of pertussis cases were reported as total annual costs and per-member-per-month (PMPM) costs for hypothetical health plans and for the U

Hepatitis B Vaccine

MedlinePlus

... a combination product containing Haemophilus influenzae type b, Hepatitis B Vaccine) ... combination product containing Diphtheria, Tetanus Toxoids, Acellular Pertussis, Hepatitis B, Polio Vaccine)

Specific detection of tetanus toxoid using an aptamer-based matrix.

PubMed

Modh, Harshvardhan B; Bhadra, Ankan K; Patel, Kinjal A; Chaudhary, Rajeev K; Jain, Nishant K; Roy, Ipsita

2016-11-20

Batch-to-batch variation of therapeutic proteins produced by biological means requires rigorous monitoring at all stages of the production process. A large number of animals are employed for risk assessment of biologicals, which has low ethical and economic acceptability. Research is now focussed on the validation of in vitro and ex vivo tests to replace live challenges. Among in vitro methods, enzyme-linked immunosorbent assay (ELISA) is considered to be the gold standard for estimation of integrity of tetanus toxoid. ELISA utilizes antibodies for detection, which, because of their biological origin and limited modifiability, may have low stability and result in irreproducibility. We have developed a method using highly specific and selective RNA aptamers for detection of tetanus toxoid. Using displacement assay, we first identified aptamers which bind to different aptatopes on the surface of the toxoid. Pairs of these aptamers were employed as capture-detection ligands in a sandwich-ALISA (aptamer-linked immobilized sorbent assay) format. The binding efficiency was confirmed by the fluorescence intensity in each microtire plate well. Using aptamers alone, detection of tetanus toxoid was possible with the same level of sensitivity as antibody. Aptamers were also used in the capture ALISA format. Adjuvanted tetanus toxoid was subjected to accelerated stress testing, including thermal, mechanical and freeze-thawing stress conditions. The loss in antigenicity of the preparation determined by ALISA in each case was found to be similar to that determined by conventional ELISA. Thus, it is possible to replace antibodies with aptamers to develop a more robust detection tool for tetanus toxoid. Copyright © 2016 Elsevier B.V. All rights reserved.

X IRRADIATION AND THE SECONDARY RESPONSE TO TETANUS TOXOID IN MICE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crook, J.C.; Ford, C.E.

1962-04-01

In 1952 it was recommended that wounded soldiers who had been actively immunized should be given a dose of tetanus toxoid and not tetanus antiserum as had been the practice previously. However, in the event of nuclear warfare, wounded soldiers might be exposed to irradiation, which would be detrimental to toxoid treatment since irradiation inhibits antibody formation. To investigate the problem, male PCT mice were immunized with two doses of tetanus toxoid at a 8- week interval, and their immune response to the second dose was tested by challenge with tetanus toxin 14 days later. Whole-body x irradiation with 35more » days before the second dose of toxoid to 7 days after. The criterion of inhibition of immune response was the percentage of deaths and paralyzed survivals occurring on the eighth day. The secondary response to tetanus toxoid was shown to be radiosensitive and to depend largely on the dose of radiation; a dose of 500 rad produced approximates 50% inhibition. Radiation given from 35 days to 1 day before the second dose of tetanus toxoid prcduced most inhibition; when given 2 days after the second dose it was less effective, and it was ineffective when given 5 or 7 days after. In the 200-rad experiment there was no evidence of inhibition at all. It is concluded that the wounded soldier should receive a booster dose of tetanus toxoid as soon as possible after wounding and probable irradiation from an atomic weapon. If a delay of a day or two occurred, the irradiated soldier might be at a stage of marked inhibition of his secondary response. If it is assumed that these findings are capable of extrapolation to man, he would not be capable of responding fully to any active immunizing procedures for a period of a few weeks at least after irradiation. (BBB)« less

Safety and Immunogenicity of Tetanus Diphtheria and Acellular Pertussis (Tdap) Immunization During Pregnancy in Mothers and Infants: A Randomized Clinical Trial

PubMed Central

Munoz, Flor M.; Bond, Nanette H.; Maccato, Maurizio; Pinell, Phillip; Hammill, Hunter A.; Swamy, Geeta K.; Walter, Emmanuel B.; Jackson, Lisa A.; Englund, Janet A.; Edwards, Morven S.; Healy, C. Mary; Petrie, Carey R.; Ferreira, Jennifer; Goll, Johannes B.; Baker, Carol J.

2015-01-01

Importance Maternal immunization with tetanus toxoid and reduced diphtheria toxoid acellular pertussis (Tdap) vaccine could prevent infant pertussis. The effect of vaccine-induced maternal antibodies on infant responses to diphtheria and tetanus toxoids acellular pertussis (DTaP) immunization is unknown. Objective To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to DTaP. Design, Setting and Participants Phase I, randomized, double-masked, placebo-controlled clinical trial conducted in private (Houston) and academic (Durham, Seattle) obstetric practices from 2008 to 2012. Forty eight healthy 18–45 year-old pregnant women received Tdap (n=33) or placebo (n=15) at 30–32 weeks’ gestation with cross-over Tdap immunization postpartum. Interventions Tdap vaccination at 30–32 weeks’ gestation or post-partum. Outcome Measures Primary: Maternal and infant adverse events, pertussis illness and infant growth and development (Bayley-III screening test) until 13 months of age. Secondary: Antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months postpartum, and in infants at birth, 2 months, and after the third (7 months) and fourth (13 months) doses of DTaP. Results All participants delivered healthy newborns. No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 78.8% (95% CI: 61.1%, 91.0%) and 80% (CI: 51.9%, 95.7%) pregnant and postpartum women, respectively. Injection site pain was the predominant symptom. Systemic symptoms were reported in 36.4% (CI: 20.4%, 54.9%) and 73.3% (CI: 44.9%, 92.2%) pregnant and postpartum women, respectively. Malaise and myalgia were most common. Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in

Co-administration of a novel Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine does not interfere with the immune response to antigens contained in infant vaccines routinely used in the United States.

PubMed

Marshall, Gary S; Marchant, Colin D; Blatter, Mark; Friedland, Leonard R; Aris, Emmanuel; Miller, Jacqueline M

2011-02-01

An investigational combined Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (HibMenCY-TT) has been developed to protect infants from invasive disease caused by Hib and these meningococcal serogroups without adding injections to the immunization schedule. Incorporation of this novel vaccine into the US vaccination schedule will require demonstration of a lack of immunologic interference with other routine pediatric vaccines. This study assessed the immune response to 7-valent pneumococcal conjugate vaccine (PCV7) and combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine (DTaP-HepB-IPV) when separately co-administered with HibMenCY-TT as compared to a US-licensed H. influenzae type b tetanus toxoid conjugate vaccine (Hib-TT) at 2, 4, 6 (N=606) and 12-15 months of age (N=366). HibMenCY-TT was non-inferior to Hib-TT in terms of antibody responses to all Streptococcus pneumoniae serotypes contained in PCV7 and the diphtheria, tetanus, pertussis, hepatitis B and poliovirus antigens contained in DTaP-HepB-IPV one month after the third vaccine dose, and the anti-tetanus geometric mean antibody concentration (GMC) was significantly higher in the HibMenCY-TT group than in the Hib-TT group. In an exploratory analysis, no significant differences in the proportion of subjects with anti-pneumococcal antibody concentrations ≥0.2 µg/ml or anti-pneumococcal GMC were seen between the two groups after the fourth vaccine dose. A schedule of HibMenCY-TT given concomitantly with PCV7 and DTaP-HepB-IPV would be expected to protect infants against all of the targeted diseases.

13-valent pneumococcal conjugate vaccine given with meningococcal C-tetanus toxoid conjugate and other routine pediatric vaccinations: immunogenicity and safety.

PubMed

Martinón-Torres, Federico; Gimenez-Sanchez, Francisco; Gurtman, Alejandra; Bernaola, Enrique; Diez-Domingo, Javier; Carmona, Alfonso; Sidhu, Mohinder; Sarkozy, Denise A; Gruber, William C; Emini, Emilio A; Scott, Daniel A

2012-04-01

As multiple vaccines are administered concomitantly during routine pediatric immunizations, it is important to ascertain the potential interference of any new vaccine on the immune response to the concomitantly administered vaccines. Immune responses to meningococcal serogroup C-tetanus toxoid conjugate vaccine (MnCC-TT) and the diphtheria and tetanus antigens in routine pediatric vaccines (diphtheria, tetanus, acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenza type b [DTaP-HBV-IPV/Hib] and DTaP-IPV+Hib) when given concomitantly with the 13-valent pneumococcal conjugate vaccine (PCV13) were compared with responses when given with PCV7. In addition, the immunogenicity and safety of PCV13 were assessed. Healthy infants were randomized to receive PCV13 or PCV7 (ages 2, 4, 6 and 15 months), concomitant with MnCC-TT (2, 4 and 15 months), DTaP-HBV-IPV/Hib (2, 4 and 6 months), and DTaP-IPV+Hib (15 months). Immune responses to MnCC-TT and to the diphtheria and tetanus antigens administered with PCV13 were noninferior to the responses observed when the vaccines were administered with PCV7; ≥96.6 (postinfant) and ≥99.4% (posttoddler) subjects achieved prespecified immune response levels to each antigen in each group. After the infant series, ≥93.0% of subjects receiving PCV13 achieved pneumococcal anticapsular immunoglobulin G concentrations ≥0.35 µg/mL for all serotypes except serotype 3 (86.2%), increasing to 98.1-100% for most serotypes (serotype 3: 93.6%) after the toddler dose. Local and systemic reactions were similar between groups. Immune responses to MnCC-TT, and other childhood vaccines (DTaP-HBV-IPV/Hib, DTaP-IPV+Hib) were noninferior when concomitantly administered with PCV13 compared with PCV7. PCV13 does not interfere with MnCC-TT. PCV13 is highly immunogenic with a favorable safety profile.

Tetanus toxoid immunization to reduce mortality from neonatal tetanus.

PubMed

Blencowe, Hannah; Lawn, Joy; Vandelaer, Jos; Roper, Martha; Cousens, Simon

2010-04-01

Neonatal tetanus remains an important and preventable cause of neonatal mortality globally. Large reductions in neonatal tetanus deaths have been reported following major increases in the coverage of tetanus toxoid immunization, yet the level of evidence for the mortality effect of tetanus toxoid immunization is surprisingly weak with only two trials considered in a Cochrane review. To review the evidence for and estimate the effect on neonatal tetanus mortality of immunization with tetanus toxoid of pregnant women, or women of childbearing age. We conducted a systematic review of multiple databases. Standardized abstraction forms were used. Individual study quality and the overall quality of evidence were assessed using an adaptation of the GRADE approach. Meta-analyses were performed. Only one randomised controlled trial (RCT) and one well-controlled cohort study were identified, which met inclusion criteria for meta-analysis. Immunization of pregnant women or women of childbearing age with at least two doses of tetanus toxoid is estimated to reduce mortality from neonatal tetanus by 94% [95% confidence interval (CI) 80-98%]. Additionally, another RCT with a case definition based on day of death, 3 case-control studies and 1 before-and-after study gave consistent results. Based on the consistency of the mortality data, the very large effect size and that the data are all from low/middle-income countries, the overall quality of the evidence was judged to be moderate. This review uses a standard approach to provide a transparent estimate of the high impact of tetanus toxoid immunization on neonatal tetanus.

Tetanus toxoid immunization to reduce mortality from neonatal tetanus

PubMed Central

Blencowe, Hannah; Lawn, Joy; Vandelaer, Jos; Roper, Martha

2010-01-01

Background Neonatal tetanus remains an important and preventable cause of neonatal mortality globally. Large reductions in neonatal tetanus deaths have been reported following major increases in the coverage of tetanus toxoid immunization, yet the level of evidence for the mortality effect of tetanus toxoid immunization is surprisingly weak with only two trials considered in a Cochrane review. Objective To review the evidence for and estimate the effect on neonatal tetanus mortality of immunization with tetanus toxoid of pregnant women, or women of childbearing age. Methods We conducted a systematic review of multiple databases. Standardized abstraction forms were used. Individual study quality and the overall quality of evidence were assessed using an adaptation of the GRADE approach. Meta-analyses were performed. Results Only one randomised controlled trial (RCT) and one well-controlled cohort study were identified, which met inclusion criteria for meta-analysis. Immunization of pregnant women or women of childbearing age with at least two doses of tetanus toxoid is estimated to reduce mortality from neonatal tetanus by 94% [95% confidence interval (CI) 80–98%]. Additionally, another RCT with a case definition based on day of death, 3 case–control studies and 1 before-and-after study gave consistent results. Based on the consistency of the mortality data, the very large effect size and that the data are all from low/middle-income countries, the overall quality of the evidence was judged to be moderate. Conclusion This review uses a standard approach to provide a transparent estimate of the high impact of tetanus toxoid immunization on neonatal tetanus. PMID:20348112

Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses.

PubMed

Bortolatto, Juliana; Mirotti, Luciana; Rodriguez, Dunia; Gomes, Eliane; Russo, Momtchilo

2015-01-01

Aluminum salts gels (alum) are TLR-independent adjuvants and have been used to boost antibody responses in alum-based vaccines such as diphtheria, pertussis, and tetanus toxoid (DPT) triple vaccine. However, the pro-Th2 activity of alum-based vaccine formulations has not been fully appreciated. Here we found that alum-based tetanus toxoid (TT) vaccine was biased toward a Th-2 profile as shown by TT-induced airway eosinophilic inflammation, type 2 cytokine production, and high levels of IgE anaphylactic antibodies. The adsorption into alum of prototypic TLR4 agonists such as lipopolysaccharides (LPS) derived from Escherichia coli consistently dampened TT-induced Th2 activities without inducing IFNγ or Th1-like responses in the lung. Conversely, adsorption of monophosphoryl lipid A (MPLA) extracted from Salmonella minnesota, which is a TIR-domain-containing adapter-inducing interferon-β- (TRIF-) biased TLR4 agonist, was less effective in decreasing Th-2 responses. Importantly, in a situation with antigenic competition (OVA plus TT), TT-specific IgG1 or IgG2a was decreased compared with TT sensitization. Notably, LPS increased the production of IgG1 and IgG2a TT-specific antibodies. In conclusion, the addition of LPS induces a more robust IgG1 and IgG2a TT-specific antibody production and concomitantly decreases Th2-cellular and humoral responses, indicating a potential use of alum/TLR-based vaccines.

Td Vaccine (Tetanus and Diphtheria): What You Need to Know

MedlinePlus

... protect adolescents and adults from both of these diseases. Both tetanus and diphtheria are infections caused by bacteria. Diphtheria ... cases of diphtheria and hundreds of cases of tetanus were reported in the United ... both diseases have dropped by about 99%. 2 Td vaccine ...

Diphtheria in Lao PDR: Insufficient Coverage or Ineffective Vaccine?

PubMed

Nanthavong, Naphavanh; Black, Antony P; Nouanthong, Phonethipsavanh; Souvannaso, Chanthasone; Vilivong, Keooudomphone; Muller, Claude P; Goossens, Sylvie; Quet, Fabrice; Buisson, Yves

2015-01-01

During late 2012 and early 2013 several outbreaks of diphtheria were notified in the North of the Lao People's Democratic Republic. The aim of this study was to determine whether the re-emergence of this vaccine-preventable disease was due to insufficient vaccination coverage or reduction of vaccine effectiveness within the affected regions. A serosurvey was conducted in the Huaphan Province on a cluster sampling of 132 children aged 12-59 months. Serum samples, socio-demographic data, nutritional status and vaccination history were collected when available. Anti-diphtheria and anti-tetanus IgG antibody levels were measured by ELISA. Overall, 63.6% of participants had detectable diphtheria antibodies and 71.2% tetanus antibodies. Factors independently associated with non-vaccination against diphtheria were the distance from the health centre (OR: 6.35 [95% CI: 1.4-28.8], p = 0.01), the Lao Theung ethnicity (OR: 12.2 [95% CI:1,74-85, 4], p = 0.01) and the lack of advice on vaccination given at birth (OR: 9.8 [95% CI: 1.5-63.8], (p = 0.01) while the level of maternal edu-cation was a protective factor (OR: 0.08 [95% CI: 0.008-0.81], p = 0.03). Most respondents claimed financial difficulties as the main reason for non-vaccination. Out of 55 children whose vaccination certificates stated that they were given all 3 doses of diphtheria-containing vaccine, 83.6% had diphtheria antibodies and 92.7% had tetanus antibodies. Furthermore, despite a high prevalence of stunted and underweight children (53% and 25.8%, respectively), the low levels of anti-diphtheria antibodies were not correlated to the nutritional status. Our data highlight a significant deficit in both the vaccination coverage and diphtheria vaccine effectiveness within the Huaphan Province. Technical deficiencies in the methods of storage and distribution of vaccines as well as unreliability of vaccination cards are discussed. Several hypotheses are advanced to explain such a decline in immunity against

Diphtheria and the Vaccine (Shot) to Prevent It: Information for Parents

MedlinePlus

... for about 2 weeks after infection. A diphtheria booster is needed to keep up protection from diphtheria ... shot does not offer lifetime protection. People need booster vaccines to keep up protection from diphtheria. Children ...

Immunity to tetanus and diphtheria in the UK in 2009.

PubMed

Wagner, Karen S; White, Joanne M; Andrews, Nick J; Borrow, Ray; Stanford, Elaine; Newton, Emma; Pebody, Richard G

2012-11-19

This study aimed to estimate the immunity of the UK population to tetanus and diphtheria, including the potential impact of new glycoconjugatate vaccines, and the addition of diphtheria to the school leaver booster in 1994. Residual sera (n=2697) collected in England in 2009/10 were selected from 18 age groups and tested for tetanus and diphtheria antibody. Results were standardised by testing a panel of sera (n=150) to enable comparison with a previously (1996) published serosurvey. Data were then standardised to the UK population. In 2009, 83% of the UK population were protected (≥0.1 IU/mL) against tetanus compared to 76% in 1996 (p=0.079), and 75% had at least basic protection against diphtheria (≥0.01 IU/mL) in 2009 compared to 60% in 1996 (p<0.001). Higher antibody levels were observed in those aged 1-3 years in 2009 compared to 1996 for both tetanus and diphtheria. Higher diphtheria immunity was observed in those aged 16-34 years in 2009 compared to 1996 (geometric mean concentration [GMC] 0.15 IU/mL vs. 0.03 IU/mL, p<0.001). Age groups with the largest proportion of susceptible individuals to both tetanus and diphtheria in 2009 were <1 year old (>29% susceptible), 45-69 years (>20% susceptible) and 70+ years (>32% susceptible). Low immunity was observed in those aged 10-11 years (>19% susceptible), between the scheduled preschool and school leaver booster administration. The current schedule appears to induce protective levels; increases in the proportions protected/GMCs were observed for the ages receiving vaccinations according to UK policy. Glycoconjugate vaccines appear to have increased immunity, in particular for diphtheria, in preschool age groups. Diphtheria immunity in teenagers and young adults has increased as a result of the addition of diphtheria to the school leaver booster. However, currently older adults remain susceptible, without any further opportunities for immunisations planned according to the present schedule. Copyright © 2012

Tetanus, diphtheria, and acellular pertussis vaccination during pregnancy and reduced risk of infant acute respiratory infections.

PubMed

Khodr, Zeina G; Bukowinski, Anna T; Gumbs, Gia R; Conlin, Ava Marie S

2017-10-09

To protect infants from pertussis infection, the Advisory Committee on Immunization Practices (ACIP) recommends women receive the tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine between 27 and 36weeks of pregnancy. Here, we assessed the association between timing of maternal Tdap vaccination during pregnancy and acute respiratory infection (ARI) in infants <2months of age. This retrospective cohort study included 99,434 infants born to active duty military women in the Department of Defense Birth and Infant Health Registry from 2006 through 2013. Multivariable log-binomial regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for the association between maternal Tdap vaccination during pregnancy and infant ARI at <2months of age. Infants of mothers who received Tdap vaccination during pregnancy vs those who did not were 9% less likely to be diagnosed with an ARI at <2months of age (RR, 0.91; 95% CI, 0.84-0.99), and the risk was 17% lower if vaccination was received between 27 and 36weeks of pregnancy (RR, 0.83; 95% CI, 0.74-0.93). Similar results were observed when comparing mothers who received Tdap vaccination prior to pregnancy in addition to Tdap vaccination between 27 and 36weeks of pregnancy versus mothers who only received vaccination prior to pregnancy (RR, 0.85; 95% CI, 0.74-0.98). Maternal Tdap vaccination between 27 and 36weeks of pregnancy was consistently protective against infant ARI in the first 2months of life vs no vaccination during pregnancy, regardless of Tdap vaccination prior to pregnancy. Our findings strongly support current ACIP guidelines recommending Tdap vaccination in late pregnancy for every pregnancy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diphtheria in Lao PDR: Insufficient Coverage or Ineffective Vaccine?

PubMed Central

Nouanthong, Phonethipsavanh; Souvannaso, Chanthasone; Vilivong, Keooudomphone; Muller, Claude P.; Goossens, Sylvie; Quet, Fabrice; Buisson, Yves

2015-01-01

Background During late 2012 and early 2013 several outbreaks of diphthe-ria were notified in the North of the Lao People’s Democratic Republic. The aim of this study was to determine whether the re-emergence of this vaccine-preventable disease was due to insufficient vaccination coverage or reduction of vaccine effectiveness within the affected regions. Methods A serosurvey was conducted in the Huaphan Province on a cluster sampling of 132 children aged 12–59 months. Serum samples, socio-demographic data, nutri-tional status and vaccination history were collected when available. Anti-diphtheria and anti-tetanus IgG antibody levels were measured by ELISA. Results Overall, 63.6% of participants had detectable diphtheria antibodies and 71.2% tetanus antibodies. Factors independently associated with non-vaccination against diphtheria were the distance from the health centre (OR: 6.35 [95% CI: 1.4–28.8], p = 0.01), the Lao Theung ethnicity (OR: 12.2 [95% CI:1,74–85, 4], p = 0.01) and the lack of advice on vac-cination given at birth (OR: 9.8 [95% CI: 1.5–63.8], (p = 0.01) while the level of maternal edu-cation was a protective factor (OR: 0.08 [95% CI: 0.008–0.81], p = 0.03). Most respondents claimed financial difficulties as the main reason for non-vaccination. Out of 55 children whose vaccination certificates stated that they were given all 3 doses of diphtheria-containing vaccine, 83.6% had diphtheria antibodies and 92.7% had tetanus antibodies. Furthermore, despite a high prevalence of stunted and underweight children (53% and 25.8%, respectively), the low levels of anti-diphtheria antibodies were not correlated to the nutritional status. Conclusions Our data highlight a significant deficit in both the vaccination coverage and diphtheria vaccine effectiveness within the Huaphan Province. Technical defi-ciencies in the methods of storage and distribution of vaccines as well as unreliability of vac-cination cards are discussed. Several hypotheses are

Immune responses of Asian elephants (Elephas maximus) to commercial tetanus toxoid vaccine.

PubMed

Lindsay, William A; Wiedner, Ellen; Isaza, Ramiro; Townsend, Hugh G G; Boleslawski, Maria; Lunn, D P

2010-02-15

Although captive elephants are commonly vaccinated annually against tetanus using commercially available tetanus toxoid vaccines marketed for use in horses and livestock, no data exists to prove that tetanus toxoid vaccination produces measurable antibody titers in elephants. An ELISA test was created to measure antibody responses to tetanus toxoid vaccinations in 22 Asian elephants ranging in age from 24 to 56 years (mean age 39 years) over a 7-month period. All animals had been previously vaccinated with tetanus toxoid vaccine, with the last booster administered 4 years before the start of the study. The great majority of elephants had titers prior to booster vaccination, and following revaccination all elephants demonstrated anamnestic increases in titers, indicating that this species does respond to tetanus vaccination. Surprisingly older animals mounted a significantly higher response to revaccination than did younger animals. Copyright 2009 Elsevier B.V. All rights reserved.

Meningococcal groups C and Y and haemophilus B tetanus toxoid conjugate vaccine (HibMenCY-TT; MenHibrix(®)): a review.

PubMed

Perry, Caroline M

2013-05-01

The meningococcal groups C and Y and Haemophilus b (Hib) tetanus toxoid conjugate vaccine (HibMenCY-TT) contains Neisseria meningitidis serogroup C and Y capsular polysaccharide antigens, and Hib capsular polysaccharide [polyribosyl-ribitol-phosphate (PRP)]. The HibMenCY-TT vaccine is available in the USA for use as active immunization to prevent invasive disease caused by N. meningitidis serogroups C (MenC) and Y (MenY), and Hib in children 6 weeks-18 months of age. HibMenCY-TT is the first meningococcal vaccine available for use in the USA that can be administered to infants as young as 6 weeks of age. In a randomized, controlled, phase III clinical trial, the HibMenCY-TT vaccine, administered to infants at 2, 4, 6 and 12-15 months of age, was immunogenic against MenC and MenY, and met the prespecified criteria for immunogenicity. Anti-PRP antibodies, which have been shown to correlate with protection against Hib invasive disease, were also induced in the infants who received the HibMenCY-TT vaccine, with induced levels of this antibody noninferior to those occurring in the control group of infants who received a Hib tetanus toxoid conjugate vaccine at 2, 4, and 6 months and a single dose of Hib conjugated to N. meningitidis outer membrane protein at 12-15 months. In several randomized, controlled clinical trials, HibMenCY-TT was coadministered with vaccines that are routinely administered to infants and toddlers in the USA. These vaccines included: diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine combined; 7-valent Streptococcus pneumoniae polysaccharide conjugate vaccine; measles, mumps and rubella vaccine; and varicella vaccine. Coadministration of these vaccines did not interfere with the immunogenicity of the HibMenCY-TT vaccine. Similarly, immune responses to the coadministered vaccines were not affected by the HibMenCY-TT vaccine. The tolerability profile of the Hib

Exit-site infections by non-diphtheria corynebacteria in CAPD.

PubMed

Schiffl, Helmut; Mücke, Claudia; Lang, Susanne M

2004-01-01

Non-diphtheria corynebacteria species cause disease in risk populations such as immunocompromised patients and patients with indwelling medical devices. Despite reports of exit-site infection and peritonitis caused by non-diphtheria corynebacteria, these organisms are frequently dismissed as contaminants. During a 10-year observation period, we prospectively identified 8 cases of exit-site/tunnel infections caused by 2 different species of corynebacteria (Corynebacterium striatum in 5 and C. jeikeium in 3 cases). Four patients experienced a second episode of exit-site infection 3 months (2 cases), 25 months, and 40 months, respectively, after termination of an oral cephalosporin therapy of 4 to 6 weeks' duration. Non-diphtheria corynebacteria accounted for 9% of all exit-site infections during the study period. All catheter-related infections healed; no catheter had to be removed. The diagnosis of catheter-related non-diphtheria corynebacteria infection may be suspected when Gram stain shows gram-positive rods and with colony morphology and commercial biochemical identification systems. Susceptibility of non-diphtheria corynebacteria to antibiotics may vary, especially in C. jeikeium. Virtually all Corynebacterium species are sensitive to vancomycin. Empirical antibiotic therapy with vancomycin should be initiated while antibiotic susceptibility testing is being carried out. Oral cephalosporin may be an alternative treatment regimen for exit-site infections if sensitive. This study highlights the importance of non-diphtheria corynebacteria as emerging nosocomial pathogens in the population of end-stage renal disease patients on on continuous ambulatory peritoneal dialysis.

Recombinant human antibody fragment against tetanus toxoid produced by phage display

PubMed Central

Neelakantam, B.; Sridevi, N. V.; Shukra, A. M.; Sugumar, P.; Samuel, S.

2014-01-01

Phage display technology is a powerful in vitro method for the identification of specific monoclonal antibodies (antibody fragments) to an antigenic target and allows the rapid generation and selection of high affinity, fully human antibodies directed toward any disease target appropriate for antibody therapy. In the present study, we exploited the phage display technology for the selection of an antigen binding fragment (Fabs) toward tetanus toxoid using human naïve phage antibody library constructed from peripheral blood lymphocytes of naïve human donors. The phages displaying Fab were subjected to three rounds of bio-panning with tetanus toxoid as antigen on a solid phase. The high affinity antibody fragments were expressed in HB2151 strain of Escherichia coli and purified by immobilized metal affinity chromatography. The binding activity and specificity of the antibody fragment was established by its reactivity toward tetanus toxoid and non-reactivity toward other related toxins as determined by enzyme-linked immunosorbent assay and immunoblot analysis. The selected Fab fragment forming the antigen-binding complexes with the toxoid in flocculation assay indicates that the Fab may have a potential neutralizing ability toward antigen. PMID:24678405

Recombinant human antibody fragment against tetanus toxoid produced by phage display.

PubMed

Neelakantam, B; Sridevi, N V; Shukra, A M; Sugumar, P; Samuel, S; Rajendra, L

2014-03-01

Phage display technology is a powerful in vitro method for the identification of specific monoclonal antibodies (antibody fragments) to an antigenic target and allows the rapid generation and selection of high affinity, fully human antibodies directed toward any disease target appropriate for antibody therapy. In the present study, we exploited the phage display technology for the selection of an antigen binding fragment (Fabs) toward tetanus toxoid using human naïve phage antibody library constructed from peripheral blood lymphocytes of naïve human donors. The phages displaying Fab were subjected to three rounds of bio-panning with tetanus toxoid as antigen on a solid phase. The high affinity antibody fragments were expressed in HB2151 strain of Escherichia coli and purified by immobilized metal affinity chromatography. The binding activity and specificity of the antibody fragment was established by its reactivity toward tetanus toxoid and non-reactivity toward other related toxins as determined by enzyme-linked immunosorbent assay and immunoblot analysis. The selected Fab fragment forming the antigen-binding complexes with the toxoid in flocculation assay indicates that the Fab may have a potential neutralizing ability toward antigen.

International External Quality Assurance for Laboratory Diagnosis of Diphtheria ▿

PubMed Central

Neal, S. E.; Efstratiou, A.

2009-01-01

The diphtheria surveillance network (DIPNET) encompassing National Diphtheria Reference Centers from 25 European countries is a Dedicated Surveillance Network recognized by the European Commission. A key DIPNET objective is the quality assessment of microbiological procedures for diphtheria across the European Union and beyond. A detailed questionnaire on the level of reference laboratory services and an external quality assessment (EQA) panel comprising six simulated throat specimens were sent to 34 centers. Twenty-three centers are designated National Diphtheria Reference Centers, with the laboratory in the United Kingdom being the only WHO Collaborating Centre. A variety of screening and identification tests were used, including the cysteinase test (20/34 centers), pyrazinamidase test (17/34 centers), and commercial kits (25/34 centers). The classic Elek test for toxigenicity testing is mostly used (28/34 centers), with variations in serum sources and antitoxin concentrations. Many laboratories reported problems obtaining Elek reagents or media. Only six centers produced acceptable results for all six specimens. Overall, 21% of identification and 13% of toxigenicity reports were unacceptable. Many centers could not isolate the target organism, and most found difficulties with the specimens that contained Corynebacterium striatum as a commensal contaminant. Nineteen centers generated either false-positive or negative toxigenic results, which may have caused inappropriate medical management. The discrepancies in this diphtheria diagnostics EQA alarmingly reflect the urgent need to improve laboratory performance in diphtheria diagnostics in Europe, standardize feasible and robust microbiological methods, and build awareness among public health authorities. Therefore, DIPNET recommends that regular workshops and EQA distributions for diphtheria diagnostics should be supported and maintained. PMID:19828749

[Effect of Corynebacterium non diphtheriae on functional activity and apoptosis of macrophages].

PubMed

Kharseeva, G G; Voronina, N A; Tiukavkina, S Iu

2014-01-01

Determine the ability of Corynebacterium non diphtheriae to induce phagocytosis and apoptosis of macrophages and evaluate regulatory effect of nuetrophilokines (NPK) induced by Corynebacterium non diphtheriae on these processes. The ability of Corynebacterium non diphtheriae, isolated from upper respiratory tract, skin and urogenital tract (UGT) were studied for the ability to induce phagocytosis and apoptosis of mice macrophages (MP; in vitro during staining by May-Grunwald with additional staining by Romanowsky-Giemsa) before and after the addition of NPK induced by Corynebacterium non diphtheriae. Phagocytic index (PI) was the same for all the Corynebacterium non diphtheriae species, phagocytic number (PN) and index of phagocytosis completion (IPC)--were minimal relative to corynebacteria isolated from UGT. All the studied corynebacteria species induced MP apoptosis; the most pronounced apoptogenic effect was detected in Corynebacterium pseudotuberculosis isolated from UGT. NPK increased PN against corynebacteria isolated from the studied biotopes, IPC--only during studies of corynebacteria isolated from skin. The effect of NPK resulted in a reduction of apoptogenic effect for almost all the Corynebacterium non diphtheriae, regardless of the isolation location. A pronounced apoptogenic effect and insufficiency of phagocytosis processes induced by corynebacteria are the means of realization of Corynebacterium non diphtheriae pathogenic effect. NPK use is possible for immune correction of immune deficiency conditions developing against the background of diseases determined by Corynebacterium non diphtheriae.

Tetanus toxoid IgE may be useful in predicting allergy during childhood.

PubMed

Ciprandi, G; De Amici, M; Quaglini, S; Labò, E; Castellazzi, A M; Miraglia Del Giudice, M; Marseglia, A; Bianchi, L; Moratti, R; Marseglia, G L

2012-01-01

Hypersensitivity reactions after immunization with tetanus toxoid are occasionally observed in atopic and non-atopic individuals. High IgE levels in infancy may predict subsequent allergy. The aims of this study were: i) to evaluate the role of specific IgE to tetanus toxoid in children in response to tetanus immunization and the possible factors associated with specific IgE levels, and ii) to investigate the correlation between specific IgE levels to tetanus toxoid and the late development of allergy (up to 12 years). Initially, 278 healthy infants (152 males and 126 females, aged 12 months) living in an urban city were screened for serum total IgE and specific IgE to tetanus toxoid, after having obtained informed consent from parents. After 12 years, 151 children could be evaluated. Total IgE summed with tetanus specific IgE were significantly associated with allergy at 12 years. In conclusion, this study demonstrates that serum total IgE and tetanus specific IgE may be predictive of subsequent allergy onset.

Induction of potential protective immunity against enterotoxemia in calves by single or multiple recombinant Clostridium perfringens toxoids.

PubMed

Jiang, Zhigang; De, Yanyan; Chang, Jitao; Wang, Fang; Yu, Li

2014-11-01

Cattle enterotoxemia caused by Clostridium perfringens toxins is a noncontagious, sporadic, and fatal disease characterized by sudden death. Strategies for controlling and preventing cattle enterotoxemia are based on systematic vaccination of herds with toxoids. Because the process of producing conventional clostridial vaccines is dangerous, expensive, and time-consuming, the prospect of recombinant toxoid vaccines against diseases caused by C. perfringens toxins is promising. In this study, nontoxic recombinant toxoids derived from α-, β- and ε-toxins of C. perfringens, namely, rCPA247-370 , rCPB and rEtxHP, respectively, were expressed in Escherichia coli. High levels of specific IgG antibodies and neutralizing antibodies against the toxins were detected in sera from calves vaccinated with either a single recombinant toxoid or a mixed cocktail of all three recombinant toxoids, indicating the potential of these recombinant toxoids to provide calves with protective immunity against enterotoxemia caused by C. perfringens. © 2014 The Societies and Wiley Publishing Asia Pty Ltd.

Vaccines for women for preventing neonatal tetanus.

PubMed

Demicheli, Vittorio; Barale, Antonella; Rivetti, Alessandro

2015-07-06

.30; 688 infants; GRADE: moderate-quality evidence). Administration of a two- or three-dose course resulted in significant protection when all causes of death are considered as an outcome (RR 0.31, 95% CI 0.17 to 0.55; 688 infants; GRADE: moderate-quality evidence). No effect was detected on causes of death other than tetanus. Cases of neonatal tetanus after at least one dose of tetanus toxoid were reduced in the tetanus toxoid group, (RR 0.20, 95% CI 0.10 to 0.40; 1182 infants; GRADE: moderate-quality evidence).Another study, involving 8641 children, assessed the effectiveness of tetanus-diphtheria toxoid in comparison with cholera toxoid in preventing neonatal mortality after one or two doses. Neonatal mortality was reduced in the tetanus-diphtheria toxoid group (RR 0.68, 95% CI 0.56 to 0.82). In preventing deaths at four to 14 days, neonatal mortality was reduced again in the tetanus-diphtheria toxoid group (RR 0.38, 95% CI 0.27 to 0.55). The quality of evidence as assessed using GRADE was found to be low.The third small trial assessed that pain at injection site was reported more frequently among pregnant women who received tetanus diphtheria acellular pertussis than placebo (RR 5.68, 95% CI 1.54 to 20.94; GRADE: moderate-quality evidence). Available evidence supports the implementation of immunisation practices on women of reproductive age or pregnant women in communities with similar, or higher, levels of risk of neonatal tetanus, to the two study sites.

Persistence of a Distinct Corynebacterium diphtheriae Clonal Group within Two Communities in the United States and Canada Where Diphtheria Is Endemic

PubMed Central

Marston, Chung K.; Jamieson, Frances; Cahoon, Fred; Lesiak, Gail; Golaz, Anne; Reeves, Mike; Popovic, Tanja

2001-01-01

Molecular characterization of 53 U.S. and Canadian Corynebacterium diphtheriae isolates by multilocus enzyme electrophoresis, ribotyping, and random amplified polymorphic DNA showed that strains with distinct molecular subtypes have persisted in the United States and Canada for at least 25 years. These strains are endemic rather than imported from countries with current endemic or epidemic diphtheria. PMID:11283092

Active Immunization—Some Present-Day Problems

PubMed Central

1941-01-01

Diphtheria.—Immunization is safe and effective. Compulsory measures are indicated, especially for the younger age-groups. The Schick test may be reserved for selected groups and to control modified methods. Proper spacing of doses of prophylactics and periodic reinoculation will ensure a high level of immunity. It is important to beware of “one-shot” methods. Indiscriminate swabbing is to be discouraged; high carrier rates are an indication for widespread diphtheria prophylaxis. Enteric fever.—Mass immunization is desirable in many areas, although there is no justification for compulsion except for people exposed to special risks. In deciding upon dosage of vaccine, more attention should be paid to physical state and body-weight. After the primary course, very small periodic doses (for example o.i.c.c) are worthy of trial. Vaccine can be given during an epidemic without increasing the chances of infection. Tetanus.—Two doses of toxoid spaced by six weeks give useful immunity. Women give significantly higher titres than men. A third dose of i.o.c.c. after a long interval—seven to nine months—often produces a dramatic rise in circulating antitoxin, and counteracts any tendency to waning immunity. Smallpox.—As vaccination has not been made compulsory in this country, infection by virulent strains from the continent may tax the resources of the public health services. Whooping-cough.—The large number of injections of vaccine usually recommended is a deterrent to mass immunization. Research into the possibility of fewer doses and wider spacing is indicated. Other diseases are considered briefly. Combined immunization.—It may be useful to combine diphtheria T.A.F. and tetanus toxoid, also tetanus toxoid and T.A.B. vaccine. T.A.F. plus T.A.B. is probably contra-indicated for adults on account of severe reactions. Diphtheria A.P.T. should not be mixed with tetanus toxoid as it may go into solution and become ineffective. Sterilization of syringes and

ANTITOXIN FORMATION BY CELLS TRANSPLANTED TO IRRADIATED ANIMALS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaulen, D.P.

1963-01-01

The aim of the work was to study, in conditions of normal subcutaneous immunization, which transplanted cells form antitoxin, the significance of the phase of antibody formation, the immunological response of cells to stimulation by 2 unrelated antigens, and to find whether transplanted cells are capable of a secondary immunological response. Donor animals were immunized subcutaneously: guinea pigs twice, with a 30-day interval, with adsorbed diphtheria toxoid, or once with native toxoid; rabbits simultaneously with 2 antigens, the diphtheria toxoid and typhoid formol vaccine, once or several times over 30 days. Recipient animals were exposed to x rays, guinea pigsmore » to 200 or 525 r, and rabbits to 550 or 800 r, and injected intravenously 2 to 4 hr later with cell suspensions prepared from donor spleen, lymphatic nodes, or bone marrow or, for controls, with cells killed by heating. In 3 trials to study the inductive phase of antibody formation, cells were taken from donors 24 hr after single immunization. In guinea pigs exposed to 200 or 525 r and in rabbits to 550 r, there was no sign of anti-diphtheria antitoxin or, in the rabbits, agglutinins during 30 days after transplantation of cells. In 4 trials of antibody production by cells taken in the reproductive phase, all transplanted tissues formed, in up to 10 days, detectable amounts of antitoxin in guinea pigs, except bone marrow in those exposed to 200 r; killed cells produced none. In rabbits exposed to 550 r, transplanted cells formed antibodies to both antigens used; they appeared by the 3rd day, reached a maximum on the 6th, fell rapidly by the 15th, and were not detectable by the 30th day. The pattern was similar for both antigens. Basically the same results were obtained in rabbits exposed to 800 r. When recipient animals were injected with diphtheria toxoid and formol vaccine on the 15th day afier transplantation, no antitoxin was formed but agglutinin titer rose in all animals, even in those

Immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV) compared to separate administration of standalone DTaP and IPV vaccines: a randomized, controlled study in infants in the Republic of Korea.

PubMed

Lee, Soo Young; Hwang, Hui Sung; Kim, Jong Hyun; Kim, Hyun Hee; Lee, Hyun Seung; Chung, Eun Hee; Park, Su Eun; Ma, Sang Hyuk; Chang, Jin Keun; Guitton, Fabrice; Ortiz, Esteban; Kang, Jin Han

2011-02-11

This randomized trial enrolled 442 infants in the Republic of Korea to assess the immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV; Tetraxim™) for primary vaccination at 2, 4 and 6 months of age compared with DTaP and IPV vaccines given separately. Immunogenicity was high in both groups; seroprotection and seroconversion rates of the combined vaccine (Group A) were non-inferior to the control vaccines (Group B). All subjects were seroprotected against poliovirus types 1, 2 and 3 (≥ 81/dil) and anti-diphtheria (≥ 0.01 IU/mL); 99.0% were seroprotected against tetanus (≥ 0.1 IU/mL). At least 93.6% had anti-diphtheria antibody titers ≥ 0.1 IU/mL. Anti-pertussis toxoid (PT) and anti-filamentous haemagglutinin (FHA) seroconversion (≥ 4-fold increase in antibody titer) rates were 96.6% and 94.4% for Group A, 92.2% and 78.4% for Group B. Most solicited reactions occurred within 4 days of vaccination, resolved within 3 days and were mild. Severe solicited reactions occurred after ≤ 0.5% of doses in Group A and ≤ 0.9% in Group B. No withdrawals occurred because of adverse events. The DTaP-IPV combined vaccine given at 2, 4, and 6 months of age was well tolerated; immunogenicity was similar to the control vaccines. Copyright © 2011 Elsevier Ltd. All rights reserved.

Safety and immunogenicity of HIV-1 Tat toxoid in immunocompromised HIV-1-infected patients.

PubMed

Gringeri, A; Santagostino, E; Muça-Perja, M; Mannucci, P M; Zagury, J F; Bizzini, B; Lachgar, A; Carcagno, M; Rappaport, J; Criscuolo, M; Blattner, W; Burny, A; Gallo, R C; Zagury, D

1998-01-01

To antagonize the deleterious effects of the HIV-1 toxin extracellular Tat on uninfected immune cells, we developed a new strategy of anti-HIV-1 vaccine using an inactivated but immunogenic Tat (Tat toxoid). Tat toxoid has been assayed for safety and immunogenicity in seropositive patients. The phase I vaccine clinical trial testing Tat toxoid preparation in Seppic Isa 51 oil adjuvant was performed on 14 HIV-1-infected asymptomatic although biologically immunocompromised individuals (500-200 CD4+ cells/mm3). Following as many as 8 injections, no clinical defects were observed. All patients exhibited an antibody (Ab) response to Tat, and some had cell-mediated immunity (CMI) as evaluated by skin test in vivo and T-cell proliferation in vitro. These results provide initial evidence of safety and potency of Tat toxoid vaccination in HIV-1-infected individuals.

Td (tetanus and diphtheria) vaccine - what you need to know

MedlinePlus

... from both of these diseases. Both diphtheria and tetanus are infections caused by bacteria. Diphtheria spreads from person to person through secretions from coughing or sneezing. Tetanus-causing bacteria enter the body through cuts, scratches, ...

Tetanus toxoid and CCL3 improve DC vaccines in mice and glioblastoma patients

PubMed Central

Mitchell, Duane A.; Batich, Kristen A.; Gunn, Michael D.; Huang, Min-Nung; Sanchez-Perez, Luis; Nair, Smita K.; Congdon, Kendra L.; Reap, Elizabeth A.; Archer, Gary E.; Desjardins, Annick; Friedman, Allan H.; Friedman, Henry S.; Herndon, James E.; Coan, April; McLendon, Roger E.; Reardon, David A.; Vredenburgh, James J.; Bigner, Darell D.; Sampson, John H.

2015-01-01

Upon stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses1. As such, autologous DCs generated ex vivo have been pulsed with tumor antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers2–4 including glioblastoma (GBM),5–7 the factors dictating DC vaccine efficacy remain poorly understood. Here we demonstrate that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumor antigen-specific DCs. To assess the impact of vaccine site pre-conditioning in humans, we randomized patients with GBM to pre-conditioning with mature DCs8 or Td unilaterally before bilateral vaccination with Cytomegalovirus pp65 RNA-pulsed DCs. We and other laboratories have shown that pp65 is expressed in > 90% of GBM specimens but not surrounding normal brain9–12, providing an unparalleled opportunity to subvert this viral protein as a tumor-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumor growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve antitumor immunotherapy. PMID:25762141

A Case-control Study of Diphtheria in the High Incidence City of Hyderabad, India.

PubMed

Allam, Ramesh Reddy; Uthappa, Chengappa Kechamada; Duerst, Rebecca; Sorley, Evan; Udaragudi, Prasada Rao; Kampa, Shankar; Dworkin, Mark S

2016-03-01

India accounts for approximately 72% of reported diphtheria cases globally, the majority of which occur in the state of Andhra Pradesh. The aim of this study is to better understand lack of knowledge on diphtheria vaccination and to determine factors associated with diphtheria and low knowledge and negative attitudes. We performed a 1:1 case-control study of hospitalized diphtheria cases in Hyderabad. Eligible case patients were 10 years of age or older, resided within the city of Hyderabad and were diagnosed with diphtheria per the case definition. Patients admitted to the hospital for nonrespiratory communicable diseases and residing in the same geographic region as that of cases were eligible for enrolment as controls : There were no statistical differences in disease outcome by gender, education, economic status and mean room per person sleeping in the house in case and control subjects. Not having heard of diphtheria (adjusted odds ratio: 3.56; 95% confidence intervals: 1.58-8.04] and not believing that vaccines can prevent people from getting diseases (adjusted odds ratio: 3.99; 95% confidence intervals: 1.18-13.45) remained significantly associated with diphtheria on multivariate analysis. To reduce the burden of diphtheria in India, further efforts to educate the public about diphtheria should be considered.

Nucleic acid aptamers as stabilizers of proteins: the stability of tetanus toxoid.

PubMed

Jain, Nishant Kumar; Jetani, Hardik C; Roy, Ipsita

2013-07-01

Exposure of tetanus toxoid to moisture leads to its aggregation and reduction of potency. The aim of this work was to use SELEX (systematic evolution of ligands by exponential enrichment) protocol and select aptamers which recognize tetanus toxoid (Mr ~150 kDa) with high affinity. Colyophilized preparations of tetanus toxoid and specific aptamers were encapsulated in PLGA microspheres and sustained release of the antigen was observed up to 55 days using different techniques. The total protein released was between 40-55% (24-45% residual antigenicity) in the presence of the aptamers as compared to 25% (11% residual antigenicity) for the antigen alone. We show that instead of inhibiting absorption of moisture, the aptamers blocked the protein unfolding upon absorption of moisture, inhibiting the initiation of aggregation. When exposed to accelerated storage conditions, some of the RNA sequences were able to inhibit moisture-induced aggregation in vitro and retain antigenicity of tetanus toxoid. Nucleic acid aptamers represent a novel class of protein stabilizers which stabilize the protein by interacting directly with it. This mechanism is unlike that of small molecules which alter the medium properties and hence depend on the stress condition a protein is exposed to.

Comparison of five commercial anti-tetanus toxoid immunoglobulin G enzyme-linked immunosorbent assays.

PubMed

Perry, A L; Hayes, A J; Cox, H A; Alcock, F; Parker, A R

2009-12-01

Five commercially available enzyme-linked immunosorbent assays for the measurement of anti-tetanus toxoid immunoglobulin G (IgG) antibodies were evaluated for performance. The data suggest that there are manufacturer-dependent differences in sensitivity and accuracy for the determination of tetanus toxoid IgG antibodies that could result in different diagnostic interpretations.

Application of PCR for detection of toxigenic Corynebacterium diphtheriae strains isolated during the Russian diphtheria epidemic, 1990 through 1994.

PubMed Central

Mikhailovich, V M; Melnikov, V G; Mazurova, I K; Wachsmuth, I K; Wenger, J D; Wharton, M; Nakao, H; Popovic, T

1995-01-01

A total of 250 Corynebacterium diphtheriae isolates from clinical cases and carriers in Russia were assayed by PCR directed at the A subunit of the diphtheria toxin gene to distinguish toxigenic from nontoxigenic strains; 170 strains were positive as indicated by the presence of the 248-bp amplicon. The results of this PCR assay were in complete concordance with those of the standard immunoprecipitation assay (Elek), and the PCR assay is a useful tool for rapid identification in clinical laboratories. PMID:8576378

Impact of rituximab therapy on response to tetanus toxoid vaccination in kidney-transplant patients.

PubMed

Puissant-Lubrano, Benedicte; Rostaing, Lionel; Kamar, Nassim; Abbal, Michel; Fort, Marylise; Blancher, Antoine

2010-03-01

Rituximab is used after kidney transplant to prevention or treat kidney-allograft rejection. However, the impact of rituximab on the ability of patients to respond to tetanus toxoid vaccination has not yet been studied. The response to tetanus toxoid vaccination was analyzed in 39 kidney transplant recipients immunosuppressed by corticoids, antiproliferative agents, and/or calcineurin inhibitors. Thirteen patients had previously received rituximab (group 1), 26 patients had not (group 2). Response to control bacterial antigens and immunologic parameters (lymphocyte count, B-cell subsets, serum immunoglobulin level) were analyzed before and at 1 month after vaccination. Thirty healthy blood donors were used as controls for the before-vaccination immunologic parameters. Before vaccination, neither patient group differed from controls in serum levels of immunoglobulins and antibodies against bacterial antigens, but they did display lower levels of CD4 T cells and B cells compared with controls. Responders to the tetanus toxoid vaccination were slightly fewer in group 1 (4/13) than in group 2 (16/26), but the intensity of the anti-tetanus toxoid response was not significantly different between these 2 groups. None of the parameters studied at the time of vaccination (anti-tetanus toxoid level, peripheral B or CD4 T-cell count, memory B-cell subsets, treatment with rituximab, time since transplant) were associated with an ability to respond to vaccination. The ability to respond to vaccination and graft outcomes were not correlated in each patient group. Rituximab impaired the secondary immune response after tetanus toxoid vaccination, but did not abolish it in all patients.

Immunochromatographic Strip Test for Rapid Detection of Diphtheria Toxin: Description and Multicenter Evaluation in Areas of Low and High Prevalence of Diphtheria

PubMed Central

Engler, K. H.; Efstratiou, A.; Norn, D.; Kozlov, R. S.; Selga, I.; Glushkevich, T. G.; Tam, M.; Melnikov, V. G.; Mazurova, I. K.; Kim, V. E.; Tseneva, G. Y.; Titov, L. P.; George, R. C.

2002-01-01

An immunochromatographic strip (ICS) test was developed for the detection of diphtheria toxin by using an equine polyclonal antibody as the capture antibody and colloidal gold-labeled monoclonal antibodies specific for fragment A of the diphtheria toxin molecule as the detection antibody. The ICS test has been fully optimized for the detection of toxin from bacterial cultures; the limit of detection was approximately 0.5 ng of diphtheria toxin per ml within 10 min. In a comparative study with 915 pure clinical isolates of Corynebacterium spp., the results of the ICS test were in complete agreement with those of the conventional Elek test. The ICS test was also evaluated for its ability to detect toxigenicity from clinical specimens (throat swabs) in two field studies conducted within areas of the former USSR where diphtheria is epidemic. Eight hundred fifty throat swabs were examined by conventional culture and by use of directly inoculated broth cultures for the ICS test. The results showed 99% concordance (848 of 850 specimens), and the sensitivity and specificity of the ICS test were 98% (95% confidence interval, 91 to 99%) and 99% (95% confidence interval, 99 to 100%), respectively. PMID:11773096

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

PubMed

Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D; Huang, Min-Nung; Sanchez-Perez, Luis; Nair, Smita K; Congdon, Kendra L; Reap, Elizabeth A; Archer, Gary E; Desjardins, Annick; Friedman, Allan H; Friedman, Henry S; Herndon, James E; Coan, April; McLendon, Roger E; Reardon, David A; Vredenburgh, James J; Bigner, Darell D; Sampson, John H

2015-03-19

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Comparative effects of carrier proteins on vaccine-induced immune response.

PubMed

Knuf, Markus; Kowalzik, Frank; Kieninger, Dorothee

2011-07-12

The efficacy of vaccines against major encapsulated bacterial pathogens -Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (Hib) - has been significantly enhanced by conjugating the respective polysaccharides with different carrier proteins: diphtheria toxoid; non-toxic cross-reactive material of diphtheria toxin(197), tetanus toxoid, N. meningitidis outer membrane protein, and non-typeable H. influenzae-derived protein D. Hib, meningococcal, and pneumococcal conjugate vaccines have shown good safety and immunogenicity profiles regardless of the carrier protein used, although data are conflicting as to which carrier protein is the most immunogenic. Coadministration of conjugate vaccines bearing the same carrier protein has the potential for inducing either positive or negative effects on vaccine immunogenicity (immune interference). Clinical studies on the coadministration of conjugate vaccines reveal conflicting data with respect to immune interference and vaccine efficacy. Copyright © 2011 Elsevier Ltd. All rights reserved.

Immunological evaluation of chitosan nanoparticles loaded with tetanus toxoid.

PubMed

Ghalavand, M; Saadati, M; Ahmadi, A; Abbasi, E; Salimian, J

2018-01-01

The present study was aimed at comparing tetanus toxoid (TT)‑loaded-chitosan nanoparticles with aluminum hydroxide as a common vaccine adjuvant. Tetanus remains to be a major public health problem. Nanoparticles have been extensively used as immune adjuvants. Tetanus toxoid (TT) encapsulated in chitosan nanoparticles is considered to be a promising tetanus vaccine candidate. TT‑loaded chitosan nanoparticles were prepared by the ionic gelation method. The nanoparticles were studied by SEM for their size and morphology. In vivo study was conducted to evaluate the immunity response using mice divided into 4 groups and injected with encapsulated toxoid. The immune responses were then measured using indirect ELISA. The purity and integrity of antigen were confirmed by SDS-PAGE electrophoresis. The size of nanoparticles was estimated at 100 nm. As a result, the IgG antibody levels were 1.9, 1.76, and 0.87 in chitosan nanoparticles, aluminum hydroxide, and TT alone groups, respectively. Also, the immune responses were significantly higher in immunized groups compared to control groups vaccinated with free adjuvant vaccines (p < 0.05). The quality and efficacy of toxoid‑loaded chitosan nanoparticles were reasonable. It enhanced the immune responses as much as aluminum hydroxide adjuvant does and thus may be a good alternative candidate (Tab. 1, Fig. 3, Ref. 16).

A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin-containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids.

PubMed

Nakayama, T; Aizawa, C; Kuno-Sakai, H

1999-02-01

The number of patients with allergic reactions after administration of gelatin-containing live vaccines is increasingly reported in Japan. These allergic reactions appear to be caused by gelatin allergy. It is still unknown how the patients were sensitized to gelatin. To determine the incidence of gelatin allergy and to identify contributing factors to gelatin allergy, we investigated the following clinical aspects: the development of IgE antibodies to gelatin and the relationship of the patients' past history of acellular pertussis vaccine combined with diphtheria and tetanus toxoid (DTaP) to the development of gelatin allergy. We evaluated 366 patient reports, submitted from 1994 to 1997, of adverse reactions after immunization with monovalent measles, mumps, and rubella vaccines containing 0.2% gelatin as stabilizer. On the basis of physician reports, the patients were categorized as to the nature of the adverse reaction. We determined the presence of IgE antibodies to gelatin and obtained past immunization history. The 366 reported patients were categorized as follows: 34 with anaphylaxis, 76 with urticaria, 215 with nonurticarial generalized eruption, and 41 with local reactions only. In 206 patients from whom serum was available, IgE antibodies to gelatin were detected in 25 of 27 (93%) with anaphylaxis, 27 of 48 (56%) with urticaria, and 8 of 90 (9%) with a generalized eruption. None of a group of 41 patients with only local reactions at the injected site and none of a control group of 29 subjects with no adverse reaction had such antibodies. Among 202 patients for whom prior vaccine information was available, all had received DTaP vaccines. Among those for whom the prior DTaP vaccine could be determined to contain gelatin or be free of gelatin, 155 of 158 (98%) subjects had received gelatin-containing DTaP vaccines. This rate is higher than would be expected on the basis of the market share of gelatin-containing (vs gelatin-free) DTaP vaccines (75

Detection of anti-tetanus toxoid antibody on modified polyacrylonitrile fibers.

PubMed

Jain, Swati; Chattopadhyay, Sruti; Jackeray, Richa; Zainul Abid, C K V; Kumar, Manoj; Singh, Harpal

2010-10-15

Accurate determination of concentration of immunoglobulin (IgG) to tetanus toxoid is important in order to evaluate the immunogenicity of tetanus toxoid vaccines, immune competence in individual patients and to measure the prevalence of immunity in populations. Surface modified polyacrylonitrile (PAN) fibers were evaluated as a matrix to develop highly sensitive method for the detection of anti-tetanus antibody in a sandwich ELISA format. In the proposed method tetanus toxoid immobilized on modified PAN fibers was used to detect anti-tetanus antibody (raised in horse hence represented as horse anti-tetanus toxoid or HAT-Ab) with horse raddish peroxidase enzyme conjugated with Rabbit anti-Horse IgG (RAH-HRP) as the label within 2.5h. A sigmoidal pattern for the detection of different concentration of antibody ranging from 1.0 to 0.0001 IU mL(-1) was validated. The immunoassay recorded a very high sensitivity as concentration as low as 0.0005 IU mL(-1) of HAT-Ab was detected. The intra- and inter-assay precision for 3 parallel measurements of 0.01 and for 0.001 IU mL(-1) of antibody varied from 5.4% to 11% and 5.7% to 20% respectively. PAN fibers were also used to qualitatively access the presence of different level of anti-tetanus antibody spiked in human blood. Seroepidemiological studies to measure the immunity against tetanus were conducted with twenty-five human beings belonging to various age groups using modified PAN-ELISA. The sensitivity, specificity and the reproducibility of the developed immunoassay indicate the potential application of modified PAN fibers in the field of immunodiagnostics. Copyright © 2010 Elsevier B.V. All rights reserved.

Resurgence of diphtheria in rural areas of North Karnataka, India.

PubMed

Parande, Mahantesh V; Roy, Subarna; Mantur, B G; Parande, Aisha M; Shinde, Rupali S

2017-01-01

A diphtheria outbreak was identified from Vijayapura (formerly Bijapur) district in the South Indian state of Karnataka in 2011. There was a surge in the number of throat swab samples received under the Integrated Disease Surveillance Programme (IDSP) in North Karnataka since then. A microbiological study was undertaken to generate information on the status of resurgence of the disease in the region. Throat swabs from 432 suspected cases of diphtheria during 2012-2015 were obtained from government hospitals and primary health centres of 8 districts in North Karnataka and were processed for the culture and identification of Corynebacterium diphtheriae. Polymerase chain reaction for the presence of toxin gene (toxA and toxB) was carried out on the isolates. Antibiotic sensitivity tests were performed on the isolates with a panel of 14 antibiotics. Thirty-eight (8.79%) out of 432 samples yielded C. diphtheriae on culture. All isolates possessed the diphtheria toxin gene. Out of the 38 confirmed cases, whereas 21 (55.26%) were between 1 and 5 years of age, 14 (36.84%) were aged between 5 and 10 years. Male children were three times more than females in confirmed cases. No information was available on the immunisation status of the cases. Emergence of resistance to penicillin was found with minimum inhibitory concentration reaching up to 6.00 μg/ml. Our study identified an upsurge in cases of diphtheria in North Karnataka, particularly in Vijayapura District, and to the best of our knowledge, reports the emergence of penicillin resistance for the first time in India. The study calls for enhanced surveillance for the disease, making antidiphtheritic serum available in key hospitals in the region and serves to provide a baseline for future assessment of the impact of the recently launched 'Mission Indradhanush' programme in strengthening Universal Immunisation Programme (UIP).

External Quality Assessments for Microbiologic Diagnosis of Diphtheria in Europe

PubMed Central

Both, Leonard; Neal, Shona; De Zoysa, Aruni; Mann, Ginder; Czumbel, Ida

2014-01-01

The European Diphtheria Surveillance Network (EDSN) ensures the reliable epidemiological and microbiologic assessment of disease prevalence in the European Union. Here, we describe a survey of current diagnostic techniques for diphtheria surveillance conducted across the European Union and report the results from three external quality assessment (EQA) schemes performed between 2010 and 2014. PMID:25297336

Diphtheria, Tetanus, Pertussis: Ask the Experts

MedlinePlus

... vaccine and may be administered at the same time as Rhogam (in a separate site with a separate syringe). Scheduling Vaccines Back to top What schedule should I use to vaccinate adolescents or adults who never received the primary series of tetanus toxoid-containing vaccine? Children, ages 7 ...

Immunogenicity and safety of one dose of diphtheria, tetanus, acellular pertussis and poliomyelitis vaccine (Repevax®) followed by two doses of diphtheria, tetanus and poliomyelitis vaccine (Revaxis®) in adults aged ≥ 40 years not receiving a diphtheria- and tetanus-containing vaccination in the last 20 years.

PubMed

Dominicus, Rolf; Galtier, Florence; Richard, Patrick; Baudin, Martine

2014-06-30

The immunogenicity and safety of one dose of Tdap-IPV (tetanus, diphtheria, acellular pertussis and inactivated poliomyelitis vaccine) and two doses of Td-IPV (tetanus, diphtheria and inactivated poliomyelitis vaccine) were assessed in adults who had not received a diphtheria- and tetanus-containing vaccine in the last 20 years. This open-label, multicentre study was conducted in adults aged ≥ 40 years with no diphtheria- and tetanus-containing vaccine in the last 20 years. Participants received one dose of Tdap-IPV followed by two doses of Td-IPV (0, 1, 6 month schedule). Primary immunogenicity objectives: to demonstrate acceptable seroprotection rates (percentage of participants with antibody titre above threshold) post-dose 3 for diphtheria (≥ 0.1IU/mL by seroneutralization assay [SNA]); tetanus (≥ 0.1IU/mL by enzyme-linked immunosorbent assay [ELISA]); and poliomyelitis (≥ 8 1/dil by SNA); and to evaluate the percentage of participants with an antibody concentration ≥ 5EU/mL (by ELISA) for pertussis antigens post-dose 1. Seroprotection rates were acceptable if the lower limit of the 95% confidence interval (CI) was >95%. Percentage of participants with basic clinical immunity against diphtheria (≥ 0.01IU/mL) was also assessed. Safety (adverse events [AEs] and serious AEs) was assessed after each dose. Overall, 336 participants were included (mean age: 60.2 years). Post-dose 3 seroprotection rates were: diphtheria, 94.6% (CI 91.5-96.8); tetanus and poliomyelitis, 100% (CI: 98.8-100). Percentage of participants with an antibody titre ≥ 5EU/mL against pertussis antigens was ≥ 95.8% for all five pertussis components. Basic clinical immunity against diphtheria was achieved in 100% (CI: 98.8-100) of participants. AEs were reported more frequently following vaccination with Tdap-IPV (post-dose 1: 65.3%) than with Td-IPV (post-dose 2: 48.3%; post-dose 3: 50.3%). This study highlights the benefits of using Tdap-IPV followed by two doses of Td-IPV in an

Immunogenicity and safety of a second booster dose of an acellular pertussis vaccine combined with reduced antigen content diphtheria-tetanus toxoids 10 years after a first booster in adolescence: An open, phase III, non-randomized, multi-center study.

PubMed

Kovac, Martina; Kostanyan, Lusiné; Mesaros, Narcisa; Kuriyakose, Sherine; Varman, Meera

2018-04-09

Pertussis is a highly contagious disease, for which periodic peaks in incidence and an increasing number of outbreaks have been observed over the last decades. The reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine (Tdap) can be used to boost individuals aged ≥10 years, vaccinated in infancy with a diphtheria-tetanus-acellular pertussis vaccine (DTaP), to reduce pertussis morbidity and maintain protection against diphtheria and tetanus throughout adolescence and adulthood. This phase III, open-label, non-randomized, multicenter follow-up study (NCT01738477) enrolled 19-30-year-old participants from the United States who had received booster vaccination 10 years earlier with either Tdap (Tdap group) or Td (Td group). In total, 128 (Tdap group) and 37 (Td group) participants received Tdap vaccination. After administration of Tdap, all participants were seroprotected (antibody concentrations ≥0.1 international units [IU]/ml) against diphtheria and tetanus. Immune responses to a second Tdap dose in the Tdap group were shown to be non-inferior to responses elicited by a first Tdap dose in the Td group for diphtheria and tetanus and to a 3-dose DTaP vaccination during infancy for pertussis antigens (primary objectives). Post-booster vaccination, all participants in both groups had antibody concentrations above assay cut-offs and antibody geometric mean concentrations increased by 3.8-15.5-fold compared to pre-booster levels for all antigens. The incidence of adverse events was similar in the Td (80.6%) and Tdap (85.6%) groups (no serious adverse events reported). A Tdap dose administered after previous Td or Tdap vaccination was shown to be immunogenic and well-tolerated in young adults, supporting repeated vaccination with Tdap at 10-year intervals.

Stabilization of tetanus toxoid formulation containing aluminium hydroxide adjuvant against freeze-thawing.

PubMed

Solanki, Vipul A; Jain, Nishant K; Roy, Ipsita

2011-07-29

Exposure to subzero temperature leads to loss of vaccine potency. This can happen due to degradation of adjuvant surface and/or inactivation of the antigen. When adsorbed on aluminium hydroxide and subjected to freeze-thawing, tetanus toxoid was desorbed from the gel matrix and the preparation was found to lose its antigenicity. Analyses showed that the gel particles were denatured after freezing. When freeze-thawing was carried out in the presence of glucose, sorbitol and arginine, the degradation of gel particles was inhibited. A higher fraction of the protein could be retained on the gel. However, the antigenicity of these preparations was quite low. In the presence of trehalose, the protein could be partially retained on aluminium hydroxide. Being a cryoprotectant, trehalose was also able to inhibit the freezing-induced denaturation of tetanus toxoid, which resulted in retention of antigenicity of the adjuvanted toxoid. Copyright © 2011 Elsevier B.V. All rights reserved.

Adult vaccination against tetanus and diphtheria: the European perspective

PubMed Central

2016-01-01

Summary Besides immunizations against influenza, Streptococcus pneumoniae and herpes zoster, which are recommended specifically for elderly people, regular booster vaccinations against tetanus, diphtheria and in some cases pertussis and polio are recommended in many European countries for adults, including elderly people. Vaccination recommendations for adults differ greatly between individual countries and coverage data is scarce. Tetanus‐specific antibody concentrations are generally higher than diphtheria‐specific antibodies, and a substantial proportion of adults, and particularly of elderly people, do not have protective antibody concentrations against diphtheria. Antibody levels increase upon booster vaccination in all age groups, but diphtheria‐specific antibody concentrations remain below protective levels in some older individuals, even immediately after vaccination and long‐term protection is frequently not achieved. Future vaccination strategies should therefore include regular and well‐documented booster shots, e.g. against tetanus and diphtheria, throughout life. PMID:27279025

Strain-specific differences in pili formation and the interaction of Corynebacterium diphtheriae with host cells

PubMed Central

2010-01-01

Background Corynebacterium diphtheriae, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about C. diphtheriae factors crucial for colonization of the host. In this study, we investigated strain-specific differences in adhesion, invasion and intracellular survival and analyzed formation of pili in different isolates. Results Adhesion of different C. diphtheriae strains to epithelial cells and invasion of these cells are not strictly coupled processes. Using ultrastructure analyses by atomic force microscopy, significant differences in macromolecular surface structures were found between the investigated C. diphtheriae strains in respect to number and length of pili. Interestingly, adhesion and pili formation are not coupled processes and also no correlation between invasion and pili formation was found. Using RNA hybridization and Western blotting experiments, strain-specific pili expression patterns were observed. None of the studied C. diphtheriae strains had a dramatic detrimental effect on host cell viability as indicated by measurements of transepithelial resistance of Detroit 562 cell monolayers and fluorescence microscopy, leading to the assumption that C. diphtheriae strains might use epithelial cells as an environmental niche supplying protection against antibodies and macrophages. Conclusions The results obtained suggest that it is necessary to investigate various isolates on a molecular level to understand and to predict the colonization process of different C. diphtheriae strains. PMID:20942914

Diphtheria toxin translocation across cellular membranes is regulated by sphingolipids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spilsberg, Bjorn; Hanada, Kentaro; Sandvig, Kirsten

2005-04-08

Diphtheria toxin is translocated across cellular membranes when receptor-bound toxin is exposed to low pH. To study the role of sphingolipids for toxin translocation, both a mutant cell line lacking the first enzyme in de novo sphingolipid synthesis, serine palmitoyltransferase, and a specific inhibitor of the same enzyme, myriocin, were used. The serine palmitoyltransferase-deficient cell line (LY-B) was found to be 10-15 times more sensitive to diphtheria toxin than the genetically complemented cell line (LY-B/cLCB1) and the wild-type cell line (CHO-K1), both when toxin translocation directly across the plasma membrane was induced by exposing cells with surface-bound toxin to lowmore » pH, and when the toxin followed its normal route via acidified endosomes into the cytosol. Toxin binding was similar in these three cell lines. Furthermore, inhibition of serine palmitoyltransferase activity by addition of myriocin sensitized the two control cell lines (LY-B/cLCB1 and CHO-K1) to diphtheria toxin, whereas, as expected, no effect was observed in cells lacking serine palmitoyltransferase (LY-B). In conclusion, diphtheria toxin translocation is facilitated by depletion of membrane sphingolipids.« less

Comparison of phenotypic and genotypic methods for detection of diphtheria toxin among isolates of pathogenic corynebacteria.

PubMed

Efstratiou, A; Engler, K H; Dawes, C S; Sesardic, D

1998-11-01

We have compared molecular, immunochemical, and cytotoxic assays for the detection of diphtheria toxin from 55 isolates of Corynebacterium diphtheriae and Corynebacterium ulcerans originally isolated in five different countries. The suitabilities and accuracies of these assays for the laboratory diagnosis of diphtheria were compared and evaluated against the "gold standard" in vivo methods. The in vivo and Vero cell cytotoxicity assays were accurate in their abilities to detect diphtheria toxin but were time-consuming; however, the cytotoxicity assay is a suitable in vitro alternative to the in vivo virulence test. There was complete concordance between all the phenotypic methods. Genotypic tests based upon PCR were rapid; however, PCR must be used with caution because some isolates of C. diphtheriae possessed toxin genes but failed to express a biologically active toxin. Therefore, phenotypic confirmation of toxigenicity for the microbiological diagnosis of diphtheria is recommended.

Bloodstream infection caused by nontoxigenic Corynebacterium diphtheriae in an immunocompromised host in the United States.

PubMed

Wojewoda, Christina M; Koval, Christine E; Wilson, Deborah A; Chakos, Mary H; Harrington, Susan M

2012-06-01

Corynebacterium species are well-known causes of catheter-related bloodstream infections. Toxigenic strains of Corynebacterium diphtheriae cause respiratory diphtheria. We report a bloodstream infection caused by a nontoxigenic strain of C. diphtheriae and discuss the epidemiology, possible sources of the infection, and the implications of rapid species identification of corynebacteria.

Bloodstream Infection Caused by Nontoxigenic Corynebacterium diphtheriae in an Immunocompromised Host in the United States

PubMed Central

Wojewoda, Christina M.; Koval, Christine E.; Wilson, Deborah A.; Chakos, Mary H.

2012-01-01

Corynebacterium species are well-known causes of catheter-related bloodstream infections. Toxigenic strains of Corynebacterium diphtheriae cause respiratory diphtheria. We report a bloodstream infection caused by a nontoxigenic strain of C. diphtheriae and discuss the epidemiology, possible sources of the infection, and the implications of rapid species identification of corynebacteria. PMID:22493337

Antibody Kinetics and Response to Routine Vaccinations in Infants Born to Women Who Received an Investigational Trivalent Group B Streptococcus Polysaccharide CRM197-Conjugate Vaccine During Pregnancy

PubMed Central

Madhi, Shabir A; Koen, Anthonet; Cutland, Clare L; Jose, Lisa; Govender, Niresha; Wittke, Frederick; Olugbosi, Morounfolu; Sobanjo-ter Meulen, Ajoke; Baker, Sherryl; Dull, Peter M; Narasimhan, Vas; Slobod, Karen

2017-01-01

Abstract Background Maternal vaccination against group B Streptococcus (GBS) might provide protection against invasive GBS disease in infants. We investigated the kinetics of transplacentally transferred GBS serotype-specific capsular antibodies in the infants and their immune response to diphtheria toxoid and pneumococcal vaccination. Methods This phase 1b/2, observer-blind, single-center study (NCT01193920) enrolled infants born to women previously randomized (1:1:1:1) to receive either GBS vaccine at dosages of 0.5, 2.5, or 5.0 μg of each of 3 CRM197-glycoconjugates (serotypes Ia, Ib, and III), or placebo. Infants received routine immunization: combination diphtheria vaccine (diphtheria-tetanus-acellular pertussis–inactivated poliovirus/Haemophilus influenzae type b vaccine; age 6/10/ 14 weeks) and 13-valent pneumococcal CRM197-conjugate vaccine (PCV13; age 6/14 weeks and 9 months). Antibody levels were assessed at birth, day (D) 43, and D91 for GBS serotypes; 1 month postdose 3 (D127) for diphtheria; and 1 month postprimary (D127) and postbooster (D301) doses for pneumococcal serotypes. Results Of 317 infants enrolled, 295 completed the study. In infants of GBS vaccine recipients, GBS serotype-specific antibody geometric mean concentrations were significantly higher than in the placebo group at all timepoints and predictably decreased to 41%–61% and 26%–76% of birth levels by D43 and D91, respectively. Across all groups, ≥95% of infants were seroprotected against diphtheria at D127 and ≥91% of infants had seroprotective antibody levels against each PCV13 pneumococcal serotype at D301. Conclusions Maternal vaccination with an investigational CRM197-glycoconjugate GBS vaccine elicited higher GBS serotype-specific antibody levels in infants until 90 days of age, compared with a placebo group, and did not affect infant immune responses to diphtheria toxoid and pneumococcal vaccination. Clinical Trials Registration NCT01193920. PMID:29029127

Characterization of OxyR as a Negative Transcriptional Regulator That Represses Catalase Production in Corynebacterium diphtheriae

PubMed Central

Kim, Ju-Sim; Holmes, Randall K.

2012-01-01

Corynebacterium diphtheriae and Corynebacterium glutamicum each have one gene (cat) encoding catalase. In-frame Δcat mutants of C. diphtheriae and C. glutamicum were hyper-sensitive to growth inhibition and killing by H2O2. In C. diphtheriae C7(β), both catalase activity and cat transcription decreased ∼2-fold during transition from exponential growth to early stationary phase. Prototypic OxyR in Escherichia coli senses oxidative stress and it activates katG transcription and catalase production in response to H2O2. In contrast, exposure of C. diphtheriae C7(β) to H2O2 did not stimulate transcription of cat. OxyR from C. diphtheriae and C. glutamicum have 52% similarity with E. coli OxyR and contain homologs of the two cysteine residues involved in H2O2 sensing by E. coli OxyR. In-frame ΔoxyR deletion mutants of C. diphtheriae C7(β), C. diphtheriae NCTC13129, and C. glutamicum were much more resistant than their parental wild type strains to growth inhibition by H2O2. In the C. diphtheriae C7(β) ΔoxyR mutant, cat transcripts were about 8-fold more abundant and catalase activity was about 20-fold greater than in the C7(β) wild type strain. The oxyR gene from C. diphtheriae or C. glutamicum, but not from E. coli, complemented the defect in ΔoxyR mutants of C. diphtheriae and C. glutamicum and decreased their H2O2 resistance to the level of their parental strains. Gel-mobility shift, DNaseI footprint, and primer extension assays showed that purified OxyR from C. diphtheriae C7(β) bound, in the presence or absence of DTT, to a sequence in the cat promoter region that extends from nucleotide position −55 to −10 with respect to the +1 nucleotide in the cat ORF. These results demonstrate that OxyR from C. diphtheriae or C. glutamicum functions as a transcriptional repressor of the cat gene by a mechanism that is independent of oxidative stress induced by H2O2. PMID:22438866

Comparison of Phenotypic and Genotypic Methods for Detection of Diphtheria Toxin among Isolates of Pathogenic Corynebacteria

PubMed Central

Efstratiou, Androulla; Engler, Kathryn H.; Dawes, Charlotte S.; Sesardic, Dorothea

1998-01-01

We have compared molecular, immunochemical, and cytotoxic assays for the detection of diphtheria toxin from 55 isolates of Corynebacterium diphtheriae and Corynebacterium ulcerans originally isolated in five different countries. The suitabilities and accuracies of these assays for the laboratory diagnosis of diphtheria were compared and evaluated against the “gold standard” in vivo methods. The in vivo and Vero cell cytotoxicity assays were accurate in their abilities to detect diphtheria toxin but were time-consuming; however, the cytotoxicity assay is a suitable in vitro alternative to the in vivo virulence test. There was complete concordance between all the phenotypic methods. Genotypic tests based upon PCR were rapid; however, PCR must be used with caution because some isolates of C. diphtheriae possessed toxin genes but failed to express a biologically active toxin. Therefore, phenotypic confirmation of toxigenicity for the microbiological diagnosis of diphtheria is recommended. PMID:9774560

Tetanus and diphtheria immunity in refugees in Europe in 2015.

PubMed

Jablonka, Alexandra; Behrens, Georg M N; Stange, Marcus; Dopfer, Christian; Grote, Ulrike; Hansen, Gesine; Schmidt, Reinhold Ernst; Happle, Christine

2017-04-01

Current political crises in the Middle East and economic discrepancies led millions of people to leave their home countries and to flee to Western Europe. This development raises unexpected challenges for receiving health care systems. Although pan-European initiatives strive for updated and optimized vaccination strategies, little data on immunity against vaccine-preventable diseases in the current refugee population exist. We quantified serum IgG against tetanus and diphtheria (TD) in n = 678 refugees currently seeking shelter in six German refugee centers. Reflecting current migration statistics in Europe, the median age within the cohort was 26 years, with only 23.9 % of female subjects. Insufficient IgG levels without long-term protection against tetanus were found in 56.3 % of all refugees. 76.1 % of refugees had no long-term protection against diphtheria. 47.7 % of subjects needed immediate vaccination against tetanus, and 47.7 % against diphtheria. For both diseases, an age-dependent decline in protective immunity occurred. We observed a considerably low rate of tetanus-protected refugees, and the frequency of diphtheria-immune refugees was far from sufficient to provide herd immunity. These findings strongly support recent intentions to implement and enforce stringent guidelines for refugee vaccination in the current crisis.

Notes from the field: respiratory diphtheria-like illness caused by toxigenic Corynebacterium ulcerans --- Idaho, 2010.

PubMed

2011-01-28

On September 12, 2010, the Idaho Department of Health and Welfare was notified of a case of respiratory diphtheria-like illness in an Idaho man aged 80 years whose pharyngeal specimens yielded Corynebacterium ulcerans. Although C. ulcerans is zoonotic, the patient reported no animal contact or consumption of an unpasteurized dairy product. His vaccination history was unknown. Respiratory diphtheria-like illness from C. ulcerans is uncommon but has been reported in industrialized countries where respiratory diphtheria is rare. The last case of diphtheria-like illness caused by C. ulcerans in the United States was reported in 2005.

Usefulness of basophil activation test for the diagnosis of IgE mediated hypersensitivity to tetanus toxoid vaccine.

PubMed

Herreros, Blanca; Méndez, Yesica; Feo-Brito, Francisco; Urra, José Miguel

2018-03-01

A great number of vaccinated patients develop specific anti-tetanus toxoid IgE, but usually do not undergo any adverse effect. Most of the allergic reactions to tetanus toxoid vaccine usually present with unspecific symptoms of local inflammation. In the presence of severe reactions, and in a special way if the vaccine is provided together with other drugs, it is difficult to establish which is the harmful drug responsible for IgE-mediated adverse reaction. A patient with an anaphylactic reaction after the administration of Toxoid Tetanic (TT) along with several drugs is described. All skin test were negative. The basophils activation test (BAT) in a clear way, identified TT as the allergen that triggered anaphylaxis. The results achieved demonstrates the usefulness of BAT to clarify patients with hypersensibility to tetanus toxoide when the clinic is severe and the vaccine has been administered together with other drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Access to diphtheria antitoxin for therapy and diagnostics.

PubMed

Both, L; White, J; Mandal, S; Efstratiou, A

2014-06-19

The most effective treatment for diphtheria is swift administration of diphtheria antitoxin (DAT) with conjunct antibiotic therapy. DAT is an equine immunoglobulin preparation and listed among the World Health Organization Essential Medicines. Essential Medicines should be available in functioning health systems at all times in adequate amounts, in appropriate dosage forms, with assured quality, and at prices individuals and the community can afford. However, DAT is in scarce supply and frequently unavailable to patients because of discontinued production in several countries, low economic viability, and high regulatory requirements for the safe manufacture of blood-derived products. DAT is also a cornerstone of diphtheria diagnostics but several diagnostic reference laboratories across the European Union (EU) and elsewhere routinely face problems in sourcing DAT for toxigenicity testing. Overall, global access to DAT for both therapeutic and diagnostic applications seems inadequate. Therefore--besides efforts to improve the current supply of DAT--accelerated research and development of alternatives including monoclonal antibodies for therapy and molecular-based methods for diagnostics are required. Given the rarity of the disease, it would be useful to organise a small stockpile centrally for all EU countries and to maintain an inventory of DAT availability within and between countries.

Targeted diphtheria toxin to treat BPDCN.

PubMed

FitzGerald, David J

2014-07-17

In this issue of Blood, Frankel et al describe a novel treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) using an engineered version of diphtheria toxin that is targeted to malignant cells via a fusion with interleukin (IL)3 (see panel A).

Molecular and Epidemiological Review of Toxigenic Diphtheria Infections in England between 2007 and 2013

PubMed Central

Both, Leonard; Collins, Sarah; de Zoysa, Aruni; White, Joanne; Mandal, Sema

2014-01-01

Human infections caused by toxigenic corynebacteria occur sporadically across Europe. In this report, we undertook the epidemiological and molecular characterization of all toxigenic corynebacterium strains isolated in England between January 2007 and December 2013. Epidemiological aspects include case demographics, risk factors, clinical presentation, treatment, and outcome. Molecular characterization was performed using multilocus sequence typing (MLST) alongside traditional phenotypic methods. In total, there were 20 cases of toxigenic corynebacteria; 12 (60.0%) were caused by Corynebacterium ulcerans, where animal contact was the predominant risk factor. The remaining eight (40.0%) were caused by Corynebacterium diphtheriae strains; six were biovar mitis, which were associated with recent travel abroad. Adults 45 years and older were particularly affected (55.0%; 11/20), and typical symptoms included sore throat and fever. Respiratory diphtheria with the absence of a pharyngeal membrane was the most common presentation (50.0%; 10/20). None of the eight C. diphtheriae cases were fully immunized. Diphtheria antitoxin was issued in two (9.5%) cases; both survived. Two (9.5%) cases died, one due to a C. diphtheriae infection and one due to C. ulcerans. MLST demonstrated that the majority (87.5%; 7/8) of C. diphtheriae strains represented new sequence types (STs). By adapting several primer sequences, the MLST genes in C. ulcerans were also amplified, thereby providing the basis for extension of the MLST scheme, which is currently restricted to C. diphtheriae. Despite high population immunity, occasional toxigenic corynebacterium strains are identified in England and continued surveillance is required. PMID:25502525

Rapid Detection and Molecular Differentiation of Toxigenic Corynebacterium diphtheriae and Corynebacterium ulcerans Strains by LightCycler PCR ▿

PubMed Central

Sing, Andreas; Berger, Anja; Schneider-Brachert, Wulf; Holzmann, Thomas; Reischl, Udo

2011-01-01

The systemic symptoms of diphtheria are caused by the tox-encoded diphtheria toxin (DT) which is produced by toxigenic Corynebacterium spp. Besides the classical agent C. diphtheriae, the zoonotic pathogen C. ulcerans has increasingly been reported as an emerging pathogen for diphtheria. The reliable detection of toxigenic Corynebacterium spp. is of substantial importance for both diphtheria surveillance in the public health sector and the clinical workup of a patient with diphtherialike symptoms. Since the respective tox genes of C. diphtheriae and C. ulcerans differ from each other in both DNA and amino acid sequence, both tox genes should be covered by novel real-time PCR methods. We describe the development and validation of a LightCycler PCR assay which reliably recognizes tox genes from both C. diphtheriae and C. ulcerans and differentiates the respective target genes by fluorescence resonance energy transfer (FRET) hybridization probe melting curve analysis. PMID:21593261

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model.

PubMed

Smith, Heidi L; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C

2016-08-17

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.

Persistence of Serogroup C Antibody Responses Following Quadrivalent Meningococcal Conjugate Vaccination in United States Military Personnel

DTIC Science & Technology

2014-05-14

Sanofi Pasteur, Swiftwater, A, USA), was used routinely in U.S. military recruits to reduce he risk of disease during basic training. However...U.S. enACWYD (Menactra®, diphtheria toxoid conjugate, Sanofi Pas- eur, Swiftwater, PA, USA) was licensed in 2005 and MenACWYCRM MenveoTM, CRM-197

Binding of Diphtheria Toxin to Phospholipids in Liposomes

NASA Astrophysics Data System (ADS)

Alving, Carl R.; Iglewski, Barbara H.; Urban, Katharine A.; Moss, Joel; Richards, Roberta L.; Sadoff, Jerald C.

1980-04-01

Diphtheria toxin bound to the phosphate portion of some, but not all, phospholipids in liposomes. Liposomes consisting of dimyristoyl phosphatidylcholine and cholesterol did not bind toxin. Addition of 20 mol% (compared to dimyristoyl phosphatidylcholine) of dipalmitoyl phosphatidic acid, dicetyl phosphate, phosphatidylinositol phosphate, cardiolipin, or phosphatidylserine in the liposomes resulted in substantial binding of toxin. Inclusion of phosphatidylinositol in dimyristol phosphatidylcholine / cholesterol liposomes did not result in toxin binding. The calcium salt of dipalmitoyl phosphatidic acid was more effective than the sodium salt, and the highest level of binding occurred with liposomes consisting only of dipalmitoyl phosphatidic acid (calcium salt) and cholesterol. Binding of toxin to liposomes was dependent on pH, and the pattern of pH dependence varied with liposomes having different compositions. Incubation of diphtheria toxin with liposomes containing dicetyl phosphate resulted in maximal binding at pH 3.6, whereas binding to liposomes containing phosphatidylinositol phosphate was maximal above pH 7. Toxin did not bind to liposomes containing 20 mol% of a free fatty acid (palmitic acid) or a sulfated lipid (3-sulfogalactosylceramide). Toxin binding to dicetyl phosphate or phosphatidylinositol phosphate was inhibited by UTP, ATP, phosphocholine, or p-nitrophenyl phosphate, but not by uracil. We conclude that (a) diphtheria toxin binds specifically to the phosphate portion of certain phospholipids, (b) binding to phospholipids in liposomes is dependent on pH, but is not due only to electrostatic interaction, and (c) binding may be strongly influenced by the composition of adjacent phospholipids that do not bind toxin. We propose that a minor membrane phospholipid (such as phosphatidylinositol phosphate or phosphatidic acid), or that some other phosphorylated membrane molecule (such as a phosphoprotein) may be important in the initial binding of

Characterization of Heat-Stable (STa) Toxoids of Enterotoxigenic Escherichia coli Fused to Double Mutant Heat-Labile Toxin Peptide in Inducing Neutralizing Anti-STa Antibodies

PubMed Central

Ruan, Xiaosai; Robertson, Donald C.; Nataro, James P.; Clements, John D.

2014-01-01

A long-standing challenge in developing vaccines against enterotoxigenic Escherichia coli (ETEC), the most common bacteria causing diarrhea in children of developing countries and travelers to these countries, is to protect against heat-stable toxin type Ib (STa or hSTa). STa and heat-labile toxin (LT) are virulence determinants in ETEC diarrhea. LT antigens are often used in vaccine development, but STa has not been included because of its poor immunogenicity and potent toxicity. Toxic STa is not safe for vaccines, but only STa possessing toxicity is believed to be able to induce neutralizing antibodies. However, recent studies demonstrated that nontoxic STa derivatives (toxoids), after being fused to an LT protein, induced neutralizing antibodies and suggested that different STa toxoids fused to an LT protein might exhibit different STa antigenic propensity. In this study, we selected 14 STa toxoids from a mini-STa toxoid library based on toxicity reduction and reactivity to anti-native STa antibodies, and genetically fused each toxoid to a monomeric double mutant LT (dmLT) peptide for 14 STa-toxoid-dmLT toxoid fusions. These toxoid fusions were used to immunize mice and were characterized for induction of anti-STa antibody response. The results showed that different STa toxoids (in fusions) varied greatly in anti-STa antigenicity. Among them, STaN12S, STaN12T, and STaA14H were the top toxoids in inducing anti-STa antibodies. In vitro neutralization assays indicated that antibodies induced by the 3×STaN12S-dmLT fusion antigen exhibited the greatest neutralizing activity against STa toxin. These results suggested 3×STaN12S-dmLT is a preferred fusion antigen to induce an anti-STa antibody response and provided long-awaited information for effective ETEC vaccine development. PMID:24549325

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model

PubMed Central

Smith, Heidi L.; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C.

2016-01-01

ABSTRACT Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16–21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38–59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans. PMID:27070129

Factors affecting the immunogenicity and potency of tetanus toxoid: implications for the elimination of neonatal and non-neonatal tetanus as public health problems.

PubMed Central

Dietz, V.; Galazka, A.; van Loon, F.; Cochi, S.

1997-01-01

An estimated 400,000 deaths occur annually from neonatal tetanus (NT). In 1989 WHO adopted the goal of eliminating NT as a public health problem worldwide. To achieve this, and to control non-neonatal tetanus (non-NT), WHO recommends that newborns be passively protected at birth by the antepartum administration of at least two doses of tetanus toxoid (TT) to their mothers and that all children subsequently receive at least three doses of diphtheria-tetanus-pertussis (DTP) vaccine. For this strategy to be effective, the TT used must be immunogenic. Potential factors that may affect TT immunogenicity need to be evaluated if NT is to be eliminated and if non-NT is to be controlled. Although data are conflicting, concurrent malarial infection may decrease the immune response to TT; however, malarial chemoprophylaxis may enhance the immune response. Malnutrition does not appear to affect immunogenicity; nevertheless, one study suggests that vitamin A deficiency is associated with an impaired immune response. Although it has been postulated that placental transfer of tetanus antibody is impaired in African women, a survey of the published literature suggests that this is not the case. Freezing TT has been shown to decrease its potency, but its impact on immunogenicity needs more evaluation. PMID:9141753

Durability of Vaccine-Induced Immunity Against Tetanus and Diphtheria Toxins: A Cross-sectional Analysis

PubMed Central

Hammarlund, Erika; Thomas, Archana; Poore, Elizabeth A.; Amanna, Ian J.; Rynko, Abby E.; Mori, Motomi; Chen, Zunqiu; Slifka, Mark K.

2016-01-01

Background. Many adult immunization schedules recommend that tetanus and diphtheria vaccination be performed every 10 years. In light of current epidemiological trends of disease incidence and rates of vaccine-associated adverse events, the 10-year revaccination schedule has come into question. Methods. We performed cross-sectional analysis of serum antibody titers in 546 adult subjects stratified by age or sex. All serological results were converted to international units after calibration with international serum standards. Results. Approximately 97% of the population was seropositive to tetanus and diphtheria as defined by a protective serum antibody titer of ≥0.01 IU/mL. Mean antibody titers were 3.6 and 0.35 IU/mL against tetanus and diphtheria, respectively. Antibody responses to tetanus declined with an estimated half-life of 14 years (95% confidence interval, 11–17 years), whereas antibody responses to diphtheria were more long-lived and declined with an estimated half-life of 27 years (18–51 years). Mathematical models combining antibody magnitude and duration predict that 95% of the population will remain protected against tetanus and diphtheria for ≥30 years without requiring further booster vaccination. Conclusions. These studies demonstrate that durable levels of protective antitoxin immunity exist in the majority of vaccinated individuals. Together, this suggests that it may no longer be necessary to administer booster vaccinations every 10 years and that the current adult vaccination schedule for tetanus and diphtheria should be revisited. PMID:27060790

Infections in Pregnancy and the Role of Vaccines.

PubMed

Fortner, Kimberly B; Nieuwoudt, Claudia; Reeder, Callie F; Swamy, Geeta K

2018-06-01

Pregnant women are at risk for infection and may have significant morbidity or mortality. Influenza, pertussis, zika, and cytomegalovirus produce mild or asymptomatic illness in the mother, but have profound implications for her fetus. Maternal immunization can prevent or mitigate infections in pregnant women and their infants. The Advisory Committee of Immunization Practices recommends 2 vaccines during pregnancy: inactivated influenza, and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis during pregnancy. The benefits of MMR, varicella, and other vaccines are reviewed. Novel vaccine studies for use during pregnancy for prevention of illness are explored. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparing Galactan Biosynthesis in Mycobacterium tuberculosis and Corynebacterium diphtheriae*

PubMed Central

Wesener, Darryl A.; Levengood, Matthew R.

2017-01-01

The suborder Corynebacterineae encompasses species like Corynebacterium glutamicum, which has been harnessed for industrial production of amino acids, as well as Corynebacterium diphtheriae and Mycobacterium tuberculosis, which cause devastating human diseases. A distinctive component of the Corynebacterineae cell envelope is the mycolyl-arabinogalactan (mAG) complex. The mAG is composed of lipid mycolic acids, and arabinofuranose (Araf) and galactofuranose (Galf) carbohydrate residues. Elucidating microbe-specific differences in mAG composition could advance biotechnological applications and lead to new antimicrobial targets. To this end, we compare and contrast galactan biosynthesis in C. diphtheriae and M. tuberculosis. In each species, the galactan is constructed from uridine 5′-diphosphate-α-d-galactofuranose (UDP-Galf), which is generated by the enzyme UDP-galactopyranose mutase (UGM or Glf). UGM and the galactan are essential in M. tuberculosis, but their importance in Corynebacterium species was not known. We show that small molecule inhibitors of UGM impede C. glutamicum growth, suggesting that the galactan is critical in corynebacteria. Previous cell wall analysis data suggest the galactan polymer is longer in mycobacterial species than corynebacterial species. To explore the source of galactan length variation, a C. diphtheriae ortholog of the M. tuberculosis carbohydrate polymerase responsible for the bulk of galactan polymerization, GlfT2, was produced, and its catalytic activity was evaluated. The C. diphtheriae GlfT2 gave rise to shorter polysaccharides than those obtained with the M. tuberculosis GlfT2. These data suggest that GlfT2 alone can influence galactan length. Our results provide tools, both small molecule and genetic, for probing and perturbing the assembly of the Corynebacterineae cell envelope. PMID:28039359

Pore-formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells.

PubMed

Svedova, Martina; Masin, Jiri; Fiser, Radovan; Cerny, Ondrej; Tomala, Jakub; Freudenberg, Marina; Tuckova, Ludmila; Kovar, Marek; Dadaglio, Gilles; Adkins, Irena; Sebo, Peter

2016-04-01

The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore-forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell-permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC.

Estimation of antigenic tetanus toxoid extracted from biodegradable microspheres.

PubMed

Xing, D K; McLellan, K; Corbel, M J; Sesardic, D

1996-03-01

Microspheres made from poly (lactic/glycolic acid) polymers have been considered as a new delivery system for single-dose tetanus toxoid (TT) vaccines. One of the most critical properties of the proposed vaccines is the loading and distribution of TT as this will have a profound effect on immunogenicity. As the concentration of TT in microspheres is very low sensitive assay methods are required. An assay incorporating monoclonal antibody (MAb) recognizing a neutralizing epitope and cross-reacting with TT was developed (MAp capture ELISA) which provided a sensitivity of 0.001 Lf/ml. An extraction procedure was devised which did not destroy the antigenicity and gave a recovery of 90.6 +/- 3.39% when applied to different preparations. The extracted TT was then quantified by MAb capture ELISA which was estimated to be 250-fold more sensitive than single-site ELISA for toxoid. The loading of 20 microspheres preparations (12 filled and 8 placebo) was determined by both protein micro-BCA assay and the developed assay for TT. The TT content obtained for the 12 filled microspheres preparations from different sources varied up to 400-fold (range 0.01-4.0 Lf/mg microspheres). The utility of the MAb capture ELISA for detection of total antigenic content in microspheres was confirmed by the observation that the determine TT loading correlated with the theoretical loading predicted from the protein content for the best preparations. Preparations with high loading gave the greatest peak response. There was no relationship between dose and the in vivo immunogenic response, suggesting that encapsulated vaccines with differential loading, release properties and presence of excipients will have different response curves in vivo. Hence, the present assay, when combined with information on toxoid release rate and presence and effect of excipients may be of value in predicting in vivo response.

Enacting cultural boundaries in French and German diphtheria serum research.

PubMed

Klöppel, Ulrike

2008-06-01

The experimental development of a therapeutic serum against diphtheria between 1891 and 1894 was characterized by a scientific competition that pitted Emil Behring from the Institute for Infectious Diseases in Berlin against Emile Roux and Elie Metschnikoff from the Pasteur Institute in Paris. In general, their competition can be regarded as an extension of the fundamental differences that separated the research schools of Robert Koch and Louis Pasteur. However, to characterize the competition for a diphtheria-serum as "national rivalry" fails to account adequately for the mutual adoption of experimental practices by the Berlin and Parisian protagonists, whose contributions to the development of a therapeutic serum were intertwined in complex ways. Nor can it be characterized as "cooperation," given their fierce public disputes over scientific concepts and the fact that these disputes also shaped the peculiarities of the experimental procedures in Berlin and Paris. A close analysis reveals a complex picture of the dynamic interaction between the conceptual and experimental activities of Behring, Roux, and Metschnikoff- interaction that defined as well as bridged the "French" and "Prussian" experimental systems of diphtheria-serum research.

Recall Responses to Tetanus and Diphtheria Vaccination Are Frequently Insufficient in Elderly Persons

PubMed Central

Weinberger, Birgit; Schirmer, Michael; Matteucci Gothe, Raffaella; Siebert, Uwe; Fuchs, Dietmar; Grubeck-Loebenstein, Beatrix

2013-01-01

Demographic changes and a more active life-style in older age have contributed to an increasing public awareness of the need for lifelong vaccination. Currently many older persons have been vaccinated against selected pathogens during childhood but lack regular booster immunizations. The impact of regular vaccinations when started late in life was analyzed in an open, explorative trial by evaluating the immune response against tetanus and diphtheria in healthy older individuals. 252 persons aged above 60 years received a booster vaccination against tetanus, diphtheria, pertussis and polio and a subcohort (n=87) was recruited to receive a second booster vaccination against tetanus, diphtheria and pertussis 5 years later. The percentage of unprotected individuals at the time of enrollment differed substantially for tetanus (12%) and diphtheria (65%). Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had again dropped below protective levels in 10% (tetanus) and 45% (diphtheria) of the cohort after 5 years. Protection was restored in almost all vaccinees after the second vaccination. No correlation between tetanus- and diphtheria-specific responses was observed, and antibody concentrations were not associated with age-related changes in the T cell repertoire, inflammatory parameters, or CMV-seropositivity suggesting that there was no general biological “non-responder type.” Post-vaccination antibody concentrations depended on pre-existing plasma cells and B cell memory as indicated by a strong positive relationship between post-vaccination antibodies and pre-vaccination antibodies as well as antibody-secreting cells. In contrast, antigen-specific T cell responses were not or only weakly associated with antibody concentrations. In conclusion, our findings demonstrate that single shot vaccinations against tetanus and/or diphtheria do not lead to long-lasting immunity in many elderly persons despite

Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.

PubMed

Baxter, Roger; Baine, Yaela; Ensor, Kathleen; Bianco, Veronique; Friedland, Leonard R; Miller, Jacqueline M

2011-03-01

An investigational quadrivalent Neisseria meningitidis serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) has been developed to expand available options for vaccination against invasive meningococcal disease. A total of 784 healthy adolescents and young adults 11 to 25 years of age were randomized (3:1) to receive a single dose of the MenACWY-TT vaccine or a licensed MenACWY diphtheria toxoid conjugate vaccine (MenACWY-DT). An additional nonrandomized group of 88 subjects 10 years of age received the MenACWY-TT vaccine only (MenACWY-TT/10). Immunogenicity was assessed 1 month postvaccination by human complement serum bactericidal assay (hSBA) for all serogroups. Solicited local and general symptoms were recorded for 8 days postvaccination and safety outcomes for 6 months. One month postvaccination, 81.9% to 96.1% of subjects had hSBA titers ≥ 1:8 in the MenACWY-TT group compared with 70.7% to 98.8% in the MenACWY-DT group. Exploratory analyses showed the proportion of subjects with hSBA titers ≥ 1:4 and ≥ 1:8 to be higher in the MenACWY-TT group than in the MenACWY-DT group for serogroups A, W-135, and Y. GMTs adjusted for age strata and baseline titer 1 month postvaccination were higher in the MenACWY-TT group than in the MenACWY-DT group for all 4 serogroups. The percentage of subjects reporting solicited local and general symptoms of any or Grade 3 severity or serious adverse events was similar between the 2 groups. Immune response and reactogenicity in the MenACWY-TT/10 group was similar to that in the MenACWY-TT group, except for higher hSBA-MenA GMTs in the MenACWY-TT/10 group. The investigational MenACWY-TT vaccine was immunogenic in adolescents and young adults, with an acceptable safety profile.

Immunogenicity and reactogenicity of a decennial booster dose of a combined reduced-antigen-content diphtheria-tetanus-acellular pertussis and inactivated poliovirus booster vaccine (dTpa-IPV) in healthy adults.

PubMed

Kovac, Martina; Rathi, Niraj; Kuriyakose, Sherine; Hardt, Karin; Schwarz, Tino F

2015-05-21

Pertussis in adults and adolescents could be reduced by replacing traditional tetanus and diphtheria (Td) boosters with reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) vaccines. This study evaluated the administration of dTpa-IPV (dTpa-inactivated poliovirus) in adults ten years after they received a booster dose of either dTpa-IPV, dTpa+IPV or Td-IPV in trial NCT01277705. Open multicentre, phase IV study (www.clinicaltrials.govNCT01323959) in which healthy adults, who had received a previous dose of dTpa-IPV, dTpa+IPV or Td-IPV ten years earlier, received a single decennial booster dose of dTpa-IPV (Boostrix-polio, GlaxoSmithKline Vaccines). Blood samples were collected before and one month after booster vaccination. Antibody concentrations against all vaccine antigens were measured and reactogenicity and safety were assessed. A total of 211 subjects (mean age 50.3 years) received vaccination of whom 201 were included in the according-to-protocol cohort for immunogenicity. Before the decennial dTpa-IPV booster, ≥71.0% subjects were seroprotected/seropositive against all vaccine antigens. One month after the booster dose, all subjects were seroprotected against tetanus and poliovirus types 2 and 3; ≥95.7% subjects were seroprotected against diphtheria and ≥98.3% against poliovirus type 1. Anti-pertussis booster responses for the various antigens were observed in ≥76.5% (pertussis toxoid; PT), ≥85.1% (filamentous haemagglutinin; FHA) and ≥63.2% (pertactin; PRN) of subjects. During the 4-day follow-up, the overall incidence of local AEs was 71.6%, 75.0% and 72.2% in dTpa-IPV, dTpa+IPV and Td-IPV groups, respectively. Pain was the most frequent solicited local adverse event (AE; ≥62.7% subjects) and fatigue the most frequent solicited general AE (≥18.5%). No serious AEs were reported during the study. A booster dose of dTpa-IPV was immunogenic and well tolerated in adults who had received a booster dose of either dTpa-IPV, d

Colonisation with toxigenic Corynebacterium diphtheriae in a Scottish burns patient, June 2015.

PubMed

Deshpande, Ashutosh; Inkster, Teresa; Hamilton, Kate; Litt, David; Fry, Norman; Kennedy, Iain T R; Shookhye-Dickson, Jacqueline; Hill, Robert L R

2015-01-01

On 12 June 2015, Corynebacterium diphtheriae was identified in a skin swab from a burns patient in Scotland. The isolate was confirmed to be genotypically and phenotypically toxigenic. Multilocus sequence typing of three patient isolates yielded sequence type ST 125. The patient was clinically well. We summarise findings of this case, and results of close contact identification and screening: 12 family and close contacts and 32 hospital staff have been found negative for C. diphtheriae.

Immunity to Diphtheria and Tetanus in Army Personnel and Adult Civilians in Mashhad, Iran.

PubMed

Hosseini Shokouh, Seyyed Javad; Mohammadi, Babak; Rajabi, Jalil; Mohammadian Roshan, Ghasem

2017-03-24

This study aimed to investigate serologic immunity to diphtheria and tetanus in army personnel and a sample population of adult civilians in Mashhad, Iran. Army personnel (n = 180) and civilians (n = 83) who presented at Mashhad army hospital participated in this study. Diphtheria and tetanus antitoxin levels were determined by enzyme-linked immunosorbent assay. Approximately 77% and 94% of army personnel aged 18-34 years had at least basic protection against diphtheria (antitoxin level ≥0.1 IU/mL) and tetanus (antitoxin level >0.1 IU/mL), respectively. For civilians in this age group, the proportions were 76% for both diseases. Antitoxin levels waned with age. Thus, participants older than 50 years had lower immunity; this decrease in immunity was more pronounced for tetanus than for diphtheria in both army personnel and civilians. For both diseases, geometric mean antitoxin titers and the proportion of participants with at least basic protection were higher in subjects with a history of vaccination in the last 10 years (P < 0.001), higher in men than women, and in army personnel than civilians in each age group. Young army personnel and civilians (18-34 years old) had adequate immunity to diphtheria and tetanus. However, the large number of susceptible older adults (>50 years old) calls for improved booster vaccination protocols.

Comparison of in vitro and in vivo methods to study stability of PLGA microencapsulated tetanus toxoid vaccines.

PubMed

Sasiak, A B; Bolgiano, B; Crane, D T; Hockley, D J; Corbel, M J; Sesardic, D

2000-11-22

The purpose of this study was to investigate the utility of various in vitro and in vivo methods to assess the stability of experimental vaccines containing tetanus toxoid (TT) within PLGA microspheres. In vitro, the breakdown of the encapsulating polymers into their acid components led to changes in the structure of TT, as determined by the physico-chemical methods, rendering it undetectable by capture ELISA and altering its structural integrity. The changes in TT were directly related to increasing acidity of the vaccine supernate. Purified toxoid (not encapsulated) exposed to low pH (2.5) underwent similar changes but re-neutralisation of buffer containing free toxoid, even after one week at pH 2.5 led to some re-folding of protein as determined by fluorescence spectroscopy and gel filtration chromatography. The microencapsulated vaccines were still able to generate an antibody response in mice even after prolonged pre-incubation at 37 degrees C and the apparent absence of detectable toxoid in the vaccine supernate. Electron microscopy demonstrated differences in the amount of degradation between different formulations of microspheres. Vaccines that had retained their spherical morphology after incubation in vitro for up to 28 days were able to induce protective antibodies response equal to that of freshly prepared vaccines, which indicates that the toxoid within intact microspheres remained immunogenic. Immunochemical and physico-chemical detection methods, performed on antigen released from PLGA vaccines in vitro, are valuable in providing information on product characteristics but may not be able to predict effectiveness and should be used with in vivo methods to evaluate the stability of such formulations.

Effects of simultaneous immunization of Haemophilus influenzae type b conjugate vaccine and diphtheria-tetanus-acellular pertussis vaccine on anti-tetanus potencies in mice, guinea pigs, and rats.

PubMed

Fukuda, Tadashi; Iwaki, Masaaki; Komiya, Takako; Shibayama, Keigo; Takahashi, Motohide; Nakashima, Hideki

2013-01-01

Haemophilus influenzae type b vaccine conjugated with tetanus toxoid (HibT) was licensed for use in childhood immunization in Japan in 2007. As adsorbed diphtheria-tetanus-acellular pertussis (DTaP) combined with HibT vaccine has not been introduced in Japan, DTaP and HibT vaccines are injected at separate sites with a similar immunization schedule. There are various interfering or stimulatory effects between components of combined vaccines contained in DTaP and HibT vaccines. In this study, we investigated the effect of HibT containing combination vaccines on anti-tetanus potencies by using animal models (mouse, guinea pig, and rat). HibT vaccine and HibT components of imported DTaP-HibT vaccine alone showed comparable or higher anti-tetanus potency than DTaP vaccine and DTaP-containing components of combination vaccines. Mixing these components before injection resulted in potencies greater than the sum of individual potencies. Injecting individual components at separate sites in animals resulted in potency roughly equivalent to the sum of the individual potencies. These results provide useful information regarding the use of HibT-containing multivalent vaccines in childhood immunization.

Tdap (tetanus, diphtheria, pertussis) Vaccine and Pregnancy

MedlinePlus

... bacteria that cause tetanus can be found in soil and animal waste. Tetanus gets into a person’s body through an open cut. Diphtheria is a bacterial infection that often starts with a fever and sore throat. A thin layer (called a membrane) can form over the back ...

Lack of significant differences in immunity against diphtheria between populations of Eastern and Western regions of Poland.

PubMed

Chudnicka, Alina; Walory, Jarosław

2003-01-01

Incidents of diphtheria in countries which were formerly part of the Soviet Union (Ukraine, Russia and Belorus) resulted in the need to evaluate thoroughly the effectiveness of preventive vaccination in Poland, especially in the border regions of the country where the biggest migration of population can be observed. The aim of this work was a comparison of the immunity to diphtheria in two geographically different regions of Poland--eastern (Lublin) and western (Zielona Gora) ones. It showed immunoprophylaxis to diphtheria that was implemented on these areas. Diphtheria antitoxin level (IgG) was determined with application of the ELISA method in 1236 (529/707) people. No significant differences were found in the level of antibodies in the groups < 2 years of age and > 19 years of age in people below the protective titre (0.1 IU/ml). The difference occurring in the interval between 2nd and 18th year of life (in western Poland 7.6% and in eastern Poland 16%) may result from different implementation of the vaccination program in these regions (booster doses). Recommendations for vaccination to diphtheria in people over 25 years of age should be implemented especially in the frontier regions of Poland adjoining countries threatened with diphtheria occurrence.

Duration of protective immunity conferred by maternal tetanus toxoid immunization: further evidence from Matlab, Bangladesh.

PubMed Central

Koenig, M A; Roy, N C; McElrath, T; Shahidullah, M; Wojtyniak, B

1998-01-01

OBJECTIVES: Although maternal tetanus immunization has been shown to be highly effective in the prevention of neonatal tetanus, unresolved questions remain concerning the required minimum number of doses and the resulting duration of effective immunity. This study examined the duration of effective immunity against neonatal tetanus provided by maternal tetanus immunization. METHODS: A randomized, double-blind cholera vaccine trial of 41,571 children and nonpregnant adult women carried out in 1974 in the Matlab comparison area of rural Bangladesh provided a unique opportunity to address dose and immunity issues. RESULTS: Children of women who received either 1 or 2 injections of tetanus toxoid experienced 4- to 14-day mortality levels consistently lower than those of children of unimmunized mothers. Analysis of neonatal-tetanus-related mortality showed that 2 injections of tetanus toxoid provided significant protection for subsequent durations of up to 12 or 13 years. CONCLUSIONS: The data demonstrate that a limited-dose regimen of maternal tetanus toxoid provides significant and extended protection against the risk of neonatal tetanus death. PMID:9618617

Acellular pertussis vaccine boosters combined with diphtheria and tetanus toxoid boosters for adolescents: safety and immunogenicity assessment when preceded by different 5-dose DTaP/DTwP schedules.

PubMed

Pichichero, Michael E; Casey, Janet R; Francis, Anne B; Marsocci, Steven M; Murphy, Marie; Hoeger, William; Cleary, Carolyn

2006-09-01

A sixth dose of tetanus, diphtheria, acellular pertussis (Tdap) vaccine in adolescents might produce a differing reactogenicity and/or immunogenicity response depending on the composition of the 5 prior doses of DTaP or DT-whole cell pertussis (DTwP) vaccine. Reactions and immune responses following receipt of the Sanofi Pasteur (Adacel) and GlaxoSmithKline (Boostrix) Tdap vaccines were assessed in 229 adolescents. No differences were observed for reactions to either Tdap vaccine regardless of the prior DTaP/DTwP vaccination history. Seroprotective levels and antibody concentrations were comparable regardless of prior DTaP/DTwP vaccine history. A sixth sequential dose of Tdap after 5 doses of DTaP appears safe and immunogenic.

Preparación toxoide a partir de la fracción hemorrágica del veneno de Bothrops asper (serpiente de América Central y del Sur) (Toxoid preparation from hemorrhagic fraction of the venom from Bothrops asper (snake from Central and South America).

PubMed

Rodríguez-Acosta, A; Aguilar, I; Girón, M E

1993-01-01

A technique is described for preparing a toxoid from the hemorrhagic fraction of the Bothrops asper venom. This method conserves a high degree of immunogenicity although it eliminates lethal effects. None of the animals vaccinated with the toxoid from this fraction had hemorrhagic lesions after they were injected the venom from the hemorrhagic fraction.

Post-marketing safety evaluation of a tetanus toxoid, reduced diphtheria toxoid and 3-component acellular pertussis vaccine administered to a cohort of adolescents in a United States health maintenance organization.

PubMed

Klein, Nicola P; Hansen, John; Lewis, Edwin; Lyon, Liisa; Nguyen, Bessie; Black, Steven; Weston, Wayde M; Wu, Sterling; Li, Ping; Howe, Barbara; Friedland, Leonard R

2010-07-01

Prelicensure clinical studies may not include sufficient numbers of subjects to assess the potential for rare postvaccination adverse events. The aim of this postlicensure study (NCT00297856) was to evaluate uncommon outcomes following vaccination with a tetanus, reduced-antigen-content diphtheria, and acellular pertussis vaccine (Tdap, Boostrix GlaxoSmithKline) in a large adolescent cohort. We monitored safety outcomes among 13,427 10 to 18-year-old adolescents enrolled in the Northern California Kaiser Permanente Health Care Plan who received Tdap vaccination as part of their normal health care. Subjects were evaluated using self-control analysis comparing days 0 to 29 to days 30 to 59 postvaccination for neurologic events, hematologic events and allergic reactions. We evaluated new onset chronic illnesses within 6 months of Tdap vaccination by comparing with historical Td controls matched for age at vaccination, season, sex, and geographic area. We also compared the incidence of events of interest between the Tdap and historical cohorts as exploratory analyses. No increased risk for medically attended neurologic (odds ratio [OR], 0.962; 95% confidence interval [CI], 0.533-1.733) or allergic reactions (OR, 1.091; 95% CI, 0.441-2.729) was observed following Tdap vaccination when comparing the first 30 postvaccination days to the second 30 postvaccination days. There was one hematologic event within 30 days of Tdap, compared with 0 events within days 30 to 59 (P = 1.0). When compared with matched historical Td recipients, no increase in new onset chronic illnesses (OR, 0.634; 95% CI, 0.475-0.840) was seen after Tdap. No deaths occurred in the Tdap cohort during the study. This study provides no evidence for an increased risk for neurologic, hematologic, allergic events, or new onset of chronic illnesses among adolescents vaccinated with Tdap.

Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS®) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio®) given as a booster dose at 6 years of age

PubMed Central

Gajdos, Vincent; Soubeyrand, Benoit; Vidor, Emmanuel; Richard, Patrick; Boyer, Julie; Sadorge, Christine

2011-01-01

This randomized, comparative, phase-IIIb study conducted in France aimed to demonstrate whether seroprotection against diphtheria, tetanus and poliomyelitis 1 month after a single dose of REVAXIS (low-dose diphtheria) is non-inferior to seroprotection 1 month after a single dose of DT Polio (standard-dose diphtheria), both vaccines being given as a second booster to healthy children at 6 years of age. Children were randomly assigned to receive a single intramuscular dose of REVAXIS or DT Polio. Primary endpoints were the 1-month post-booster seroprotection rates for diphtheria, tetanus and poliovirus type-1, -2 and -3 antigens. Secondary endpoints were immunogenicity and safety observations. Of 788 children screened, 760 were randomized: REVAXIS group, 384 children; DT Polio group, 376 children. No relevant difference in demographic characteristics at baseline was observed between REVAXIS and DT Polio groups. Noninferiority of REVAXIS compared with DT Polio for seroprotection was demonstrated against diphtheria (respectively 98.6% and 99.3%), tetanus (respectively 99.6% and 100%) and poliovirus antigens (100% for each types in both groups). No allergic reactions to REVAXIS were reported. A benefit/risk ratio in favor of REVAXIS was suggested by the trend towards a better tolerability of REVAXIS compared with DT Polio regarding the rate of severe solicited injection-site reactions. The results support the use of REVAXIS as a booster at 6 years of age in infants who previously received a three-dose primary series within the first 6 months of life and a first booster including diphtheria, tetanus and poliovirus vaccine(s) given before 2 years of age. PMID:21441781

Molecular Characterization of Corynebacterium diphtheriae Outbreak Isolates, South Africa, March-June 2015.

PubMed

du Plessis, Mignon; Wolter, Nicole; Allam, Mushal; de Gouveia, Linda; Moosa, Fahima; Ntshoe, Genevie; Blumberg, Lucille; Cohen, Cheryl; Smith, Marshagne; Mutevedzi, Portia; Thomas, Juno; Horne, Valentino; Moodley, Prashini; Archary, Moherndran; Mahabeer, Yesholata; Mahomed, Saajida; Kuhn, Warren; Mlisana, Koleka; McCarthy, Kerrigan; von Gottberg, Anne

2017-08-01

In 2015, a cluster of respiratory diphtheria cases was reported from KwaZulu-Natal Province in South Africa. By using whole-genome analysis, we characterized 21 Corynebacterium diphtheriae isolates collected from 20 patients and contacts during the outbreak (1 patient was infected with 2 variants of C. diphtheriae). In addition, we included 1 cutaneous isolate, 2 endocarditis isolates, and 2 archived clinical isolates (ca. 1980) for comparison. Two novel lineages were identified, namely, toxigenic sequence type (ST) ST-378 (n = 17) and nontoxigenic ST-395 (n = 3). One archived isolate and the cutaneous isolate were ST-395, suggesting ongoing circulation of this lineage for >30 years. The absence of preexisting molecular sequence data limits drawing conclusions pertaining to the origin of these strains; however, these findings provide baseline genotypic data for future cases and outbreaks. Neither ST has been reported in any other country; this ST appears to be endemic only in South Africa.

Impaired human responses to tetanus toxoid in vitamin A-deficient SCID mice reconstituted with human peripheral blood lymphocytes.

PubMed Central

Molrine, D C; Polk, D B; Ciamarra, A; Phillips, N; Ambrosino, D M

1995-01-01

Vitamin A deficiency is associated with increased childhood morbidity and mortality from respiratory and diarrheal diseases. In order to evaluate the effect of vitamin A on human antibody responses, we developed a vitamin A-deficient severe combined immunodeficient (SCID) mouse model. Vitamin A-deficient mice were produced by depriving them of vitamin A at day 7 of gestation. Mice were reconstituted with human peripheral blood lymphocytes (huPBL) from tetanus toxoid immune donors at 6 weeks of age and immunized with tetanus toxoid at 6 and 8 weeks of age. Secondary human antibody responses were determined 10 days later. The geometric mean human anti-tetanus toxoid immunoglobulin G concentrations were 3.75 micrograms/ml for the deficient mice and 148 micrograms/ml for controls (P = 0.0005). Vitamin A-deficient mice had only a 2.9-fold increase in human anti-tetanus toxoid antibody compared with a 74-fold increase in controls (P < 0.01). Supplementation with vitamin A prior to reconstitution restored human antibody responses to normal. These data suggest that vitamin A deficiency impairs human antibody responses. We speculate that impaired responses could increase susceptibility to certain infections. Furthermore, we propose that effects of other nutritional deficiencies on the human immune system could be evaluated in the SCID-huPBL model. PMID:7622207

Biodegradable and biocompatible poly(DL-lactide-co-glycolide) microspheres as an adjuvant for staphylococcal enterotoxin B toxoid which enhances the level of toxin-neutralizing antibodies.

PubMed Central

Eldridge, J H; Staas, J K; Meulbroek, J A; Tice, T R; Gilley, R M

1991-01-01

Microspheres composed of biocompatible, biodegradable poly(DL-lactide-co-glycolide) (DL-PLG) and staphylococcal enterotoxin B (SEB) toxoid were evaluated as a vaccine delivery system when subcutaneously injected into mice. As measured by circulating immunoglobulin G (IgG) antitoxin titers, the delivery of SEB toxoid via DL-PLG microspheres, 1 to 10 microns in diameter, induced an immune response which was approximately 500 times that seen with nonencapsulated toxoid. The kinetics, magnitude, and duration of the antitoxin response induced with microencapsulated toxoid were similar to those obtained when an equal toxoid dose was administered as an emulsion with complete Freund adjuvant. However, the microspheres did not induce the inflammation and granulomata formation seen with complete Freund adjuvant. The adjuvant activity of the microspheres was not dependent on the superantigenicity of SEB toxin and was equally effective at potentiating circulating IgG antitrinitrophenyl levels in response to microencapsulated trinitrophenyl-keyhole limpet hemocyanin. Empty DL-PLG microspheres were not mitogenic, and SEB toxoid injected as a mixture with empty DL-PLG microspheres was no more effective as an immunogen than toxoid alone. Antigen-containing microspheres 1 to 10 microns in diameter exhibited stronger adjuvant activity than those greater than 10 microns, which correlated with the delivery of the 1- to 10-microns, but not the greater than 10-microns, microspheres into the draining lymph nodes within macrophages. The antibody response induced through immunization with microencapsulated SEB toxoid was protective against the weight loss and splenic V beta 8+ T-cell expansion induced by intravenous toxin administration. These results show that DL-PLG microsphere vaccine delivery systems, which are composed of pharmaceutically acceptable components, possess a strong adjuvant activity for their encapsulated antigens. PMID:1879922

A combined Haemophilus influenzae type B Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when coadministered with diphtheria, tetanus, acellular pertussis hepatitis B-inactivated poliovirus at 3, 5 and 11 months of age: results of an open, randomized, controlled study.

PubMed

Vesikari, Timo; Forstén, Aino; Desole, Maria Guiseppina; Ferrera, Giuseppe; Caubet, Magalie; Mesaros, Narcisa; Boutriau, Dominique

2013-05-01

This study evaluated the immunogenicity, reactogenicity and safety of the combined Haemophilus influenzae type B Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) coadministered with diphtheria, tetanus, acellular pertussis hepatitis B-inactivated poliovirus (DTPa-HBV-IPV) as 2 primary and 1 booster doses at 3, 5 and 11 months of age. In this phase III open study (NCT00327184), 709 infants were randomized in 2 parallel groups (1:1) to receive either Hib-MenC-TT coadministered with DTPa-HBV-IPV or control vaccines (MenC-TT coadministered with DTPa-HBV-IPV/Hib). Serum bactericidal activity for MenC (rSBA-MenC) and antibody concentrations against polyribosylribitol phosphate from Hib (anti-PRP) and hepatitis B (anti-HBs) were measured at 1 month after dose 2, before booster and 1 month after booster dose. Solicited (local/general) and unsolicited symptoms were assessed up to 4 and 31 days, respectively, after each vaccination. Serious adverse events were recorded throughout the study. One month after dose 2, high percentages of infants in both groups had rSBA-MenC titers ≥ 8 (≥ 99.1%), anti-PRP concentrations ≥ 0.15 μg/mL (≥ 96.5%) and anti-HBs concentrations ≥ 10 mIU/mL (≥ 95.3%), which persisted up to the booster vaccination (≥ 94.5%, ≥ 86.1%, ≥ 94.2%) and increased again after the booster dose (100%, 100%, ≥ 99%). Exploratory analyses indicated that rSBA-MenC geometric mean titers were lower and anti-PRP geometric mean concentrations were higher in the infants vaccinated with Hib-MenC-TT compared with the control vaccines at all time points. The safety profiles of the coadministered vaccines were similar in both groups. The Hib-MenC-TT and DTPa-HBV-IPV vaccines are immunogenic with a clinically acceptable safety profile when coadministered as 2 primary doses during infancy and 1 booster dose at 11 months of age.

Immunoglobulin G (IgG) Subclass Distribution and IgG1 Avidity of Antibodies in Human Immunodeficiency Virus-Infected Individuals after Revaccination with Tetanus Toxoid

PubMed Central

Kroon, F. P.; van Tol, M. J. D.; Jol-van der Zijde, C. M.; van Furth, R.; van Dissel, J. T.

1999-01-01

In human immunodeficiency virus (HIV)-infected individuals the amount of antibodies formed after vaccination with T-cell-dependent recall antigens such as tetanus toxoid is proportional to the peripheral blood CD4+ T-lymphocyte counts. To investigate whether the immunoglobulin G (IgG) subclass distribution and avidity of the antibodies produced after vaccination are affected as well, we gave 13 HIV-infected adults with low CD4+ T-lymphocyte counts (<200 × 106/liter; group I), 11 HIV-infected adults with intermediate CD4+ T-lymphocyte counts (≥200 × 106/liter; group II), and 5 healthy controls booster immunizations with tetanus toxoid. The prevaccination antibody concentrations against tetanus toxoid were similar in the HIV-infected and healthy adults. After vaccination the total IgG and the IgG1 anti-tetanus toxoid antibody concentrations were significantly lower in group I than in group II and the controls. The avidity of the IgG1 anti-tetanus toxoid antibodies formed by HIV-infected adults was within the range for healthy controls, irrespective of their CD4+ T-lymphocyte counts. PMID:10225835

Air conditioning a vaccine laboratory. [Connaught Medical Research Laboratory, Toronto, Canada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ross J.

1976-05-01

In 1974, the new Bacterial Vaccine Building of Connaught Medical Research Laboratories, Toronto, Canada, was opened to produce such vaccines as pertussis, typhoid, paratyphoids, and cholera and such toxoids as staphylococcus, diphtheria, and tetanus. It also produces other medicinal products. The layout of the complex and the air conditioning system necessary in all zones are described and schematically shown. (MCW)

Comparative Immunogenicity of the Tetanus Toxoid and Recombinant Tetanus Vaccines in Mice, Rats, and Cynomolgus Monkeys.

PubMed

Yu, Rui; Fang, Ting; Liu, Shuling; Song, Xiaohong; Yu, Changming; Li, Jianmin; Fu, Ling; Hou, Lihua; Xu, Junjie; Chen, Wei

2016-06-25

Tetanus is caused by the tetanus neurotoxin (TeNT) and is one of the most dreaded diseases especially in the developing countries. The current vaccine against tetanus is based on an inactivated tetanus toxin, which is effective but has many drawbacks. In our previous study, we developed a recombinant tetanus vaccine based on protein TeNT-Hc, with clear advantages over the toxoid vaccine in terms of production, characterization, and homogeneity. In this study, the titers, growth extinction, and persistence of specific antibodies induced by the two types of vaccine in mice, rats, and cynomolgus monkeys were compared. The booster vaccination efficacy of the two types of vaccines at different time points and protection mechanism in animals were also compared. The recombinant tetanus vaccine induced persistent and better antibody titers and strengthened the immunity compared with the commercially available toxoid vaccine in animals. Our results provide a theoretical basis for the development of a safe and effective recombinant tetanus vaccine to enhance the immunity of adolescents and adults as a substitute for the current toxoid vaccine.

Comparative Immunogenicity of the Tetanus Toxoid and Recombinant Tetanus Vaccines in Mice, Rats, and Cynomolgus Monkeys

PubMed Central

Yu, Rui; Fang, Ting; Liu, Shuling; Song, Xiaohong; Yu, Changming; Li, Jianmin; Fu, Ling; Hou, Lihua; Xu, Junjie; Chen, Wei

2016-01-01

Tetanus is caused by the tetanus neurotoxin (TeNT) and is one of the most dreaded diseases especially in the developing countries. The current vaccine against tetanus is based on an inactivated tetanus toxin, which is effective but has many drawbacks. In our previous study, we developed a recombinant tetanus vaccine based on protein TeNT-Hc, with clear advantages over the toxoid vaccine in terms of production, characterization, and homogeneity. In this study, the titers, growth extinction, and persistence of specific antibodies induced by the two types of vaccine in mice, rats, and cynomolgus monkeys were compared. The booster vaccination efficacy of the two types of vaccines at different time points and protection mechanism in animals were also compared. The recombinant tetanus vaccine induced persistent and better antibody titers and strengthened the immunity compared with the commercially available toxoid vaccine in animals. Our results provide a theoretical basis for the development of a safe and effective recombinant tetanus vaccine to enhance the immunity of adolescents and adults as a substitute for the current toxoid vaccine. PMID:27348002

Induction of diphtheria toxin-resistant mutants in human cells by ultraviolet light

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rocchi, P.; Ferreri, A.M.; Capucci, A.

1981-01-01

Stable spontaneous mutants resistant to the protein synthesis inhibitor diphtheria toxin (DT) have been selected in human cell line EUE at a very low frequency (less than 8 x 10(-6)). U.v.-induced mutation has been quantitatively measured: treatment of cells with u.v. light increased the frequencies of diphtheria toxin resistant (DTr) mutants up to 1000-fold. The maximum recovery of DTr mutants was observed after a short expression period, for all u.v. doses tested, and was followed by a decrease in mutation frequency on subsequent passages.

Induction of diphtheria toxin-resistant mutants in human cells by ultraviolet light

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rocchi, P.; Ferreri, A.M.; Capucci, A.

1981-01-01

Stable spontaneous mutants resistant to the protein synthesis inhibitor diphtheria toxin (DT) have been selected in human cell line EUE at a very low frequency (< 8 x 10/sup -6/). U.v.-induced mutation has been quantitatively measured: treatment of cells with u.v. light increased the frequencies of diphtheria toxin resistant (DTsup(r)) mutants up to 1000-fold. The maximum recovery of DTsup(r) mutants was observed after a short expression period, for all u.v. doses tested, and was followed by a decrease in mutation frequency on subsequent passages.

Diphtheria Antibodies and T lymphocyte Counts in Patients Infected With HIV-1.

PubMed

Speranza, Francisco A B; Ishii, Solange K; Thuler, Luiz C S; Damasco, Paulo V; Hirata, Raphael; Mattos-Guaraldi, Ana L; Milagres, Lucimar G

2012-07-01

We assessed the IgG levels anti-diphtheria (D-Ab) and T cell counts (CD4+ and CD8+) in HIV-1 infected subjects undergoing or not highly active antiretroviral therapy (HAART). Approximately 70% of all HIV-1 patients were unprotected against diphtheria. There were no differences in D-Ab according to CD4 counts. Untreated patients had higher D-Ab (geometric mean of 0.62 IU/ml) than HAART-patients (geometric mean of 0.39 IU/ml). The data indicated the necessity of keeping all HIV-1 patients up-to-date with their vaccination.

THE PRODUCTION OF DIPHTHERIA TOXIN

PubMed Central

Park, W. H.; Williams, A. W.

1896-01-01

Toxin of sufficient strength to kill a 400-gramme guinea-pig in three days and a half in a dose of 0·cubic centimetre developed in suitable bouillon, contained in ordinary Erlenmeyer flasks, within a period of twenty-four hours. In such boullon the toxin reached its greatest strength in from four to seven days (0·005 cubic centimetre killing a 500-gramme guinea-pig in three days). This period of time covered that of the greatest growth of the bacilli, as shown both by the appearance of the culture and by the number of colonies developing an agar plates. The bodies of the diphtheria bacili did not at any time contain toxin in cosiderable amounts. The type of growth of the bacili and the rapidity and extent of the production of toxin depended more on the reaction of the bouillon than upon any other single factor. The best results were obtained in bouillon which, after being neutralized to litmus, had about seven cubic centimetres of normal soda solution added to each litre. An excessive amount of either acid or alkali prevented the development of toxin. Strong toxin was produced in bouillon containing peptone ranging from one to ten per cent. The strength of toxin averaged greater in the two and four-per-cent peptone solutions than in the one-percent. When the stage of acid reaction was brief and the degree of acidity probably slight, strong toxin developed while the culture bouillon was still acid; but when the stage of acid reaction was prolonged, little if any toxin was produced until just before the fluid became alkaline. Glucose is deleterious to the growth of the diphtheria bacillus and to the production of toxin when it is present in sufficient amounts to cause by its disintegration too great a degree of acidity in the fluid culture. When the acid resulting from decomposition of glucose is neutralized by the addition of alkali the diphtheria bacilus again grows abundantly. Glucose is not present, at least as a rule, in sufficient amounts in the meat as

Your Child's Immunizations: Diphtheria, Tetanus & Pertussis Vaccine (DTaP)

MedlinePlus

... Safe Videos for Educators Search English Español Your Child's Immunizations: Diphtheria, Tetanus & Pertussis Vaccine (DTaP) KidsHealth / For ... child outweigh the potential risks. Caring for Your Child After DTaP Immunization Your child may have a ...

Mutant with diphtheria toxin receptor and acidification function but defective in entry of toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kohno, Kenji; Hayes, H.; Mekada, Eisuke

1987-09-01

A mutant of Chinese hamster ovary cells, GE1, that is highly resistant to diphtheria toxin was isolated. The mutant contains 50% ADP-ribosylatable elongation factor 2, but its protein synthesis was not inhibited by the toxin even at concentrations above 100 {mu}g/ml. {sup 125}I-labeled diphtheria toxin was associated with GE1 cells as well as with the parent cells but did not block protein synthesis of GE1 cells even when the cells were exposed to low pH in the presence or absence of NH{sub 4}Cl. The infections of GE1 cells and the parent cells by vesicular stomatitis virus were similar. GE1 cellsmore » were cross-resistant to Pseudomonas aeruginosa exotoxin A and so were about 1,000 times more resistant to this toxin than the parent cells. Hybrids of GE1 cells and the parent cells or mutant cells lacking a functional receptor were more sensitive to diphtheria toxin than GE1 cells. These results suggest that entry of diphtheria toxin into cells requires a cellular factor(s) in addition to those involved in receptor function and acidification of endosomes and that GE1 cells do not express this cellular factor. This character is recessive in GE1 cells.« less

Safety and immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus influenzae Type b combination vaccine compared with separate administration of licensed equivalent vaccines in Chinese infants and toddlers for primary and booster immunization.

PubMed

Li, Guifan; Zhang, Huajie; Zhou, Weizhong; Ye, Qiang; Li, Fengxiang; Wang, Hua; Hou, Qiming; Xu, Yinghua; Ma, Xiao; Tan, Yajun; Wang, Lichan; Li, Yanan; Li, Hong; Meng, Fanyue; Liang, Qi; Liu, Aimin; Qin, Chengkui; Wei, Wenjin; Liu, Jiankai; Ruan, Chengmai; Tao, Wenjian; Zhang, Shumin; Zheng, Haifa; Zhu, Fengcai

2010-06-07

To evaluate the safety and immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus infuenzae Type b (DTaP/Hib) combination vaccine first developed by a Chinese manufacturer, a randomized, two-stage, parallel controlled, single center clinical trial was conducted in Dafeng, Jiangsu Province of China. A total of 720 infants were enrolled and randomly assigned to two groups with a 2:1 allocation. In Stage I, 480 subjects in Group T were administered with 3 doses of the DTaP/Hib vaccine at 3, 4 and 5 months of age, respectively, while 240 subjects in Group C received separate licensed DTaP vaccine and Hib conjugate vaccine on the same schedule. In Stage II, 633 primed toddlers (431 of Group T and 202 of Group C) were given a booster dose at 18 months of age. Sera samples were collected at pre-dose 1, 4 weeks post-dose 3, pre-dose 4 and 4 weeks post-dose 4, respectively. Levels of protective antibodies were measured by Enzyme Linked Immunoadsorbent Assay (ELISA). Immunogenicity was evaluated with regard to geometric mean concentrations (GMCs), seroconversion rates and seroprotection rates of the antibodies. Solicited adverse reactions were recorded for 3 days after each dose; unsolicited adverse events and serious adverse events were monitored for 28 days after vaccination. Results showed that seroconversion rates of anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-diphtheria toxoid (DT), anti-tetanus toxid (TT) and anti-polyribosyl-ribitol-phosphate (PRP) in Group T (Stage I: 98.06%, 97.33%, 100%, 100%, 98.79%; Stage II: 99.18%, 83.42%, 99.18%, 63.32%, 85.05%) were comparable to that of Group C (Stage I: 95.26%, 93.16%, 100%, 100%, 98.42%; Stage II: 98.89%, 83.89%, 98.33%, 53.89%, 76.67%). Nearly 100% of the subjects in both groups achieved seroprotective levels of anti-DT (> or = 0.1IU/ml), anti-TT (> or = 0.1IU/ml) and anti-PRP (> or = 0.15 microg/ml) after primary and booster vaccination. The frequencies of local induration

Quantification of diphtheria toxin mediated ADP-ribosylation in a solid-phase assay.

PubMed

Bachran, Christopher; Sutherland, Mark; Bachran, Diana; Fuchs, Hendrik

2007-09-01

Because of reduced vaccination programs, the number of diphtheria infections has increased in the last decade. Diphtheria toxin (DT) is expressed by Corynebacterium diphtheriae and is responsible for the lethality of diphtheria. DT inhibits cellular protein synthesis by ADP-ribosylation of the eukaryotic elongation factor 2 (eEF2). No in vitro system for the quantification of DT enzymatic activity exists. We developed a solid-phase assay for the specific detection of ADP-ribosylation by DT. Solid phase-bound his-tag eEF2 is ADP-ribosylated by toxins using biotinylated NAD(+) as substrate, and the transferred biotinylated ADP-ribose is detected by streptavidin-peroxidase. DT enzymatic activity correlated with absorbance. We measured the amount of ADP-ribosylated eEF2 after precipitation with streptavidin-Sepharose. Quantification was done after Western blotting and detection with anti-his-tag antibody using an LAS-1000 System. The assay detected enzymatically active DT at 30 ng/L, equivalent to 5 mU/L ADP-ribosylating activity. Pseudomonas exotoxin A (PE) activity was also detected at 100 ng/L. We verified the assay with chimeric toxins composed of the catalytic domain of DT or PE and a tumor-specific ligand. These chimeric toxins revealed increased signals at 1000 ng/L. Heat-inactivated DT and cholera toxin that ADP-ribosylates G-proteins did not show any signal increase. The assay may be the basis for the development of a routine diagnostic assay for the detection of DT activity and highly specific inhibitors of DT.

Diphtheria Antibodies and T lymphocyte Counts in Patients Infected With HIV-1

PubMed Central

Speranza, Francisco A. B.; Ishii, Solange K.; Thuler, Luiz C. S.; Damasco, Paulo V.; Jr, Raphael Hirata; Mattos-Guaraldi, Ana L.; Milagres, Lucimar G.

2012-01-01

We assessed the IgG levels anti-diphtheria (D-Ab) and T cell counts (CD4+ and CD8+) in HIV-1 infected subjects undergoing or not highly active antiretroviral therapy (HAART). Approximately 70% of all HIV-1 patients were unprotected against diphtheria. There were no differences in D-Ab according to CD4 counts. Untreated patients had higher D-Ab (geometric mean of 0.62 IU/ml) than HAART-patients (geometric mean of 0.39 IU/ml). The data indicated the necessity of keeping all HIV-1 patients up-to-date with their vaccination. PMID:24031911

Enterotoxigenic Escherichia coli heat-stable toxin and heat-labile toxin toxoid fusion 3xSTaN12S-dmLT induces neutralizing anti-STa antibodies in subcutaneously immunized mice.

PubMed

Nandre, Rahul; Ruan, Xiaosai; Duan, Qiangde; Zhang, Weiping

2016-11-02

Enterotoxigenic Escherichia coli (ETEC) bacteria producing heat-stable toxin (STa) and/or heat-labile toxin (LT) are among top causes of children's diarrhea and travelers' diarrhea. Currently no vaccines are available for ETEC associated diarrhea. A major challenge in developing ETEC vaccines is the inability to stimulate protective antibodies against the key STa toxin which is potently toxic and also poorly immunogenic. A recent study suggested toxoid fusion 3xSTa N12S -dmLT, which consists of a monomer LT toxoid (LT R192G/L211A ) and three copies of STa toxoid STa N12S , may represent an optimal immunogen inducing neutralizing antibodies against STa toxin [IAI 2014, 82(5):1823-32]. In this study, we immunized mice with this fusion protein following a different parenteral route and using different adjuvants to further characterize immunogenicity of this toxoid fusion. Data from this study showed that 3xSTa N12S -dmLT toxoid fusion induced neutralizing anti-STa antibodies in the mice following subcutaneous immunization, as effectively as in the mice under intraperitoneal route. Data also indicated that double mutant LT (dmLT) can be an effective adjuvant for this toxoid fusion in mice subcutaneous immunization. Results from this study affirmed that toxoid fusion 3xSTa N12S -dmLT induces neutralizing antibodies against STa toxin, suggesting this toxoid fusion is potentially a promising immunogen for ETEC vaccine development. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Interaction of Drugs, Biologics, and Chemicals in U.S. Military Forces: Current and Future Issues.

DTIC Science & Technology

1996-12-01

receive the following on entering ac- tive duty: "* poliovirus vaccine, live oral trivalent type 1, 2, and 3; "* measles and rubella virus vaccine live or...selected individuals. Reserve component personnel usually receive oral poliovirus vaccine, diphtheria-tetanus toxoid, and influenza virus vaccines... reproductive toxicity, neurotoxicity, and carcinogenicity). However, to conserve resources and as a starting point, the committee sug- gests the following

Diphtheria toxin IgG levels in military and civilian blood donors in Rio de Janeiro, Brazil.

PubMed

Speranza, F A B; Ishii, S K; Hirata, R; Mattos-Guaraldi, A L; Milagres, L G

2010-01-01

Serologic data on diseases that are preventable by vaccines are necessary to evaluate the success of immunization programs and to identify susceptible subgroups. In the present study, we determined serum IgG levels against diphtheria toxin of military and civilian blood donors (N = 75; 69.3% males and 30.7% females) aged 18-64 years, from the Brazilian Army Biology Institute, Rio de Janeiro, using a commercial diphtheria kit (Diphtheria IgG ELISA; IBL, Germany). Most (63%) unprotected military donors were from the older age group of 41 to 64 years. In contrast, the majority (71%) of young military donors (18 to 30 years) were fully protected. About half of the military donors aged 31 to 40 years were protected against diphtheria. Among the civilians, about 50% of persons aged 18 to 30 years and 31 to 40 years had protective antibody levels against diphtheria as also did 64% of individuals aged 41 to 64 years. All civilians had a similar antibody response (geometric mean = 0.55 IU/mL) independent of age group. Military donors aged 18-30 years had higher IgG levels (geometric mean = 0.82 IU/mL) than military donors of 41-64 years (geometric mean = 0.51 IU/mL; P > 0.05). In conclusion, the existence of a considerable proportion of susceptible adults supports the position that reliable data on the immune status of the population should be maintained routinely and emphasizes the importance of adequate immunization during adulthood.

Tetanus toxoid vaccination coverage and differential between urban and rural areas of Bangladesh.

PubMed

Rahman, Mosiur

2009-04-01

Government commitment and support from a range of partnerships have led to a massive increase in tetanus toxoid immunization coverage among women of childbearing age, ensuring that both mothers and babies are protected against tetanus infection in Bangladesh. In order to control and eliminate the vaccine preventable diseases it is important to know the vaccination coverage. The major objective of this study is to determine the complete vaccination rate and the predictors that influence vaccination of mothers during pregnancy and to see whether there is any gap lies between the women of urban and rural areas regarding the tetanus toxoid injection receiving. This study utilizes the data extracted from Bangladesh Demographic and Health Survey 2004 (BDHS).To meets the objectives this study considers bivariate and multivariate analysis. The study represents that 88 per cent urban mothers and 84 per cent rural mothers receive tetanus toxoid injection during their pregnancy period. Logistic regression model is adjusted by wealth index, mother's age at last birth, education, husband's occupation, ever using contraception, fertility preference, wanted last child, having permission to go to hospital/health center, telling about pregnancy complications and mass media exposure for receiving TT injection. All these explanatory variables come out to be as significant determinants of receiving TT injection for all mothers as well as for rural mothers in Bangladesh. On the other hand ever using contraception, wanted last child, telling about pregnancy complications, mass media exposure and wealth index are the significant determinants of receiving TT injection for mothers of urban area.

Do unsafe tetanus toxoid injections play a significant role in the transmission of HIV/AIDS? Evidence from seven African countries.

PubMed

de Walque, D

2008-04-01

Although sexual transmission is generally considered to be the main factor driving the HIV/AIDS epidemic in Africa, recent studies have claimed that iatrogenic transmission should be considered as an important source of HIV infection. In particular, receipt of tetanus toxoid injections during pregnancy has been reported to be associated with HIV infection in Kenya. The objective of this paper is to assess the robustness of this association among women in nationally representative HIV surveys in seven African countries. The association between prophylactic tetanus toxoid injections during pregnancy and HIV infection was analysed, using individual-level data from women who gave birth in the past five years. These data are from the nationally representative Demographic and Health Surveys, which included HIV testing in seven African countries: Burkina Faso 2003 (N = 2424), Cameroon 2004 (N = 2600), Ethiopia 2005 (N = 2886), Ghana 2003 (N = 2560), Kenya 2003 (N = 1617), Lesotho 2004 (N = 1278) and Senegal 2005 (N = 2126). Once the odds ratios (OR) were adjusted for five-year age groups and for ethnic, urban and regional indicators, the association between prophylactic tetanus toxoid injections during pregnancy and HIV infection was never statistically significant in any of the seven countries. Only in Cameroon was there an association between previous tetanus toxoid injection and HIV positivity but it became weaker (OR 1.53, 95% CI 0.91 to 2.57) once urban location and ethnic group were adjusted for. Although the risk of HIV infection through unsafe injections and healthcare should not be ignored and should be reduced, it does not seem that there is, at present and in the seven countries studied, strong evidence supporting the claim that unsafe tetanus toxoid injections are a major factor driving the HIV epidemic.

Long-Term Protection against Diphtheria in the Netherlands after 50 Years of Vaccination: Results from a Seroepidemiological Study

PubMed Central

Swart, E. M.; van Gageldonk, P. G. M.; de Melker, H. E.; van der Klis, F. R.; Berbers, G. A. M.; Mollema, L.

2016-01-01

Background and Aims To evaluate the National Immunisation Programme (NIP) a population-based cross-sectional seroepidemiological study was performed in the Netherlands. We assessed diphtheria antitoxin levels in the general Dutch population and in low vaccination coverage (LVC) areas where a relatively high proportion of orthodox Protestants live who decline vaccination based on religious grounds. Results were compared with a nationwide seroepidemiological study performed 11 years earlier. Methods In 2006/2007 a national serum bank was established. Blood samples were tested for diphtheria antitoxin IgG concentrations using a multiplex immunoassay for 6383 participants from the national sample (NS) and 1518 participants from LVC municipalities. A cut-off above 0.01 international units per ml (IU/ml) was used as minimum protective level. Results In the NS 91% of the population had antibody levels above 0.01 IU/ml compared to 88% in the 1995/1996 serosurvey (p<0.05). On average, 82% (vs. 78% in the 1995/1996 serosurvey, p<0.05) of individuals from the NS born before introduction of diphtheria vaccination in the NIP and 46% (vs. 37% in the 1995/1996 serosurvey, p = 0.11) of orthodox Protestants living in LVC areas had antibody levels above 0.01 IU/ml. Linear regression analysis among fully immunized individuals (six vaccinations) without evidence of revaccination indicated a continuous decline in antibodies in both serosurveys, but geometric mean antibodies remained well above 0.01 IU/ml in all age groups. Conclusions The NIP provides long-term protection against diphtheria, although antibody levels decline after vaccination. As a result of natural waning immunity, a substantial proportion of individuals born before introduction of diphtheria vaccination in the NIP lack adequate levels of diphtheria antibodies. Susceptibility due to lack of vaccination is highest among strictly orthodox Protestants. The potential risk of spread of diphtheria within the geographically

Vaccination Coverage Disparities Between Foreign-Born and U.S.-Born Children Aged 19-35 Months, United States, 2010-2012.

PubMed

Varan, Aiden K; Rodriguez-Lainz, Alfonso; Hill, Holly A; Elam-Evans, Laurie D; Yankey, David; Li, Qian

2017-08-01

Healthy People 2020 targets high vaccination coverage among children. Although reductions in coverage disparities by race/ethnicity have been described, data by nativity are limited. The National Immunization Survey is a random-digit-dialed telephone survey that estimates vaccination coverage among U.S. children aged 19-35 months. We assessed coverage among 52,441 children from pooled 2010-2012 data for individual vaccines and the combined 4:3:1:3*:3:1:4 series (which includes ≥4 doses of diphtheria, tetanus, and acellular pertussis vaccine/diphtheria and tetanus toxoids vaccine/diphtheria, tetanus toxoids, and pertussis vaccine, ≥3 doses of poliovirus vaccine, ≥1 dose of measles-containing vaccine, ≥3 or ≥4 doses of Haemophilus influenzae type b vaccine (depending on product type of vaccine; denoted as 3* in the series name), ≥3 doses of hepatitis B vaccine, ≥1 dose of varicella vaccine, and ≥4 doses of pneumococcal conjugate vaccine). Coverage estimates controlling for sociodemographic factors and multivariable logistic regression modeling for 4:3:1:3*:3:1:4 series completion are presented. Significantly lower coverage among foreign-born children was detected for DTaP, hepatitis A, hepatitis B, Hib, pneumococcal conjugate, and rotavirus vaccines, and for the combined series. Series completion disparities persisted after control for demographic, access-to-care, poverty, and language effects. Substantial and potentially widening disparities in vaccination coverage exist among foreign-born children. Improved immunization strategies targeting this population and continued vaccination coverage monitoring by nativity are needed.

A case of respiratory toxigenic diphtheria: contact tracing results and considerations following a 30-year disease-free interval, Catalonia, Spain, 2015.

PubMed

Jané, Mireia; Vidal, Maria José; Camps, Neus; Campins, Magda; Martínez, Ana; Balcells, Joan; Martin-Gomez, Maria Teresa; Bassets, Gloria; Herrera-León, Silvia; Foguet, Anton; Maresma, Mar; Follia, Nuria; Uriona, Sonia; Pumarola, Tomàs

2018-03-01

In May 2015, following a 30-year diphtheria-free interval in Catalonia, an unvaccinated 6-year-old child was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae . After a difficult search for equine-derived diphtheria antitoxin (DAT), the child received the DAT 4 days later but died at the end of June. Two hundred and seventeen contacts were identified in relation to the index case, and their vaccination statuses were analysed, updated and completed. Of these, 140 contacts underwent physical examination and throat swabs were taken from them for analysis. Results were positive for toxigenic C. diphtheriae in 10 contacts; nine were asymptomatic vaccinated children who had been in contact with the index case and one was a parent of one of the nine children. Active surveillance of the 217 contacts was initiated by healthcare workers from hospitals and primary healthcare centres, together with public health epidemiological support. Lack of availability of DAT was an issue in our case. Such lack could be circumvented by the implementation of an international fast-track procedure to obtain it in a timely manner. Maintaining primary vaccination coverage for children and increasing booster-dose immunisation against diphtheria in the adult population is of key importance.

A case of respiratory toxigenic diphtheria: contact tracing results and considerations following a 30-year disease-free interval, Catalonia, Spain, 2015

PubMed Central

Jané, Mireia; Vidal, Maria José; Camps, Neus; Campins, Magda; Martínez, Ana; Balcells, Joan; Martin-Gomez, Maria Teresa; Bassets, Gloria; Herrera-León, Silvia; Foguet, Anton; Maresma, Mar; Follia, Nuria; Uriona, Sonia; Pumarola, Tomàs

2018-01-01

In May 2015, following a 30-year diphtheria-free interval in Catalonia, an unvaccinated 6-year-old child was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae. After a difficult search for equine-derived diphtheria antitoxin (DAT), the child received the DAT 4 days later but died at the end of June. Two hundred and seventeen contacts were identified in relation to the index case, and their vaccination statuses were analysed, updated and completed. Of these, 140 contacts underwent physical examination and throat swabs were taken from them for analysis. Results were positive for toxigenic C. diphtheriae in 10 contacts; nine were asymptomatic vaccinated children who had been in contact with the index case and one was a parent of one of the nine children. Active surveillance of the 217 contacts was initiated by healthcare workers from hospitals and primary healthcare centres, together with public health epidemiological support. Lack of availability of DAT was an issue in our case. Such lack could be circumvented by the implementation of an international fast-track procedure to obtain it in a timely manner. Maintaining primary vaccination coverage for children and increasing booster-dose immunisation against diphtheria in the adult population is of key importance. PMID:29616610

Immune response to pneumococcus and tetanus toxoid in patients with moderate-to-severe psoriasis following long-term ustekinumab use.

PubMed

Brodmerkel, Carrie; Wadman, Eric; Langley, Richard G; Papp, Kim A A; Bourcier, Marc; Poulin, Yves; Ho, Vincent; Guenther, Lyn; Kunynetz, Rod; Nigen, Simon; Vender, Ronald; Wasel, Norman; Hsu, Ming-Chun; Szapary, Philippe

2013-10-01

Little is known about the impact of long-term use of immunosuppressive agents on immune response. Assess the impact of continuous maintenance ustekinumab treatment on patients' ability to mount immune responses to pneumococcal (T-cell-independent) and tetanus toxoid (T-cell-dependent) vaccines. Ustekinumab-treated patients with moderate-to-severe psoriasis treated in the long-term extension of the Phase 3 PHOENIX 2 trial (n=60) were compared with control psoriasis patients not receiving systemic therapy (n=56). Patients were vaccinated with both 23-valent pneumococcal and tetanus toxoid vaccines. Serum samples collected pre-vaccination and 4 weeks post-vaccination were assessed for antibody responses. No differences in the ability of ustekinumab-treated patients to respond to pneumococcal or tetanus toxoid vaccinations were observed compared with controls. A ≥2-fold increase in antibody levels in ≥7 of 14 serotypes of the pneumococcal vaccine was observed in ustekinumab-treated (96.6%) and untreated control (92.6%) patients following vaccination. Ustekinumab-treated patients achieved a ≥4-fold increase (84.7%) in anti-tetanus antibody vs. 77.8% in the control group. No differences were detected in ex-vivo responses to anti-CD3/CD28 or tetanus toxoid between ustekinumab-treated and control groups. Long-term treatment (≥3 years) with ustekinumab does not compromise the immune response to T-cell-dependent/-independent vaccines in patients with moderate-to-severe psoriasis.

The problem of the periodicity of the epidemic process. [solar activity effects on diphtheria outbreak

NASA Technical Reports Server (NTRS)

Yagodinskiy, V. N.; Konovalenko, Z. P.; Druzhinin, I. P.

1974-01-01

An analysis of data from epidemics makes it possible to determine their principal causes, governed by environmental factors (solar activity, etc.) The results of an analysis of the periodicity of the epidemic process in the case of diphtheria are presented which was conducted with the aid of autocorrelation and spectral methods of analysis. Numerical data (annual figures) are used on the dynamics of diphtheria in 50 regions (points) with a total duration of 2,777 years.

The Druggable Pocketome of Corynebacterium diphtheriae: A New Approach for in silico Putative Druggable Targets

PubMed Central

Hassan, Syed S.; Jamal, Syed B.; Radusky, Leandro G.; Tiwari, Sandeep; Ullah, Asad; Ali, Javed; Behramand; de Carvalho, Paulo V. S. D.; Shams, Rida; Khan, Sabir; Figueiredo, Henrique C. P.; Barh, Debmalya; Ghosh, Preetam; Silva, Artur; Baumbach, Jan; Röttger, Richard; Turjanski, Adrián G.; Azevedo, Vasco A. C.

2018-01-01

Diphtheria is an acute and highly infectious disease, previously regarded as endemic in nature but vaccine-preventable, is caused by Corynebacterium diphtheriae (Cd). In this work, we used an in silico approach along the 13 complete genome sequences of C. diphtheriae followed by a computational assessment of structural information of the binding sites to characterize the “pocketome druggability.” To this end, we first computed the “modelome” (3D structures of a complete genome) of a randomly selected reference strain Cd NCTC13129; that had 13,763 open reading frames (ORFs) and resulted in 1,253 (∼9%) structure models. The amino acid sequences of these modeled structures were compared with the remaining 12 genomes and consequently, 438 conserved protein sequences were obtained. The RCSB-PDB database was consulted to check the template structures for these conserved proteins and as a result, 401 adequate 3D models were obtained. We subsequently predicted the protein pockets for the obtained set of models and kept only the conserved pockets that had highly druggable (HD) values (137 across all strains). Later, an off-target host homology analyses was performed considering the human proteome using NCBI database. Furthermore, the gene essentiality analysis was carried out that gave a final set of 10-conserved targets possessing highly druggable protein pockets. To check the target identification robustness of the pipeline used in this work, we crosschecked the final target list with another in-house target identification approach for C. diphtheriae thereby obtaining three common targets, these were; hisE-phosphoribosyl-ATP pyrophosphatase, glpX-fructose 1,6-bisphosphatase II, and rpsH-30S ribosomal protein S8. Our predicted results suggest that the in silico approach used could potentially aid in experimental polypharmacological target determination in C. diphtheriae and other pathogens, thereby, might complement the existing and new drug-discovery pipelines

[New Swiss recommendations for adult boosters against pertussis, tetanus and diphtheria].

PubMed

Siegrist, C-A

2012-01-18

Pertussis remains frequent in Switzerland (4000 yearly cases), where 80% of infants are infected by their family. To better protect parents and infants, a diphtheria-tetanus-pertussis (dTpa) booster is thus recommended at 25 years (catch-up 26-29 years), and to adults of any age in personal or professional contacts with infants < or = 6 months. In contrast, diphtheria-tetanus boosters may be spaced every 20 years (dTpa at 25, dT at 45 and 65 years), avoiding useless immunizations. A 10-year interval remains recommended after the age of 65. The Swiss immunization plan thus adapts to recent evidence, to the risk of pushing the habits! Fortunately, a Swiss electronic immunization record allowing a vaccine check (www.myvaccines.ch) is now available for free to both the public and the professio-

Possible alternative to European Pharmacopoeia's method of analysis Test for Fc Function of Immunoglobulin (2.7.9) by using tetanus toxoid as antigen.

PubMed

Perez-del-Pulgar, S; Lopez, M; Gensana, M; Jorquera, J I

2006-08-01

Preparations of intravenous immunoglobulins must keep functional integrity throughout the purification process. In order to assess Fc fragment functionality, the European Pharmacopoeia proposes the Test for Fc function of immunoglobulin (2.7.9), which is based on a rubella antigen of high titre. Sometimes, such antigen is difficult to obtain. In the present study, we develop the same assay using tetanus toxoid instead of rubella antigen, adapting the procedure for the use of tetanus toxoid. The comparison between rubella-based and tetanus-based assays showed that the slopes of the haemolysis curves were higher if red blood cells had been sensitised with the rubella antigen than with tetanus toxoid. Nonetheless, the tetanus-based assay gave satisfactory results and it could be a good alternative antigen target.

The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages.

PubMed

Guo, Jian-Kan; Shi, Hongmei; Koraishy, Farrukh; Marlier, Arnaud; Ding, Zhaowei; Shan, Alan; Cantley, Lloyd G

2013-11-01

Biomedical research often requires primary cultures of specific cell types, which are challenging to obtain at high purity in a reproducible manner. Here we engineered the murine Rosa26 locus by introducing the diphtheria toxin receptor flanked by loxP sites. The resultant strain was nicknamed the Terminator mouse. This approach results in diphtheria toxin-receptor expression in all non-Cre expressing cell types, making these cells susceptible to diphtheria toxin exposure. In primary cultures of kidney cells derived from the Terminator mouse, over 99.99% of cells were dead within 72 h of diphtheria toxin treatment. After crossing the Terminator with the podocin-Cre (podocyte specific) mouse or the Ggt-Cre (proximal tubule specific) mouse, diphtheria toxin treatment killed non-Cre expressing cells but spared podocytes and proximal tubule cells, respectively, enriching the primary cultures to over 99% purity, based on both western blotting and immunostaining of marker proteins. Thus, the Terminator mouse can be a useful tool to selectively and reproducibly obtain even low-abundant cell types at high quantity and purity.

Synthesis of antifungal vaccines by conjugation of β-1,2 trimannosides with T-cell peptides and covalent anchoring of neoglycopeptide to tetanus toxoid.

PubMed

Cartmell, Jonathan; Paszkiewicz, Eugenia; Dziadek, Sebastian; Tam, Pui-Hang; Luu, Thanh; Sarkar, Susmita; Lipinski, Tomasz; Bundle, David R

2015-02-11

Selective strategies for the construction of novel three component glycoconjugate vaccines presenting Candida albicans cell wall glycan (β-1,2 mannoside) and polypeptide fragments on a tetanus toxoid carrier are described. The first of two conjugation strategies employed peptides bearing an N-terminal thiopropionyl residue for conjugation to a trisaccharide equipped with an acrylate linker and a C-terminal S-acetyl thioglycolyl moiety for subsequent linking of neoglycopeptide to bromoacetylated tetanus toxoid. Michael addition of acrylate trisaccharides to peptide thiol under mildly basic conditions gave a mixture of N- and C- terminal glyco-peptide thioethers. An adaptation of this strategy coordinated S-acyl protection with anticipated thioester exchange equilibria. This furnished a single chemically defined fully synthetic neoglycopeptide conjugate that could be anchored to a tetanus toxoid carrier and avoids the introduction of exogenous antigenic groups. The second strategy retained the N-terminal thiopropionyl residue but replaced the C-terminal S-acetate functionality with an azido group that allowed efficient, selective formation of neoglycopeptide thioethers and subsequent conjugation of these with propargylated tetanus toxoid, but introduced potentially antigenic triazole linkages. Copyright © 2014 Elsevier Ltd. All rights reserved.

[A historical survey of diphtheria in the Western World, China and Japan. Part II: Modern age (from sixteenth century to the beginning of nineteenth century)].

PubMed

Nakamura, A

1996-09-01

In Europe and North America, literatures on diphtheritic diseases was increasing from sixteenth to eighteenth century. In New England of North America, diphtheria and scarlet fever occurred epidemically in mingled form from 1735 to the succeeding year. Thereafter, many physicians in Europe and America treated patients of diphtheria and had different opinions about the nature of croup and diphtheria. In China, its own clinical medicine progressed extraordinarily during the modern age. Laryngeal specialists appeared and wrote special monographs about the pharynx and larynx. A physician wrote about "epidemic exanthem", which the author presumes to be a complicated form of scarlet fever and diphtheria. In Japan, diphtheria occurred in sporadic form usually, and in epidemic form occasionally. Japanese physicians studied medicine from China since the ancient age, and also introduced European medicine through the Netherlands in the eighteenth century. So Japanese physicians learned knowledge about throat diseases and diphtheria from Chinese and European medicine.

Neonatal tetanus in rural Bangladesh: risk factors and toxoid efficacy.

PubMed Central

Hlady, W G; Bennett, J V; Samadi, A R; Begum, J; Hafez, A; Tarafdar, A I; Boring, J R

1992-01-01

OBJECTIVES. Tetanus continues to be a leading cause of neonatal death in Bangladesh as in other developing countries, yet little is known about risk factors or the efficacy of tetanus toxoid in this setting. METHODS. In May 1990, mothers of 6148 infants born alive between March 15, 1989, and March 14, 1990, in 30 rural unions of Rajshahi Division in Bangladesh were interviewed. Three surviving controls for each neonatal tetanus death were matched for sex, residence, and date of birth. RESULTS. Of 330 neonatal deaths, 112 met the case definition for tetanus. Risk was increased with a history of neonatal tetanus in a previous child, application of coconut oil to the vagina, and use of multiple ties on the umbilical cord. Risk was reduced by the birth attendant washing hands and using a cleaned cord-cutting tool. Risk was not reduced by a maternal history of two doses of tetanus toxoid (TT2), although estimated efficacy of TT2 was 45% (95% confidence interval = 16% to 64%). Subsequent to the survey, a reference laboratory reported to potency in three consecutive lots of tetanus vaccine from the production laboratory in Bangladesh. CONCLUSIONS. These findings identify high-risk mothers, stress the importance of washing hands and cleaning the cord-cutting tool, and demand improved quality control of tetanus vaccine production. PMID:1415861

Prevalence of diphtheria and tetanus antibodies among adults in Singapore: a national serological study to identify most susceptible population groups.

PubMed

Ang, L W; James, L; Goh, K T

2016-03-01

In view of waning antitoxin titres over time after the last vaccine dose against diphtheria and tetanus, we determined the immunity levels in adults to identify most susceptible groups for protection in Singapore. Our study involved residual sera from 3293 adults aged 18-79 who had participated in a national health survey in 2010. IgG antibody levels were determined using commercial enzyme-linked immunosorbent assay. Overall, 92.0% (95% confidence interval [CI]: 91.1-92.9%) had at least basic protection against diphtheria (antibody levels ≥0.01 IU/ml), while 71.4% (95% CI: 69.8-72.9%) had at least short-term protection against tetanus (antibody levels >0.1 IU/ml). The seroprevalence declined significantly with age for both diseases; the drop was most marked in the 50- to 59-year age group for diphtheria and 60- to 69-year age group for tetanus. There was a significant difference in seroprevalence by residency for diphtheria (92.8% among Singapore citizens versus 87.1% among permanent residents; P = 0.001). The seroprevalence for tetanus was significantly higher among males (83.2%) than females (62.4%) (P < 0.0005). It may be of value to consider additional vaccination efforts to protect older adults at higher risk for exposure against diphtheria and tetanus, particularly those travelling to areas where diphtheria is endemic or epidemic. © The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Structural correlates of carrier protein recognition in tetanus toxoid-conjugated bacterial polysaccharide vaccines.

PubMed

Lockyer, Kay; Gao, Fang; Derrick, Jeremy P; Bolgiano, Barbara

2015-03-10

An analysis of structure-antibody recognition relationships in nine licenced polysaccharide-tetanus toxoid (TT) conjugate vaccines was performed. The panel of conjugates used included vaccine components to protect against disease caused by Haemophilus influenzae type b, Neisseria meningitidis groups A, C, W and Y and Streptococcus pneumoniae serotype 18C. Conformation and structural analysis included size exclusion chromatography with multi-angle light scattering to determine size, and intrinsic fluorescence spectroscopy and fluorescence quenching to evaluate the protein folding and exposure of Trp residues. A capture ELISA measured the recognition of TT epitopes in the conjugates, using four rat monoclonal antibodies: 2 localised to the HC domain, and 2 of which were holotoxoid conformation-dependent. The conjugates had a wide range of average molecular masses ranging from 1.8×10(6) g/mol to larger than 20×10(6) g/mol. The panel of conjugates were found to be well folded, and did not have spectral features typical of aggregated TT. A partial correlation was found between molecular mass and epitope recognition. Recognition of the epitopes either on the HC domain or the whole toxoid was not necessarily hampered by the size of the molecule. Correlation was also found between the accessibility of Trp side chains and polysaccharide loading, suggesting also that a higher level of conjugated PS does not necessarily interfere with toxoid accessibility. There were different levels of carrier protein Trp side-chain and epitope accessibility that were localised to the HC domain; these were related to the saccharide type, despite the conjugates being independently manufactured. These findings extend our understanding of the molecular basis for carrier protein recognition in TT conjugate vaccines. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Structural correlates of carrier protein recognition in tetanus toxoid-conjugated bacterial polysaccharide vaccines

PubMed Central

Lockyer, Kay; Gao, Fang; Derrick, Jeremy P.; Bolgiano, Barbara

2015-01-01

An analysis of structure-antibody recognition relationships in nine licenced polysaccharide-tetanus toxoid (TT) conjugate vaccines was performed. The panel of conjugates used included vaccine components to protect against disease caused by Haemophilus influenzae type b, Neisseria meningitidis groups A, C, W and Y and Streptococcus pneumoniae serotype 18C. Conformation and structural analysis included size exclusion chromatography with multi-angle light scattering to determine size, and intrinsic fluorescence spectroscopy and fluorescence quenching to evaluate the protein folding and exposure of Trp residues. A capture ELISA measured the recognition of TT epitopes in the conjugates, using four rat monoclonal antibodies: 2 localised to the HC domain, and 2 of which were holotoxoid conformation-dependent. The conjugates had a wide range of average molecular masses ranging from 1.8 × 106 g/mol to larger than 20 × 106 g/mol. The panel of conjugates were found to be well folded, and did not have spectral features typical of aggregated TT. A partial correlation was found between molecular mass and epitope recognition. Recognition of the epitopes either on the HC domain or the whole toxoid was not necessarily hampered by the size of the molecule. Correlation was also found between the accessibility of Trp side chains and polysaccharide loading, suggesting also that a higher level of conjugated PS does not necessarily interfere with toxoid accessibility. There were different levels of carrier protein Trp side-chain and epitope accessibility that were localised to the HC domain; these were related to the saccharide type, despite the conjugates being independently manufactured. These findings extend our understanding of the molecular basis for carrier protein recognition in TT conjugate vaccines. PMID:25640334

[Preclinical studies of an adsorbed diphtheria-tetanus-pertussis vaccine (ADTP-vaccine) with acellular pertussis component].

PubMed

Zaĭtsev, E M; Britsina, M V; Bazhanova, I G; Mertsalova, N U; Ozeretskovskaia, M N; Ermolova, E V; Plekhanova, N G; Mikhaĭlova, N A; Kolyshkin, V A; Zverev, V V

2013-01-01

Evaluate standardness of antigenic composition of pertussis component, completeness of sorption of pertussis, diphtheria and tetanus components, specific activity and safety of experimental series ofADTP-vaccine with acellular pertussis component (ADTaP-vaccine). The content of separate antigens (pertussis toxin, filamentous hemagglutinin and agglutinogens 1, 2, 3) in samples of acellular pertussis component of ADTaP-vaccine and completeness of sorption of pertussis component of ADTaP-vaccine were evaluated by using enzyme immunoassay. Completeness of sorption of diphtheria and tetanus components were determined in flocculation reaction and antitoxin-binding reactions, respectively. Protective activity ofADTaP-vaccine was studied in model ofmeningoencephalitis development in mice infected with Bordetella pertussis (strain 18323) neurotropic virulent culture, protective activity oftetanus component - by survival of mice after administration of tetanus toxin, protective activity of diphtheria component - by survival of guinea pigs after administration of diphtheria toxin. Safety of preparations was evaluated in tests of acute and chronic toxicity with carrying out pathomorphologic studies including immature animals. All the studied experimental series ofADTaP-vaccine were standard by content of separate antigens of pertussis microbe. All the ADTaP-vaccine components were completely sorbed on aluminium hydroxide gel. By protective activity ADTaP preparations satisfied the WHO requirements. The preparations were non-toxic in acute and chronic toxicity and did not induce pathomorphologic changes including immature animals. Experimental samples of ADTaP-vaccine by specific activity and safety satisfied WHO requirements.

Association of Health Insurance Status and Vaccination Coverage among Adolescents 13-17 Years of Age.

PubMed

Lu, Peng-Jun; Yankey, David; Jeyarajah, Jenny; O'Halloran, Alissa; Fredua, Benjamin; Elam-Evans, Laurie D; Reagan-Steiner, Sarah

2018-04-01

To assess selected vaccination coverage among adolescents by health insurance status and other access-to-care characteristics. The 2015 National Immunization Survey-Teen data were used to assess vaccination coverage disparities among adolescents by health insurance status and other access-to-care variables. Multivariable logistic regression analysis and a predictive marginal modeling were conducted to evaluate associations between health insurance status and vaccination coverage. Overall, vaccination coverage was significantly lower among uninsured compared with insured adolescents for all vaccines assessed for except ≥3 doses of human papillomavirus vaccine (HPV) among male adolescents. Among adolescents 13-17 years of age, vaccination of uninsured compared with insured adolescents, respectively, for tetanus toxoid, reduced content diphtheria toxoid, and acellular pertussis vaccine was 77.4% vs 86.8%; for ≥1 dose of meningococcal conjugate vaccine was 72.9% vs 81.7%; for ≥1 dose of HPV was 38.8% vs 50.2% among male and 42.9% vs 63.8% among female adolescents; for 3 doses of HPV was 24.9% vs 42.8% among female adolescents. In addition, vaccination coverage differed by the following: type of insurance among insured adolescents, having a well-child visit at 11-12 years of age, and number of healthcare provider contacts in the past year. Uninsured were less likely than insured adolescents to be vaccinated for HPV (female: ≥1 dose and 3 doses; and male: ≥1 doses) after adjusting for confounding variables. Overall, vaccination coverage was lower among uninsured adolescents. HPV vaccination coverage was lower than tetanus toxoid, reduced content diphtheria toxoid, and acellular pertussis vaccine Tdap and meningococcal conjugate vaccine in both insured and uninsured adolescents. Wider implementation of effective evidence-based strategies is needed to help improve vaccination coverage among adolescents, particularly for those who are uninsured. Limitation of

Autoradiographic assay of mutants resistant to diphtheria toxin in mammalian cells in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ronen, A.; Gingerich, J.D.; Duncan, A.M.V.

1984-10-01

Diptheria toxin kills mammalian cells by ribosylating elongation factor 2, a protein factor necessary for protein synthesis. The frequency of cells able to form colonies in the presence of the toxin can be used as an assay for mutation to diphtheria toxin resistance. Resistance to diphtheria toxin can also be detected autoradiographically in cells exposed to (/sup 3/H)leucine after treatment with the toxin. In cultures of Chinese hamster ovary cells, the frequency of such resistant cells is increased by exposure of the cells to ..gamma..-rays, ultraviolet light, ethylnitrosourea, mitomycin c, ethidium bromide, and 5-bromo-2'-deoxyuridine in a dose- and time-dependent manner.more » The resistant cells form discrete microcolonies if they are allowed to divide several times before intoxication which indicates that they are genuine mutants. The assay is potentially adaptable to any cell population that can be intoxicated with diphtheria toxin and labeled with (/sup 3/H)leucine, whether or not the cells can form colonies. It may be useful, therefore, for measuring mutation rates in slowly growing or nondividing cell populations such as breast, brain, and liver, as well as in cells that do divide but cannot be readily cloned, such as the colonic epithelium. 23 references, 6 figures.« less

Efficacy of a multivalent modified-live virus vaccine containing a Mannheimia haemolytica toxoid in calves challenge exposed with Bibersteinia trehalosi.

PubMed

Bowersock, Terry L; Sobecki, Brian E; Terrill, Sarah J; Martinon, Nathalie C; Meinert, Todd R; Leyh, Randy D

2014-08-01

To determine the efficacy of a multivalent modified-live virus (MLV) vaccine containing a Mannheimia haemolytica toxoid to reduce pneumonia and mortality rate when administered to calves challenge exposed with virulent Bibersteinia trehalosi. Animals-74 Holstein calves. Calves were assigned to 2 treatment groups. Calves in the control group (n = 36) were vaccinated by SC administration of 2 mL of a commercial 5-way MLV vaccine, and calves in the other group (38) were vaccinated by SC administration of a 2-mL dose of a 5-way MLV vaccine containing M haemolytica toxoid (day 0). On day 21, calves were transtracheally administered B trehalosi. Serum was obtained for analysis of antibody titers against M haemolytica leukotoxin. Nasopharyngeal swab specimens were collected from calves 1 day before vaccination (day -1) and challenge exposure (day 20) and cultured to detect bacterial respiratory pathogens. Clinical scores, rectal temperature, and death attributable to the challenge-exposure organism were recorded for 6 days after challenge exposure. Remaining calves were euthanized at the end of the study. Necropsy was performed on all calves, and lung lesion scores were recorded. Calves vaccinated with the MLV vaccine containing M haemolytica toxoid had significantly lower lung lesion scores, mortality rate, and clinical scores for respiratory disease, compared with results for control calves. Administration of a multivalent MLV vaccine containing M haemolytica toxoid protected calves against challenge exposure with virulent B trehalosi by reducing the mortality rate, lung lesion scores, and clinical scores for respiratory disease.

Polymerase chain reaction for screening clinical isolates of corynebacteria for the production of diphtheria toxin.

PubMed

Pallen, M J; Hay, A J; Puckey, L H; Efstratiou, A

1994-04-01

To assess the performance of the polymerase chain reaction (PCR) when used to screen rapidly large numbers of corynebacteria for toxin production; and to determine the incidence of false positive PCR results with non-toxigenic Corynebacterium diphtheriae isolates. Eighty seven recent British isolates of corynebacteria were assayed by PCR. All isolates were assayed from both blood and tellurite agar within a five day period. Thirty three non-toxigenic isolates of C diphtheriae from six countries were also tested by PCR and by the Elek immunodiffusion assay. There was complete concordance between the results of PCR and traditional methods on the recent British isolates, with one exception: an Elek positive "C ulcerans" isolate, which was PCR positive from tellurite but not from blood agar. One of the thirty three (3%) non-toxigenic isolates of C diphtheriae was PCR positive. These results suggest that PCR compares favourably with traditional methods for the detection of toxigenic corynebacteria and that it represents a powerful new tool in the diagnosis of an old disease.

Polymerase chain reaction for screening clinical isolates of corynebacteria for the production of diphtheria toxin.

PubMed Central

Pallen, M J; Hay, A J; Puckey, L H; Efstratiou, A

1994-01-01

AIMS--To assess the performance of the polymerase chain reaction (PCR) when used to screen rapidly large numbers of corynebacteria for toxin production; and to determine the incidence of false positive PCR results with non-toxigenic Corynebacterium diphtheriae isolates. METHODS--Eighty seven recent British isolates of corynebacteria were assayed by PCR. All isolates were assayed from both blood and tellurite agar within a five day period. Thirty three non-toxigenic isolates of C diphtheriae from six countries were also tested by PCR and by the Elek immunodiffusion assay. RESULTS--There was complete concordance between the results of PCR and traditional methods on the recent British isolates, with one exception: an Elek positive "C ulcerans" isolate, which was PCR positive from tellurite but not from blood agar. One of the thirty three (3%) non-toxigenic isolates of C diphtheriae was PCR positive. CONCLUSIONS--These results suggest that PCR compares favourably with traditional methods for the detection of toxigenic corynebacteria and that it represents a powerful new tool in the diagnosis of an old disease. Images PMID:8027375

Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines.

PubMed

Huebner, Robin E; Nicol, Mark; Mothupi, Rosalia; Käyhty, Helena; Mbelle, Nontombi; Khomo, Esther; Klugman, Keith P

2004-12-21

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 microg) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of > or =1.25 microg of HibCRM197 vaccine produced mean anti-PRP responses at 18 weeks of > or =5.72 microg/ml and > or =0.15 microg/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of > or =1.0 microg/ml. Concentrations of > or =1.25 microg of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of > or =8.63 microg/ml and > or =0.15 microg/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of > or =1.0 microg/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of > or =0.15 microg/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses > or =1.25 microg of HibCRM197 and Hib-tetanus to mean concentrations > or =37.71 and 16.07 microg/ml, respectively. There were no differences in antibody responses for vaccine doses > or =1.25 microg of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of > or =1.25 microg may be sufficient to

Human T lymphotropic virus type II infection and humoral responses to pneumococcal polysaccharide and tetanus toxoid vaccines.

PubMed

Jarvis, Gary A; Janoff, Edward N; Cheng, Hui; Devita, Deborah; Fasching, Claudine; McCulloch, Charles E; Murphy, Edward L

2005-04-15

Infection with human T lymphotropic virus type II (HTLV-II) has been linked to an increased incidence of bacterial pneumonia. To determine whether HTLV-II infection is associated with impaired humoral immune responses, we immunized a cohort of HTLV-II-infected subjects and matched uninfected control subjects with 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines. The pneumococcal polysaccharide vaccine elicited comparable and significant increases in concentrations of IgG against all 5 serotypes tested at 1 and 6 months after immunization in both groups. The avidity and opsonophagocytic functions of the anticapsular IgG were similar. The concentrations of tetanus toxoid-specific IgG also increased comparably and significantly over time in both groups. Thus, HTLV-II-infected persons develop robust humoral responses to potentially protective polysaccharide and protein vaccines.

Diphtheria toxin-induced channels in Vero cells selective for monovalent cations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sandvig, K.; Olsnes, S.

1988-09-05

Ion fluxes associated with translocation of diphtheria toxin across the surface membrane of Vero cells were studied. When cells with surface-bound toxin were exposed to low pH to induce toxin entry, the cells became permeable to Na+, K+, H+, choline+, and glucosamine+. There was no increased permeability to Cl-, SO4(-2), glucose, or sucrose, whereas the uptake of /sup 45/Ca2+ was slightly increased. The influx of Ca2+, which appears to be different from that of monovalent cations, was reduced by several inhibitors of anion transport and by verapamil, Mn2+, Co2+, and Ca2+, but not by Mg2+. The toxin-induced fluxes of N+,more » K+, and protons were inhibited by Cd2+. Cd2+ also protected the cells against intoxication by diphtheria toxin, suggesting that the open cation-selective channel is required for toxin translocation. The involvement of the toxin receptor is discussed.« less

Clinical Study of New Tetravalent (Type A, B, E, and F) Botulinum Toxoid Vaccine Derived from M Toxin in Japan.

PubMed

Torii, Yasushi; Sugimoto, Nakaba; Kohda, Tomoko; Kozaki, Shunji; Morokuma, Kazunori; Horikawa, Yoshikane; Ginnaga, Akihiro; Yamamoto, Akihiko; Takahashi, Motohide

2017-07-24

Botulinum toxin is the most poisonous substance known, and is believed to be a highly lethal as a biological weapon; researchers of the toxin are exposed to this hazard. Botulinum toxoid vaccines have been produced and used in Japan. However, since clinical studies involving these vaccines were conducted before establishment of the Ethical Guidelines for Clinical Research in Japan, their immunogenicity and safety were not systematically assessed. In this study, we produced a new tetravalent (type A, B, E, and F) botulinum toxoid vaccine, the first ever to be derived from M toxin, and conducted quality control tests with reference to the Minimum Requirements in Japan for adsorbed tetanus toxoid vaccine. Subsequently, a clinical study using the new vaccine in 48 healthy adult volunteers was conducted according to the guidelines in Japan. No clinically serious adverse event was noted. Neutralizing antibody titers for each type of toxin in the participants' sera, 1 month after the 4th injection were more than 0.25 IU/mL, indicating sufficient protection. This study demonstrated that the vaccine has marked immunogenicity and is safe for use in humans.

Toxigenic Corynebacterium ulcerans isolated from a hunting dog and its diphtheria toxin antibody titer.

PubMed

Katsukawa, Chihiro; Komiya, Takako; Umeda, Kaoru; Goto, Minami; Yanai, Tokuma; Takahashi, Motohide; Yamamoto, Akihiko; Iwaki, Masaaki

2016-03-01

Toxigenic Corynebacterium ulcerans is a zoonotic pathogen that produces diphtheria toxin and causes a diphtheria-like illness in humans. The organism is known to infect and circulate among dogs, which can then transmit it to humans. Furthermore, previous studies have found that C. ulcerans is carried by wild animals, including game animals. In the present study, we tested hunting and companion dogs for the presence of toxigenic C. ulcerans and succeeded in isolating the bacterium from a hunting dog. Moreover, several hunting dogs had serum diphtheria antitoxin titers that were higher than the titers required for protection in humans, suggesting a history of exposure to toxigenic Corynebacterium strains. Notably, ribotyping, pulsed-field gel electrophoresis and tox gene sequencing demonstrated that the isolate from the hunting dog clustered with previously characterized C. ulcerans strains isolated from wild animals, as opposed to groups of isolates from humans and companion dogs. Interestingly, the wild animal cluster also contains an isolate from an outdoor breeding dog, which could have formed a bridge between isolates from wild animals and those from companion dogs. The results presented herein provide insight into the mechanism by which the zoonotic pathogen C. ulcerans circulates among wild animals, hunting and companion dogs, and humans. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

Immunogenicity of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria, tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study.

PubMed

John, T; Voysey, M; Yu, L M; McCarthy, N; Baudin, M; Richard, P; Fiquet, A; Kitchin, N; Pollard, A J

2015-08-26

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap-IPV, Repevax(®); Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis(®); Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap-IPV, Tetravac(®); Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection. All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap-IPV, Tdap+OPV and DTap-IPV, respectively, had protective antitoxin levels greater than 0.1IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV. Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Determination of free polysaccharide in Vi glycoconjugate vaccine against typhoid fever.

PubMed

Giannelli, C; Cappelletti, E; Di Benedetto, R; Pippi, F; Arcuri, M; Di Cioccio, V; Martin, L B; Saul, A; Micoli, F

2017-05-30

Glycoconjugate vaccines based on the Vi capsular polysaccharide directed against Salmonella enterica serovar Typhi are licensed or in development against typhoid fever, an important cause of morbidity and mortality in developing countries. Quantification of free polysaccharide in conjugate vaccines is an important quality control for release, to monitor vaccine stability and to ensure appropriate immune response. However, we found that existing separation methods based on size are not appropriate as free Vi non-specifically binds to unconjugated and conjugated protein. We developed a method based on free Vi separation by Capto Adhere resin and quantification by HPAEC-PAD. The method has been tested for conjugates of Vi derived from Citrobacter freundii with different carrier proteins such as CRM 197 , Tetanus Toxoid and Diphtheria Toxoid. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Modulation of carcinogen bioavailability by immunisation with benzo[a]pyrene-conjugate vaccines.

PubMed

Grova, Nathalie; Prodhomme, Emmanuel J F; Schellenberger, Mario T; Farinelle, Sophie; Muller, Claude P

2009-06-24

Benzo[a]pyrene (B[a]P) conjugate vaccines based on ovalbumin, tetanus toxoid and diphtheria toxoid (DT) as carrier proteins were developed to investigate the effect of specific antibodies on the bioavailability of this ubiquitous carcinogen and its metabolites. After metabolic activation of this prototype carcinogen, B[a]P forms DNA adducts which initiate chemical carcinogenesis. B[a]P-DT conjugate induced the most robust immune response. The antibodies reacted not only with B[a]P but also with the proximate carcinogen 7,8-diol-B[a]P. Antibodies modulated the bioavailability of B[a]P and its metabolic activation in a dose-dependent manner by sequestration in the blood. Our results showed that this immune prophylactic strategy influences the pharmacokinetic of B[a]P and further studies to investigate their effects on chemical carcinogenesis are warranted.

Influence of the Co-Administration of Heptavalent Conjugate Vaccine PCV7-TT on the Immunological Response Elicited by VA-MENGOC-BC® and Heberpenta®-L in Rabbits.

PubMed

Espinosa-Viñals, Carlos; García-Rivera, Dagmar; Rodríguez Noda, Laura; Amador Gómez, Aylín; Nicot, Milagros; Valle, Orialys; Núñez, Juan F; Martin, Yanet; Santana, Darielys; Valdés, Yury; Vérez Bencomo, Vicente

2017-05-01

Finlay Vaccine Institute is developing a new heptavalent conjugate vaccine against Streptococcus pneumoniae. As infants are the target population, PCV7-TT will be necessarily co-administered with other vaccines, and then, the interactions represent a concern. The aim of this work is to evaluate the possible immunological interferences in rabbits as animal experimental model. Rabbits were immunized with Heberpenta®-L, VA-MENGOC-BC®, and PCV7-TT. Blood samples were taken fourteen days after final immunization for obtaining sera. Antibody responses to all antigens were evaluated by indirect ELISA. Functional responses against diphtheria and tetanus toxoid were done by in vivo seroneutralization assay. No interference was observed by PCV7-TT over the humoral response against diphtheria toxoid and meningococcal antigens (p > 0.05). A nonstatistically significant reduction (p > 0.05) was observed in the case of the humoral response against Haemophilus influenzae type b oligosaccharide. Concomitant administration of Heberpenta®-L and PCV7-TT increased twice the antibody titers as well as the protective activity against tetanus toxoid, but no statistical differences were found. The co-administration did not induce a reduction in the percent of responders against pneumococcal polysaccharides contained in PCV7-TT vaccine. Concomitant administration of PCV7-TT did not induce interferences over the evaluated antigens of Heberpenta®-L and VA-MENGOC-BC®. Also, no interference was observed on the immune response elicited by PCV7-TT. These preclinical results suggest that PCV7-TT will not result in a serious problem over the immune response elicited by the licensed vaccines Heberpenta®-L and VA-MENGOC-BC®. However, the clinical interference could be strictly studied during clinical trials in infants.

[Laryngeal diphtheria in a young woman causes diagnostic difficulties--case report].

PubMed

Garlicki, A; Bociaga, M; Krukowiecki, J; Kluba-Wojewoda, U

1996-01-01

A case of severe laryngeal diphtheria in a young woman was presented. Initially, the presence of a foreign body in the larynx of this patient was suspected. The differential diagnosis of a foreign body should include diphtheric laryngitis as this may cause obstruction of the respiratory tract. This can lead to severe complications.

CD4 T-helper cell cytokine phenotypes and antibody response following tetanus toxoid booster immunization

USDA-ARS?s Scientific Manuscript database

Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify tetanus toxoid- (TT) specific Th1, Th2, Th17 and IL10+ cells. Eight healthy subjects were given a TT booster vacci...

Corynebacterium diphtheriae invasion-associated protein (DIP1281) is involved in cell surface organization, adhesion and internalization in epithelial cells

PubMed Central

2010-01-01

Background Corynebacterium diphtheriae, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about C. diphtheriae factors crucial for colonization of the host. In this study, we investigated the function of surface-associated protein DIP1281, previously annotated as hypothetical invasion-associated protein. Results Microscopic inspection of DIP1281 mutant strains revealed an increased size of the single cells in combination with an altered less club-like shape and formation of chains of cells rather than the typical V-like division forms or palisades of growing C. diphtheriae cells. Cell viability was not impaired. Immuno-fluorescence microscopy, SDS-PAGE and 2-D PAGE of surface proteins revealed clear differences of wild-type and mutant protein patterns, which were verified by atomic force microscopy. DIP1281 mutant cells were not only altered in shape and surface structure but completely lack the ability to adhere to host cells and consequently invade these. Conclusions Our data indicate that DIP1281 is predominantly involved in the organization of the outer surface protein layer rather than in the separation of the peptidoglycan cell wall of dividing bacteria. The adhesion- and invasion-negative phenotype of corresponding mutant strains is an effect of rearrangements of the outer surface. PMID:20051108

Translocation of the Catalytic Domain of Diphtheria Toxin across Planar Phospholipid Bilayers by Its Own T Domain

NASA Astrophysics Data System (ADS)

Oh, Kyoung Joon; Senzel, Lisa; Collier, R. John; Finkelstein, Alan

1999-07-01

The T domain of diphtheria toxin is known to participate in the pH-dependent translocation of the catalytic C domain of the toxin across the endosomal membrane, but how it does so, and whether cellular proteins are also required for this process, remain unknown. Here, we report results showing that the T domain alone is capable of translocating the entire C domain across model, planar phospholipid bilayers in the absence of other proteins. The T domain therefore contains the entire molecular machinery for mediating transfer of the catalytic domain of diphtheria toxin across membranes.

Diagnosis in France of a Non-Toxigenic tox Gene-Bearing Strain of Corynebacterium diphtheriae in a Young Male Back From Senegal

PubMed Central

Rouyer, Cécile; Walewski, Violaine; Badell-Ocando, Edgar; Dumas, Marc; Zumelzu, Coralie; Jaureguy, Françoise; Brisse, Sylvain; Caux, Frédéric; Bouchaud, Olivier; Carbonnelle, Etienne

2017-01-01

Abstract Cutaneous diphtheria is uncommon in Europe. In this study, we report a case of imported cutaneous infection due to a non-toxigenic but tox gene-bearing (NTTB) strain of Corynebacterium diphtheriae. The NTTB strains are recognized as emerging pathogens across Europe, and physicians and bacteriologists should be aware of the circulation of these strains. PMID:28480263

Poor Immune Responses to a Birth Dose of Diphtheria, Tetanus, and Acellular Pertussis Vaccine

PubMed Central

Halasa, Natasha B.; O’Shea, Alice; Shi, Jian R.; Lafleur, Bonnie J.; Edwards, Kathryn M.

2013-01-01

Objectives To evaluate the safety and immunogenicity of an additional birth dose of diphtheria, tetanus, and acellular pertussis vaccine (DTaP). Study design Fifty infants between 2 to 14 days of age were randomly assigned to receive either DTaP and hepatitis B vaccines (experimental) or hepatitis B alone (control) at birth. At 2, 4, 6, and 17 months of age, DTaP and routine vaccines were administered to both groups. Safety data were collected after each dose, and sera were obtained at birth, 6, 7, 17, and 18 months. Immune responses to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae were measured by enzyme-linked immunosorbent assay; responses to other vaccines were assessed. Results No differences were seen between the 2 groups in either local or systemic reactions; all vaccines were well tolerated. Compared with the control group, infants in the experimental group demonstrated significantly lower geometric mean antibody concentrations for pertussis toxin and pertactin 6, 7, and 18 months, for fimbrae at 6, 7, 17, and 18 months, and for FHA at 18 months, and lower geometric mean antibody concentrations for diphtheria at 7 months. Immune responses to all other vaccine antigens were comparable. Conclusion Administration of an additional dose of DTaP at birth was safe but was associated with a significantly lower response to diphtheria and 3 of 4 pertussis antigens compared with controls. PMID:18534242

Factors that influence parental vaccination decisions for adolescents, 13 to 17 years old: National Immunization Survey-Teen, 2010.

PubMed

Dorell, Christina; Yankey, David; Kennedy, Allison; Stokley, Shannon

2013-02-01

We aim to describe factors that influence parental decisions to vaccinate their adolescents. Data from the July to December 2010 National Immunization Survey-Teen Parental Concerns Module were analyzed to determine factors that influence parental decisions to vaccinate their adolescents. Parents reported that their adolescent's health care provider recommended tetanus toxoid/tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Td/Tdap; 74.4%), meningococcal conjugate (MenACWY; 60.3%), and human papillomavirus (HPV; 71.3%). Vaccination coverage estimates were significantly higher among parents who reported receiving a provider recommendation: 85.2% versus 76.7% (Td/Tdap), 77.3% versus 49.7% (MenACWY), and 62.2% versus 21.5% (HPV). Compared with Td/Tdap and MenACWY, fewer HPV vaccination conversations included recommendations for vaccination. Other than health care providers, school requirements (46.1%), news coverage (31.2%), and family (31.0%) were most frequently reported influences on parental vaccination decisions. Many factors influence parental decisions to vaccinate their adolescents; one of the most important factors is the provider recommendation. Missed opportunities for vaccination persist when strong vaccination recommendations are not given or are delayed.

Outbreak investigation for toxigenic Corynebacterium diphtheriae wound infections in refugees from Northeast Africa and Syria in Switzerland and Germany by whole genome sequencing.

PubMed

Meinel, D M; Kuehl, R; Zbinden, R; Boskova, V; Garzoni, C; Fadini, D; Dolina, M; Blümel, B; Weibel, T; Tschudin-Sutter, S; Widmer, A F; Bielicki, J A; Dierig, A; Heininger, U; Konrad, R; Berger, A; Hinic, V; Goldenberger, D; Blaich, A; Stadler, T; Battegay, M; Sing, A; Egli, A

2016-12-01

Toxigenic Corynebacterium diphtheriae is an important and potentially fatal threat to patients and public health. During the current dramatic influx of refugees into Europe, our objective was to use whole genome sequencing for the characterization of a suspected outbreak of C. diphtheriae wound infections among refugees. After conventional culture, we identified C. diphtheriae using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and investigated toxigenicity by PCR. Whole genome sequencing was performed on a MiSeq Illumina with >70×coverage, 2×250 bp read length, and mapping against a reference genome. Twenty cases of cutaneous C. diphtheriae in refugees from East African countries and Syria identified between April and August 2015 were included. Patients presented with wound infections shortly after arrival in Switzerland and Germany. Toxin production was detected in 9/20 (45%) isolates. Whole genome sequencing-based typing revealed relatedness between isolates using neighbour-joining algorithms. We detected three separate clusters among epidemiologically related refugees. Although the isolates within a cluster showed strong relatedness, isolates differed by >50 nucleotide polymorphisms. Toxigenic C. diphtheriae associated wound infections are currently observed more frequently in Europe, due to refugees travelling under poor hygienic conditions. Close genetic relatedness of C. diphtheriae isolates from 20 refugees with wound infections indicates likely transmission between patients. However, the diversity within each cluster and phylogenetic time-tree analysis suggest that transmissions happened several months ago, most likely outside Europe. Whole genome sequencing offers the potential to describe outbreaks at very high resolution and is a helpful tool in infection tracking and identification of transmission routes. Copyright © 2016. Published by Elsevier Ltd.

Seroprevalence and Determinants of Immunity to Diphtheria for Children Living in Two Districts of Contrasting Incidence During an Outbreak in East Java, Indonesia.

PubMed

Hughes, Gareth J; Mikhail, Amy F W; Husada, Dominicus; Irawan, Eveline; Kafatos, George; Bracebridge, Samantha; Pebody, Richard; Efstratiou, Androulla

2015-11-01

In 2012, an ongoing outbreak of diphtheria in Indonesia was focused in the province of East Java. There was a need to assess vaccine coverage and immunity gaps in children. We conducted a cross-sectional seroprevalence and vaccine coverage survey of children 1-15 years of age in 2 districts of East Java: one of high incidence (on the island of Madura) and one of low incidence (on the mainland). From each district, we sampled 150 children (10 children per year of age). Sera and throat swabs were taken to determine immunity and carriage status. Immunity was defined as ≥0.1 international unit/mL of antibody to diphtheria toxin. A total of 297 children were selected to participate in the study. Coverage of three doses of combined vaccine for diphtheria, tetanus and pertussis was significantly lower (P < 0.001) in the high incidence district compared with the low [57%, 95% confidence interval (CI): 36-78 vs. 97%, 95% CI: 93-100]. Despite this higher vaccine coverage, seroprevalence of immunity was lower in the low incidence district compared with the high (71%, 95% CI: 63-80 vs. 83%, 95% CI: 76-90). Immunity in the high incidence district was associated with increased age, increased prevalence of toxigenic Corynebacterium diphtheriae carriers and with receipt of multiple (and likely more recent) boosters. Significant variation exists in vaccine coverage and seroprevalence of immunity to diphtheria in East Java. Immunity in high incidence districts is likely because of natural immunity acquired through exposure to toxigenic C. diphtheriae. Booster vaccines are essential for achieving protective levels of immunity.

Toxicity and immunogenicity of Enterotoxigenic Escherichia coli heat-labile and heat-stable toxoid fusion 3xSTa(A14Q)-LT(S63K/R192G/L211A) in a murine model.

PubMed

Zhang, Chengxian; Knudsen, David E; Liu, Mei; Robertson, Donald C; Zhang, Weiping

2013-01-01

Diarrhea is the second leading cause of death to young children. Enterotoxigenic Escherichia coli (ETEC) are the most common bacteria causing diarrhea. Adhesins and enterotoxins are the virulence determinants in ETEC diarrhea. Adhesins mediate bacterial attachment and colonization, and enterotoxins including heat-labile (LT) and heat-stable type Ib toxin (STa) disrupt fluid homeostasis in host cells that leads to fluid hyper-secretion and diarrhea. Thus, adhesins and enterotoxins have been primarily targeted in ETEC vaccine development. A recent study reported toxoid fusions with STa toxoid (STa(P13F)) fused at the N- or C-terminus, or inside the A subunit of LT(R192G) elicited neutralizing antitoxin antibodies, and suggested application of toxoid fusions in ETEC vaccine development (Liu et al., Infect. Immun. 79:4002-4009, 2011). In this study, we generated a different STa toxoid (STa(A14Q)) and a triple-mutant LT toxoid (LT(S63K/R192G/L211A), tmLT), constructed a toxoid fusion (3xSTa(A14Q)-tmLT) that carried 3 copies of STa(A14Q) for further facilitation of anti-STa immunogenicity, and assessed antigen safety and immunogenicity in a murine model to explore its potential for ETEC vaccine development. Mice immunized with this fusion antigen showed no adverse effects, and developed antitoxin antibodies particularly through the IP route. Anti-LT antibodies were detected and were shown neutralizing against CT in vitro. Anti-STa antibodies were also detected in the immunized mice, and serum from the IP immunized mice neutralized STa toxin in vitro. Data from this study indicated that toxoid fusion 3xSTa(A14Q)-tmLT is safe and can induce neutralizing antitoxin antibodies, and provided helpful information for vaccine development against ETEC diarrhea.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy.

PubMed

Burton, C T; Goodall, R L; Samri, A; Autran, B; Kelleher, A D; Poli, G; Pantaleo, G; Gotch, F M; Imami, N

2008-05-01

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index > or = 3 and Delta counts per minute > or = 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0.2, P = 0.4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0.8, P = 0.7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered.

More than 20 years after re-emerging in the 1990s, diphtheria remains a public health problem in Latvia

PubMed Central

Kantsone, Ieva; Lucenko, Irina; Perevoscikovs, Jurijs

2016-01-01

In 1994, the World Health Organization (WHO) declared the goal of eliminating diphtheria within the WHO European Region by the year 2000. However, in 1990 an epidemic emerged within the Russian Federation and spread to other countries, including Latvia, by 1994. We describe national surveillance and immunisation coverage data in Latvia from 1994 to 2014 and present historical data from 1946. We defined a laboratory-confirmed case as a clinical case in which toxin-producing Corynebacterium diphtheriae, C. ulcerans or C. pseudotuberculosis was isolated. From 1994 to 2014, 1,515 cases were reported, giving an average annual incidence of 3.2 cases per 100,000 inhabitants (range 0.1–14.8), with the highest incidence in age groups 5–19 and 40–49 years (4.4 and 4.3/100,000, respectively); 111 deaths were reported, 83.8% cases were laboratory-confirmed. Most cases occurred in unvaccinated adults. To improve disease control a supplementary immunisation campaign for adults was initiated in 1995, and by the end of 1998 national coverage among adults reached 70%, and reached 77% in 2003, but declined to 59% by 2014. Diphtheria remains a problem in Latvia with continued circulation of toxin-producing strains of C. diphtheriae. We recommend to strengthen immunisation to cover adults, as well as the education of health professionals and a serological survey. PMID:27934582

More than 20 years after re-emerging in the 1990s, diphtheria remains a public health problem in Latvia.

PubMed

Kantsone, Ieva; Lucenko, Irina; Perevoscikovs, Jurijs

2016-12-01

In 1994, the World Health Organization (WHO) declared the goal of eliminating diphtheria within the WHO European Region by the year 2000. However, in 1990 an epidemic emerged within the Russian Federation and spread to other countries, including Latvia, by 1994. We describe national surveillance and immunisation coverage data in Latvia from 1994 to 2014 and present historical data from 1946. We defined a laboratory-confirmed case as a clinical case in which toxin-producing Corynebacterium diphtheriae, C. ulcerans or C. pseudotuberculosis was isolated. From 1994 to 2014, 1,515 cases were reported, giving an average annual incidence of 3.2 cases per 100,000 inhabitants (range 0.1-14.8), with the highest incidence in age groups 5-19 and 40-49 years (4.4 and 4.3/100,000, respectively); 111 deaths were reported, 83.8% cases were laboratory-confirmed. Most cases occurred in unvaccinated adults. To improve disease control a supplementary immunisation campaign for adults was initiated in 1995, and by the end of 1998 national coverage among adults reached 70%, and reached 77% in 2003, but declined to 59% by 2014. Diphtheria remains a problem in Latvia with continued circulation of toxin-producing strains of C. diphtheriae. We recommend to strengthen immunisation to cover adults, as well as the education of health professionals and a serological survey. This article is copyright of The Authors, 2016.

Elevated levels of maternal anti-tetanus toxin antibodies do not suppress the immune response to a Haemophilus influenzae type b polyribosylphosphate-tetanus toxoid conjugate vaccine.

PubMed Central

Panpitpat, C.; Thisyakorn, U.; Chotpitayasunondh, T.; Fürer, E.; Que, J. U.; Hasler, T.; Cryz, S. J.

2000-01-01

Reported are the effects of elevated levels of anti-tetanus antibodies on the safety and immune response to a Haemophilus influenzae type b polyribosylphosphate (PRP)-tetanus toxoid conjugate (PRP-T) vaccine. A group of Thai infants (n = 177) born to women immunized against tetanus during pregnancy were vaccinated with either a combined diphtheria-tetanus-pertussis (DTP) PRP-T vaccine or DTP and a PRP-conjugate vaccine using Neisseria meningitidis group B outer-membrane proteins as a carrier (PedVax HIB). Although most infants possessed high titres (> 1 IU/ml) of anti-tetanus antibodies, the DTP-PRP-T combined vaccine engendered an excellent antibody response to all vaccine components. In both vaccine groups > 98% of infants attained anti-PRP antibody titres > or = 0.15 microgram/ml. The geometric mean anti-PRP antibody titres were 5.41 micrograms/ml and 2.1 micrograms/ml for infants immunized with three doses of PRP-T versus two doses of PedVax HIB vaccines, respectively (P < 0.005). Similarly, the proportion of infants who achieved titres > or = 1 microgram/ml was higher in the PRP-T group (87.8%) than in the group immunized with PedVax HIB (74.2%) (P = 0.036). A subgroup analysis showed that there was no significant difference in the anti-PRP antibody response for infants exhibiting either < 1 IU of anti-tetanus antibody per millilitre or > or = 1 IU/ml at baseline. These finding indicate that pre-existing anti-carrier antibody does not diminish the immune response to the PRP moiety. All infants possessed protective levels of anti-D and anti-T antibody levels after immunization. PMID:10812736

A SEROLOGICAL AND ELECTROPHORETIC STUDY OF DIPHTHERIA ANTISERA IRRADIATED WITH STERILIZING DOSES OF $gamma$-RAYS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaulen, D.R.; Chakhava, O.V.

1958-01-01

The effects of irradiation on the antitoxic, anaphylactic, and electrophoretic properties of diphtheria antisera were studied at the various doses used for sterilization. Both crude and purified diphtheria antitoxic antisera were used. Irradiations were carried out with a cobalt-60 source with a total power of 5 kc. The dosage rate was 600 r/min. Data are tabulated. The results demonstrate considerable changes in the properties of antisera taking place as a result of exposure to large doses of gamma radiation. In all experiments a regular fall in the antitoxin titre was demonstrated. A greater destruction of antitoxin was observed in themore » crude antiserum than in the purified. Possible reaction mechanisms involved are discussed. (C.H.)« less

A phase III, randomized controlled study to assess the safety and immunogenicity of a semi-synthetic diphtheria, tetanus and whole-cell pertussis vaccine in Indian infants.

PubMed

Sharma, Hitt; Patil, Vishwanath; Sharma, Dharambhushan; Kapre, Subhash; Jadhav, Suresh; Ravetkar, Satish; Kumar, Rakesh; Bahl, Sunil; Parekh, Sameer; Chakravarty, Anita

2012-09-21

Reactions to DTwP vaccine are well known and are a matter of great concern, much for the development of next generation combination vaccines. To avoid such reactions which occur from foreign compounds, WHO suggested manufacture of DTwP vaccine using semi-synthetic medium. The phase III trial reported here was conducted to assess the immunogenicity, tolerability and safety of a new DTwP vaccine manufactured using semi-synthetic medium for both tetanus and diphtheria toxoids in comparison with the routinely manufactured DTwP vaccine. In all, 331 infants aged 6-8 weeks were enrolled, out of which 308 completed the study. The vaccination was done at 6-10-14 weeks following EPI/WHO recommended immunization schedule. Blood samples were collected prior to the administration of first dose and one month after the third dose. Postvaccination, geometric mean titres for each component did not differ significantly amongst the two study groups. Though, the immunogenicity results were comparable between the two vaccines, the incidence of adverse events was comparatively low in semi-synthetic vaccine as against the routine vaccine group for all the three doses. The semi-synthetic DTwP vaccine was immunogenic and showed a significant lower incidence of local adverse events in comparison to the routine vaccine. This vaccine is now being used in the routine vaccination programme both as a triple antigen (DTwP alone) as well as a combination with Hepatitis B and/or Haemophilus influenzae type b vaccine. Copyright © 2012 Elsevier Ltd. All rights reserved.

Vaccines and pregnancy: past, present, and future.

PubMed

Rasmussen, Sonja A; Watson, Amelia K; Kennedy, Erin D; Broder, Karen R; Jamieson, Denise J

2014-06-01

Vaccination during pregnancy with certain vaccines can prevent morbidity and mortality in pregnant women and their infants. However, previous recommendations often focused on the potential risks of vaccines to the fetus when used during pregnancy. In recent years, additional data have become available on the absence of increased risks for adverse events associated with vaccines when administered during pregnancy and on their benefits to mothers and infants. Currently two vaccines - (i) inactivated influenza, and (ii) tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) - are recommended for use by all pregnant women by the United States Advisory Committee on Immunization Practices. Here we review the history of vaccination during pregnancy, the current status of recommendations for vaccination during pregnancy in the USA, and the potential for future advances in this area, including key barriers that must be overcome to accommodate these advances. Published by Elsevier Ltd.

Impaired cellular immune response to tetanus toxoid but not to cytomegalovirus in effectively HAART-treated HIV-infected children.

PubMed

Alsina, Laia; Noguera-Julian, Antoni; Fortuny, Clàudia

2013-05-07

Despite of highly active antiretroviral therapy, the response to vaccines in HIV-infected children is poor and short-lived, probably due to a defect in cellular immune responses. We compared the cellular immune response (assessed in terms of IFN-γ production) to tetanus toxoid and to cytomegalovirus in a series of 13 HIV-perinatally-infected children and adolescents with optimal immunovirological response to first line antiretroviral therapy, implemented during chronic infection. A stronger cellular response to cytomegalovirus (11 out of 13 patients) was observed, as compared to tetanus toxoid (1 out of 13; p=0.003). These results suggest that the repeated exposition to CMV, as opposed to the past exposition to TT, is able to maintain an effective antigen-specific immune response in stable HIV-infected pediatric patients and strengthen current recommendations on immunization practices in these children. Copyright © 2013. Published by Elsevier Ltd.

Identification of human antibody fragment clones specific for tetanus toxoid in a bacteriophage. lambda. immunoexpression library

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mullinax, R.L.; Gross, E.A.; Amberg, J.R.

1990-10-01

The authors have applied a molecular biology approach to the identification of human monoclonal antibodies. Human peripheral blood lymphocyte mRNA was converted to cDNA and a select subset was amplified by the polymerase chain reaction. These products, containing coding sequences for numerous immunoglobulin heavy- and {kappa} light-chain variable and constant region domains, were inserted into modified bacteriophase {lambda} expression vectors and introduced into Escherichia coli by infection to yield a combinatorial immunoexpression library. Clones with binding activity to tetanus toxoid were identified by filter hybridization with radiolabeled antigen and appeared at a frequency of 0.2{percent} in the library. These humanmore » antigen binding fragments, consisting of a heavy-chain fragment covalently linked to a light chain, displayed high affinity of binding to tetanus toxoid with equilibrium constants in the nanomolar range but did not cross-react with other proteins tested. They estimate that this human immunoexpression library contains 20,000 clones with high affinity and specificity to our chosen antigen.« less

Use of Amplified Fragment Length Polymorphisms for Typing Corynebacterium diphtheriae

PubMed Central

De Zoysa, Aruni; Efstratiou, Androulla

2000-01-01

Amplified fragment length polymorphism (AFLP) was investigated for the differentiation of Corynebacterium diphtheriae isolates. Analysis using Taxotron revealed 10 distinct AFLP profiles among 57 isolates. Strains with ribotype patterns D1, D4, and D12 could not be distinguished; however, the technique discriminated isolates of ribotype patterns D3, D6, and D7 further. AFLP was rapid, fairly inexpensive, and reproducible and could be used as an alternative to ribotyping. PMID:11015416

Genotypic and Phenotypic Characteristics of Corynebacterium diphtheriae Strains Isolated from Patients in Belarus during an Epidemic Period

PubMed Central

Titov, Leonid; Kolodkina, Valentina; Dronina, Alina; Grimont, Francine; Grimont, Patrick A. D.; Lejay-Collin, Monique; de Zoysa, Aruni; Andronescu, Constantin; Diaconescu, Angela; Marin, Byanca; Efstratiou, Androulla

2003-01-01

One hundred two Corynebacterium diphtheriae strains (93 of the gravis biotype and nine of the mitis biotype) isolated from clinical cases during the Belarus diphtheria epidemic were characterized by biotyping, toxigenicity testing by the Elek test and an indirect hemagglutination assay, phage typing, and ribotyping. The gravis biotype strains were characterized as high and medium toxin producers, and strains of biotype mitis were characterized as low and medium toxin producers. Most strains (82 of 102) were distributed among five phage types. Seventy-two strains (64 of the gravis biotype and 8 of the mitis biotype) belonged to phage type VI ls5,34add. Hybridization of genomic DNA digested with BstEII and PvuII revealed five ribotype patterns, namely, D1, D4, D6, D7, and D13. The majority of gravis biotype strains belonged to ribotypes D1 (49 of 93) and D4 (33 of 93) and included one clonal group of C. diphtheriae. This clone predominated in all regions in Belarus. There was a statistical association between ribotypes and phage types but not between ribotypes and levels of toxin production. PMID:12624069

Antibody levels to tetanus, diphtheria, measles and varicella in patients with primary immunodeficiency undergoing intravenous immunoglobulin therapy: a prospective study

PubMed Central

2014-01-01

Background Patients with antibody deficiencies depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG) to ensure continued protection against pathogens. Few studies have examined levels of antibodies to specific pathogens in IVIG preparations and little is known about the specific antibody levels in patients under regular IVIG treatment. The current study determined the range of antibodies to tetanus, diphtheria, measles and varicella in IVIG products and the levels of these antibodies in patients undergoing IVIG treatment. Methods We selected 21 patients with primary antibody deficiencies who were receiving regular therapy with IVIG. Over a period of one year, we collected four blood samples from each patient (every 3 months), immediately before immunoglobulin infusion. We also collected samples from the IVIG preparation the patients received the month prior to blood collection. Antibody levels to tetanus, diphtheria, measles and varicella virus were measured in plasma and IVIG samples. Total IgG levels were determined in plasma samples. Results Antibody levels to tetanus, diphtheria, varicella virus and measles showed considerable variation in different IVIG lots, but they were similar when compared between commercial preparations. All patients presented with protective levels of antibodies specific for tetanus, measles and varicella. Some patients had suboptimal diphtheria antibody levels. There was a significant correlation between serum and IVIG antibodies to all pathogens, except tetanus. There was a significant correlation between diphtheria and varicella antibodies with total IgG levels, but there was no significant correlation with antibodies to tetanus or measles. Conclusions The study confirmed the variation in specific antibody levels between batches of the same brand of IVIG. Apart from the most common infections to which these patients are susceptible, health care providers must be aware of other vaccine

An open-label randomized clinical trial of prophylactic paracetamol coadministered with 7-valent pneumococcal conjugate vaccine and hexavalent diphtheria toxoid, tetanus toxoid, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b vaccine.

PubMed

Rose, Markus A; Juergens, Christine; Schmoele-Thoma, Beate; Gruber, William C; Baker, Sherryl; Zielen, Stefan

2013-06-21

In two clinical trials, low-grade fever was observed more frequently after coadministration than after separate administration of two recommended routine pediatric vaccines. Since fever is an important issue with vaccine tolerability, we performed this open-label study on the efficacy and safety of prophylactic use of paracetamol (acetaminophen, Benuron®) in children administered routine 7-valent pneumococcal conjugate vaccine (PCV-7) coadministered with hexavalent vaccine (diphtheria-tetanus-acellular pertussis-hepatitis B, poliovirus, Haemophilus influenzae type b vaccine [DTPa-HBV-IPV/Hib]) in Germany. Healthy infants (N = 301) who received a 3-dose infant series of PCV-7 and DTPa-HBV-IPV/Hib plus a toddler dose were randomly assigned 1:1 to prophylactic paracetamol (125 mg or 250 mg suppositories, based on body weight) at vaccination, and at 6-8 hour intervals thereafter, or a control group that received no paracetamol. Rectal temperature and local and other systemic reactions were measured for 4 days post vaccination; adverse events were collected throughout the study. In the intent-to-treat population, paracetamol reduced the incidence of fever ≥38°C, but this reduction was only significant for the infant series, with computed efficacy of 43.0% (95% confidence interval [CI]: 17.4, 61.2), and not significant after the toddler dose (efficacy 15.9%; 95% CI: -19.9, 41.3); results were similar in the per protocol (PP) population. Fever >39°C was rare during the infant series, such that there were too few cases for assessment. After the toddler dose, paracetamol effectively reduced fever >39°C, reaching statistical significance in the PP population only (efficacy 79%; 95% CI: 3.9, 97.7). Paracetamol also reduced reactogenicity, but there were few significant differences between groups after any dose. No vaccine-related serious adverse events were reported. Paracetamol effectively prevented fever and other reactions, mainly during the infant series

Determinants of tetanus, diphtheria and poliomyelitis vaccinations among Hajj pilgrims, Marseille, France.

PubMed

Gautret, Philippe; Yong, Winnie; Soula, Georges; Parola, Philippe; Brouqui, Philippe; DelVecchio Good, Mary-Jo

2010-08-01

It has been observed that Muslim pilgrims departing France for Mecca have low national immunization rates against tetanus, diphtheria and poliomyelitis (TdP). Our purpose is to identify immigration, socio-economic and socio-cultural determinants of vaccination coverage against TdP. A cross-sectional survey study was conducted in late 2006 among 580 pilgrims in preparation who attended the Infectious and Tropical Medicine ward in Hôpital Nord at Marseille to receive their N. meningitidis vaccine required for travel to Mecca. Total vaccination rates for tetanus (18.9%), diphtheria (14.7%) and poliomyelitis (15.0%) were comparable. Pilgrim's characteristic lower socio-economic and social status, in addition to their unifying linguistic, cultural and religious identity defines them as a particularly disadvantageous group in France. French citizenship, higher level of education, better French fluency and no previous travel to country of origin were the strongest and most significant determinants of TdP vaccination status. These results suggest that the Muslim community in France is at risk from inequities of national preventive care efforts.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy

PubMed Central

Burton, C T; Goodall, R L; Samri, A; Autran, B; Kelleher, A D; Poli, G; Pantaleo, G; Gotch, F M; Imami, N; Imami, N

2008-01-01

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index ≥ 3 and Δ counts per minute ≥ 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0·2, P = 0·4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0·8, P = 0·7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered. PMID:18410636

Washington State Pediatricians' Attitudes Toward Alternative Childhood Immunization Schedules

PubMed Central

Wightman, Aaron; Marcuse, Edgar K.; Taylor, James A.

2011-01-01

OBJECTIVE: To determine the frequency of parents' requests for alternative childhood immunization schedules (ACISs) and pediatricians' comfort with and willingness to use ACISs. METHODS: Washington State primary care pediatricians were asked to complete an Internet-based survey on ACISs. The main outcome measures were the frequency of parents' requests for ACISs, pediatricians' comfort with their use, and pediatricians' willingness to use ACISs for individual vaccines. In addition, respondents were asked to characterize their practices and to provide demographic information. RESULTS: Of the 311 respondents (response rate: 65%), 209 met inclusion criteria and were included in analyses. Overall, 77% of eligible respondents reported that parents sometimes or frequently requested ACISs, and 61% were comfortable using an ACIS if requested by a parent. Pediatricians were least willing to consider using ACISs for diphtheria-tetanus toxoids-acellular pertussis vaccine, Haemophilus influenzae type b vaccine, and pneumococcal conjugate vaccine. Pediatricians who practiced in a neighborhood or community clinic were less comfortable using ACISs than were those in a 1- or 2-physician practice (odds ratio: 0.10). CONCLUSIONS: Washington State pediatricians are regularly being asked to use ACISs, and most of them are comfortable using them if requested. Pediatricians are least willing to delay H influenzae type b vaccine, diphtheria-tetanus toxoids-acellular pertussis vaccine, and pneumococcal conjugate vaccine, which suggests prioritization of immunizations that protect against potentially devastating bacterial infections of infancy and early childhood. PMID:22123877

Antibody responses of Macaca fascicularis against a new inactivated polio vaccine derived from Sabin strains (sIPV) in DTaP-sIPV vaccine.

PubMed

Sato, Y; Shiosaki, K; Goto, Y; Sonoda, K; Kino, Y

2013-05-01

Antibody responses of Macaca fascicularis against a new tetravalent vaccine composed of diphtheria toxoid, tetanus toxoid, acellular pertussis antigens, and inactivated poliovirus derived from Sabin strains (sIPV) was investigated to predict an optimal dose of sIPV in a new tetravalent vaccine (DTaP-sIPV) prior to conducting a dose-defined clinical study. Monkeys were inoculated with DTaP-sIPVs containing three different antigen units of sIPVs: Vaccine A (types 1:2:3 = 3:100:100 DU), Vaccine B (types 1:2:3 = 1.5:50:50 DU), and Vaccine C (types 1:2:3 = 0.75:25:25 DU). There was no difference in the average titers of neutralizing antibody against the attenuated or virulent polioviruses between Vaccines A and B. The average neutralizing antibody titers of Vaccine C tended to be lower than those of Vaccines A and B. The sIPV antigens did not affect the anti-diphtheria or anti-tetanus antibody titers of DTaP-sIPV. Furthermore, the average neutralizing antibody titers of Vaccine A against the attenuated and virulent polioviruses were comparable between M. fascicularis and humans. These results suggest that M. fascicularis may be a useful animal model for predicting the antibody responses to sIPVs in humans, and that it may be likely to reduce the amount of sIPVs contained in DTaP-sIPVs, even for humans. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Safety and immunogenicity of a booster dose of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults: A randomized phase 1 study.

PubMed

Marshall, Helen; Nissen, Michael; Richmond, Peter; Shakib, Sepehr; Jiang, Qin; Cooper, David; Rill, Denise; Baber, James; Eiden, Joseph; Gruber, William C; Jansen, Kathrin U; Anderson, Annaliesa S; Zito, Edward T; Girgenti, Douglas

2016-11-01

A 2-stage, phase 1, randomized, placebo-controlled study in healthy adults to assess immunogenicity and safety of a booster dose at three dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) containing recombinant clumping factor A (ClfA) and capsular polysaccharides 5 and 8 (CP5 and CP8) conjugated to a diphtheria toxoid. Six months after initial single vaccination, in Stage 2, SA3Ag recipients were randomized (1:1) to booster vaccination or placebo, while Stage 1 placebo recipients received placebo again. Pre- and post-vaccination blood samples were analyzed. In Stage 2 (n = 345), pre-booster CP5 and CP8 titers remained high with no increase post-booster. ClfA titers remained high after initial vaccination and increased post-booster, approaching the peak response to the initial dose. Post-booster local reactions were more frequent and of greater severity than reported after the initial vaccination, particularly for the high-dose level recipients. Post hoc analysis showed no dose-response pattern and no obvious association between diphtheria toxoid titers and local reactions after initial or booster vaccination. Immune responses after the initial vaccination persisted for the 12 months studied, with little additional response after the booster dose at 6 months. Post-booster injection site reactions were more frequent and more severe but self-limiting. CLINICALTRIALS. NCT01018641. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Evaluation of a Botulinum Toxoid, Type B, for the Prevention of Shaker Foal Syndrome,

DTIC Science & Technology

1981-11-06

available at this time, To be published in The Proceeding of the 27ta Annual Meeting of the American Association of Equine Practitioners, Nov 28-Dec 2...1981. 19. KEY WORDS (Continu, on reveres aide If necaeewy and Identify by block number) :.~ Toxoid Toxicoinfection Horse BouimPassive Transfer...SFS) is a highly fatal taxicoinfectious form of botulism occurring most often in horses 2 to 8 weeks of age. Clinically SFS is an acute neuromuscular

The preteen visit: an opportunity for prevention.

PubMed

Campos-Outcalt, Doug

2006-12-01

All early adolescents should visit a physician at age 11 or 12 years to receive a set of recommended vaccines. Two vaccines are recommended for boys in this age group-quadrivalent meningococcal conjugate vaccine (MCV4) and tetanus toxoid, reduced diphtheria, and acellular pertussis vaccine (Tdap). Three vaccines are recommended for girls--MCV4, Tdap, and human papilloma virus (HPV) vaccine. In addition, 2 doses of varicella vaccine are now recommended before age 5 years; both boys and girls at age 11 or 12 who have received only 1 dose should be given a second.

A nonadjuvanted transcutaneous tetanus patch is effective in boosting anti-tetanus toxoid immune responses.

PubMed

Seid, Robert C; Reinisch, Christoph; Schlegl, Robert; Moehlen, Michael; Meinke, Andreas; Lundberg, Urban

2014-02-01

Dry tetanus toxoid (TTx) patches were formulated without any adjuvant, with excipients to impart antigen stabilization and to enhance skin delivery. The booster effects of the TTx patches were assessed using a guinea pig model. The study revealed significant rises in TTx IgG titers induced by the TTx patches after a low-dose subcutaneous (s.c.) prime with TTx adsorbed to aluminum hydroxide. The TTx patch can therefore be considered an effective alternative to a subcutaneous booster.

Lymphocyte responses to influenza and tetanus toxoid in vitro following intensive exercise and carbohydrate ingestion on consecutive days.

PubMed

Bishop, Nicolette C; Walker, Gary J; Bowley, Lee A; Evans, Kate F; Molyneux, Karen; Wallace, Fiona A; Smith, Alice C

2005-10-01

The effect of carbohydrate (CHO) ingestion on antigen- (rather than mitogen-) stimulated T-cell responses to prolonged, intensive exercise may give a more realistic insight into the effect of CHO on T-cell functional capacity and subsequent infection risk. This study investigated the effect of CHO ingestion during prolonged, intensive exercise on influenza- and tetanus toxoid-stimulated T-cell cytokine mRNA expression and proliferation. Mitogen- [phytohemagglutinin (PHA)] stimulated proliferation was assessed for comparison. Responses were assessed following exercise on consecutive mornings to determine any carryover effect. Fifteen male games players performed two exercise trials in a double-blind, randomized, crossover design. Each trial comprised 90 min of intensive, intermittent running on consecutive mornings, with either CHO (6.4% wt/vol) or placebo (PLA) beverage ingestion before, during, and after each bout of exercise. Postexercise CD3(+) cell counts were higher in PLA than CHO on both days (P < 0.05). Antigen-stimulated T-cell cytokine mRNA expression was unaffected by exercise or CHO ingestion. Before exercise on day 2, T-cell proliferative responses to PHA, influenza, and tetanus toxoid were higher in CHO than PLA by 99, 80, and 58%, respectively (P < 0.01 for PHA, P < 0.05 for influenza and tetanus toxoid). At 1 h postexercise on day 2, PHA-induced proliferation was 70% higher in CHO than PLA (P < 0.05), yet there were no differences between trials for antigen-induced proliferative responses. Therefore, mitogen-induced T-cell proliferation following strenuous exercise and CHO does not necessarily reflect responses to specific antigens and, consequently, may not provide a good model for the situation in vivo.

Channels Formed by Botulinum, Tetanus, and Diphtheria Toxins in Planar Lipid Bilayers: Relevance to Translocation of Proteins across Membranes

NASA Astrophysics Data System (ADS)

Hoch, David H.; Romero-Mira, Miryam; Ehrlich, Barbara E.; Finkelstein, Alan; Dasgupta, Bibhuti R.; Simpson, Lance L.

1985-03-01

The heavy chains of both botulinum neurotoxin type B and tetanus toxin form channels in planar bilayer membranes. These channels have pH-dependent and voltage-dependent properties that are remarkably similar to those previously described for diphtheria toxin. Selectivity experiments with anions and cations show that the channels formed by the heavy chains of all three toxins are large; thus, these channels could serve as ``tunnel proteins'' for translocation of active peptide fragments. These findings support the hypothesis that the active fragments of botulinum neurotoxin and tetanus toxin, like that of diphtheria toxin, are translocated across the membranes of acidic vesicles.

Collaborative study for the calibration of a replacement International Standard for Tetanus Toxoid Adsorbed.

PubMed

Tierney, Rob; Stickings, Paul; Hockley, Jason; Rigsby, Peter; Iwaki, Masaaki; Sesardic, Dorothea

2011-11-01

We present the results of a collaborative study for the establishment of a replacement International Standard (IS) for Tetanus Toxoid Adsorbed. Two candidate preparations were included in the study, one of which was established as the 4th IS for Tetanus Toxoid Adsorbed at the WHO Expert Committee on Biological Standardization meeting in October 2010. This preparation was found to have a unitage of 490 IU/ampoule, based on calibration in guinea pig challenge assays. Results from mouse challenge assays suggest that the relative performance of two candidate preparations may differ significantly between guinea pigs and mice. The authors note that the number of laboratories that performed guinea pig challenge assays, which are used to calibrate and assign IU, is much lower than in previous collaborative studies and this may have implications for calibration of replacement standards in the future. The issue of assigning separate units to the IS for guinea pig and mouse assays is discussed. The study also assessed performance of the replacement standard in serological assays which are used as alternative procedures to challenge assays for tetanus potency testing. Results suggest that the replacement standard is suitable for use as the reference vaccine in serological assays. Copyright © 2011 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Antibodies derived from a toxoid MEFA (multiepitope fusion antigen) show neutralizing activities against heat-labile toxin (LT), heat-stable toxins (STa, STb), and Shiga toxin 2e (Stx2e) of porcine enterotoxigenic Escherichia coli (ETEC).

PubMed

Rausch, Dana; Ruan, Xiaosai; Nandre, Rahul; Duan, Qiangde; Hashish, Emad; Casey, Thomas A; Zhang, Weiping

2017-04-01

Enterotoxigenic Escherichia coli (ETEC) strains are the main cause of diarrhea in pigs. Pig diarrhea especially post-weaning diarrhea remains one of the most important swine diseases. ETEC bacterial fimbriae including K88, F18, 987P, K99 and F41 promote bacterial attachment to intestinal epithelial cells and facilitate ETEC colonization in pig small intestine. ETEC enterotoxins including heat-labile toxin (LT) and heat-stable toxins type Ia (porcine-type STa) and type II (STb) stimulate fluid hyper-secretion, leading to watery diarrhea. Blocking bacteria colonization and/or neutralizing enterotoxicity of ETEC toxins are considered effective prevention against ETEC diarrhea. In this study, we applied the MEFA (multiepitope fusion antigen) strategy to create toxoid MEFAs that carried antigenic elements of ETEC toxins, and examined for broad antitoxin immunogenicity in a murine model. By embedding STa toxoid STa P12F (NTFYCCELCCNFACAGCY), a STb epitope (KKDLCEHY), and an epitope of Stx2e A subunit (QSYVSSLN) into the A1 peptide of a monomeric LT toxoid (LT R192G ), two toxoid MEFAs, 'LT R192G -STb-Stx2e-STa P12F ' and 'LT R192G -STb-Stx2e-3xSTa P12F ' which carried three copies of STa P12F , were constructed. Mice intraperitoneally immunized with each toxoid MEFA developed IgG antibodies to all four toxins. Induced antibodies showed in vitro neutralizing activities against LT, STa, STb and Stx2e toxins. Moreover, suckling piglets born by a gilt immunized with 'LT R192G -STb-Stx2e-3xSTa P12F ' were protected when challenged with ETEC strains, whereas piglets born by a control gilt developed diarrhea. Results from this study showed that the toxoid MEFA induced broadly antitoxin antibodies, and suggested potential application of the toxoid MEFA for developing a broad-spectrum vaccine against ETEC diarrhea in pigs. Copyright © 2016 Elsevier B.V. All rights reserved.

21 CFR 522.1083 - Gonadotropin releasing factor analog-diphtheria toxoid conjugate.

Code of Federal Regulations, 2012 CFR

2012-04-01

... castration (suppression of testicular function) and reduction of boar taint in intact male pigs intended for slaughter. (3) Limitations. Not approved for use in female pigs and barrows. Do not use in intact male pigs... to use by or on the order of a licensed veterinarian. Pigs should be slaughtered no earlier than 3...

21 CFR 522.1083 - Gonadotropin releasing factor analog-diphtheria toxoid conjugate.

Code of Federal Regulations, 2014 CFR

2014-04-01

... castration (suppression of testicular function) and reduction of boar taint in intact male pigs intended for... veterinarian. Pigs should be slaughtered no earlier than 3 weeks and no later than 10 weeks after the second...

21 CFR 522.1083 - Gonadotropin releasing factor analog-diphtheria toxoid conjugate.

Code of Federal Regulations, 2013 CFR

2013-04-01

... castration (suppression of testicular function) and reduction of boar taint in intact male pigs intended for slaughter. (3) Limitations. Not approved for use in female pigs and barrows. Do not use in intact male pigs... to use by or on the order of a licensed veterinarian. Pigs should be slaughtered no earlier than 3...

Comparison of Three Enzyme-Linked Immunosorbent Assays for Detection of Immunoglobulin G Antibodies to Tetanus Toxoid with Reference Standards and the Impact on Clinical Practice▿

PubMed Central

van Hoeven, Karen H.; Dale, Connie; Foster, Phil; Body, Barbara

2008-01-01

Accurate determination of the concentrations of immunoglobulin G (IgG) antibody to tetanus toxoid is important in order to evaluate the immunogenicity of tetanus toxoid vaccines, determine immune competence in individual patients, and measure the prevalence of immunity in populations. The performance of three commercially available enzyme-linked immunosorbent assays (ELISAs) for IgG antibodies to tetanus toxoid were evaluated. Serially diluted NIBSC 76/589 and TE-3 human tetanus IgG immunoglobulin international reference standards were analyzed in quadruplicate using ELISAs manufactured by The Binding Site, Inc. (VaccZyme); Scimedx; and Euroimmun. In addition, IgG antibodies to tetanus toxoid were measured in 83 deidentified serum specimens using each manufacturer's ELISA. Each ELISA provided linear results when evaluated with the reference preparations. The Binding Site ELISA provided results that closely corresponded to the reference preparations (y = 1.09x − 0.08), whereas the Scimedx ELISA gave results that were consistently lower (y = 0.21x − 0.07) and the Euroimmun ELISA gave results that were consistently higher (y = 1.5x + 0.30) than the reference preparation concentrations. Using the recommended cutoff for each ELISA (<0.10 IU/ml), the overall agreement of all of the ELISA methods was 78%. Three of eighty-three (3.6%) human serum samples demonstrated inadequate immunity with all three assays. The Binding Site ELISA yielded nonprotective antibody concentrations in only these 3 samples, whereas 19 samples (22.9%) according to the Scimedx ELISA and 6 samples (7.2%) according to the Euroimmun ELISA demonstrated nonprotective concentrations. The performance characteristics of ELISAs for tetanus immunoglobulin titers were manufacturer dependent, and the differences translated into important disparities in reported results. PMID:18845832

Immunogenicity and safety of the quadrivalent meningococcal vaccine MenACWY-TT co-administered with a combined diphtheria-tetanus-acellular pertussis vaccine versus their separate administration in adolescents and young adults: A phase III, randomized study.

PubMed

Rivera, Luis; Schwarz, Tino F; Kim, Kyung-Hyo; Kim, Yun-Kyung; Behre, Ulrich; Cha, Sung-Ho; Jo, Dae Sun; Lee, Jacob; Lee, Jin-Soo; Cheuvart, Brigitte; Jastorff, Archana; Van der Wielen, Marie

2018-06-27

This study evaluated the immunogenicity and safety of quadrivalent meningococcal conjugate vaccine using tetanus (T) toxoid as carrier protein (MenACWY-TT) co-administered with combined diphtheria-tetanus-acellular pertussis vaccine (Tdap) versus their separate administration in adolescents and young adults. In this phase III, randomized, partially-blind study (NCT01767376), healthy 11-25-year-olds (N = 660) were randomized (1:1:1) to receive MenACWY-TT and Tdap at Month 0 (Co-ad group), MenACWY-TT at Month 0 and Tdap at Month 1 (ACWY_Tdap group) or Tdap at Month 0 and MenACWY-TT at Month 1 (Tdap_ACWY group). Immune responses to MenACWY-TT were measured by serum bactericidal assay using rabbit complement (rSBA). Anti-diphtheria (D), anti-tetanus (T), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations were assessed using enzyme-linked immunosorbent assays. Non-inferiority of immunogenicity was assessed using pre-defined clinical criteria. Safety was also evaluated. Non-inferiority of immunogenicity of MenACWY-TT and Tdap when co-administered versus their separate administration was demonstrated in terms of rSBA geometric mean titers (GMTs) for 4 meningococcal serogroups and of the percentage of participants with antibody concentrations >1 IU/ml for D and T. Among the pertussis antigens, non-inferiority criteria for geometric mean concentrations (GMCs) were reached for PT, but not met for FHA and PRN. Across all groups, ≥93.2% of participants had vaccine responses to each meningococcal serogroup, ≥99.1% were seroprotected against T and D, and ≥85.5% had booster responses to each pertussis antigen. Robust increases in antibody GMTs/GMCs were observed for all antigens between pre-and post-vaccination. Both vaccines had clinically acceptable safety profiles. Immune responses to MenACWY-TT and to the T and D antigens from Tdap were not impacted by their co-administration. The lower antibody

Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses to a booster dose of DTaP-IPV.

PubMed

Gajdos, Vincent; Vidor, Emmanuel; Richard, Patrick; Tran, Clément; Sadorge, Christine

2015-07-31

This follow-up study assessed the 5-year persistence of vaccine-induced antibodies (Td-IPV or DT-IPV) and the immune response to a booster dose of DTaP-IPV. This was an open-label, parallel-group (two arms), multicentre trial performed at 44 study sites in France. Children aged 11-13 years, of either sex, who received Td-IPV (Revaxis(®)) and DT-IPV (DT Polio(®)) vaccines at 6 years of age in one previous open-label trial with no further vaccination against diphtheria, tetanus, pertussis or poliomyelitis, were enrolled. All participants received a single intramuscular booster dose (0.5mL) of DTaP-IPV vaccine (Tetravac-Acellulaire(®)). Study endpoints were based on antibody persistence and post-booster immune responses. Safety was monitored throughout the study. Descriptive statistics were used for all analyses. Of the 758 children included in the previous study, 274 were included in this follow-up study; 129 had previously been vaccinated with Td-IPV, and 145 had previously received DT-IPV. At least 96.5% of participants in both groups presented an anti-diphtheria and anti-tetanus concentration ≥0.01IU/mL, and anti-poliovirus types 1-3 titres≥8 (1/dilution). Following vaccination with DTaP-IPV, anti-diphtheria and anti-tetanus antibody concentrations ≥0.1IU/mL and anti-poliovirus types 1-3 antibody titres ≥8 (1/dilution) were achieved in all participants. DTaP-IPV was well tolerated in this study. There were no serious adverse events during the study, and no participant withdrew because of adverse events. The present study confirmed the long-term immunity conferred by Td-IPV when given as a booster dose, and supports the use of Td-IPV as a second booster at 6 years of age in children previously vaccinated against diphtheria, tetanus and poliomyelitis types 1-3. Copyright © 2015 Elsevier Ltd. All rights reserved.

Determinants of tetanus toxoid immunization in pregnancy in rural Bihar.

PubMed

Thind, Amardeep

2005-04-01

In order to increase the uptake of tetanus toxoid (TT) vaccination, we need to understand the factors that underlie the decision of the pregnant woman to undergo vaccination, especially in rural areas, where 75% of India's population resides. This paper constructs a model from a data-set of 2398 women in order to understand the determinants ofTTvaccine immunization by women during their most recent pregnancy and applies it to the National Family Health Survey-2 data. The object of the model is to predict the likelyhood of a pregnant woman receiving the recommended two doses of TT vaccine subject to other factors such as birth order, maternal education, prenatal care provider, household standard of living, health-care-seeking decision-maker and service availability. Policy implications of these findings are discussed.

pH-dependent conformational changes of diphtheria toxin adsorbed to lipid monolayers by neutron and X-ray reflection

NASA Astrophysics Data System (ADS)

Kent, Michael; Yim, Hyun; Satija, Sushil; Kuzmenko, Ivan

2006-03-01

Several important bacterial toxins, such as diphtheria, tetanus, and botulinum, invade cells through a process of high affinity binding, internalization via endosome formation, and subsequent membrane penetration of the catalytic domain activated by a pH drop in the endosome. These toxins are composed of three domains: a binding domain, a translocation domain, and an enzyme. The translocation process is not well understood with regard to the detailed conformational changes that occur at each step, To address this, we performed neutron reflectivity measurements for diphtheria toxin bound to lipid monolayers as a function of pH. While the final membrane inserted conformation will not be reproduced with the present monolayer system, important insights can still be gained into several intermediate stages. In particular, we show that no adsorption occurs at pH = 7.6, but strong adsorption occurs over at a pH range from 6.5 to 6.0. Following binding, at least two stages of conformational change occur, as the thickness increases from pH 6.3 to 5.3 and then decreases from pH 5.3 to 4.5. In addition, the dimension of the adsorbed layer substantially exceeds that of the largest dimension in the crystal structure of monomeric diphtheria, suggesting that the toxin may be present as multimers.

Solution conformation and flexibility of capsular polysaccharides from Neisseria meningitidis and glycoconjugates with the tetanus toxoid protein

NASA Astrophysics Data System (ADS)

Abdelhameed, Ali Saber; Morris, Gordon A.; Almutairi, Fahad; Adams, Gary G.; Duvivier, Pierre; Conrath, Karel; Harding, Stephen E.

2016-10-01

The structural integrity of meningococcal native, micro-fluidized and activated capsular polysaccharides and their glycoconjugates - in the form most relevant to their potential use as vaccines (dilute solution) - have been investigated with respect to their homogeneity, conformation and flexibility. Sedimentation velocity analysis showed that the polysaccharide size distributions were generally bimodal with some evidence for higher molar mass forms at higher concentration. Weight average molar masses Mw where lower for activated polysaccharides. Conjugation with tetanus toxoid protein however greatly increased the molar mass and polydispersity of the final conjugates. Glycoconjugates had an approximately unimodal log-normal but broad and large molar mass profiles, confirmed by sedimentation equilibrium “SEDFIT MSTAR” analysis. Conformation analysis using HYDFIT (which globally combines sedimentation and viscosity data), “Conformation Zoning” and Wales-van Holde approaches showed a high degree of flexibility - at least as great as the unconjugated polysaccharides, and very different from the tetanus toxoid (TT) protein used for the conjugation. As with the recently published finding for Hib-TT complexes, it is the carbohydrate component that dictates the solution behaviour of these glycoconjugates, although the lower intrinsic viscosities suggest some degree of compaction of the carbohydrate chains around the protein.

Solution conformation and flexibility of capsular polysaccharides from Neisseria meningitidis and glycoconjugates with the tetanus toxoid protein.

PubMed

Abdelhameed, Ali Saber; Morris, Gordon A; Almutairi, Fahad; Adams, Gary G; Duvivier, Pierre; Conrath, Karel; Harding, Stephen E

2016-10-26

The structural integrity of meningococcal native, micro-fluidized and activated capsular polysaccharides and their glycoconjugates - in the form most relevant to their potential use as vaccines (dilute solution) - have been investigated with respect to their homogeneity, conformation and flexibility. Sedimentation velocity analysis showed that the polysaccharide size distributions were generally bimodal with some evidence for higher molar mass forms at higher concentration. Weight average molar masses M w where lower for activated polysaccharides. Conjugation with tetanus toxoid protein however greatly increased the molar mass and polydispersity of the final conjugates. Glycoconjugates had an approximately unimodal log-normal but broad and large molar mass profiles, confirmed by sedimentation equilibrium "SEDFIT MSTAR" analysis. Conformation analysis using HYDFIT (which globally combines sedimentation and viscosity data), "Conformation Zoning" and Wales-van Holde approaches showed a high degree of flexibility - at least as great as the unconjugated polysaccharides, and very different from the tetanus toxoid (TT) protein used for the conjugation. As with the recently published finding for Hib-TT complexes, it is the carbohydrate component that dictates the solution behaviour of these glycoconjugates, although the lower intrinsic viscosities suggest some degree of compaction of the carbohydrate chains around the protein.

Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception.

PubMed

Cerpa, V; Gonzalez, A; Richerson, G B

2014-10-24

In genetically-modified Lmx1b(f/f/p) mice, selective deletion of LMX1B in Pet-1 expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal thermoregulation. This mouse model has been valuable in defining the normal role of 5-HT neurons, but it is possible that developmental compensation reduces the severity of observed deficits. Here we studied mice genetically modified to express diphtheria toxin receptors (DTR) on Pet-1 expressing neurons (Pet-1-Cre/floxed DTR or Pet1/DTR mice). These mice developed with a normal complement of 5-HT neurons. As adults, systemic treatment with 2-35μg of diphtheria toxin (DT) reduced the number of tryptophan hydroxylase-immunoreactive (TpOH-ir) neurons in the raphe nuclei and ventrolateral medulla by 80%. There were no effects of DT on minute ventilation (VE) or the ventilatory response to hypercapnia or hypoxia. At an ambient temperature (TA) of 24°C, all Pet1/DTR mice dropped their body temperature (TB) below 35°C after DT treatment, but the latency was shorter in males than females (3.0±0.37 vs. 4.57±0.29days, respectively; p<0.001). One week after DT treatment, mice were challenged by dropping TA from 37°C to 24°C, which caused TB to decrease more in males than in females (29.7±0.31°C vs. 33.0±1.3°C, p<0.01). We conclude that the 20% of 5-HT neurons that remain after DT treatment in Pet1/DTR mice are sufficient to maintain normal baseline breathing and a normal response to CO2, while those affected include some essential for thermoregulation, in males more than females. In comparison to models with deficient embryonic development of 5-HT neurons, acute deletion of 5-HT neurons in adults leads to a greater defect in thermoregulation, suggesting that significant developmental compensation can occur. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Real time and accelerated stability studies of Tetanus toxoid manufactured in public sector facilities of Pakistan.

PubMed

Parveen, Ghazala; Hussain, Shahzad; Malik, Farnaz; Begum, Anwar; Mahmood, Sidra; Raza, Naeem

2013-11-01

Tetanus is an acute illness represented by comprehensive increased inflexibility and spastic spasms of skeletal muscles. The poor quality tetanus toxoid vaccine can raise the prevalence of neonatal tetanus. WHO has taken numerous steps to assist national regulatory authorities and vaccine manufacturers to ensure its quality and efficacy. It has formulated international principles for stability evaluation of each vaccine, which are available in the form of recommendations and guidelines. The aim of present study was to ensure the stability of tetanus vaccines produced by National Institute of Health, Islamabad, Pakistan by employing standardized methods to ensure constancy of tetanus toxoid at elevated temperature, if during storage/transportation cold chain may not be maintained in hot weather. A total of three batches filled during full-scale production were tested. All Stability studies determination were performed on final products stored at 2-8°C and elevated temperatures in conformance with the ICH Guideline of Stability Testing of Biological Products. These studies gave comparison between real time shelf-life stability and accelerated stability studies. The findings indicate long﷓term thermo stability and prove that this tetanus vaccine can remain efficient under setting of routine use when suggested measures for storage and handling are followed in true spirit.

Microbiological and molecular characterization of Corynebacterium diphtheriae isolated in Algeria between 1992 and 2015.

PubMed

Benamrouche, N; Hasnaoui, S; Badell, E; Guettou, B; Lazri, M; Guiso, N; Rahal, K

2016-12-01

The objectives of this study were to undertake the microbiological and molecular characterization of Corynebacterium diphtheriae isolates collected in Algeria during epidemic and post-epidemic periods between 1992 and 2015. Microbiological characterization includes the determination of biotype and toxigenicity status using phenotypic and genotypic methods. Antimicrobial susceptibility was determined by the E-test method. Molecular characterization was performed by multi-locus sequence typing. In total, there were 157 cases of C. diphtheriae isolates, 127 in patients with respiratory diphtheria and 30 with ozena. Isolates with a mitis biotype were predominant (122 out of 157; 77.7%) followed by belfanti (28 out of 157; 17.8%) and gravis biotype (seven out of 157; 4.5%). Toxigenic isolates were predominant in the period 1992-2006 (74 out of 134) whereas in the period 2007-2015, only non-toxigenic isolates circulated (23 out of 23). All 157 isolates were susceptible to erythromycin, gentamicin, vancomycin and cotrimoxazole. Reduced susceptibility to penicillin G, cefotaxime, tetracycline and chloramphenicol was detected in 90 (57.3%), 88 (56.1%), 112 (71.3%) and 90 (57.3%) isolates, respectively. Multi-locus sequence typing analysis indicates that sequence type 116 (ST-116) was the most frequent, with 65 out of 100 isolates analysed, in particular during the epidemic period 1992-1999 (57 out of 65 isolates). In the post-epidemic period, 2000-2015, 13 different sequence types were isolated. All belfanti isolates (ten out of 100 isolates) belonged to closely related sequence types grouped in a phylogenetically distinct eBurst group and were collected exclusively in ozena cases. In conclusion, the epidemic period was associated with ST-116 while the post-epidemic period was characterized by more diversity. Belfanti isolates are grouped in a phylogenetically distinct clonal complex. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases

Mechanism of Metal Ion Activation of the Diphtheria Toxin Repressor DtxR

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Aquino,J.; Tetenbaum-Novatt, J.; White, A.

2005-01-01

The diphtheria toxin repressor (DtxR) is a metal ion-activated transcriptional regulator that has been linked to the virulence of Corynebacterium diphtheriae. Structure determination has shown that there are two metal ion binding sites per repressor monomer, and site-directed mutagenesis has demonstrated that binding site 2 (primary) is essential for recognition of the target DNA repressor, leaving the role of binding site 1 (ancillary) unclear. Calorimetric techniques have demonstrated that although binding site 1 (ancillary) has high affinity for metal ion with a binding constant of 2 x 10{sup -7}, binding site 2 (primary) is a low-affinity binding site with amore » binding constant of 6.3 x 10{sup -4}. These two binding sites act in an independent fashion, and their contribution can be easily dissected by traditional mutational analysis. Our results clearly demonstrate that binding site 1 (ancillary) is the first one to be occupied during metal ion activation, playing a critical role in stabilization of the repressor. In addition, structural data obtained for the mutants Ni-DtxR(H79A, C102D), reported here, and the previously reported DtxR(H79A) have allowed us to propose a mechanism of metal activation for DtxR.« less

Mechanism of Metal Ion Activation of the Diphtheria Toxin Repressor DtxR

NASA Astrophysics Data System (ADS)

D'Aquino, J. Alejandro; Ringe, Dagmar

2006-08-01

The diphtheria toxin repressor, DtxR, is a metal ion-activated transcriptional regulator that has been linked to the virulence of Corynebacterium diphtheriae. Structure determination has shown that there are two metal ion binding sites per repressor monomer, and site-directed mutagenesis has demonstrated that binding site 2 (primary) is essential for recognition of the target DNA repressor, leaving the role of binding site 1 (ancillary) unclear (1 - 3). Calorimetric techniques have demonstrated that while binding site 1 (ancillary) has high affinity for metal ion with a binding constant of 2 × 10-7, binding site 2 (primary) is a low affinity binding site with a binding constant of 6.3 × 10-4. These two binding sites act independently and their contribution can be easily dissected by traditional mutational analysis. Our results clearly demonstrate that binding site 1 (ancillary) is the first one to be occupied during metal ion activation, playing a critical role in stabilization of the repressor. In addition, structural data obtained for the mutants Ni-DtxR(H79A,C102D), reported here and the previously reported DtxR(H79A) (4) has allowed us to propose a mechanism of metal ion activation for DtxR.

Complete Closed Genome Sequence of Nontoxigenic Invasive Corynebacterium diphtheriae bv. mitis Strain ISS 3319.

PubMed

Azevedo Antunes, Camila; Richardson, Emily J; Quick, Joshua; Fuentes-Utrilla, Pablo; Isom, Georgia L; Goodall, Emily C; Möller, Jens; Hoskisson, Paul A; Mattos-Guaraldi, Ana Luiza; Cunningham, Adam F; Loman, Nicholas J; Sangal, Vartul; Burkovski, Andreas; Henderson, Ian R

2018-02-01

The genome sequence of the human pathogen Corynebacterium diphtheriae bv. mitis strain ISS 3319 was determined and closed in this study. The genome is estimated to have 2,404,936 bp encoding 2,257 proteins. This strain also possesses a plasmid of 1,960 bp. Copyright © 2018 Azevedo Antunes et al.

[A large-scale epidemic of diphtheria in Moscow in recent years: patterns of development].

PubMed

Chistiakova, G G; Filatov, N N; Korzhenkova, M P; Solodovnikov, Iu P; Lytkina, I N; Maksimova, N M; Markina, S S

2001-01-01

Data on the dynamics of diphtheria morbidity in Moscow in 1958-1999 are presented. The last epidemic which started at the end of the 1980s and reached its peak in 1994, giving a 59-fold rise in morbidity in comparison with the pre-epidemic period, is characterized in detail. During the epidemic 12,267 persons fell ill, 454 of them died (mortality rate was 4%). Having started in Moscow, the epidemic gradually spread not only over the territory of Russia, but also over some other republics of the former Soviet Union (Ukraine, Belarus, etc.). Possible causes of this epidemic emergency are considered. The ever increasing share of adult population among persons affected by the epidemic (75%) is noted. The infection adults is characterized by severity of clinical manifestations and increased morbidity among adults, is shown. Under complicated social and economic conditions (crisis situation) the increase of groups of high risk which included unemployed adults of working age, retirees as well as socially non-adapted persons, was registered. Mainly these groups determined tense epidemiological situation in diphtheria in Moscow.

Stabilization of Tetanus Toxoid Encapsulated in PLGA Microspheres

PubMed Central

Jiang, Wenlei; Schwendeman, Steven P.

2014-01-01

Delivery of vaccine antigens from controlled-release poly(lactic/glycolic acid) (PLGA) microspheres is a novel approach to reduce the number of antigen doses required for protection against infection. A major impediment to developing single-shot vaccines is encapsulated antigen instability during months of exposure to physiological conditions. For example, efforts to control neonatal tetanus in developing countries with a single-dose TT vaccine have been plagued by poor stability of the 150 kDa formaldehyde-detoxified protein antigen, tetanus toxoid (TT) in PLGA microspheres. We examined the denatured states of PLGA-encapsulated TT, revealing two primary TT instability mechanisms: 1) protein aggregation mediated by formaldehyde and 2) acid-induced protein unfolding and epitope damage. Further, we systemically identified excipients which can efficiently inhibit TT aggregation and retain TT antigenicity under simulated deleterious conditions, i.e., elevated temperature and humidity. By employing these novel additives in the PLGA system, we report the slow and continuous release of high doses of TT for one month with retained antigen stability during bioerosion of PLGA. PMID:18710256

Stabilization of tetanus toxoid encapsulated in PLGA microspheres.

PubMed

Jiang, Wenlei; Schwendeman, Steven P

2008-01-01

Delivery of vaccine antigens from controlled-release poly(lactic/glycolic acid) (PLGA) microspheres is a novel approach to reduce the number of antigen doses required for protection against infection. A major impediment to developing single-shot vaccines is encapsulated antigen instability during months of exposure to physiological conditions. For example, efforts to control neonatal tetanus in developing countries with a single-dose TT vaccine based on PLGA microspheres have been plagued by poor stability of the 150 kDa formaldehyde-detoxified protein antigen, tetanus toxoid (TT), in the polymer. We examined the denatured states of PLGA-encapsulated TT, revealing two primary TT instability mechanisms: (1) protein aggregation mediated by formaldehyde and (2) acid-induced protein unfolding and epitope damage. Further, we systematically identified excipients, which can efficiently inhibit TT aggregation and retain TT antigenicity under simulated deleterious conditions, i.e., elevated temperature and humidity. By employing these novel additives in the PLGA system, we report the slow and continuous release of high doses of TT for one month with retained antigen stability during bioerosion of PLGA.

ACTION OF TRITIATED TETANUS TOXIN AND TOXOID UPTON THE NERVOUS SYSTEM AND UPON THE ANTIBOYD FORMING MECHANISM. Period covered: April 1, 1959-March 31, 1961

DOE Office of Scientific and Technical Information (OSTI.GOV)

Speirs, R.S.

1961-10-31

>Progress is reported in studies on the action of tritiated tetanus toxin and toxoid upon the nervous system and upon the antibody forming mechanisms in mice. Procedures are described for the preparation of purified tritiated tetanus toxin. The tritiated toxin was injected into mice immunized to tetanus toxoid. Distinct differences were noted in the cellular reaction to the tritiated antigen in immunized and control animals. The data suggest that antibody-producing cells contain antigen at the time antibody is being produced. A quantitative procedure was developed for determining the number of cells responding during an inflammation. Procedures were developed for themore » automatic processing of radioautograms. ( C.H.)« less

Reduction of human anti-tetanus toxoid antibody in hu-PBL-SCID mice by immunodominant peptides of tetanus toxoid

PubMed Central

Jackson, D J; Elson, C J; Kumpel, B M

2004-01-01

Immunotherapy of murine autoimmune and allergic diseases by administration of peptides corresponding to the dominant T cell epitope is a reality. However, problems remain in applying this therapy to reduce antibody responses in humans. To overcome these difficulties, a preclinical system was developed to test the effect of immunodominant peptides from a common antigen, tetanus toxoid (TT), on the long-term human anti-TT response. Individuals whose T cells proliferated against dominant TT peptides were identified. Peripheral blood leucocytes (PBL) from these donors were injected intraperitoneally (i.p.) into mice with severe combined immunodeficiency (SCID) that had been depleted of murine natural killer (NK) cells (hu-PBL-SCID mice). Peptides or PBS were injected i.p. before a further injection of PBL and immunization with TT. The concentration of human IgG and anti-TT in murine plasma was followed for 10 weeks. The total IgG was similar in both groups. By contrast, there was a statistically significant reduction in IgG anti-TT from eight weeks onwards. It is considered that the hu-PBL-SCID model system may provide a means by which the efficacy of peptide immunotherapy for reduction of pathological antibodies in humans can be examined. PMID:15270840

Booster Vaccination: The Role of Reduced Antigen Content Vaccines as a Preschool Booster

PubMed Central

Conversano, Michele; Zivelonghi, Giambattista; Zoppi, Giorgio

2014-01-01

The need for boosters for tetanus, diphtheria, pertussis, and polio, starting from preschool age, is related to the waning immune protection conferred by vaccination, the elimination/reduction of natural boosters due to large-scale immunization programs, and the possibility of reintroduction of wild agents from endemic areas. Taking into account the relevance of safety/tolerability in the compliance with vaccination among the population, it have been assessed whether today enough scientific evidences are available to support the use of dTap-IPV booster in preschool age. The review of the literature was conducted using the PubMed search engine. A total of 41 works has been selected; besides, the documentation produced by the World Health Organization, the European Centre for Disease Control, and the Italian Ministry of Health has been consulted. Many recent papers confirm the opportunity to use a low antigenic dose vaccine starting from 4 to 6 years of age. There is also evidence that 10 years after immunization the rate of seroprotected subjects against diphtheria does not differ significantly between those vaccinated with paediatric dose (DTaP) or reduced dose (dTaP or dTap) product. The dTpa vaccine is highly immunogenic for diphtheria toxoids regardless of prior vaccination history (2 + 1 and 3 + 1 schedules). PMID:24678509

[Relationship between the culture medium and the fatty acid composition of diphtheria and non-pathogenic corynebacteria].

PubMed

Vasiurenko, Z P; Siniak, K M

1977-04-01

The gasochromatic method was applied to the study of the cellular fatty acids composition in diphtheria and nonpathogenic corynebacteria (diphtheroids and psendo diptheria bacillus). Marked differences in the content of unsaturated fatty acids were revealed in them. Thus, palmito leic acid served the preponderant unsaturated fatty acid in Corynebacteria diphtheriae, and unsaturated fatty acids with 18 carbon atoms (octadeconoic and linoleic)--in nonpathogenic corynebacteria. The mentioned changes permit use this sign as differential. When grown on Loeffler's medium all the corynebacteria under study had a similar fatty acid composition characterized by the prevalence of unsaturated fatty acids with 18 carbon atoms. On the basis of studying the fatty acid spectrum of the nutrient media used it is supposed that one of the factors determining the revealed dependence of the corynebacterial fatty acid composition on the culture medium was the fatty acid composition of the latter.

Tetanus toxoid coverage as an indicator of serological protection against neonatal tetanus.

PubMed Central

Deming, Michael S.; Roungou, Jean-Baptiste; Kristiansen, Max; Heron, Iver; Yango, Alphonse; Guenengafo, Alexis; Ndamobissi, Robert

2002-01-01

OBJECTIVE: A Multiple-Indicator Cluster Survey (MICS) was conducted at mid-decade in more than 60 developing countries to measure progress towards the year 2000 World Summit for Children goals. These goals included the protection of at least 90% of children against neonatal tetanus through the immunization of their mothers, as measured by tetanus toxoid (TT) coverage. In the Central African Republic (CAR), serological testing was added to the MICS to understand better the relationship between survey estimates of TT coverage and the prevalence of serological protection. METHODS: In the CAR MICS, mothers of children younger than one year of age gave verbal histories of the TT vaccinations they had received, using the MICS TT questionnaire. A subsample of mothers was tested for tetanus antitoxin, using a double-antigen enzyme-linked immunoadsorbent assay (ELISA). Seropositivity was defined as a titre of > or =0.01 IU/ml, and TT coverage was defined as the proportion of mothers protected at delivery, according to their history of TT vaccinations. FINDINGS: Among the 222 mothers in the subsample, weighted TT coverage was 74.4% (95% Confidence Interval (CI); 67.0% - 81.7%) and tetanus antitoxin seroprevalence was 88.7% (95% CI; 83.2% - 94.2%). The weighted median antitoxin titre was 0.35 IU/ml. CONCLUSIONS: Tetanus toxoid coverage in the CAR was lower than the prevalence of serological protection against neonatal tetanus. If this relationship holds for other countries, TT coverage estimates from the MICS may underestimate the extent to which the year 2000 goal for protecting children against neonatal tetanus was reached. We also showed that a high level of serological protection had been achieved in a country facing major public health challenges and resource constraints. PMID:12378286

Rapid microbiochemical identification of Corynebacterium diphtheriae and other medically important corynebacteria.

PubMed Central

Thompson, J S; Gates-Davis, D R; Yong, D C

1983-01-01

A rapid biochemical method based on the fermentation of carbohydrates, the hydrolysis of urea, and the reduction of nitrate was used to identify Corynebacterium diphtheriae, C. ulcerans, C. pseudodiphtheriticum, C. haemolyticum, C. pseudotuberculosis, C. pyogenes, C. ovis, the Centers for Disease Control JK group, and Rhodococcus (Corynebacterium) equi. With this procedure identification was confirmed for 133 stock cultures and clinical isolates of corynebacteria. Most were identified within 1 h and all were identified within 4 h after inoculation into the test substrates. PMID:6355166

Orally administered recombinant Lactobacillus casei vector vaccine expressing β-toxoid of Clostridium perfringens that induced protective immunity responses.

PubMed

Alimolaei, Mojtaba; Golchin, Mehdi; Ezatkhah, Majid

2017-12-01

Clostridium perfringens types B and C cause enteritis and enterotoxemia in animals. The conventional vaccine production systems need time-consuming detoxification and difficult quality control steps. In this study, a modified β-toxoid gene was synthesized, cloned into the pT1NX vector, and electroporated into Lactobacillus casei competent cells to yield L. casei-β recombinant strain. Surface expression of the recombinant β-toxoid was evaluated by ELISA and confirmed by immunofluorescence microscopy. Vaccinated BALB/c mice with L. casei-β induced potent humoral and cell-mediated immune responses that were protective against lethal challenges with 100 MLD/mL of the β-toxin. Safety and efficacy of the recombinant clone was evaluated and the presumptive toxicity of L. casei-β was studied by toxicity test and histopathological findings, which were the same as negative controls. Our results support the use of L. casei as a live oral vector vaccine, and that the recombinant L. casei-β is a potential candidate for being used in the control of enterotoxemia diseases caused by C. perfringens types B and C. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Recombinant Probiotic, Lactobacillus casei, Expressing the Clostridium perfringens α-toxoid, as an Orally Vaccine Candidate Against Gas Gangrene and Necrotic Enteritis.

PubMed

Alimolaei, Mojtaba; Golchin, Mehdi; Abshenas, Jalil; Ezatkhah, Majid; Bafti, Mehrdad Shamsaddini

2018-06-01

The alpha-toxin is one of the virulence factors of Clostridium perfringens for gas gangrene in humans and animals or necrotic enteritis in poultry. The C-terminal domain of this toxin ( cpa 247-370 ) was synthesized and cloned into pT1NX vector to construct the pT1NX-alpha plasmid. This surface-expressing plasmid was electroporated into Lactobacillus casei ATCC 393, generating the recombinant L. casei strain expressing alpha-toxoid (LC-α strain). Expression of this modified alpha-toxoid was confirmed by SDS-PAGE, immunoblotting, and direct immunofluorescence microscopy. BALB/c mice, immunized orally by the recombinant LC-α strain, elicited mucosal and significantly humoral immune responses (p < 0.05) and developed a protection against 900 MLD/mL of the standard alpha-toxin. This study showed that this recombinant LC-α strain could be a promising vaccine candidate against gas gangrene and necrotic enteritis.

TETANUS PROPHYLAXIS IN THE UNIMMUNIZED—Administration of Oxytetracycline and Intradermal Toxoid, with Restricted Use of Tetanus Antitoxin

PubMed Central

McDonald, Richard T.; Kirtland, Howard B.; Brown, Roland G.

1962-01-01

Prophylactic tetanus antitoxin is ineffective in the prevention of experimental tetanus. That this may be true clinically is indicated by the fact that there are increasing numbers of cases of tetanus in humans after prophylactic tetanus antitoxin. Despite this known ineffectiveness and the high rate of reaction to antitoxin (5 per cent), many physicians continue to use it prophylactically, apparently for medical legal reasons. Since tetanus in civilian wounds is so rare, occurring approximately once in every million wounds, the routine use of tetanus antitoxin will probably cause more harm than good. It has been demonstrated experimentally that oxytetracycline is the most effective antimicrobial in the prevention of tetanus. It is, therefore, believed that adequate tetanus prophylaxis may be obtained by meticulous debridement and cleansing of the wound, by the administration of 1 gm. oxytetracycline daily for five days, and by intradermal administration of tetanus toxoid on the first, fourth and seventh days. Tetanus antitoxin is not given unless contaminated wounds have ben neglected for eight hours or more. In these instances, 15,000 units or more of tetanus antitoxin is given. Tetanus toxoid remains the best wound prophylaxis and greater emphasis should be placed on immunizing entire populations. PMID:18732507

[Prevalence of hyperimmunization against tetanus and systematic adverse reactions to tetanus toxoid in children].

PubMed

Szenborn, Leszek; Saraczyńska, Elzbieta; Ilnicki, Lucjan

2008-01-01

during the last 30 years we have observed only two children (aged 6 and 3 years) with systemic reactions after tetanus vaccine, given unnecessarily 5 and 10 months after appropriate primary immunization. The adverse reactions after tetanic toxoid appear to be directly related to excessive titre of protecting antibodies. The aim of this paper is to investigate the concentration of tetanus antibodies, which may help to define the risk of adverse reactions. tests were carried out in 190 children (86 male, 104 female) aged 7 (n=95) and 14 (n=95) years. Antibodies to tetanus toxoid were determined using a commercial EIA. all examined children had protective concentration of tetanus antibodies (above 0.01 IU/ml; range from 0.1 to 6.0 IU/mL). There were significant differences between antibodies concentrations (GMC) in children aged 7 and 14 years (0.93 vs. 1,76 IU/ml; p=0.048). The antibodies concentrations above 1 IU/ml which indicate long term protection were more frequently observed in children aged 14 than those aged 7 years (73 vs. 59%; not statistically significant). Only 6.84% of all examined children (n=190) had high antibodies concentration above 5 IU/ml, which could increase the risk of side effects if the next booster would be given during the next 5 years. children in Poland are only slightly exposed to risk of severe side effects after vaccination against tetanus. The tetanus immunity in examined children can be assessed as very good.

Improved stability and immunological potential of tetanus toxoid containing surface engineered bilosomes following oral administration.

PubMed

Jain, Sanyog; Harde, Harshad; Indulkar, Anura; Agrawal, Ashish Kumar

2014-02-01

The present study was designed with the objective to investigate the stability and potential of glucomannan-modified bilosomes (GM-bilosomes) in eliciting immune response following oral administration. GM-bilosomes exhibited desired quality attributes simultaneously maintaining the chemical and conformation stability of the tetanus toxoid (TT) entrapped in to freeze dried formulations. The GM-bilosomes exhibited excellent stability in different simulated biological fluids and sustained release profile up to 24 h. GM-bilosomes elicited significantly higher (P<0.05) systemic immune response (serum IgG level) as compared to bilosomes, niosomes and alum adsorbed TT administered through oral route. More importantly, GM-bilosomes were found capable of inducing mucosal immune response, i.e. sIgA titre in salivary and intestinal secretions as well as cell mediated immune response (IL-2 and IFN-γ levels in spleen homogenate) which was not induced by i.m. TT, the conventional route of immunization. Conclusively, GM-bilosomes could be considered as a promising carrier and adjuvant system for oral mucosal immunization. This team reports on the development and effects of a glucomannan-modified bilosome as an oral vaccine vector, using tetanus toxoid in the experiments. These GM-bilosomes not only elicited significantly higher systemic immune response as compared to bilosomes, niosomes and alum adsorbed orally administered TT, but also demonstrated mucosal immune response induction as well as cell mediated immune responses, which were not induced by the conventional route of immunization. © 2014.

ENHANCED ANTITOXIN RESPONSES IN IRRADIATED MICE ELICITED BY COMPLEXES OF TETANUS TOXOID AND SPECIFIC ANTIBODY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoner, R.D.; Terres, G.

1963-12-01

Enhanced primary antitoxin responses were obtained in mice immunized by intravenous injection with complexes of tetanus toxoid and mouse antitoxin, presumably formed either in vivo, or prepared in vitro in antigen-antibody ratios of antibody excess, equivalence, and antigen excess. The demonstration of the enhancement phenomenon elicited by complexes of toxoid and isologous mouse antitoxin provide conclusive evidence that the antibody portion of the complex does not need to be of heterologous origin in order to elicit enhanced primary antibody responses in mice. Intravenous immunization with the above complexes elicited enhanced primary responses in irradiated animals, whereas minimal responses were obtainedmore » with antigen only. Littie difference was observed in primary responses in nonirradiated mice when antigen only or antigen complexed with specific antibody is given by subcutaneous injection. However, enhanced primary antitoxin responses were obtained in irradiated mice (400 rad) immunized with the various complexes over the responses observed in irradiated animals immunlzed with antigen only. The greatest degree of enhancement occurred when the complexes were prepared in the region of equivalence and antigen excess. Secondary antitoxin responses were repressed when the same complexes of antigen and antibody were injected to elicit secondary responses. A corresponding repression of secondary responses was observed in irradiated mice when radiation doses of 300 rad were delivered 24 hr before the second injection of antigen complexed with specific mouse antitoxin. (BBB)« less

Enhanced immunogenicity of a tricomponent mannan tetanus toxoid conjugate vaccine targeted to dendritic cells via Dectin-1 by incorporating β-glucan.

PubMed

Lipinski, Tomasz; Fitieh, Amira; St Pierre, Joëlle; Ostergaard, Hanne L; Bundle, David R; Touret, Nicolas

2013-04-15

In a previous attempt to generate a protective vaccine against Candida albicans, a β-mannan tetanus toxoid conjugate showed poor immunogenicity in mice. To improve the specific activation toward the fungal pathogen, we aimed to target Dectin-1, a pattern-recognition receptor expressed on monocytes, macrophages, and dendritic cells. Laminarin, a β-glucan ligand of Dectin-1, was incorporated into the original β-mannan tetanus toxoid conjugate providing a tricomponent conjugate vaccine. A macrophage cell line expressing Dectin-1 was employed to show binding and activation of Dectin-1 signal transduction pathway by the β-glucan-containing vaccine. Ligand binding to Dectin-1 resulted in the following: 1) activation of Src family kinases and Syk revealed by their recruitment and phosphorylation in the vicinity of bound conjugate and 2) translocation of NF-κB to the nucleus. Treatment of immature bone marrow-derived dendritic cells (BMDCs) with tricomponent or control vaccine confirmed that the β-glucan-containing vaccine exerted its enhanced activity by virtue of dendritic cell targeting and uptake. Immature primary cells stimulated by the tricomponent vaccine, but not the β-mannan tetanus toxoid vaccine, showed activation of BMDCs. Moreover, treated BMDCs secreted increased levels of several cytokines, including TGF-β and IL-6, which are known activators of Th17 cells. Immunization of mice with the novel type of vaccine resulted in improved immune response manifested by high titers of Ab recognizing C. albicans β-mannan Ag. Vaccine containing laminarin also affected distribution of IgG subclasses, showing that vaccine targeting to Dectin-1 receptor can benefit from augmentation and immunomodulation of the immune response.

T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment.

PubMed

Winthrop, Kevin L; Korman, Neil; Abramovits, William; Rottinghaus, Scott T; Tan, Huaming; Gardner, Annie; Mukwaya, Geoffrey; Kaur, Mandeep; Valdez, Hernan

2018-06-01

Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients. Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses. Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration. There was no placebo control. Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Vaccine responsiveness in premature infants.

PubMed

Baxter, David

2010-06-01

The purpose of this review is to document adaptive immune responses in premature infants with a gestational age ≤32 weeks to the different vaccines used in the primary immunisation programme in the UK. Evidence suggests that these infants have impaired immune functioning that is consequent on maturational status and which resolve at variable time periods after birth - this impacts both on their risk of infection and response to vaccination. Assessing vaccine responsiveness can help establish whether the administration of additional vaccines is appropriate for a premature infant, and this may be determined either by vaccine immunogenicity or efficacy studies. The focus of the paper is immunogenicity studies for the following vaccines: tetanus, and diphtheria (toxoid vaccines), Haemophilus influenzae type b (Hib), meningococcal C (Men C) and pneumococcal (PnC) (subunit glycoconjugate vaccines), pertussis (subunit vaccine) and polio (inactivated vaccine). Data show that immunogenicity in premature infants is vaccine specific and whilst highly protective for the toxoid and inactivated preparations, responses to the subunit preparations are less optimal and consequently additional vaccinations or serology testing for ≤32 week gestation infants be considered.

Liposomes containing NY‑ESO‑1/tetanus toxoid and adjuvant peptides targeted to human dendritic cells via the Fc receptor for cancer vaccines.

PubMed

Cruz, Luis J; Rueda, Felix; Simón, Lorena; Cordobilla, Begoña; Albericio, Fernando; Domingo, Joan C

2014-04-01

To improve the immunological response against tumors, a vaccine based on nanoliposomes targeted to the Fcg-receptor was developed to enhance the immunogenicity of tumor-associated antigens (TAAs). Using human dendritic cells in vitro, a fragment of the TAA NY-ESO-1 combined with a T-helper peptide from the tetanus toxoid encapsulated in nanoliposomes was evaluated. In addition, peptides Palm-IL-1 and MAP-IFN-g were coadministered as adjuvants to enhance the immunological response. Coadministration of Palm-IL-1 or MAP-IFN-g peptide adjuvants and the hybrid NY-ESO-1-tetanus toxoid (soluble or encapsulated in nanoliposomes without targeting) increased immunogenicity. However, the most potent immunological response was obtained when the peptide adjuvants were encapsulated in liposomes targeted to human dendritic cells via the Fc receptor. This targeted vaccine strategy is a promising tool to activate and deliver antigens to dendritic cells, thus improving immunotherapeutic response in situations in which the immune system is frequently compromised, as in advanced cancers.

Scaling up interventions to eliminate neonatal tetanus: factors associated with the coverage of tetanus toxoid and clean deliveries among women in Vientiane, Lao PDR.

PubMed

Masuno, Kanako; Xaysomphoo, Duangpachan; Phengsavanh, Alongkone; Douangmala, Somthana; Kuroiwa, Chushi

2009-07-09

The Lao People's Democratic Republic (PDR) is one of seven countries that have not eliminated maternal and neonatal tetanus in more than 50% of districts. We conducted a community-based household survey to assess the achievements of strategies towards maternal and neonatal tetanus elimination in the capital province. The coverage of tetanus toxoid (TT) was 79.7% by the protection-at-birth (PAB) method. The percentages of deliveries attended by skilled personnel and of deliveries at a health facility were 68.4% and 63.7%, respectively. The progress towards eliminating neonatal tetanus in Lao PDR is not sufficient despite the study sites being placed in the capital province. The lack of continuum of care for mothers and newborns is the major obstacle to scale up the tetanus toxoid coverage and PAB as well as clean deliveries.

Inhibitory activity of fenoterol on Dermatophagoides-, Parietaria-, tetanus-toxoid-, and Candida albicans-stimulated blood mononuclear cells: differences in beta2-adrenoreceptor stimulation but not in cell apoptosis.

PubMed

Silvestri, M; Oddera, S; Scarso, L; Pistoia, V; Tasso, P; Rossi, G A

2000-05-01

beta2-adrenoreceptor agonists have the ability to downregulate in vitro the proliferative response of peripheral blood mononuclear cells (BMCs). This activity could be related to a variety of beta2-adrenoreceptor-mediated functions, including induction of cell apoptosis in activated T-cells. To test this hypothesis, BMCs from atopic subjects, sensitized to house dust mites (Dermatophagoides [Der p]) and/or to Parietaria were incubated with fenoterol (10(-8)-10(-5) M) in the presence of (a) purified allergen extracts (Der p [5 microg/mL] or Parietaria [5 microg/mL]) or (b) antigens (tetanus toxoid [1 microg/mL] or Candida albicans [5 x 10(5) bodies/mL]). The BMC proliferation was assessed by [3H] thymidine incorporation and cell apoptosis was assessed by evaluating DNA fragmentation by a fluorescence technique, using propidium iodide. In cultures stimulated with Der p or with Parietaria, fenoterol induced a dose-dependent inhibition of BMC proliferation, significant also at the lowest concentration tested (10(-8) M) (p < 0.05, each comparison). In contrast, the inhibitory activity of the drug on tetanus-toxoid-stimulated BMCs was significant only at the highest dose tested (10(-5)M) (p < 0.05), whereas no effect was seen when BMCs were stimulated with C. albicans extract (p > 0.05). The different inhibitory efficacy of fenoterol appeared to be related to the degree of activation of beta2-adrenoreceptors on the different BMC populations that responded to the different stimuli. Indeed, in the presence of fenoterol (10(-6) and 10(-5)M), a significant increase in cyclic adenosine monophosphate (cAMP) levels was seen in Der p- or Parietaria-stimulated cells (p < 0.05; each comparison), but not in cell cultures stimulated with tetanus toxoid or with C. albicans extracts (p > 0.05; each comparison). Finally, the percentage of cells with fragmented DNA was lower in cultures stimulated with Der p or Parietaria than in those stimulated with tetanus toxoid or C. albicans, and

Immunogenicity and Safety of a Booster Injection of DTap-IPV//Hib (Pentaxim) Administered Concomitantly With Tetravalent Dengue Vaccine in Healthy Toddlers 15-18 Months of Age in Mexico: A Randomized Trial.

PubMed

Melo, Flor Irene Rodriguez; Morales, José Juan Renteria; De Los Santos, Abiel Homero Mascareñas; Rivas, Enrique; Vigne, Claire; Noriega, Fernando

2017-06-01

The live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in a number of dengue endemic countries for individuals ≥9 years of age. Before the integration of any vaccine into childhood vaccination schedules, a lack of immune interference and acceptable safety when coadministered with other recommended vaccines should be demonstrated. This randomized, multi-center phase III trial was conducted in Mexico. Healthy toddlers (n = 732) received a booster dose of a licensed pentavalent combination vaccine [diphtheria, tetanus, acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b (DTaP-IPV//Hib)] either concomitantly or sequentially, with the second dose of CYD-TDV administered as a 3-dose schedule. Antibody titers against diphtheria toxoid, tetanus toxoid and pertussis antigens were measured by enzyme-linked immunosorbent assay. Antibodies against poliovirus and dengue serotypes were measured using a plaque reduction neutralization test. Noninferiority was demonstrated for each of the DTaP-IPV//Hib antigens if the lower limit of the 2-sided 95% confidence interval of the difference in seroconversion rates between the 2 groups (CYD-TDV and placebo) was ≥10%. Safety of both vaccines was assessed. Noninferiority in immune response was demonstrated for all DTaP-IPV//Hib antigens. After 3 doses of CYD-TDV, no difference was observed in the immune response for CYD-TDV between groups. There were no safety concerns during the study. Coadministration of the DTaP-IPV//Hib booster vaccine with CYD-TDV has no observed impact on the immunogenicity or safety profile of the DTaP-IPV//Hib booster vaccine. No difference was observed on the CYD-TDV profile when administered concomitantly or sequentially with the DTaP-IPV//Hib booster vaccine.

Pregnancy dose Tdap and postpartum cocooning to prevent infant pertussis: a decision analysis.

PubMed

Terranella, Andrew; Asay, Garrett R Beeler; Messonnier, Mark L; Clark, Thomas A; Liang, Jennifer L

2013-06-01

Infants <2 months of age are at highest risk of pertussis morbidity and mortality. Until recently, the US Advisory Committee on Immunization Practices (ACIP) recommended protecting young infants by "cocooning" or vaccination of postpartum mothers and other close contacts with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap) booster vaccine. ACIP recommends pregnancy vaccination as a preferred and safe alternative to postpartum vaccination. The ACIP cocooning recommendation has not changed. We used a cohort model reflecting US 2009 births and the diphtheria-tetanus-acellular pertussis schedule to simulate a decision and cost-effectiveness analysis of Tdap vaccination during pregnancy compared with postpartum vaccination with or without vaccination of other close contacts (ie, cocooning). We analyzed infant pertussis cases, hospitalizations, and deaths, as well as direct disease, indirect, and public health costs for infants in the first year of life. All costs were updated to 2011 US dollars. Pregnancy vaccination could reduce annual infant pertussis incidence by more than postpartum vaccination, reducing cases by 33% versus 20%, hospitalizations by 38% versus 19%, and deaths by 49% versus 16%. Additional cocooning doses in a father and 1 grandparent could avert an additional 16% of cases but at higher cost. The cost per quality-adjusted life-year saved for pregnancy vaccination was substantially less than postpartum vaccination ($414 523 vs $1 172 825). Tdap vaccination during pregnancy could avert more infant cases and deaths at lower cost than postpartum vaccination, even when postpartum vaccination is combined with additional cocooning doses. Pregnancy dose vaccination is the preferred alternative to postpartum vaccination for preventing infant pertussis.

Non-specific immunological effects of selected routine childhood immunisations: systematic review.

PubMed

Kandasamy, Rama; Voysey, Merryn; McQuaid, Fiona; de Nie, Karlijn; Ryan, Rebecca; Orr, Olivia; Uhlig, Ulrike; Sande, Charles; O'Connor, Daniel; Pollard, Andrew J

2016-10-13

 To identify and characterise non-specific immunological effects after routine childhood vaccines against BCG, measles, diphtheria, pertussis, and tetanus.  Systematic review of randomised controlled trials, cohort studies, and case-control studies.  Embase, PubMed, Cochrane library, and Trip searched between 1947 and January 2014. Publications submitted by a panel of experts in the specialty were also included.  All human studies reporting non-specific immunological effects after vaccination with standard childhood immunisations. Studies using recombinant vaccines, no vaccine at all, or reporting only vaccine specific outcomes were excluded. The primary aim was to systematically identify, assemble, and review all available studies and data on the possible non-specific or heterologous immunological effects of BCG; measles; mumps, measles, and rubella (MMR); diphtheria; tetanus; and pertussis vaccines.  The initial search yielded 11 168 references; 77 manuscripts met the inclusion criteria for data analysis. In most included studies (48%) BCG was the vaccine intervention. The final time point of outcome measurement was primarily performed (70%) between one and 12 months after vaccination. There was a high risk of bias in the included studies, with no single study rated low risk across all assessment criteria. A total of 143 different immunological variables were reported, which, in conjunction with differences in measurement units and summary statistics, created a high number of combinations thus precluding any meta-analysis. Studies that compared BCG vaccinated with unvaccinated groups showed a trend towards increased IFN-γ production in vitro in the vaccinated groups. Increases were also observed for IFN-γ measured after BCG vaccination in response to in vitro stimulation with microbial antigens from Candida albicans, tetanus toxoid, Staphylococcus aureas, lipopolysaccharide, and hepatitis B. Cohort studies of measles vaccination showed an increase in

The combined use of analytical tools for exploring tetanus toxin and tetanus toxoid structures.

PubMed

Bayart, Caroline; Peronin, Sébastien; Jean, Elisa; Paladino, Joseph; Talaga, Philippe; Borgne, Marc Le

2017-06-01

Aldehyde detoxification is a process used to convert toxin into toxoid for vaccine applications. In the case of tetanus toxin (TT), formaldehyde is used to obtain the tetanus toxoid (TTd), which is used either for the tetanus vaccine or as carrier protein in conjugate vaccines. Several studies have already been conducted to better understand the exact mechanism of this detoxification. Those studies led to the identification of a number of formaldehyde-induced modifications on lab scale TTd samples. To obtain greater insights of the changes induced by formaldehyde, we used three industrial TTd batches to identify repeatable modifications in the detoxification process. Our strategy was to combine seven analytical tools to map these changes. Mass spectrometry (MS), colorimetric test and amino acid analysis (AAA) were used to study modifications on amino acids. SDS-PAGE, asymmetric flow field flow fractionation (AF4), fluorescence spectroscopy and circular dichroism (CD) were used to study formaldehyde modifications on the whole protein structure. We identified 41 formaldehyde-induced modifications across the 1315 amino acid primary sequence of TT. Of these, five modifications on lysine residues were repeatable across TTd batches. Changes in protein conformation were also observed using SDS-PAGE, AF4 and CD techniques. Each analytical tool brought a piece of information regarding formaldehyde induced-modifications, and all together, these methods provided a comprehensive overview of the structural changes that occurred with detoxification. These results could be the first step leading to site-directed TT mutagenesis studies that may enable the production of a non-toxic equivalent protein without using formaldehyde. Copyright © 2017 Elsevier B.V. All rights reserved.

Physico-chemical and immunological examination of the thermal stability of tetanus toxoid conjugate vaccines.

PubMed

Ho, Mei M; Mawas, Fatme; Bolgiano, Barbara; Lemercinier, Xavier; Crane, Dennis T; Huskisson, Rachel; Corbel, Michael J

2002-10-04

The thermal stability of meningococcal C (MenC)- and Haemophilus influenzae b (Hib)-tetanus toxoid (TT) conjugate vaccines was investigated using spectroscopic and chromatographic techniques and immunogenicity assays in animal models. In this stability study, both the bulk concentrate and final fills were incubated at -20, 4, 23, 37 or 55 degrees C for 5 weeks or subjected to cycles of freeze-thawing. The structural stability, hydrodynamic size and molecular integrity of the treated vaccines were monitored by circular dichroism (CD), fluorescence and nuclear magnetic resonance (NMR) spectroscopic techniques, size exclusion chromatography (FPLC-SEC), and high performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD). Only storage at 55 degrees C for 5 weeks caused some slight unfolding and modification in the tertiary structure of the carrier protein in the MenC-TT conjugate. Substantial loss of saccharide content from the MenC conjugates was observed at 37 and 55 degrees C. Unexpectedly, the experimental immunogenicity of MenC-TT vaccine adsorbed to Alhydrogel was significantly reduced only by repeated freeze-thawing, but not significantly decreased by thermal denaturation. Neither the molecular integrity nor the immunogenicity of the lyophilised Hib-TT vaccines was significantly affected by freeze-thawing or by storage at high temperature. In conclusion, the MenC- and Hib-TT conjugate vaccines were relatively stable when stored at higher temperatures, though when MenC-TT vaccine was adsorbed to Alhydrogel, it was more vulnerable to repeated freeze-thawing. When compared with CRM(197) conjugate vaccines studied previously using similar techniques, the tetanus toxoid conjugates were found to have higher relative thermal stability in that they retained immunogenicity following storage at elevated temperatures.

Evaluation of biological safety in vitro and immunogenicity in vivo of recombinant Escherichia coli Shiga toxoids as candidate vaccines in cattle.

PubMed

Kerner, Katharina; Bridger, Philip S; Köpf, Gabriele; Fröhlich, Julia; Barth, Stefanie; Willems, Hermann; Bauerfeind, Rolf; Baljer, Georg; Menge, Christian

2015-04-10

Cattle are the most important reservoir for enterohemorrhagic Escherichia coli (EHEC), a subset of shigatoxigenic E. coli (STEC) capable of causing life-threatening infectious diseases in humans. In cattle, Shiga toxins (Stx) suppress the immune system thereby promoting long-term STEC shedding. First infections of animals at calves' age coincide with the lack of Stx-specific antibodies. We hypothesize that vaccination of calves against Shiga toxins prior to STEC infection may help to prevent the establishment of a persistent type of infection. The objectives of this study were to generate recombinant Shiga toxoids (rStx1mut & rStx2mut) by site-directed mutagenesis and to assess their immunomodulatory, antigenic, and immunogenic properties. Cultures of bovine primary immune cells were used as test systems. In ileal intraepithelial lymphocytes both, recombinant wild type Stx1 (rStx1WT) and rStx2WT significantly induced transcription of IL-4 mRNA. rStx1WT and rStx2WT reduced the expression of Stx-receptor CD77 (syn. Globotriaosylceramide, Gb3) on B and T cells from peripheral blood and of CD14 on monocyte-derived macrophages. At the same concentrations, rStx1mut and rStx2mut exhibited neither of these effects. Antibodies in sera of cattle naturally infected with STEC recognized the rStxmut toxoids equally well as the recombinant wild type toxins. Immunization of calves with rStx1mut plus rStx2mut led to induction of antibodies neutralizing Stx1 and Stx2. While keeping their antigenicity and immunogenicity recombinant Shiga toxoids are devoid of the immunosuppressive properties of the corresponding wild type toxins in cattle and candidate vaccines to mitigate long-term STEC shedding by the reservoir host.

A thiol-disulfide oxidoreductase of the Gram-positive pathogen Corynebacterium diphtheriae is essential for viability, pilus assembly, toxin production and virulence

PubMed Central

Reardon-Robinson, Melissa E.; Osipiuk, Jerzy; Jooya, Neda; Chang, Chungyu; Joachimiak, Andrzej; Das, Asis; Ton-That, Hung

2016-01-01

Summary The Gram-positive pathogen Corynebacterium diphtheriae exports through the Sec apparatus many extracellular proteins that include the key virulence factors diphtheria toxin and the adhesive pili. How these proteins attain their native conformations after translocation as unfolded precursors remains elusive. The fact that the majority of these exported proteins contain multiple cysteine residues and that several membrane-bound oxidoreductases are encoded in the corynebacterial genome suggests the existence of an oxidative protein-folding pathway in this organism. Here we show that the shaft pilin SpaA harbors a disulfide bond in vivo and alanine substitution of these cysteines abrogates SpaA polymerization and leads to the secretion of degraded SpaA peptides. We then identified a thiol-disulfide oxidoreductase (MdbA), whose structure exhibits a conserved thioredoxin-like domain with a CPHC active site. Remarkably, deletion of mdbA results in a severe temperature-sensitive cell division phenotype. This mutant also fails to assemble pilus structures and is greatly defective in toxin production. Consistent with these defects, the ΔmdbA mutant is attenuated in a guinea pig model of diphtheritic toxemia. Given its diverse cellular functions in cell division, pilus assembly and toxin production, we propose that MdbA is a component of the general oxidative folding machine in C. diphtheriae. PMID:26294390

Towards Rational Design of a Toxoid Vaccine against the Heat-Stable Toxin of Escherichia coli

PubMed Central

Taxt, Arne M.; Diaz, Yuleima; Aasland, Rein; Clements, John D.; Nataro, James P.; Sommerfelt, Halvor

2016-01-01

Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrheal disease and death in children <5 years old. ETEC strains that express the heat-stable toxin (ST), with or without the heat-labile toxin, are among the four most important diarrhea-causing pathogens. This makes ST an attractive target for an ETEC vaccine. An ST vaccine should be nontoxic and elicit an immune response that neutralizes native ST without cross-reacting with the human endogenous guanylate cyclase C receptor ligands. To identify variants of ST with no or low toxicity, we screened a library of all 361 possible single-amino-acid mutant forms of ST by using the T84 cell assay. Moreover, we identified mutant variants with intact epitopes by screening for the ability to bind neutralizing anti-ST antibodies. ST mutant forms with no or low toxicity and intact epitopes are termed toxoid candidates, and the top 30 candidates all had mutations of residues A14, N12, and L9. The identification of nontoxic variants of L9 strongly suggests that it is a novel receptor-interacting residue, in addition to the previously identified N12, P13, and A14 residues. The screens also allowed us to map the epitopes of three neutralizing monoclonal antibodies, one of which cross-reacts with the human ligand uroguanylin. The common dominant epitope residue for all non-cross-reacting antibodies was Y19. Our results suggest that it should be possible to rationally design ST toxoids that elicit neutralizing immune responses against ST with minimal risk of immunological cross-reactivity. PMID:26883587

The adjuvant activity of aliphatic nitrogenous bases

PubMed Central

Gall, D.

1966-01-01

By the use of diphtheria toxoid in guinea-pigs, high adjuvant activity has been found in a number of aliphatic nitrogenous bases including amines, quaternary ammonium compounds, guanidines, benzamidines and thiouroniums. Activity appears to depend on a combination of basicity and a long aliphatic chain of twelve or more carbon atoms. Such adjuvants tend to be haemolytic, and cause damage to tissue culture monolayers. It is suggested that their activity is connected with their surface activity and hence their ability to alter cell membranes, but that the basicity plays a further as yet undetermined role. ImagesFIG. 1-2FIG. 3-4 PMID:5924622

Risk analysis of the 1970 san antonio diphtheria epidemic*.

PubMed

Quesada, G M; Cameron, J M; Anderson, D E; Kaufert, J M

1978-12-01

Prediction of disease patterns for communicable diseases with low prevalence rates is difficult because of the random variations inherent in the data Smoothing of prevalence or incidence data prior to the analysis may facilitate these predictions. All of the analyses are based on census tract characterisiics. The disadvantages of this type of data are that the boundaries are arbitraty and lead to some heterogenous tracts. Also, the analyses depend totally on aggregate rather than individual data. The advantage of working with this type of data is its availability for all metropolitan areas. The San Antonio diphtheria epidemic has been previously referred to as an ethnic epidemic. This paper shows that it is even more an epidemic of lower socioeconomic groups. In this region of the country, socioeconomic characteristics are almost indistinguishable.

Diphtheria, tetanus, poliomyelitis, yellow fever and hepatitis B seroprevalence among HIV1-infected migrants. Results from the ANRS VIHVO vaccine sub-study.

PubMed

Mullaert, Jimmy; Abgrall, Sophie; Lele, Nathalie; Batteux, Frederic; Slama, Lilia Ben; Meritet, Jean-Francois; Lebon, Pierre; Bouchaud, Olivier; Grabar, Sophie; Launay, Odile

2015-09-11

Few data are available on the seroprotection status of HIV1-infected patients with respect to vaccine-preventable diseases. To describe, in a population of HIV1-infected migrants on stable, effective ART therapy, the seroprevalence of diphtheria, poliomyelitis, tetanus, yellow fever antibodies and serostatus for hepatitis B, and to identify factors associated with seroprotection. Vaccine responses against diphtheria, tetanus, poliomyelitis and yellow fever were also studied. Sub-Saharan African patients participating in the ANRS-VIHVO cohort were enrolled prior to travel to their countries of origin. Serologic analyses were performed in a central laboratory before and after the trip. Univariate and multivariate logistic regression was used to identify factors associated with initial seroprotection. 250 patients (99 men and 151 women) were included in the seroprevalence study. Median age was 45 years (IQR 39-52), median CD4 cell count was 440/μL (IQR 336-571), and 237 patients (95%) had undetectable HIV1 viral load. The initial seroprevalence rates were 69.0% (95%CI 63.2-74.7) for diphtheria, 70.7% (95%CI 65.0-76.3) for tetanus, and 85.9% (95%CI 81.6-90.2) for yellow fever. Only 64.4% (95%CI 58.5-70.3) of patients had protective antibody titers against all three poliomyelitis vaccine strains before travel. No serological markers of hepatitis B were found in 18.6% of patients (95%CI 13.7-23.3). Patient declaration of prior vaccination was the only factor consistently associated with initial seroprotection. We found a low prevalence of seroprotection against diphtheria, poliomyelitis, tetanus and hepatitis B. HIV infected migrants living in France and traveling to their native countries need to have their vaccine schedule completed. Copyright © 2015 Elsevier Ltd. All rights reserved.

A thiol-disulfide oxidoreductase of the Gram-positive pathogen Corynebacterium diphtheriae is essential for viability, pilus assembly, toxin production and virulence.

PubMed

Reardon-Robinson, Melissa E; Osipiuk, Jerzy; Jooya, Neda; Chang, Chungyu; Joachimiak, Andrzej; Das, Asis; Ton-That, Hung

2015-12-01

The Gram-positive pathogen Corynebacterium diphtheriae exports through the Sec apparatus many extracellular proteins that include the key virulence factors diphtheria toxin and the adhesive pili. How these proteins attain their native conformations after translocation as unfolded precursors remains elusive. The fact that the majority of these exported proteins contain multiple cysteine residues and that several membrane-bound oxidoreductases are encoded in the corynebacterial genome suggests the existence of an oxidative protein-folding pathway in this organism. Here we show that the shaft pilin SpaA harbors a disulfide bond in vivo and alanine substitution of these cysteines abrogates SpaA polymerization and leads to the secretion of degraded SpaA peptides. We then identified a thiol-disulfide oxidoreductase (MdbA), whose structure exhibits a conserved thioredoxin-like domain with a CPHC active site. Remarkably, deletion of mdbA results in a severe temperature-sensitive cell division phenotype. This mutant also fails to assemble pilus structures and is greatly defective in toxin production. Consistent with these defects, the ΔmdbA mutant is attenuated in a guinea pig model of diphtheritic toxemia. Given its diverse cellular functions in cell division, pilus assembly and toxin production, we propose that MdbA is a component of the general oxidative folding machine in C. diphtheriae. © 2015 John Wiley & Sons Ltd.

Immunoadjuvant potential of cross-linked dextran microspheres mixed with chitosan nanospheres encapsulated with tetanus toxoid.

PubMed

Pirouzmand, Haniyeh; Khameneh, Bahman; Tafaghodi, Mohsen

2017-12-01

Nasal mucosa is a desirable route for mucosal vaccine delivery. Mucosal co-administration of chitosan nanoparticles with absorption enhancers such as cross-linked dextran microspheres (CDM, Sephadex ® ) is a promising antigen delivery system. In the current study, the chitosan nanospheres loaded with tetanus toxoid (CHT:TT NPs) was prepared and characterized. The immune responses against tetanus toxoid after nasal administration of CHT:TT NPs alone or mixed with CDM were also determined. Chitosan nanospheres were prepared by ionic gelation method. Particle size, releasing profile and antigen stability were evaluated by dynamic light scattering, diffusion chamber and SDS-PAGE methods, respectively. Rabbits were nasally immunized with different formulations loaded with 40 Lf TT. After three times immunizations with 2 weeks intervals, sera IgG titres and nasal lavage sIgA titres were determined. Mean size of CHT NPs and CHT:TT NPs were 205 ± 42 nm and 432 ± 85 nm, respectively. The release profile showed that 42.4 ± 10.5% of TT was released after 30 min and reached to a steady state after 1.5 h. Stability of encapsulated TT in nanospheres was confirmed by SDS-PAGE. The antibody titres showed that CHT:TT NPs-induced antibody titres were higher than TT solution. CHT NPs mixed with CDM induced the systemic IgG and nasal lavage sIgA titres higher than intranasal administration of TT solution (p < 0.001). As the results indicated, these CHT:TT NPs when co-administered with CDM were able to induce more immune responses and have the potential to be used in mucosal immunization.

Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid.

PubMed

Laferriere, Craig; Ravenscroft, Neil; Wilson, Seanette; Combrink, Jill; Gordon, Lizelle; Petre, Jean

2011-10-01

The introduction of type b Haemophilus influenzae conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.

Irradiation of the Crude Venom of Bothrops jararacussu to Obtain Toxoid

NASA Astrophysics Data System (ADS)

Ferreira, Camila G.; Avalloni, Tânia M.; Oshima-Franco, Yoko; de J. Oliveira, Sara; de Oliveira, José M.; Cogo, José C.

2011-08-01

The aim of this work was to reduce the toxicity of Bothrops jararacussu venom using gamma-rays of low-energy coming from a source of Americium-241 (E = 59.6 keV and 3.7×109 Bq of activity) in order to obtain a toxoid. The radiation dose that each sample received was controlled by exposure time of the venom to the radiation beam. Mouse nerve phrenic-diaphragm preparation was used for testing the loss of venom toxicity, since the venom causes an irreversible neuromuscular blockade. In this condition, the several samples of irradiated venom, when assayed in neuromuscular preparation showed that with a dose of 0.051 Gy the paralysis caused by the irradiated venom was of 91%, at 0.360 Gy was of 79%, at 1.662 Gy was of 50% and at 2.448 Gy was of 42%. Therefore, it can be concluded that the irradiation model was able to induce a progressive loss of the venom toxicity.

Self-reported history of vaccination and disease and immunity against hepatitis A, hepatitis B, tetanus, diphtheria and varicella among Spanish military recruits.

PubMed

Arteaga, Alejandro; Desviat, Pilar Vallejo; Jaqueti, Jeronimo; Santos, Juana; de Miguel, Angel Gil; Garcia, Rodrigo Jiménez

2010-02-01

This study aims to evaluate the immune status against hepatitis A, hepatitis B, tetanus, diphtheria and varicella in military recruits and the validity of self-reporting of their disease and vaccination history. A total of 226 participants were studied (mean age, 20.2 years; SD 1.7). 10.4% presented antibodies to hepatitis A, 78.3% to hepatitis B, 94.2% to tetanus, 77.4% to diphtheria and 81.9% to varicella. The relationship between self-reporting of vaccination history and seroprotection showed a high Positive Predictive Value for tetanus (98.8%) and a high Negative Predictive Value for hepatitis A (91%). Hepatitis A vaccination and serology testing for varicella and Hepatitis B on joining the Spanish armed forces are recommended.

Higher Tetanus Toxoid Immunity 2 Years After PsA-TT Introduction in Mali.

PubMed

Basta, Nicole E; Borrow, Ray; Berthe, Abdoulaye; Onwuchekwa, Uma; Dembélé, Awa Traoré Eps; Almond, Rachael; Frankland, Sarah; Patel, Sima; Wood, Daniel; Nascimento, Maria; Manigart, Olivier; Trotter, Caroline L; Greenwood, Brian; Sow, Samba O

2015-11-15

In 2010, mass vaccination with a then-new meningococcal A polysaccharide-tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1- to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying age- and sex-specific immunity prior to and 2 years after introduction. Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels ≥0.1 IU/mL (indicating short-term protection) and ≥1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre-PsA-TT, significantly higher GMCs in all age-sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6-36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7-43.3; P < .0001) pre- and postvaccination. Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Higher Tetanus Toxoid Immunity 2 Years After PsA-TT Introduction in Mali

PubMed Central

Basta, Nicole E.; Borrow, Ray; Berthe, Abdoulaye; Onwuchekwa, Uma; Dembélé, Awa Traoré Eps; Almond, Rachael; Frankland, Sarah; Patel, Sima; Wood, Daniel; Nascimento, Maria; Manigart, Olivier; Trotter, Caroline L.; Greenwood, Brian; Sow, Samba O.

2015-01-01

Background. In 2010, mass vaccination with a then-new meningococcal A polysaccharide–tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1- to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying age- and sex-specific immunity prior to and 2 years after introduction. Methods. Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels ≥0.1 IU/mL (indicating short-term protection) and ≥1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. Results. Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre–PsA-TT, significantly higher GMCs in all age–sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6–36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7–43.3; P < .0001) pre- and postvaccination. Conclusions. Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity. PMID:26553691

Preventing the preventable through effective surveillance: the case of diphtheria in a rural district of Maharashtra, India

PubMed Central

2013-01-01

Background Epidemic diphtheria is still poorly understood and continues to challenge both developing and developed countries. In the backdrop of poor immunization coverage, non-existent adult boosters, weak case based surveillance and persistence of multiple foci, there is a heightened risk of re-emergence of the disease in epidemic forms in India. Investigating each outbreak to understand the epidemiology of the disease and its current status in the country is therefore necessary. Dhule a predominantly tribal and rural district in Northern Maharashtra has consistently recorded low vaccination coverages alongside sporaidic cases of diphtheria over the last years. Methods This study reports the findings of an onsite survey conducted to assess a recent outbreak of diphtheria in Dhule district and the response mounted to it. Secondary data regarding outbreak detection and response were obtained from the district surveillance office. Clinical data were extracted from hospital records of eleven lab confirmed cases including one death case. Frequency distributions were calculated for each identified clinical and non- clinical variable using Microsoft™ Excel® 2010. Results Our findings suggest a shift in the median age of disease to adolescents (10-15 years) without gender differences. Two cases (18%) reported disease despite immunization. Clinical symptoms included cough (82%), fever (73%), and throat congestion (64%). About 64% and 36% of the 11 confirmed cases presented with a well defined pseudomembrane and a tonsillar patch respectively. Drug resistance was observed in all three culture positive cases. One death occurred despite the administration of Anti-Diphtheric Serum in a partially immunized case (CFR 9%). Genotyping and toxigenicity of strain was not possible due to specimen contamination during transport as testing facilities were unavailable in the district. Conclusions The outbreak raises several concerns regarding the epidemiology of diphtheria in

A glycoconjugate of Haemophilus influenzae Type b capsular polysaccharide with tetanus toxoid protein: hydrodynamic properties mainly influenced by the carbohydrate.

PubMed

Abdelhameed, Ali Saber; Adams, Gary G; Morris, Gordon A; Almutairi, Fahad M; Duvivier, Pierre; Conrath, Karel; Harding, Stephen E

2016-02-26

Three important physical properties which may affect the performance of glycoconjugate vaccines against serious disease are molar mass (molecular weight), heterogeneity (polydispersity), and conformational flexibility in solution. The dilute solution behaviour of native and activated capsular polyribosylribitol (PRP) polysaccharides extracted from Haemophilus influenzae type b (Hib), and the corresponding glycoconjugate made by conjugating this with the tetanus toxoid (TT) protein have been characterized and compared using a combination of sedimentation equilibrium and sedimentation velocity in the analytical ultracentrifuge with viscometry. The weight average molar mass of the activated material was considerably reduced (Mw ~ 0.24 × 10(6) g.mol(-1)) compared to the native (Mw ~ 1.2 × 10(6) g.mol(-1)). Conjugation with the TT protein yielded large polydisperse structures (of Mw ~ 7.4 × 10(6) g.mol(-1)), but which retained the high degree of flexibility of the native and activated polysaccharide, with frictional ratio, intrinsic viscosity, sedimentation conformation zoning behaviour and persistence length all commensurate with highly flexible coil behaviour and unlike the previously characterised tetanus toxoid protein (slightly extended and hydrodynamically compact structure with an aspect ratio of ~3). This non-protein like behaviour clearly indicates that it is the carbohydrate component which mainly influences the physical behaviour of the glycoconjugate in solution.

Levels of Antibodies Specific to Tetanus Toxoid, Haemophilus influenzae Type b, and Pneumococcal Capsular Polysaccharide in Healthy Children and Adults

PubMed Central

Schauer, Uwe; Stemberg, Frank; Rieger, Christian H. L.; Büttner, Wolfgang; Borte, Michael; Schubert, Simone; Möllers, Helga; Riedel, Frank; Herz, Udo; Renz, Harald; Herzog, Wilhelm

2003-01-01

Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) and for tetanus toxoid were measured in serum samples of 386 age-stratified subjects. The study group consists of healthy adult blood donors and hospitalized children undergoing elective surgery, excluding individuals with a history of infection. In children, anti-tetanus toxoid antibody levels displayed two peaks of 1.20 IU/ml (20.4 mg/liter) and 1.65 IU/ml (28.1 mg/liter) related to the schedule of routine childhood immunization in the first year and at 8 years of age. Eighty percent of the antibodies are of the immunoglobulin G1 (IgG1) isotype. For pneumococcal capsular polysaccharide (PCP), the specific antibody levels represent the acquisition of natural immunity. The initial concentration of 9.2 mg/liter was low in infancy (0.5 to 1 years of age) and remained low until 3 to 4 years of age (14.6 mg/liter). During this period PCP antibodies were almost 100% of the IgG2 subclass. Thereafter, IgG anti-PCP antibody titers increased steadily to adult levels (59.5 mg/liter). The data are intended to provide reference ranges to aid in the interpretation of specific antibody determinations in the clinical setting. PMID:12626443

Non-invasive, epicutaneous immunisation with toxoid in deformable vesicles protects mice against tetanus, chiefly owing to a Th2 response.

PubMed

Chopra, Amla; Cevc, Gregor

2014-06-02

A non-invasive, intra/transcutaneous immunisation of mice with a suitable combination of tetanus toxoid, ultradeformable vesicle (Transfersome®) carrier, and monophosphoryl lipid A adjuvant targets immuno-competent cells in a body and can protect 100% of the tested mice against an otherwise lethal (50×LD50) parenteral tetanus toxin challenge. The late immune response to the epicutaneously applied tetanus toxoid in such vesicles consists chiefly of circulating IgG1 and IgG2b antibody isotypes, indicative of a specific Th2 cellular response bias. Immunisations by subcutaneous injections moreover protect 100% of mice against a similar, otherwise lethal, dose of tetanus toxin. However, the immune response to transcutaneous and invasive immunisation differs. The latter elicits mainly IgG1 and IgG2b as well as IgG2a antibody isotypes, indicative of a mixed Th1/Th2 response. The cytokine response of the intra/transcutaneously and subcutaneously immunised mice reflects the difference in the organ-specific manner. IFN-γ concentration is appreciably increased in the draining lymph nodes and IL-10 in spleen. Since tetanus is a neutral antigen, both the Th1-specific IFN-γ and the Th-2 specific-IL-10 are observable. Copyright © 2014 Elsevier B.V. All rights reserved.

DIPHTHERIA TOXIN OBTAINED ON MEDIA STERILIZED BY GAMMA RAYS (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaulen, D.R.

1959-08-01

The possibility of radiation sterilization of liquid nntritive media for cultivating diphtheritic bacteria was studied. Gamma rays were employed at doses of 600,000, by irradiation does not deteriorate their nutritive properties, while the biochemical indices remain almost unchanged. The diphtheria toxin titer obtained on media sterilized by irradiation is not inferior to that derived from autoclaved media, while in a number of instances (irradiation with 600,000 r) it even surpasses it. Anatorins made of toxins from irradiated media were not inferior by their immunogenic and antigenic properties to the control preparations. These experimental data point to the possibility of cold''more » sterilization of liquid nutritive media. (auth)« less

IMMUNOGENICITY AND SAFETY OF QUINVAXEM® (DIPHTHERIA, TETANUS, WHOLE-CELL PERTUSSIS, HEPATITIS B AND HAEMOPHILUS INFLUENZAE TYPE B VACCINE) GIVEN TO VIETNAMESE INFANTS AT 2 TO 4 MONTHS OF AGE.

PubMed

Huu, Tran Ngoc; Phuong, Nguyen Thi Minh; Toan, Nguyen Trong; Thang, Ho Vinh

2015-07-01

Vietnam plans to replace the routine childhood diphtheria, pertussis and tetanus combination (DPT) vaccine with a pentavalent vaccine. The present study was performed to assess the immunogenicity and safety of the combined diphtheria, tetanus, whole-cell pertussis, hepatitis B (HepB), and Haemophilus influenzae type b (Hib) (DTwP-HepB-Hib) Quinvaxem® vaccine in children. A total of 131 infants received the Quinvaxem® vaccine at 2, 3 and 4 months. Antibody levels were measured at baseline, at one month after the third injection and one year after the first injection. Seroprotection rates were high for each vaccine antigen at one month after the third dose: 93.1% for diphtheria, 98.5% for tetanus, 99.2% for pertussis (seroconversion rate), 93.1% for HepB, and 100% for Hib (anti-PRP ≥ 0.15 µg/ml). The rate of children with protective antibodies persisting at one year after the first dose was 88.4% for diphtheria, 49.6% for pertussis, 82.2% for tetanus, 76.7% for HepB and 97.7% for Hib (anti-PRP ≥ 0.15 µg/ml). The Quinvaxem® vaccine was well tolerated and has a low rate of adverse events. Quinvaxem® given at 2, 3 and 4 months of age was immunogenic and safe for primary immunization among infants in Vietnam.

A slow-forming isopeptide bond in the structure of the major pilin SpaD from Corynebacterium diphtheriae has implications for pilus assembly

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Hae Joo; Paterson, Neil G.; Kim, Chae Un

2014-05-01

Two crystal structures of the major pilin SpaD from C. diphtheriae have been determined at 1.87 and 2.5 Å resolution. The N-terminal domain is found to contain an isopeptide bond that forms slowly over time in the recombinant protein. Given its structural context, this provides insight into the relationship between internal isopeptide-bond formation and pilus assembly. The Gram-positive organism Corynebacterium diphtheriae, the cause of diphtheria in humans, expresses pili on its surface which it uses for adhesion and colonization of its host. These pili are covalent protein polymers composed of three types of pilin subunit that are assembled by specificmore » sortase enzymes. A structural analysis of the major pilin SpaD, which forms the polymeric backbone of one of the three types of pilus expressed by C. diphtheriae, is reported. Mass-spectral and crystallographic analysis shows that SpaD contains three internal Lys–Asn isopeptide bonds. One of these, shown by mass spectrometry to be located in the N-terminal D1 domain of the protein, only forms slowly, implying an energy barrier to bond formation. Two crystal structures, of the full-length three-domain protein at 2.5 Å resolution and of a two-domain (D2-D3) construct at 1.87 Å resolution, show that each of the three Ig-like domains contains a single Lys–Asn isopeptide-bond cross-link, assumed to give mechanical stability as in other such pili. Additional stabilizing features include a disulfide bond in the D3 domain and a calcium-binding loop in D2. The N-terminal D1 domain is more flexible than the others and, by analogy with other major pilins of this type, the slow formation of its isopeptide bond can be attributed to its location adjacent to the lysine used in sortase-mediated polymerization during pilus assembly.« less

Depletion of alveolar macrophages in CD11c diphtheria toxin receptor mice produces an inflammatory response

PubMed Central

Roberts, Lydia M; Ledvina, Hannah E; Tuladhar, Shraddha; Rana, Deepa; Steele, Shaun P; Sempowski, Gregory D; Frelinger, Jeffrey A

2015-01-01

Alveolar macrophages play a critical role in initiating the immune response to inhaled pathogens and have been shown to be the first cell type infected following intranasal inoculation with several pathogens, including Francisella tularensis. In an attempt to further dissect the role of alveolar macrophages in the immune response to Francisella, we selectively depleted alveolar macrophages using CD11c.DOG mice. CD11c.DOG mice express the diphtheria toxin receptor (DTR) under control of the full CD11c promoter. Because mice do not express DTR, tissue restricted expression of the primate DTR followed by treatment with diphtheria toxin (DT) has been widely used as a tool in immunology to examine the effect of acute depletion of a specific immune subset following normal development. We successfully depleted alveolar macrophages via intranasal administration of DT. However, alveolar macrophage depletion was accompanied by many other changes to the cellular composition and cytokine/chemokine milieu in the lung that potentially impact innate and adaptive immune responses. Importantly, we observed a transient influx of neutrophils in the lung and spleen. Our experience serves as a cautionary note to other researchers using DTR mice given the complex changes that occur following DT treatment that must be taken into account when analyzing data. PMID:26029367

Nano-sized Soluplus® polymeric micelles enhance the induction of tetanus toxin neutralising antibody response following transcutaneous immunisation with tetanus toxoid.

PubMed

Saydam, Manolya; Cheng, Woei Ping; Palmer, Nathan; Tierney, Robert; Francis, Robert; MacLellan-Gibson, Kirsty; Khan, Ambreen; Mawas, Fatme

2017-04-25

The use of Soluplus® polymeric micelles as a novel adjuvant for tetanus toxoid (TTxd) in transcutaneous immunisation was evaluated. TTxd was added to Soluplus® polymeric micelles to form TTxd-Soluplus® nano-aggregates with a size of 68nm. Non-adjuvanted TTxd commonly induces very poor antibody response by the transcutaneous route. However, in this study, the use of TTxd-Soluplus® resulted in a significant increase in the antibody response to TTxd, which was similar to that induced in the presence of CPG-oligodeoxynucleotides (CPG-ODNs) adjuvant. The toxin neutralising potency of the immune sera induced by TTxd-Soluplus® was also much stronger than that from TTxd alone, in a passive transfer experiment in mice. Soluplus® also enhanced the immunogenicity of the toxoid when TTxd-Soluplus® was stored at 4°C for 4weeks, but not at higher temperatures. Confocal microscopy imaging showed a much higher uptake of TTxd in the epidermis and dermis layers of the skin when it was associated with Soluplus®, suggesting that the mechanism for Soluplus® adjuvanticity is through enhanced uptake of the TTxd through the skin. Overall, our findings demonstrated that Soluplus® is an effective novel adjuvant for transcutaneous immunisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chitosan-HPMC-blended microspheres as a vaccine carrier for the delivery of tetanus toxoid.

PubMed

Arthanari, Saravanakumar; Mani, Ganesh; Peng, Mei Mei; Jang, Hyun Tae

2016-01-01

The purpose of this research was to develop a suitable and alternate adjuvant for the tetanus toxoid (TT) vaccine that induces long term immunity after a single-dose immunization. In our study, the preformulation studies were carried out by using different ratios (7/3, 8/2, and 9/1) of chitosan-hydroxypropyl methylcellulose (HPMC)-blended empty microspheres. Moreover, TT was stabilized with heparin (at heparin concentrations of 1%, 2%, 3%, and 4% w/v) and encapsulated in ideal chitosan - HPMC (CHBMS) microspheres, by the water-in-oil-in-water (W/O/W) multiple emulsion method. The vaccine entrapment and the in vitro release efficiency of the CHBMS was evaluated for a period of 90 days. The release of antigens from the microspheres was determined by ELISA. Antigen integrity was investigated by SDS-PAGE. From the optimization studies, it was found that a chitosan/HPMC ratio of 8/2 produced a good yield, with microspheres that were spherical, regular and uniformly-sized. In the CHBMS, a heparin concentration of 3% w/v resulted in well-sustained antigen delivery for a period of 90 days. It was found that the characteristics of initial release could be observed in 2 days, followed by a constant release, and an almost 100% complete release in 90 days. From the in vitro release characteristics, the ideal batch of CHBMS (3% w/v heparin) was evaluated for in vivo studies by the antibody induction method. The antibody levels were measured for different combinations for the period of 9 months, and finally, with a second booster dose after 1 year. In conclusion, it was observed that CHBMS (combination-1) resulted in the antibody level of 4.5 IU/mL of guinea pig serum, and the level was 3.5 IU/mL for the Central Research Institute's alum-adsorbed tetanus toxoid (CRITT) (combination 2), after 1 year, with a second booster dose. This novel approach of using CHBMS may have potential advantages for single-step immunization with vaccines.

Experience with monocomponent acellular pertussis combination vaccines for infants, children, adolescents and adults--a review of safety, immunogenicity, efficacy and effectiveness studies and 15 years of field experience.

PubMed

Thierry-Carstensen, Birgit; Dalby, Tine; Stevner, Michael A; Robbins, John B; Schneerson, Rachel; Trollfors, Birger

2013-10-25

Combination vaccines containing a monocomponent acellular pertussis (aP) vaccine, manufactured at Statens Serum Institut (SSI), Denmark, have successfully controlled Bordetella pertussis infections in Denmark since 1997. The efficacy of this aP vaccine was 71% in a double-blind, randomised and controlled clinical trial. Its safety and immunogenicity have been demonstrated in infants, children, adolescents and adults. In approximately 500,000 children it was effective against pertussis requiring hospitalisation (VE: 93% after 3 doses) and against pertussis not requiring hospitalisation (VE: 78% after 3 doses). IgG antibodies against pertussis toxin (IgG anti-PT) response rates after booster vaccination of adults with tetanus, diphtheria and aP combination vaccine (TdaP) were considerably higher for this monocomponent aP vaccine containing 20μg pertussis toxoid, inactivated by hydrogen peroxide (92.0%), than for two multicomponent aP vaccines inactivated by formaldehyde and/or glutaraldehyde: 3-component aP with 8μg pertussis toxoid (77.2%) and 5-component aP with 2.5μg pertussis toxoid (47.1%), without compromising the safety profile. In Denmark where this monocomponent aP vaccine has been the only pertussis vaccine in use for 15 years, there has been no pertussis epidemic since 2002 (population incidence 36 per 100,000), in contrast to neighbouring countries, where epidemics have occurred. This monocomponent aP vaccine can be used in combination vaccines for primary and booster vaccination against pertussis in all age groups and is an important tool for successful pertussis control. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effect of rituximab on human in vivo antibody immune responses.

PubMed

Pescovitz, Mark D; Torgerson, Troy R; Ochs, Hans D; Ocheltree, Elizabeth; McGee, Paula; Krause-Steinrauf, Heidi; Lachin, John M; Canniff, Jennifer; Greenbaum, Carla; Herold, Kevan C; Skyler, Jay S; Weinberg, Adriana

2011-12-01

B-lymphocyte depletion with rituximab has been shown to benefit patients with various autoimmune diseases. We have previously demonstrated that this benefit is also apparent in patients with newly diagnosed type 1 diabetes. The effect of rituximab on in vivo antibody responses, particularly during the period of B-lymphocyte depletion, is incompletely determined. This study was designed to assess this knowledge void. In patients with recent-onset type 1 diabetes treated with rituximab (n = 46) or placebo (n = 29), antibody responses to neoantigen phiX174 during B-lymphocyte depletion and with hepatitis A (as a second neoantigen) and tetanus/diphtheria (as recall antigens) after B-lymphocyte recovery were studied. Anti- tetanus, diphtheria, mumps, measles, and rubella titers were measured before and after treatment by means of ELISA. Antibody titers and percentage IgM versus percentage IgG to phiX174 were measured by means of phage neutralization. B-lymphocyte subsets were determined by means of flow cytometry. No change occurred in preexisting antibody titers. Tetanus/diphtheria and hepatitis A immunization responses were protective in the rituximab-treated subjects, although significantly blunted compared with those seen in the controls subjects, when immunized at the time of B-lymphocyte recovery. Anti-phiX174 responses were severely reduced during the period of B-lymphocyte depletion, but with B-lymphocyte recovery, anti-phiX174 responses were within the normal range. During the time of B-lymphocyte depletion, rituximab recipients had a decreased antibody response to neoantigens and significantly lower titers after recall immunization with diphtheria and tetanus toxoid. With recovery, immune responses return toward normal. Immunization during the time of B-lymphocyte depletion, although ineffective, does not preclude a subsequent response to the antigen. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights

Long-Term Effects of Tetanus Toxoid Inoculation on the Demography and Life Expectancy of the Cayo Santiago Rhesus Macaques

PubMed Central

KESSLER, MATTHEW J.; PACHECO, RAISA HERNÁNDEZ; RAWLINS, RICHARD G.; RUIZ-LAMBRIDES, ANGELINA; DELGADO, DIANA L.; SABAT, ALBERTO M.

2014-01-01

Tetanus was a major cause of mortality in the free-ranging population of rhesus monkeys on Cayo Santiago prior to 1985 when the entire colony was given its first dose of tetanus toxoid. The immediate reduction in mortality that followed tetanus toxoid inoculation (TTI) has been documented, but the long-term demographic effects of eliminating tetanus infections have not. This study uses the Cayo Santiago demographic database to construct comparative life tables 12 years before, and 12 years after, TTI. Life tables and matrix projection models are used to test for differences in: (i) survival among all individuals as well as among social groups, (ii) long-term fitness of the population, (iii) age distribution, (iv) reproductive value, and (v) life expectancy. A retrospective life table response experiment (LTRE) was performed to determine which life cycle transition contributed most to observed changes in long-term fitness of the population post-TTI. Elimination of clinical tetanus infections through mass inoculation improved the health and well-being of the monkeys. It also profoundly affected the population by increasing survivorship and long-term fitness, decreasing the differences in survival rates among social groups, shifting the population’s age distribution towards older individuals, and increasing reproductive value and life expectancy. These findings are significant because they demonstrate the long-term effects of eradicating a major cause of mortality at a single point in time on survival, reproduction, and overall demography of a naturalistic population of primates. PMID:25230585

Long-term effects of tetanus toxoid inoculation on the demography and life expectancy of the Cayo Santiago rhesus macaques.

PubMed

Kessler, Matthew J; Hernández Pacheco, Raisa; Rawlins, Richard G; Ruiz-Lambrides, Angelina; Delgado, Diana L; Sabat, Alberto M

2015-02-01

Tetanus was a major cause of mortality in the free-ranging population of rhesus monkeys on Cayo Santiago prior to 1985 when the entire colony was given its first dose of tetanus toxoid. The immediate reduction in mortality that followed tetanus toxoid inoculation (TTI) has been documented, but the long-term demographic effects of eliminating tetanus infections have not. This study uses the Cayo Santiago demographic database to construct comparative life tables 12 years before, and 12 years after, TTI. Life tables and matrix projection models are used to test for differences in: (i) survival among all individuals as well as among social groups, (ii) long-term fitness of the population, (iii) age distribution, (iv) reproductive value, and (v) life expectancy. A retrospective life table response experiment (LTRE) was performed to determine which life cycle transition contributed most to observed changes in long-term fitness of the population post-TTI. Elimination of clinical tetanus infections through mass inoculation improved the health and well-being of the monkeys. It also profoundly affected the population by increasing survivorship and long-term fitness, decreasing the differences in survival rates among social groups, shifting the population's age distribution towards older individuals, and increasing reproductive value and life expectancy. These findings are significant because they demonstrate the long-term effects of eradicating a major cause of mortality at a single point in time on survival, reproduction, and overall demography of a naturalistic population of primates. © 2014 Wiley Periodicals, Inc.

Evaluation of humoral immunity and protective efficacy of biofilm producing Staphylococcus aureus bacterin-toxoid prepared from a bovine mastitis isolate in rabbit

PubMed Central

A., Raza; G., Muhammad; S. U., Rahman; I., Rashid; K., Hanif; A., Atta; S., Sharif

2015-01-01

Mastitis is a one of the major diseases of dairy animals. Staphylococcus aureus is the most common microorganism associated with this dairy scourge. Cure rates of mastitis associated with this pathogen are appallingly low. Biofilm is an important virulence factor and immunogenic structure of S. aureus that makes it resistant to phagocytosis and antibiotics. Reports on the efficacy of vaccine prepared from a biofilm producing S. aureus are infrequent. The present study was designed to evaluate the role of a bacterin-toxoid prepared from a strong biofilm producing S. aureus in effective immunization of rabbits. The strong biofilm producing S. aureus selected from 64 isolates of staphylococci was used to prepare bacterin-toxoid and aluminum hydroxide gel was added as an adjuvant. The vaccine was evaluated in rabbits by challenge protection assay and humoral immune response. The mortality rates in control and vaccinated groups were 80% and 10% at day 7 post challenge and 100% and 20% at day 15 post challenge, respectively. Serum antibody titer (GMT) was significantly higher (294.0) in vaccinated group as compared to control group of rabbits (2.63) at day 45. The results showed that the vaccine has significantly elicited humoral immune response in rabbit and developed protective efficacy against new infections. PMID:27175154

Enterotoxigenic Escherichia coli Adhesin-Toxoid Multiepitope Fusion Antigen CFA/I/II/IV-3xSTaN12S-mnLTG192G/L211A-Derived Antibodies Inhibit Adherence of Seven Adhesins, Neutralize Enterotoxicity of LT and STa Toxins, and Protect Piglets against Diarrhea.

PubMed

Nandre, Rahul; Ruan, Xiaosai; Lu, Ti; Duan, Qiangde; Sack, David; Zhang, Weiping

2018-03-01

Enterotoxigenic Escherichia coli (ETEC) strains are a leading cause of children's diarrhea and travelers' diarrhea. Vaccines inducing antibodies to broadly inhibit bacterial adherence and to neutralize toxin enterotoxicity are expected to be effective against ETEC-associated diarrhea. 6×His-tagged adhesin-toxoid fusion proteins were shown to induce neutralizing antibodies to several adhesins and LT and STa toxins (X. Ruan, D. A. Sack, W. Zhang, PLoS One 10:e0121623, 2015, https://doi.org/10.1371/journal.pone.0121623). However, antibodies derived from His-tagged CFA/I/II/IV-2xSTa A14Q -dmLT or CFA/I/II/IV-2xSTa N12S -dmLT protein were less effective in neutralizing STa enterotoxicity and were not evaluated in vivo for efficacy against ETEC diarrhea. Additionally, His-tagged proteins are considered less desirable for human vaccines. In this study, we produced a tagless adhesin-toxoid MEFA (multiepitope fusion antigen) protein, enhanced anti-STa immunogenicity by including a third copy of STa toxoid STa N12S , and examined antigen immunogenicity in a murine model. Moreover, we immunized pregnant pigs with the tagless adhesin-toxoid MEFA protein and evaluated passive antibody protection against STa + or LT + ETEC infection in a pig challenge model. Results showed that tagless adhesin-toxoid MEFA CFA/I/II/IV-3xSTa N12S -mnLT R192G/L211A induced broad antiadhesin and antitoxin antibody responses in the intraperitoneally immunized mice and the intramuscularly immunized pigs. Mouse and pig serum antibodies significantly inhibited adherence of seven colonization factor antigen (CFA) adhesins (CFA/I and CS1 to CS6) and effectively neutralized both toxins. More importantly, suckling piglets born to the immunized mothers acquired antibodies and were protected against STa + ETEC and LT + ETEC diarrhea. These results indicated that tagless CFA/I/II/IV-3xSTa N12S -mnLT R192G/L211A induced broadly protective antiadhesin and antitoxin antibodies and demonstrate that this adhesin-toxoid

Evaluation of De-O-Acetylated Meningococcal C Polysaccharide-Tetanus Toxoid Conjugate Vaccine in Infancy: Reactogenicity, Immunogenicity, Immunologic Priming, and Bactericidal Activity against O-Acetylated and De-O-Acetylated Serogroup C Strains

PubMed Central

Richmond, Peter; Borrow, Ray; Findlow, Jamie; Martin, Sarah; Thornton, Carol; Cartwright, Keith; Miller, Elizabeth

2001-01-01

The polysaccharide capsule of serogroup C Neisseria meningitidis (MenC) has been integral to vaccine development. Licensed MenC vaccines contain the O-acetylated (OAc+) form of polysaccharide. Some MenC strains have de-O-acetylated (OAc−) polysaccharide, which may affect antibody specificity and functional activity when used in a vaccine. We evaluated an OAc-MenC conjugate-tetanus toxoid conjugate (MCC-TT) vaccine given concomitantly with whole-cell diphtheria-tetanus-pertussis, Haemophilus influenzae type b, and oral polio immunization in 83 infants at 2, 3, and 4 months of age. Serum bactericidal activities (SBA) against OAc+ and OAc− MenC strains and OAc+ and OAc− polysaccharide-specific immunoglobulin G (IgG) levels were evaluated. MCC-TT vaccine was well tolerated. All infants produced SBA titers of ≥8 after a single dose at 2 months of age. The SBA geometric mean titer for OAc+ strain C11 increased from 2.7 (95% confidence interval [CI] 2.2 to 3.2) to 320 (95% CI, 237 to 432), 773 (95% CI, 609 to 982), and 1,063 (95% CI, 856 to 1319) after one, two, and three doses of MCC-TT, respectively. OAc− IgG levels were twice as high as OAc+ IgG levels after the primary series of MCC-TT vaccine, and the SBA was significantly higher against the OAc− MenC strain. Antibody responses to booster vaccination with either OAc+ MenC polysaccharide vaccine (MACP) or a fourth dose of MCC-TT at 14 months of age provided evidence of immunologic memory. The acetylation status of the booster vaccine influenced the specificity of the response, with significantly higher OAc− IgG levels and SBA after MCC-TT vaccine compared to MACP vaccine but similar OAc+ antibody levels. MCC-TT vaccine is highly immunogenic and primes for immunologic memory against OAc+ and OAc− MenC strains in infancy. PMID:11254596

Mechanism of Diphtheria Toxin Catalytic Domain Delivery to the Eukaryotic Cell Cytosol and the Cellular Factors that Directly Participate in the Process

PubMed Central

Murphy, John R.

2011-01-01

Research on diphtheria and anthrax toxins over the past three decades has culminated in a detailed understanding of their structure function relationships (e.g., catalytic (C), transmembrane (T), and receptor binding (R) domains), as well as the identification of their eukaryotic cell surface receptor, an understanding of the molecular events leading to the receptor-mediated internalization of the toxin into an endosomal compartment, and the pH triggered conformational changes required for pore formation in the vesicle membrane. Recently, a major research effort has been focused on the development of a detailed understanding of the molecular interactions between each of these toxins and eukaryotic cell factors that play an essential role in the efficient translocation of their respective catalytic domains through the trans-endosomal vesicle membrane pore and delivery into the cell cytosol. In this review, I shall focus on recent findings that have led to a more detailed understanding of the mechanism by which the diphtheria toxin catalytic domain is delivered to the eukaryotic cell cytosol. While much work remains, it is becoming increasingly clear that the entry process is facilitated by specific interactions with a number of cellular factors in an ordered sequential fashion. In addition, since diphtheria, anthrax lethal factor and anthrax edema factor all carry multiple coatomer I complex binding motifs and COPI complex has been shown to play an essential role in entry process, it is likely that the initial steps in catalytic domain entry of these divergent toxins follow a common mechanism. PMID:22069710

Analyzing titers of antibodies against bacterial and viral antigens, and bacterial toxoids in the intravenous immunoglobulins utilized in Taiwan.

PubMed

Wu, Chi-Yu; Wang, Hsiu-Chi; Wang, Kun-Teng; Yang-Chih Shih, Daniel; Lo, Chi-Fang; Wang, Der-Yuan

2013-03-01

Intravenous immunoglobulin (IVIG) manufactured from human plasma contains IgG as the primary ingredient, and is used for indications such as immunodeficiency syndrome. Available IVIGs in Taiwan are either manufactured from Taiwanese or North American plasma. The effectiveness of the national immunization program of Taiwan can be evaluated by analyzing and comparing IVIG antibody titers that are induced through the corresponding vaccines (tetanus, diphtheria, and pertussis, measles, rubella, hepatitis A, hepatitis B and varicella). Both enzyme-linked immunosorbent assay (ELISA) and the in vitro neutralization test demonstrated that all IVIGs provide adequate clinical protection against diphtheria and tetanus toxins. ELISA results further revealed that plasma of Taiwanese subjects contains higher levels of pertussis toxin and filamentous hemagglutinin antibodies, when compared to foreign IVIGs. This may be related to the later adoption of acellular pertussis vaccine in Taiwan. Antibodies titers against measles, rubella, hepatitis A, and varicella-zoster virus were otherwise low. Low titers of hepatitis B surface antigen antibodies are present in Taiwanese plasma IVIG, indicating immune memory decline or loss. In conclusion, our results show that Taiwanese IVIG contains varying titers of vaccine-induced antibodies, and serves as a guide for future amendments to Taiwan's immunization program. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Immunogenicity and reactogenicity of Infanrix™ when co-administered with meningococcal MenACWY-TT conjugate vaccine in toddlers primed with MenHibrix™ and Pediarix™.

PubMed

Leonardi, Michael; Latiolais, Thomas; Sarpong, Kwabena; Simon, Michael; Twiggs, Jerry; Lei, Paul; Rinderknecht, Stephen; Blatter, Mark; Bianco, Veronique; Baine, Yaela; Friedland, Leonard R; Baccarini, Carmen; Miller, Jacqueline M

2015-02-11

Co-administration of an investigational quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) with the fourth dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP) at age 15-18 months was investigated in 3-dose Haemophilus influenzae type b-meningococcal serogroups C/Y conjugate vaccine (HibMenCY-TT)-primed toddlers. Infants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and DTaP-hepatitis B-inactivated poliovirus (DTaP-HBV-IPV) vaccine, or Hib-TT and DTaP-HBV-IPV (Control). HibMenCY-TT+ DTaP-HBV-IPV vaccinees were re-randomized (2:2:1) to receive MenACWY-TT at 12-15 months and DTaP at 15-18 months (MenACWY-TT group); MenACWY-TT co-administered with DTaP at 15-18 months (Coad group); or HibMenCY-TT at 12-15 months and DTaP at 15-18 months (HibMenCY-TT group). Controls received DTaP at 15-18 months. Only children in the HibMenCY-TT group received a fourth dose of Hib conjugate vaccine due to Hib conjugate vaccine shortage at the time of the study. DTaP immunogenicity and reactogenicity were assessed one month post-vaccination. Pre-defined statistical non-inferiority criteria between Coad and Control groups were met for diphtheria, tetanus and filamentous haemagglutinin but not pertussis toxoid and pertactin. Following vaccination ≥99% of children had anti-diphtheria/anti-tetanus concentrations ≥1.0 IU/ml. Pertussis GMCs were lower in all investigational groups versus Control. In post hoc analyses, pertussis antibody concentrations were above those in infants following 3-dose DTaP primary vaccination in whom efficacy against pertussis was demonstrated (Schmitt, von König, et al., 1996; Schmitt, Schuind, et al., 1996). The reactogenicity profile of the Coad group was similar to DTaP administered alone. Routine booster DTaP was immunogenic with an acceptable safety profile when co-administered with MenACWY-TT vaccine in HibMenCY-TT-primed toddlers. These data support the

Evaluation of components of X-ray irradiated 7-valent pneumococcal conjugate vaccine and pneumococcal vaccine polyvalent and X-ray and gamma-ray irradiated acellular pertussis component of DTaP vaccine products

NASA Astrophysics Data System (ADS)

May, J. C.; Rey, L.; Lee, Chi-Jen; Arciniega, Juan

2004-09-01

Samples of pneumococcal vaccine polyvalent, 7-valent pneumococcal conjugate vaccine, and two different diphtheria and tetanus toxoids and acellular pertussis vaccines adsorbed were irradiated with X-rays and/or gamma-rays (Co-60). Mouse IgG and IgM antibody responses (ELISA) for types 9V, 14, 18C, and 19F pneumococcal polysaccharides and conjugates indicated that the polysaccharides were more tolerant of the radiation than the conjugates. The mouse antibody response for the detoxified pertussis toxin (PT) antigen, filamentous hemagglutinin antigen (FHA), pertactin (PRN), and fimbriae types 2 and 3 (FIM) antigens for the appropriate vaccine type indicated that the antibody response was not significantly changed in the 25 kGy X-ray irradiated vaccines frozen in liquid nitrogen compared to the control vaccine.

The Immune System of HIV-Exposed Uninfected Infants.

PubMed

Abu-Raya, Bahaa; Kollmann, Tobias R; Marchant, Arnaud; MacGillivray, Duncan M

2016-01-01

Infants born to human immunodeficiency virus (HIV) infected women are HIV-exposed but the majority remains uninfected [i.e., HIV-exposed uninfected (HEU)]. HEU infants suffer greater morbidity and mortality from infections compared to HIV-unexposed (HU) peers. The reason(s) for these worse outcomes are uncertain, but could be related to an altered immune system state. This review comprehensively summarizes the current literature investigating the adaptive and innate immune system of HEU infants. HEU infants have altered cell-mediated immunity, including impaired T-cell maturation with documented hypo- as well as hyper-responsiveness to T-cell activation. And although prevaccination vaccine-specific antibody levels are often lower in HEU than HU, most HEU infants mount adequate humoral immune response following primary vaccination with diphtheria toxoid, haemophilus influenzae type b, whole cell pertussis, measles, hepatitis B, tetanus toxoid, and pneumococcal conjugate vaccines. However, HEU infants are often found to have lower absolute neutrophil counts as compared to HU infants. On the other hand, an increase of innate immune cytokine production and expression of co-stimulatory markers has been noted in HEU infants, but this increase appears to be restricted to the first few weeks of life. The immune system of HEU children beyond infancy remains largely unexplored.

Protein carriers of conjugate vaccines

PubMed Central

Pichichero, Michael E

2013-01-01

The immunogenicity of polysaccharides as human vaccines was enhanced by coupling to protein carriers. Conjugation transformed the T cell-independent polysaccharide vaccines of the past to T cell-dependent antigenic vaccines that were much more immunogenic and launched a renaissance in vaccinology. This review discusses the conjugate vaccines for prevention of infections caused by Hemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis. Specifically, the characteristics of the proteins used in the construction of the vaccines including CRM, tetanus toxoid, diphtheria toxoid, Neisseria meningitidis outer membrane complex, and Hemophilus influenzae protein D are discussed. The studies that established differences among and key features of conjugate vaccines including immunologic memory induction, reduction of nasopharyngeal colonization and herd immunity, and antibody avidity and avidity maturation are presented. Studies of dose, schedule, response to boosters, of single protein carriers with single and multiple polysaccharides, of multiple protein carriers with multiple polysaccharides and conjugate vaccines administered concurrently with other vaccines are discussed along with undesirable consequences of conjugate vaccines. The clear benefits of conjugate vaccines in improving the protective responses of the immature immune systems of young infants and the senescent immune systems of the elderly have been made clear and opened the way to development of additional vaccines using this technology for future vaccine products. PMID:23955057

Inbreeding effects on immune response in free-living song sparrows (Melospiza melodia).

PubMed

Reid, Jane M; Arcese, Peter; Keller, Lukas F; Elliott, Kyle H; Sampson, Laura; Hasselquist, Dennis

2007-03-07

The consequences of inbreeding for host immunity to parasitic infection have broad implications for the evolutionary and dynamical impacts of parasites on populations where inbreeding occurs. To rigorously assess the magnitude and the prevalence of inbreeding effects on immunity, multiple components of host immune response should be related to inbreeding coefficient (f) in free-living individuals. We used a pedigreed, free-living population of song sparrows (Melospiza melodia) to test whether individual responses to widely used experimental immune challenges varied consistently with f. The patagial swelling response to phytohaemagglutinin declined markedly with f in both females and males in both 2002 and 2003, although overall inbreeding depression was greater in males. The primary antibody response to tetanus toxoid declined with f in females but not in males in both 2004 and 2005. Primary antibody responses to diphtheria toxoid were low but tended to decline with f in 2004. Overall inbreeding depression did not solely reflect particularly strong immune responses in outbred offspring of immigrant-native pairings or weak responses in highly inbred individuals. These data indicate substantial and apparently sex-specific inbreeding effects on immune response, implying that inbred hosts may be relatively susceptible to parasitic infection to differing degrees in males and females.

The safety and reactogenicity of a reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) booster vaccine in healthy Vietnamese children.

PubMed

Anh, Dang Duc; Jayadeva, Girish; Kuriyakose, Sherine; Han, Htay Htay

2016-08-17

Despite effective infant immunization against pertussis, the disease continues to circulate due to waning immunity. Booster vaccinations against pertussis beyond infancy are widely recommended. In Vietnam, however, no recommendations for pertussis boosters beyond the second year of life exist. This open-label, single-centre study was designed to assess the safety of a single booster dose of reduced-antigen-content-diphtheria-tetanus-acellular-pertussis vaccine (dTpa) in 300 healthy Vietnamese children (mean age 7.9years), who had completed primary vaccination against diphtheria, tetanus and pertussis. Solicited symptoms were recorded for 4days and unsolicited and serious adverse events (SAEs) for 31days post-vaccination. Pain and fatigue were the most common solicited local and general symptoms in 35.0% and 14.0% of children, respectively. Grade 3 swelling occurred in 3 children; no large injection site reactions or SAEs were reported. The dTpa booster vaccine was well tolerated and this study supports its administration in school age Vietnamese children. Copyright © 2016 GSK group of companies. Published by Elsevier Ltd.. All rights reserved.

Combined Immunosuppression Impairs Immunogenicity to Tetanus and Pertussis Vaccination Among Patients with Inflammatory Bowel Disease.

PubMed

Dezfoli, Seper; Horton, Henry A; Thepyasuwan, Nattapaun; Berel, Dror; Targan, Stephan R; Vasiliauskas, Eric A; Dubinsky, Marla; Shih, David Q; Kaur, Manreet; McGovern, Dermot P B; Ippoliti, Andrew; Feldman, Edward J; Melmed, Gil Y

2015-08-01

Pertussis epidemics have recently emerged across the United States, prompting broad public health recommendations for adult Tdap vaccination (tetanus, diphtheria, acellular pertussis). The impact of immunosuppressive regimens for inflammatory bowel disease (IBD) on vaccine responses to the Tdap vaccine is not known. We performed a prospective controlled trial between April 2011 and March 2012. Adults with IBD were consecutively stratified based on therapeutic regimen into one of 5 groups: A: no IBD therapy or 5-aminosalicylates alone; B: maintenance biologic monotherapy; C: maintenance immunomodulator monotherapy; D: combined biologic and immunomodulator therapy; and E: healthy age-matched controls. Subjects received Tdap, and serum antibody levels against tetanus toxoid, pertussis toxoid, and filamentous hemagglutinin (FHA) were drawn just before and approximately 4 weeks after vaccination. The primary outcome was the booster response rate to each antigen. Secondary outcomes included the differences in pregeometric and postgeometric mean titers. A total of 98 subjects enrolled, and 84 completed the study. Tetanus response rates were 55%, 56%, 40%, 27%, and 63% across groups A to E, respectively. Group D rates were lower than those of group B (P = 0.02). Postvaccination pertussis toxoid responses were 59%, 72%, 47%, 45%, and 75%, while FHA responses were 86%, 72%, 80%, 64%, and 75% across groups A to E, respectively. Prevaccination and postvaccination geometric mean titer differences for FHA were lower in group D than those in group A (P = 0.05). Antibody responses to tetanus and pertussis vaccination may be affected by therapeutic drug regimen. Patients with IBD should optimally receive Tdap before starting immunomodulators, particularly when used in combination with anti-tumor necrosis factor alpha agents.

Transgenic tomatoes express an antigenic polypeptide containing epitopes of the diphtheria, pertussis and tetanus exotoxins, encoded by a synthetic gene.

PubMed

Soria-Guerra, Ruth Elena; Rosales-Mendoza, Sergio; Márquez-Mercado, Crisóforo; López-Revilla, Rubén; Castillo-Collazo, Rosalba; Alpuche-Solís, Angel Gabriel

2007-07-01

A current priority of vaccinology is the development of multicomponent vaccines that protect against several pathogens. The diphtheria-pertussis-tetanus (DPT) vaccine prevents the symptoms of three serious and often fatal diseases due to the exotoxins produced by Corynebacterium diphteriae, Bordetella pertussis and Clostridium tetani. We are attempting to develop an edible DPT multicomponent vaccine in plants, based on the fusion of protective exotoxin epitopes encoded by synthetic genes. By means of Agrobacterium mediated transformation we generated transgenic tomatoes with a plant-optimised synthetic gene encoding a novel polypeptide containing two adjuvant and six DPT immunoprotective exotoxin epitopes joined by peptide linkers. In transformed tomato plants, integration of the synthetic DPT (sDPT) gene detected by PCR was confirmed by Southern blot, and specific transcripts of the expected molecular size were detected by RT-PCR. Expression of the putative polypeptide encoded by the sDPT gene was detected by immunoassay with specific antibodies to the diphtheria, pertussis and tetanus exotoxins. The sDPT gene is therefore integrated, transcribed and translated as the expected recombinant sDPT multiepitope polypeptide in transgenic tomatoes that constitute a potential edible vaccine.

Maternal antibodies against tetanus toxoid do not inhibit potency of antibody responses to autologous antigen in newborn rhesus monkeys.

PubMed

Veazey, Ronald S; Lu, Yingjie; Xu, Huanbin; Ziani, Widade; Doyle-Meyers, Lara A; Ratterree, Marion S; Wang, Xiaolei

2018-02-01

Our previous study suggested newborns have competent immune systems with the potential to respond to foreign antigens and vaccines. In this study, we examined infant immune responses to tetanus toxoid (TT) vaccination in the presence of maternal antibody to TT. We examined changes in plasma levels of tetanus toxoid-specific IgG1 (anti-TT IgG1) in a total of eight infant rhesus macaques from birth through 6 months of age using a commercial Monkey Anti-TT IgG1 ELISA kit. A significant correlation between anti-TT IgG1 levels in vaccinated dams and their paired newborn infants was detected in control (non-vaccinated) infants as previously reported. Maternal anti-TT IgG1 levels declined rapidly within 1 month of birth in non-vaccinated infants (n=4). In four infants vaccinated with TT at birth, we found two had rapid and robust antibody responses to vaccination. Interestingly, the other two first showed declining TT antibody levels for 2 weeks followed by increasing levels without additional vaccine boosts, indicating all four had good antibody responses to primary TT vaccination at birth, despite the presence of high levels of maternal antibodies to TT in all four infants. Our data indicate that newborn macaques have competent immune systems that are capable of generating their own primary antibody responses to vaccination, at least to tetanus antigens. Maternal antibodies thus do not significantly impair antibody response to the vaccination, even when received on the day of birth in infant rhesus macaques. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A phase I clinical study of immunotherapy for advanced colorectal cancers using carcinoembryonic antigen-pulsed dendritic cells mixed with tetanus toxoid and subsequent IL-2 treatment.

PubMed

Liu, Ko-Jiunn; Chao, Tsu-Yi; Chang, Jang-Yang; Cheng, Ann-Lii; Ch'ang, Hui-Ju; Kao, Woei-Yau; Wu, Yu-Chen; Yu, Wei-Lan; Chung, Tsai-Rong; Whang-Peng, Jacqueline

2016-08-24

To better evaluate and improve the efficacy of dendritic cell (DC)-based cancer immunotherapy, we conducted a clinical study of patients with advanced colorectal cancer using carcinoembryonic antigen (CEA)-pulsed DCs mixed with tetanus toxoid and subsequent interleukin-2 treatment. The tetanus toxoid in the vaccine preparation serves as an adjuvant and provides a non-tumor specific immune response to enhance vaccine efficacy. The aims of this study were to (1) evaluate the toxicity of this treatment, (2) observe the clinical responses of vaccinated patients, and (3) investigate the immune responses of patients against CEA before and after treatment. Twelve patients were recruited and treated in this phase I clinical study. These patients all had metastatic colorectal cancer and failed standard chemotherapy. We first subcutaneously immunized patients with metastatic colorectal cancer with 1 × 10(6) CEA-pulsed DCs mixed with tetanus toxoid as an adjuvant. Patients received 3 successive injections with 1 × 10(6) CEA-pulsed DCs alone. Low-dose interleukin-2 was administered subcutaneously following the final DC vaccination to boost the growth of T cells. Patients were evaluated for adverse event and clinical status. Blood samples collected before, during, and after treatment were analyzed for T cell proliferation responses against CEA. No severe treatment-related side effects or toxicity was observed in patients who received the regular 4 DC vaccine injections. Two patients had stable disease and 10 patients showed disease progression. A statistically significant increase in proliferation against CEA by T cells collected after vaccination was observed in 2 of 9 patients. The results of this study indicate that it is feasible and safe to treat colorectal cancer patients using this protocol. An increase in the anti-CEA immune response and a clinical benefit was observed in a small fraction of patients. This treatment protocol should be further evaluated in

Quantification of residual EDU (N-ethyl-N'-(dimethylaminopropyl) carbodiimide (EDC) hydrolyzed urea derivative) and other residual by LC-MS/MS.

PubMed

Lei, Q Paula; Lamb, David H; Shannon, Anthony G; Cai, Xinxing; Heller, Ronald K; Huang, Michael; Zablackis, Earl; Ryall, Robert; Cash, Patricia

2004-12-25

An LC-MS/MS method for determination of the break down product of N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) urea derivative, EDU, has been developed and validated for monitoring the residual coupling reagents. Results indicate that the method exhibits suitable specificity, sensitivity, precision, linearity and accuracy for quantification of residual EDU in the presence of meningococcal polysaccharide-diphtheria toxoid conjugate vaccine and other vaccine matrix compounds. The assay has been validated for a detection range of 10-100 ng/mL and then successfully transferred to quality control (QC) lab. This same method has also been applied to the determination of residual diaminohexane (DAH) in the presence of EDU. LC-MS/MS has proven to be useful as a quick and sensitive approach for simultaneous determination of multiple residual compounds in glycoconjugate vaccine samples.

[Local reactions after diphtheria-tetanus-acellular pertussis vaccines in mice; changes in histopathology at the injection site].

PubMed

Nagaoka, Chiharu; Katsuta, Tomohiro; Honjo, Ayako; Tateyama, Satoshi; Tokutake, Tadaomi; Arimoto, Yutaka; Nakajima, Natsuki; Goshima, Toshiro; Kato, Tatsuo

2006-03-01

Diphtheria-tetanus-acellular pertussis vaccine (DTaP) developed in Japan is now widely used worldwide. DTaP is safer than the diphtheria-tetanus-whole-cell pertussis vaccine (DTwP) and has fewer severe side effects, but local reactions such as redness, swelling, and induration are still reported. The pathophysiological mechanism of these reactions is controversial. To clarify the cause of local reactions, we conducted studies using the mouse model. After administering either one or two abdominal subcutaneous DTaP inoculations, we observed changes in histopathology at the injection site at 24h, 48h, and 7 days. The control group, inoculated with physiologic saline, showed no significant changes either pathologically or with the naked eye. All mice after DTaP vaccination showed indurations at the injection site. Pathologically, we watched leukocyte invasion into or around the site, especially neutrophils and eosinophils. After the first vaccination, the extent of the invasion was strong 24h and 7 days later. At 24h following the second vaccination, a dramatic leukocyte invasion seen persisted at 7days. At 7 days after the first vaccination, peripheral fibrosis had begun, and when a second vaccination was administered, it began even earlier at the second site. These histopathological changes show that local reactions are caused by both inflammatory and allergic responses. Because this mouse study resulted in the same pattern of reactions observed in humans, this method will be useful for studies focusing on local reactions.

Bone erosion and subacromial bursitis caused by diphtheria-tetanus-poliomyelitis vaccine.

PubMed

Salmon, J H; Geoffroy, M; Eschard, J P; Ohl, X

2015-11-17

Revaxis(®) is a vaccine against diphtheria, tetanus and poliomyelitis (dT-IPV). This vaccine should not be administered by the intradermal or intravenous route. Poor injection techniques and related consequences are rare. We report a case of bursitis associated with reactive glenohumeral effusion complicated by bone erosion occurring after injection of the dT-IPV vaccine. A 26 year old patient was admitted for painful left shoulder causing functional impairment. Control magnetic resonance imaging showed bone oedema on the upper outer part of the humeral head, with a slight cortical irregularity, indicating that the vaccine was injected in contact with the bone at this location, causing erosion. Outcome was favourable after intra-articular corticosteroids. Reports of articular or periarticular injury after vaccination are extremely rare, in view of the substantial number of vaccines administered every year. The potential complications of vaccination are well known to general practitioners but under-reported in the literature. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antibody Persistence in Young Children 5 Years after Vaccination with a Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C Conjugate Vaccine Coadministered with Diphtheria-Tetanus-Acellular Pertussis-Based and Pneumococcal Conjugate Vaccines

PubMed Central

Tejedor, Juan Carlos; Brzostek, Jerzy; Konior, Ryszard; Grunert, Detlef; Kolhe, Devayani; Baine, Yaela

2016-01-01

We evaluated antibody persistence in children up to 5 years after administration of a combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine coadministered with a pneumococcal conjugate vaccine. This is the follow-up study of a randomized trial (ClinicalTrials.gov registration no. NCT00334334/00463437) in which healthy children were vaccinated (primary vaccinations at 2, 4, and 6 months of age and booster vaccination at 11 to 18 months of age) with Hib-MenC-TT or a control MenC conjugate vaccine, coadministered with diphtheria-tetanus-acellular pertussis (DTPa)-based combination vaccines (DTPa/Hib for control groups) and a pneumococcal conjugate vaccine (10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine [PHiD-CV] or 7-valent cross-reacting material 197 [CRM197] conjugate vaccine [7vCRM]). MenC antibody titers were measured with a serum bactericidal antibody (SBA) assay using rabbit complement (i.e., rabbit SBA [rSBA]), and antibodies against Hib polyribosylribitol phosphate (PRP) were measured with an enzyme-linked immunosorbent assay. Antibody persistence up to 5 years after booster vaccination is reported for 530 children ∼6 years of age. The percentages of children with seroprotective rSBA-MenC titers were between 24.2% and 40.1% in all groups approximately 5 years after booster vaccination. More than 98.5% of children in each group retained seroprotective anti-PRP concentrations. No vaccine-related serious adverse events and no events related to a lack of vaccine efficacy were reported. Approximately 5 years after booster vaccination, the majority of children retained seroprotective anti-PRP antibody concentrations. The percentage of children retaining seroprotective rSBA-MenC titers was low (≤40%), suggesting that a significant proportion of children may be unprotected against MenC disease. (This study has been registered at ClinicalTrials.gov under

Antibody Persistence in Young Children 5 Years after Vaccination with a Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C Conjugate Vaccine Coadministered with Diphtheria-Tetanus-Acellular Pertussis-Based and Pneumococcal Conjugate Vaccines.

PubMed

Tejedor, Juan Carlos; Brzostek, Jerzy; Konior, Ryszard; Grunert, Detlef; Kolhe, Devayani; Baine, Yaela; Van Der Wielen, Marie

2016-07-01

We evaluated antibody persistence in children up to 5 years after administration of a combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine coadministered with a pneumococcal conjugate vaccine. This is the follow-up study of a randomized trial (ClinicalTrials.gov registration no. NCT00334334/00463437) in which healthy children were vaccinated (primary vaccinations at 2, 4, and 6 months of age and booster vaccination at 11 to 18 months of age) with Hib-MenC-TT or a control MenC conjugate vaccine, coadministered with diphtheria-tetanus-acellular pertussis (DTPa)-based combination vaccines (DTPa/Hib for control groups) and a pneumococcal conjugate vaccine (10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine [PHiD-CV] or 7-valent cross-reacting material 197 [CRM197] conjugate vaccine [7vCRM]). MenC antibody titers were measured with a serum bactericidal antibody (SBA) assay using rabbit complement (i.e., rabbit SBA [rSBA]), and antibodies against Hib polyribosylribitol phosphate (PRP) were measured with an enzyme-linked immunosorbent assay. Antibody persistence up to 5 years after booster vaccination is reported for 530 children ∼6 years of age. The percentages of children with seroprotective rSBA-MenC titers were between 24.2% and 40.1% in all groups approximately 5 years after booster vaccination. More than 98.5% of children in each group retained seroprotective anti-PRP concentrations. No vaccine-related serious adverse events and no events related to a lack of vaccine efficacy were reported. Approximately 5 years after booster vaccination, the majority of children retained seroprotective anti-PRP antibody concentrations. The percentage of children retaining seroprotective rSBA-MenC titers was low (≤40%), suggesting that a significant proportion of children may be unprotected against MenC disease. (This study has been registered at ClinicalTrials.gov under

Conjugation of tetanus toxoid with Salmonella typhimurium PTCC 1735 O-specific polysaccharide and its effects on production of opsonizing antibodies in a mouse model.

PubMed

Jazani, Nima Hosseini; Worobec, Elizabeth; Shahabi, Shahram; Nejad, Ghorban Behzadian

2005-04-01

Serious enteric and extra-intestinal infections with Salmonella typhimurium are very common in many human populations. Phagocytosis is the main defense mechanism against this bacterium; however, the unique structure of S. typhimurium lipopolysaccharide (LPS) makes it resistant to opsonization by complement components. In the present study, the S. typhimurium LPS O-chain was purified and conjugated with tetanus toxoid and the effects of the conjugated vaccine (O-specific polysaccharide tetanus toxoid (O-SP-TT)) on induction of specific antibodies were investigated in a mouse model. In vitro assays measuring phagocytosis in the presence of opsonizing antibodies were performed. Three subcutaneous injections of the O-SP-TT conjugate conferred protection against the intraperitoneal challenge with S. typhimurium and the LD50 was greater for immunized animals than for controls. The mean number of ingested S. typhimirium / mouse peritoneal cell in the presence of sera obtained from immunized mice with purified O-chain, O-SP-TT conjugate, heat-killed bacteria, and negative control were 6.96, 14.24, 15.96, and 6.67, respectively. In summary, we developed an O-SP-TT conjugate that induced opsonizing antibodies that increased phagocytosis, as determined by in vitro assays. In addition, chemiluminescence results, an indicator of oxidative burst, indicated that peritoneal cells respond better to live S. typhimurium cells in the presence of sera obtained from O-SP-TT conjugate immunized mice.

Sequence of ligand binding and structure change in the diphtheria toxin repressor upon activation by divalent transition metals.

PubMed

Rangachari, Vijayaraghavan; Marin, Vedrana; Bienkiewicz, Ewa A; Semavina, Maria; Guerrero, Luis; Love, John F; Murphy, John R; Logan, Timothy M

2005-04-19

The diphtheria toxin repressor (DtxR) is an Fe(II)-activated transcriptional regulator of iron homeostatic and virulence genes in Corynebacterium diphtheriae. DtxR is a two-domain protein that contains two structurally and functionally distinct metal binding sites. Here, we investigate the molecular steps associated with activation by Ni(II)Cl(2) and Cd(II)Cl(2). Equilibrium binding energetics for Ni(II) were obtained from isothermal titration calorimetry, indicating apparent metal dissociation constants of 0.2 and 1.7 microM for two independent sites. The binding isotherms for Ni(II) and Cd(II) exhibited a characteristic exothermic-endothermic pattern that was used to infer the metal binding sequence by comparing the wild-type isotherm with those of several binding site mutants. These data were complemented by measuring the distance between specific backbone amide nitrogens and the first equivalent of metal through heteronuclear NMR relaxation measurements. Previous studies indicated that metal binding affects a disordered to ordered transition in the metal binding domain. The coupling between metal binding and structure change was investigated using near-UV circular dichroism spectroscopy. Together, the data show that the first equivalent of metal is bound by the primary metal binding site. This binding orients the DNA binding helices and begins to fold the N-terminal domain. Subsequent binding at the ancillary site completes the folding of this domain and formation of the dimer interface. This model is used to explain the behavior of several mutants.

Asialoglycoprotein receptor mediates the toxic effects of an asialofetuin-diphtheria toxin fragment A conjugate on cultured rat hepatocytes.

PubMed Central

Cawley, D B; Simpson, D L; Herschman, H R

1981-01-01

We have constructed a toxic hybrid protein that is recognized by asialoglycoprotein (ASGP) receptors of cultured rat hepatocytes. The conjugate consists of fragment A of diphtheria toxin (DTA) linked by a disulfide bond to asialofetuin (ASF). This conjugate is highly toxic, inhibiting protein synthesis in primary rat hepatocytes at concentrations as low as 10 pM. The ASF-DTA conjugate was 600 and 1800 times as toxic as diphtheria toxin and DTA, respectively, on primary rat hepatocytes. The ASGP receptor recognizes galactose-terminated proteins. We tested a series of glycoproteins for their ability to block the action of the ASF-DTA conjugate. Fetuin and orosomucoid, two glycoproteins with terminal sialic acid on their oligosaccharide chains, did not block the action of the conjugate. Their galactose-terminated asialo derivatives, ASF and asialoorosomucoid, as expected, did block the action of the conjugate. The N-acetylglucosaminyl-terminated derivative (asialogalactoorsomucoid) had no appreciable effect on the activity of the conjugate. We tested the ASF-DTA conjugate on six cell types; except for primary rat hepatocytes, none of them were affected by a high concentration (10 nM) of ASF-DTA conjugate. A fetuin-DTA conjugate was less toxic by a factor of 300 than the ASF-DTA conjugate and exerted its effects primarily through non-receptor-mediated mechanisms. The highly toxic ASF-DTA conjugate is cell-type specific, and its action is mediated by a well-characterized receptor, whose mechanism of receptor-ligand internalization has been extensively investigated. Images PMID:6167984

Diphtheria toxin resistance in human lymphocytes and lymphoblasts in the in vivo somatic cell mutation test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomkins, D.J.; Wei, L.; Laurie, K.E.

1985-01-01

It has been shown that circulating peripheral blood lymphocytes can be used for the enumeration of 6-thioguanine-resistant cells that presumably arise by mutation in vivo. This somatic cell mutation test has been studied in lymphocytes from human populations exposed to known mutagens and/or carcinogens. The sensitivity of the test could be further enhanced by including other gene markers, since there is evidence for locus-specific differences in response to mutagens. Resistance to diphtheria toxin (Dip/sup r/) seemed like a potential marker to incorporate into the test because the mutation acts codominantly, can readily be selected in human diploid fibroblasts and Chinesemore » hamster cells with no evidence for cell density or cross-feeding effects, and can be assayed for in nondividing cells by measuring protein synthesis inhibition. Blood samples were collected from seven individuals, and fresh, cryopreserved, or Epstein-Barr virus (EBV)-transformed lymphocytes were tested for continued DNA synthesis (TH-thymidine, autoradiography) or protein synthesis (TVS-methionine, scintillation counting). Both fresh and cryopreserved lymphocytes, stimulated to divide with phytohemagglutinin (PHA), continued to synthesize DNA in the presence of high doses of diphtheria toxin (DT). Similarly, both dividing (PHA-stimulated) and nondividing fresh lymphocytes carried on significant levels of protein synthesis even 68 hr after exposure to 100 flocculating units (LF)/ml DT. The results suggest that human T and B lymphocytes may not be as sensitive to DT protein synthesis inhibition as human fibroblast and Chinese hamster cells. For this reason, Dip/sup r/ may not be a suitable marker for the somatic cell mutation test.« less

Carrier priming or suppression: understanding carrier priming enhancement of anti-polysaccharide antibody response to conjugate vaccines.

PubMed

Pobre, Karl; Tashani, Mohamed; Ridda, Iman; Rashid, Harunor; Wong, Melanie; Booy, Robert

2014-03-14

With the availability of newer conjugate vaccines, immunization schedules have become increasingly complex due to the potential for unpredictable immunologic interference such as 'carrier priming' and 'carrier induced epitopic suppression'. Carrier priming refers to an augmented antibody response to a carbohydrate portion of a glycoconjugate vaccine in an individual previously primed with the carrier protein. This review aims to provide a critical evaluation of the available data on carrier priming (and suppression) and conceptualize ways by which this phenomenon can be utilized to strengthen vaccination schedules. We conducted this literature review by searching well-known databases to date to identify relevant studies, then extracted and synthesized the data on carrier priming of widely used conjugate polysaccharide vaccines, such as, pneumococcal conjugate vaccine (PCV), meningococcal conjugate vaccine (MenCV) and Haemophilus influenzae type b conjugate vaccines (HibV). We found evidence of carrier priming with some conjugate vaccines, particularly HibV and PCV, in both animal and human models but controversy surrounds MenCV. This has implications for the immunogenicity of conjugate polysaccharide vaccines following the administration of tetanus-toxoid or diphtheria-toxoid containing vaccine (such as DTP). Available evidence supports a promising role for carrier priming in terms of maximizing the immunogenicity of conjugate vaccines and enhancing immunization schedule by making it more efficient and cost effective. Copyright © 2014 Elsevier Ltd. All rights reserved.

Vaccination against group B streptococcus.

PubMed

Heath, Paul T; Feldman, Robert G

2005-04-01

Streptococcus agalactiae (Group B streptococcus) is an important cause of disease in infants, pregnant women, the elderly and in immunosuppressed adults. An effective vaccine is likely to prevent the majority of infant disease (both early and late onset), as well as Group B streptococcus-related stillbirths and prematurity, to avoid the current real and theoretical limitations of intrapartum antibiotic prophylaxis, and to be cost effective. The optimal time to administer such a vaccine would be in the third trimester of pregnancy. The main limitations on the production of a Group B streptococcus vaccine are not technical or scientific, but regulatory and legal. A number of candidates including capsular conjugate vaccines using traditional carrier proteins such as tetanus toxoid and mutant diphtheria toxin CRM197, as well as Group B streptococcus-specific proteins such as C5a peptidase, protein vaccines using one or more Group B streptococcus surface proteins and mucosal vaccines, have the potential to be successful vaccines. The capsular conjugate vaccines using tetanus and CRM197 carrier proteins are the most advanced candidates, having already completed Phase II human studies including use in the target population of pregnant women (tetanus toxoid conjugate), however, no definitive protein conjugates have yet been trialed. However, unless the regulatory environment is changed specifically to allow the development of a Group B streptococcus vaccine, it is unlikely that one will ever reach the market.

Genetic construction and properties of a diphtheria toxin-related substance P fusion protein: in vitro destruction of cells bearing substance P receptors.

PubMed Central

Fisher, C E; Sutherland, J A; Krause, J E; Murphy, J R; Leeman, S E; vanderSpek, J C

1996-01-01

We have genetically replaced the native receptor binding domain of diphtheria toxin with an extended form of substance P (SP): SP-glycine (SP-Gly). The resulting fusion protein, DAB389SP-Gly, is composed of the catalytic and transmembrane domains of diphtheria toxin genetically coupled to SP-Gly. Because native SP requires a C-terminal amide moiety to bind with high affinity to the SP receptor, the precursor form of the fusion toxin, DAB389SP-Gly, was converted to DAB389SP by treatment with peptidylglycine-alpha-amidating monooxygenase. We demonstrate that following conversion, DAB389SP is selectively cytotoxic for cell lines that express either the rat or the human SP receptor. We also demonstrate that the cytotoxic action of DAB389SP is mediated via the SP receptor and dependent upon passage through an acidic compartment. To our knowledge, this is the first reported use of a neuropeptide as the targeting ligand for a fusion toxin; and the first instance in which an inactive precursor form of a fusion toxin is converted to the active form by a posttranslational modification. Images Fig. 2 PMID:8692995

Optimization of tetanus toxoid ammonium sulfate precipitation process using response surface methodology.

PubMed

Brgles, Marija; Prebeg, Pero; Kurtović, Tihana; Ranić, Jelena; Marchetti-Deschmann, Martina; Allmaier, Günter; Halassy, Beata

2016-10-02

Tetanus toxoid (TTd) is a highly immunogenic, detoxified form of tetanus toxin, a causative agent of tetanus disease, produced by Clostridium tetani. Since tetanus disease cannot be eradicated but is easily prevented by vaccination, the need for the tetanus vaccine is permanent. The aim of this work was to investigate the possibility of optimizing TTd purification, i.e., ammonium sulfate precipitation process. The influence of the percentage of ammonium sulfate, starting amount of TTd, buffer type, pH, temperature, and starting purity of TTd on the purification process were investigated using optimal design for response surface models. Responses measured for evaluation of the ammonium sulfate precipitation process were TTd amount (Lf/mL) and total protein content. These two parameters were used to calculate purity (Lf/mgPN) and the yield of the process. Results indicate that citrate buffer, lower temperature, and lower starting amount of TTd result in higher purities of precipitates. Gel electrophoresis combined with matrix-assisted laser desorption ionization-mass spectrometric analysis of precipitates revealed that there are no inter-protein cross-links and that all contaminating proteins have pIs similar to TTd, so this is most probably the reason for the limited success of purification by precipitation.

Selective primary health care: an interim strategy for disease control in developing countries.

PubMed

Walsh, J A; Warren, K S

1979-11-01

Priorities among the infectious diseases affecting the three billion people in the less developed world have been based on prevalence, morbidity, mortality and feasibility of control. With these priorities in mind a program of selective primary health care is compared with other approaches and suggested as the most cost-effective form of medical intervention in the least developed countries. A flexible program delivered by either fixed or mobile units might include measles and diphtheria-pertussis-tetanus vaccination, treatment for febrile malaria and oral rehydration for diarrhea in children, and tetanus toxoid and encouragement of breast feeding in mothers. Other interventions might be added on the basis of regional needs and new developments. For major diseases for which control measures are inadequate, research is an inexpensive approach on the basis of cost per infected person per year.

Studies of guinea pig immunoglobulin isotype, idiotype and antiidiotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tirrell, S.M.

1988-01-01

Immunization of Guinea pigs with diphtheria toxoid generated antibodies of the IgG class that were capable of neutralizing native toxin in vivo. Sera from these animals were used to affinity purify idiotypic antibodies (AB1). AB1 vaccines derived from the IgG1 class and from F(ab{prime}){sub 2} of IgG1 + IgG2 (IgG1/2) classes were effective in inducing a syngeneic anti-idiotype (AB2) response. Animals immunized with AB1 consisting of both IgG1/2 did not elicit a detectable AB2 response. Binding of homologous {sup 125}I-F(ab{prime}){sub 2} (AB1) to the antiidiotype was inhibited 90% in the presence of DT.F(ab{prime}){sub 2} derived from preimmune serum or hadmore » no inhibitory effects on the idiotype-antiidiotype interactions. Two groups of outbred guinea pigs were vaccinated with alum absorbed F(ab{prime}){sub 2} of anti-idiotype IgG1/2 (AB2). Of the ten animals inoculated with AB2, three tested positive by RIA against {sup 125}I-DT. Two of the RIA positive sera contained antibodies that neutralized diphtheria toxin in a rabbit intracutaneous assay. Purification of guinea pig IgG by protein A-Sepharose affinity chromatography resulted in the separation of three distinct IgG populations.« less

Effect of skin barrier disruption on immune responses to topically applied cross-reacting material, CRM(197), of diphtheria toxin.

PubMed

Godefroy, S; Peyre, M; Garcia, N; Muller, S; Sesardic, D; Partidos, C D

2005-08-01

The high accessibility of the skin and the presence of immunocompetent cells in the epidermis makes this surface an attractive route for needle-free administration of vaccines. However, the lining of the skin by the stratum corneum is a major obstacle to vaccine delivery. In this study we examined the effect of skin barrier disruption on the immune responses to the cross-reacting material CRM(197), a nontoxic mutant of diphtheria toxin (DTx) that is considered as a vaccine candidate. Application of CRM(197), together with cholera toxin (CT), onto the tape-stripped skin of mice elicited antibody responses that had anti-DTx neutralizing activity. Vaccine delivery onto mildly ablated skin or intact skin did not elicit any detectable anti-CRM(197) antibodies. Mice immunized with CRM(197) alone onto the tape-stripped skin mounted a vigorous antigen-specific proliferative response. In contrast, the induction of cellular immunity after CRM(197) deposition onto mildly ablated or intact skin was adjuvant dependent. Furthermore, epidermal cells were activated and underwent apoptosis that was more pronounced when the stratum corneum was removed by tape stripping. Overall, these findings highlight the potential for transcutaneous delivery of CRM(197) and establish a correlation between the degree of barrier disruption and levels of antigen-specific immune responses. Moreover, these results provide the first evidence that the development of a transcutaneous immunization strategy for diphtheria, based on simple and practical methods to disrupt the skin barrier, is feasible.

Diphtheria toxin can simultaneously bind to its receptor and adenylyl-(3',5')-uridine 3'-monophosphate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barbieri, J.T.; Collins, C.M.; Collier, R.J.

1986-10-21

Diphtheria toxin (DT) that was bound to receptors on BS-C-1 cells was able to bind approximately 1 molar equiv of adenylyl-(3',5')-uridine 3'-monophosphate (ApUp). In contrast, receptor-bound CRM197, a mutant form of toxin with greatly diminished affinity for dinucleotides, did not bind ApUp. Affinity of the dinucleotide for receptor-bound toxin differed from that for free toxin by less than an order of magnitude. These results indicate that the receptor site and the ApUp site on the toxin do not significantly overlap. BS-C-1 cells were incubated with or without /sup 125/I-DT or CRM 197. They were then incubated with (/sup 32/P)ApUp, andmore » assayed.« less

Asialoglycoprotein receptor mediates the toxic effects of an asialofetuin-diphtheria toxin fragment A conjugate on cultured rat hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cawley, D.B.; Simpson, D.L.; Herschman, H.R.

1981-06-01

We have constructed a toxic hybrid protein that is recognized by asialoglycoprotein (ASGP) receptors of cultured rat hepatocytes. The conjugate consists of fragment A of diphtheria toxin (DTA) linked by a disulfide bond to asialofetuin (ASF). This conjugate is highly toxic, inhibiting protein synthesis in primary rat hepatocytes at concentrations as low as 10 pM. The ASF-DTA conjugate was 600 and 1800 times as toxic as diphtheria toxin and DTA, respectively, on primary rat hepatocytes. The ASGP receptor recognizes galactose-terminated proteins. We tested a series of glycoproteins for their ability to block the action of the ASF-DTA conjugate. Fetuin andmore » orosomucoid, two glycoproteins with terminal sialic acid on their oligosaccharide chains, did not block the action of the conjugate. Their galactose-terminated asialo derivatives, ASF and asialoorosomucoid, as expected, did block the action of the conjugate. The N-acetylglucosaminyl-terminated derivative (asialoagalactoorosomucoid) had no appreciable effect on the activity of the conjugate. We tested the ASF-DTA conjugate on six cell types; except for primary rat hepatocytes, none of them were affected by a high concentration (10 nM) of ASF-DTA conjugate. A fetuin-DTA conjugate was less toxic by a factor of 300 than the ASF-DTA conjugate and exerted its effects primarily through non-receptor-mediated mechanisms. The highly toxic ASF-DTA conjugate is cell-type specific, and its action is mediated by a well-characterized receptor, whose mechanism of receptor-ligand internalization has been extensively investigated.« less

A Belgian Serosurveillance/Seroprevalence Study of Diphtheria, Tetanus and Pertussis Using a Luminex xMAP Technology-Based Pentaplex.

PubMed

Caboré, Raissa Nadège; Piérard, Denis; Huygen, Kris

2016-05-10

Serosurveillance and seroprevalence studies are an essential tool to monitor vaccine-preventable diseases. We have developed a magnetic bead-based pentaplex immunoassay (MIA) for the simultaneous detection of IgG antibodies against diphtheria toxin (DT), tetanus toxin (TT), pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (Prn). The in-house pentaplex MIA showed a good correlation with commercial ELISAs with correlation coefficients between 0.89 for PT and 0.98 for TT. Intra- and inter-assay variability was <10%. A total of 670 anonymized serum samples collected in 2012 in Belgian adults (ages 20-29.9 years) were analyzed. Geometric mean concentrations (GMC) were 0.2 (0.13-0.29) IU/mL for DT, 0.63 (0.45-0.82) IU/mL for TT, 3.9 (2.6-5.8) IU/mL for PT, 16.3 (11.7-22.7) IU/mL for FHA and 15.4 (10.1-23.6) IU/mL for Prn. Antibody concentrations were below the protective level of 0.1 IU/mL in 26.4% of the sera for DT and in 8.6% of the sera for TT. Anti-PT IgG concentrations indicative of recent pertussis infection (>125 IU/mL) were detected in 1.2% of the subjects. High anti-PT antibodies were not correlated with high antibodies against any of the four other vaccine antigens. This pentaplex MIA will be used for a new large-scale Belgian serosurveillance/seroprevalence study of diphtheria, tetanus and pertussis.

Genetic Fusions of a CFA/I/II/IV MEFA (Multiepitope Fusion Antigen) and a Toxoid Fusion of Heat-Stable Toxin (STa) and Heat-Labile Toxin (LT) of Enterotoxigenic Escherichia coli (ETEC) Retain Broad Anti-CFA and Antitoxin Antigenicity

PubMed Central

Ruan, Xiaosai; Sack, David A.; Zhang, Weiping

2015-01-01

Immunological heterogeneity has long been the major challenge in developing broadly effective vaccines to protect humans and animals against bacterial and viral infections. Enterotoxigenic Escherichia coli (ETEC) strains, the leading bacterial cause of diarrhea in humans, express at least 23 immunologically different colonization factor antigens (CFAs) and two distinct enterotoxins [heat-labile toxin (LT) and heat-stable toxin type Ib (STa or hSTa)]. ETEC strains expressing any one or two CFAs and either toxin cause diarrhea, therefore vaccines inducing broad immunity against a majority of CFAs, if not all, and both toxins are expected to be effective against ETEC. In this study, we applied the multiepitope fusion antigen (MEFA) strategy to construct ETEC antigens and examined antigens for broad anti-CFA and antitoxin immunogenicity. CFA MEFA CFA/I/II/IV [CVI 2014, 21(2):243-9], which carried epitopes of seven CFAs [CFA/I, CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)] expressed by the most prevalent and virulent ETEC strains, was genetically fused to LT-STa toxoid fusion monomer 3xSTaA14Q-dmLT or 3xSTaN12S-dmLT [IAI 2014, 82(5):1823-32] for CFA/I/II/IV-STaA14Q-dmLT and CFA/I/II/IV-STaN12S-dmLT MEFAs. Mice intraperitoneally immunized with either CFA/I/II/IV-STa-toxoid-dmLT MEFA developed antibodies specific to seven CFAs and both toxins, at levels equivalent or comparable to those induced from co-administration of the CFA/I/II/IV MEFA and toxoid fusion 3xSTaN12S-dmLT. Moreover, induced antibodies showed in vitro adherence inhibition activities against ETEC or E. coli strains expressing these seven CFAs and neutralization activities against both toxins. These results indicated CFA/I/II/IV-STa-toxoid-dmLT MEFA or CFA/I/II/IV MEFA combined with 3xSTaN12S-dmLT induced broadly protective anti-CFA and antitoxin immunity, and suggested their potential application in broadly effective ETEC vaccine development. This MEFA strategy may be generally used in multivalent

Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity.

PubMed

Ruan, Xiaosai; Sack, David A; Zhang, Weiping

2015-01-01

Immunological heterogeneity has long been the major challenge in developing broadly effective vaccines to protect humans and animals against bacterial and viral infections. Enterotoxigenic Escherichia coli (ETEC) strains, the leading bacterial cause of diarrhea in humans, express at least 23 immunologically different colonization factor antigens (CFAs) and two distinct enterotoxins [heat-labile toxin (LT) and heat-stable toxin type Ib (STa or hSTa)]. ETEC strains expressing any one or two CFAs and either toxin cause diarrhea, therefore vaccines inducing broad immunity against a majority of CFAs, if not all, and both toxins are expected to be effective against ETEC. In this study, we applied the multiepitope fusion antigen (MEFA) strategy to construct ETEC antigens and examined antigens for broad anti-CFA and antitoxin immunogenicity. CFA MEFA CFA/I/II/IV [CVI 2014, 21(2):243-9], which carried epitopes of seven CFAs [CFA/I, CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)] expressed by the most prevalent and virulent ETEC strains, was genetically fused to LT-STa toxoid fusion monomer 3xSTaA14Q-dmLT or 3xSTaN12S-dmLT [IAI 2014, 82(5):1823-32] for CFA/I/II/IV-STaA14Q-dmLT and CFA/I/II/IV-STaN12S-dmLT MEFAs. Mice intraperitoneally immunized with either CFA/I/II/IV-STa-toxoid-dmLT MEFA developed antibodies specific to seven CFAs and both toxins, at levels equivalent or comparable to those induced from co-administration of the CFA/I/II/IV MEFA and toxoid fusion 3xSTaN12S-dmLT. Moreover, induced antibodies showed in vitro adherence inhibition activities against ETEC or E. coli strains expressing these seven CFAs and neutralization activities against both toxins. These results indicated CFA/I/II/IV-STa-toxoid-dmLT MEFA or CFA/I/II/IV MEFA combined with 3xSTaN12S-dmLT induced broadly protective anti-CFA and antitoxin immunity, and suggested their potential application in broadly effective ETEC vaccine development. This MEFA strategy may be generally used in multivalent

Safety and reactogenicity of the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b (DTPa-IPV/Hib) vaccine in healthy Vietnamese toddlers: An open-label, phase III study.

PubMed

Anh, Dang Duc; Van Der Meeren, Olivier; Karkada, Naveen; Assudani, Deepak; Yu, Ta-Wen; Han, Htay Htay

2016-03-03

The introduction of combination vaccines plays a significant role in increasing vaccine acceptance and widening vaccine coverage. Primary vaccination against diphtheria, tetanus, pertussis, poliomyelitis and Haemophilus influenza type b (Hib) diseases has been implemented in Vietnam. In this study we evaluated the safety and reactogenicity of combined diphtheria-tetanus-pertussis-inactivated polio (DTPa-IPV)/Hib vaccine when administered as a booster dose in 300 healthy Vietnamese children <2 years of age (mean age: 15.8 months). During the 4-day follow-up period, pain (31.7%) and redness (27.3%) were the most frequent solicited local symptoms. Pain (2%) was also the most frequent grade 3 local symptom. One subject reported 2 serious adverse events that were not causally related to the study vaccine. DTPa-IPV/Hib conjugate vaccine was well tolerated as a booster dose in healthy Vietnamese children aged <2 years.

Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice.

PubMed

Hu, Lingxiang; Lu, Jingrong; Chiang, Hao; Wu, Hao; Edge, Albert S B; Shi, Fuxin

2016-09-07

Cochlear hair cells (HCs), the sensory cells that respond to sound, do not regenerate after damage in adult mammals, and their loss is a major cause of deafness. Here we show that HC regeneration in newborn mouse ears occurred spontaneously when the original cells were ablated by treatment with diphtheria toxin (DT) in ears that had been engineered to overexpress the DT receptor, but was not detectable when HCs were ablated in vivo by the aminoglycoside antibiotic neomycin. A variety of Wnts (Wnt1, Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt7b, Wnt9a, Wnt9b, and Wnt11) and Wnt pathway component Krm2 were upregulated after DT damage. Nuclear β-catenin was upregulated in HCs and supporting cells of the DT-damaged cochlea. Pharmacological inhibition of Wnt decreased spontaneous regeneration, confirming a role of Wnt signaling in HC regeneration. Inhibition of Notch signaling further potentiated supporting cell proliferation and HC differentiation that occurred spontaneously. The absence of new HCs in the neomycin ears was correlated to less robust Wnt pathway activation, but the ears subjected to neomycin treatment nonetheless showed increased cell division and HC differentiation after subsequent forced upregulation of β-catenin. These studies suggest, first, that Wnt signaling plays a key role in regeneration, and, second, that the outcome of a regenerative response to damage in the newborn cochlea is determined by reaching a threshold level of Wnt signaling rather than its complete absence or presence. Sensory HCs of the inner ear do not regenerate in the adult, and their loss is a major cause of deafness. We found that HCs regenerated spontaneously in the newborn mouse after diphtheria toxin (DT)-induced, but not neomycin-induced, HC death. Regeneration depended on activation of Wnt signaling, and regeneration in DT-treated ears correlated to a higher level of Wnt activation than occurred in nonregenerating neomycin-treated ears. This is significant because insufficient

Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice

PubMed Central

Hu, Lingxiang; Lu, Jingrong; Chiang, Hao; Shi, Fuxin

2016-01-01

Cochlear hair cells (HCs), the sensory cells that respond to sound, do not regenerate after damage in adult mammals, and their loss is a major cause of deafness. Here we show that HC regeneration in newborn mouse ears occurred spontaneously when the original cells were ablated by treatment with diphtheria toxin (DT) in ears that had been engineered to overexpress the DT receptor, but was not detectable when HCs were ablated in vivo by the aminoglycoside antibiotic neomycin. A variety of Wnts (Wnt1, Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt7b, Wnt9a, Wnt9b, and Wnt11) and Wnt pathway component Krm2 were upregulated after DT damage. Nuclear β-catenin was upregulated in HCs and supporting cells of the DT-damaged cochlea. Pharmacological inhibition of Wnt decreased spontaneous regeneration, confirming a role of Wnt signaling in HC regeneration. Inhibition of Notch signaling further potentiated supporting cell proliferation and HC differentiation that occurred spontaneously. The absence of new HCs in the neomycin ears was correlated to less robust Wnt pathway activation, but the ears subjected to neomycin treatment nonetheless showed increased cell division and HC differentiation after subsequent forced upregulation of β-catenin. These studies suggest, first, that Wnt signaling plays a key role in regeneration, and, second, that the outcome of a regenerative response to damage in the newborn cochlea is determined by reaching a threshold level of Wnt signaling rather than its complete absence or presence. SIGNIFICANCE STATEMENT Sensory HCs of the inner ear do not regenerate in the adult, and their loss is a major cause of deafness. We found that HCs regenerated spontaneously in the newborn mouse after diphtheria toxin (DT)-induced, but not neomycin-induced, HC death. Regeneration depended on activation of Wnt signaling, and regeneration in DT-treated ears correlated to a higher level of Wnt activation than occurred in nonregenerating neomycin-treated ears. This is significant

Effect of Spirulina (Arthrospira) supplementation on the immune response to tetanus toxoid vaccination in a mouse model.

PubMed

Chu, Wan-Loy; Quynh, Le Van; Radhakrishnan, Ammu Kutty

2013-09-01

The aim of this study was to investigate whether Spirulina (Arthrospira) supplementation could enhance the immune response to tetanus toxoid (TT) vaccine in a mouse model. Vaccination of TT was performed on day 7 and 21 in mice fed daily with Spirulina (50 and 150 mg/kg body weight). Both Spirulina supplementation and TT vaccination did not significantly affect body weight gain of the mice. Supplementation of Spirulina significantly enhanced IgG level (p = .01) after the first but not after the second TT vaccination. The anti-TT IgG levels of the groups that received low dose and high dose of Spirulina were not significantly different. Spirulina supplementation did not show significant effects on in vitro splenocyte proliferation and cytokine (IFN-γ and IL-4) production induced by Con A and TT. This study showed that Spirulina supplementation could enhance primary immune response in terms of antibody production, but not secondary immune response following TT vaccination in a mouse model.

Removal of gelatin from live vaccines and DTaP-an ultimate solution for vaccine-related gelatin allergy.

PubMed

Kuno-Sakai, Harumi; Kimura, Mikio

2003-12-01

From the early 1990s infants started to receive acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) before live vaccines such as measles, rubella, and mumps vaccines, which contained gelatin as a stabilizer. Then, an increasing number of cases of anaphylactic/allergic reactions to those live vaccines were reported. Almost all these cases had a previous history of receiving three or four doses of DTaP containing gelatin.Anaphylactic/allergic reactions to live measles vaccine were analyzed using information obtained from the Reporting System, a retrospective study, as well as from the Monitoring System, a prospective study. Dramatic decreases in anaphylactic/allergic reactions to live measles vaccines were observed immediately after each manufacturer marketed gelatin-free or gelatin (hypo-allergic)-containing live measles vaccine, and since the end of 1998 reports on anaphylactic/allergic reactions to live measles vaccine have almost ceased.

The influence of conjugation variables on the design and immunogenicity of a glycoconjugate vaccine against Salmonella Typhi

PubMed Central

Arcuri, M.; Di Benedetto, R.; Cunningham, A. F.; Saul, A.; MacLennan, C. A.

2017-01-01

In recent years there have been major efforts to develop glycoconjugate vaccines based on the Vi polysaccharide that will protect against Salmonella enterica Typhi infections, particularly typhoid fever, which remains a major public health concern in low-income countries. The design of glycoconjugate vaccines influences the immune responses they elicit. Here we systematically test the response in mice to Vi glycoconjugates that differ in Vi chain length (full-length and fragmented), carrier protein, conjugation chemistry, saccharide to protein ratio and size. We show that the length of Vi chains, but not the ultimate size of the conjugate, has an impact on the anti-Vi IgG immune response induced. Full-length Vi conjugates, independent of the carrier protein, induce peak IgG responses rapidly after just one immunization, and secondary immunization does not enhance the magnitude of these responses. Fragmented Vi linked to CRM197 and diphtheria toxoid, but not to tetanus toxoid, gives lower anti-Vi antibody responses after the first immunization than full-length Vi conjugates, but antibody titres are similar to those induced by full-length Vi conjugates following a second dose. The chemistry to conjugate Vi to the carrier protein, the linker used, and the saccharide to protein ratio do not significantly alter the response. We conclude that Vi length and carrier protein are the variables that influence the anti-Vi IgG response to immunization the most, while other parameters are of lesser importance. PMID:29287062

A cohort study of developmental polychlorinated biphenyl (PCB) exposure in relation to post-vaccination antibody response at 6-months of age

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jusko, Todd A., E-mail: juskota@niehs.nih.gov; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA; De Roos, Anneclaire J.

2010-05-15

Background: Extensive experimental data in animals indicate that exposure to polychlorinated biphenyls (PCBs) during pregnancy leads to changes in offspring immune function during the postnatal period. Whether developmental PCB exposure influences immunologic development in humans has received little study. Methods: The study population was 384 mother-infant pairs recruited from two districts of eastern Slovakia for whom prospectively collected maternal, cord, and 6-month infant blood specimens were available. Several PCB congeners were measured in maternal, cord, and 6-month infant sera by high-resolution gas chromatography with electron capture detection. Concentrations of IgG-specific anti-haemophilus influenzae type b, tetanus toxoid, and diphtheria toxoid weremore » assayed in 6-month infant sera using ELISA methods. Multiple linear regression was used to estimate the relation between maternal, cord, and 6-month infant PCB concentrations and the antibody concentrations evaluated at 6-months of age. Results: Overall, there was little evidence of an association between infant antibody concentrations and PCB measures during the pre- and early postnatal period. In addition, our results did not show specificity in terms of associations limited to a particular developmental period (e.g. pre- vs. postnatal), a particular antibody, or a particular PCB congener. Conclusions: At the PCB concentrations measured in this cohort, which are high relative to most human populations today, we did not detect an association between maternal or early postnatal PCB exposure and specific antibody responses at 6-months of age.« less

Maternal tetanus toxoid vaccination and neonatal mortality in rural north India.

PubMed

Singh, Abhishek; Pallikadavath, Saseendran; Ogollah, Reuben; Stones, William

2012-01-01

Preventable neonatal mortality due to tetanus infection remains common. We aimed to examine antenatal vaccination impact in a context of continuing high neonatal mortality in rural northern India. Using the third round of the Indian National Family Health Survey (NFHS) 2005-06, mortality of most recent singleton births was analysed in discrete-time logistic model with maternal tetanus vaccination, together with antenatal care utilisation and supplementation with iron and folic acid. 59% of mothers reported receiving antenatal care, 48% reported receiving iron and folic acid supplementation and 68% reported receiving two or more doses of tetanus toxoid (TT) vaccination. The odds of all-cause neonatal death were reduced following one or more antenatal dose of TT with odds ratios (OR) of 0.46 (95% CI 0.26 to 0.78) after one dose and 0.45 (95% CI 0.31 to 0.66) after two or more doses. Reported utilisation of antenatal care and iron-folic acid supplementation did not influence neonatal mortality. In the statistical model, 16% (95% CI 5% to 27%) of neonatal deaths could be attributed to a lack of at least two doses of TT vaccination during pregnancy, representing an estimated 78,632 neonatal deaths in absolute terms. Substantial gains in newborn survival could be achieved in rural North India through increased coverage of antenatal TT vaccination. The apparent substantial protective effect of a single antenatal dose of TT requires further study. It may reflect greater population vaccination coverage and indicates that health programming should prioritise universal antenatal coverage with at least one dose.

Booster vaccination of pre-school children with reduced-antigen-content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine co-administered with measles-mumps-rubella-varicella vaccine

PubMed Central

Ferrera, Giuseppe; Cuccia, Mario; Mereu, Gabriele; Icardi, Giancarlo; Bona, Gianni; Esposito, Susanna; Marchetti, Federico; Messier, Marc; Kuriyakose, Sherine; Hardt, Karin

2012-01-01

Background: Pertussis occurs in older children, adolescents and adults due to waning immunity after primary vaccination. Booster vaccination for pre-school children has been recommended in Italy since 1999. In this study (NCT00871000), the immunogenicity, safety and reactogenicity of a booster dose of reduced-antigen content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV; GSK Biologicals Boostrix™-Polio; 3-component pertussis) vs. full-strength DTPa-IPV vaccine (sanofi-pasteur—MSD Tetravac™; 2-component pertussis) was evaluated in pre-school Italian children.   Methods: Healthy children aged 5–6 y primed in a routine vaccination setting with three doses of DTPa-based vaccines were enrolled and randomized (1:1) in this phase IIIb, booster study to receive a single dose of dTpa-IPV or DTPa-IPV; the MMRV vaccine was co-administered. Antibody concentrations/titers against diphtheria, tetanus, pertussis and poliovirus 1–3 were measured before and one month post-booster. Reactogenicity and safety was assessed. Results: 305 subjects were enrolled of whom 303 (dTpa-IPV = 151; DTPa-IPV = 152) received booster vaccination. One month post-booster, all subjects were seroprotected/seropositive for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA and anti-poliovirus 1–3; 99.3% of dTpa-IPV and 60.4% of DTPa-IPV subjects were seropositive for anti-PRN; 98–100% of subjects were seropositive against MMRV antigens post-booster. Pain at the injection site (dTpa-IPV: 63.6%; DTPa-IPV: 63.2%) and fatigue (dTpa-IPV: 26.5%; DTPa-IPV: 23.7%) were the most commonly reported solicited local and general symptoms, during the 4-d follow-up period. No SAEs or fatalities were reported. Conclusions: The reduced-antigen-content dTpa-IPV vaccine was non-inferior to full-strength DTPa-IPV vaccine with respect to immunogenicity. The vaccine was well-tolerated and can be confidently used as a booster dose in pre-school children. PMID:22327497

Improved immunogenicity of tetanus toxoid by Brucella abortus S19 LPS adjuvant.

PubMed

Mohammadi, Mohsen; Kianmehr, Zahra; Kaboudanian Ardestani, Sussan; Gharegozlou, Behnaz

2014-09-01

Adjuvants are used to increase the immunogenicity of new generation vaccines, especially those based on recombinant proteins. Despite immunostimulatory properties, the use of bacterial lipopolysaccharide (LPS) as an adjuvant has been hampered due to its toxicity and pyrogenicity. Brucella abortus LPS is less toxic and has no pyrogenic properties compared to LPS from other gram negative bacteria. To evaluate the adjuvant effect of B. abortus (vaccine strain, S19) LPS for tetanus toxoid antigen (TT) and to investigate the protective effect of different tetanus vaccine preparations. LPS was extracted and purified from B. abortus S19 and KDO, glycan, phosphate content, and protein contamination were measured. Adipic acid dihydrazide (ADH) was used as a linker for conjugation of TT to LPS. Different amounts of B. abortus LPS, TT, TT conjugated with LPS, and TT mixed with LPS or complete Freund's adjuvant (CFA) were injected into mice and antibody production against TT was measured. The protective effect of induced antibodies was determined by LD50. Immunization of mice with TT+LPS produced the highest anti-TT antibody titer in comparison to the group immunized with TT without any adjuvant or the groups immunized with TT-LPS or TT+CFA. Tetanus toxid-S19 LPS also produced a 100% protective effect against TT in immunized mice. These data indicate that B. abortus LPS enhances the immune responses to TT and suggest the possible use of B. abortus LPS as an adjuvant in vaccine preparations.

Assessing immune competence in pigs by immunization with tetanus toxoid.

PubMed

Gimsa, U; Tuchscherer, A; Gimsa, J; Tuchscherer, M

2018-01-01

Immune competence can be tested by challenging organisms with a set of infectious agents. However, disease control requirements impose restrictions on the infliction of infections upon domestic pigs. Alternatively, vaccinations induce detectable immune responses that reflect immune competence. Here, we tested this approach with tetanus toxoid (TT) in young domestic pigs. To optimize the vaccination protocol, we immunized the pigs with a commercial TT vaccine at the age of 21 or 35 days. Booster immunizations were performed either 14 or 21 days later. TT-specific antibodies in plasma as well as lymphoproliferative responses were determined both 7 and 14 days after booster immunization using ELISA and lymphocyte transformation tests, respectively. In addition, general IgG and IgM plasma concentrations and mitogen-induced proliferation were measured. The highest TT-specific antibody responses were detected when blood samples were collected 1 week after a booster immunization conducted 21 days after primary immunization. The pigs' age at primary immunization did not have a significant influence on TT-specific antibody responses. Similarly, the TT-specific proliferative responses were highest when blood samples were collected 1 week after booster immunization, while age and time of primary and booster immunization were irrelevant in our setup. While general IgG and IgM plasma levels were highly age dependent, there were no significant age effects for TT-specific immune responses. In addition, mitogen-induced proliferation was independent of immunization as well as blood sampling protocols. In summary, our model of TT vaccination provides an interesting approach for the assessment of immune competence in young pigs. The detected vaccination effects were not biased by age, even though our data were acquired from immune systems that were under development during our tests.

Coverage with Tetanus, Diphtheria, and Acellular Pertussis Vaccine and Influenza Vaccine Among Pregnant Women - Minnesota, March 2013-December 2014.

PubMed

Barber, Alexandra; Muscoplat, Miriam Halstead; Fedorowicz, Anna

2017-01-20

Pertussis and influenza infections can result in severe disease in infants. The diphtheria, tetanus, acellular pertussis (DTaP) vaccine is recommended for infants beginning at age 2 months, and influenza vaccine is recommended for infants aged ≥6 months. Vaccination of pregnant women induces the production of antibodies that are transferred across the placenta to the fetus and provide passive protection until infants are old enough to receive DTaP and influenza vaccines (1-3). To protect young infants before they are age-eligible for vaccination, the Advisory Committee on Immunization Practices (ACIP) has recommended since 2004 that all women who are or will be pregnant during influenza season receive inactivated influenza vaccine (1), and since 2013 that all pregnant women receive the tetanus, diphtheria, acellular pertussis (Tdap) vaccine (3). Tdap and influenza vaccination coverage was assessed among pregnant women in Minnesota. Vital records data containing maternal demographic characteristics, prenatal care data, and delivery payment methods were matched with vaccination data from the Minnesota Immunization Information Connection (MIIC) to assess vaccination coverage. MIIC stores vaccination records for Minnesota residents. Overall, coverage with Tdap vaccine was 58.2% and with influenza vaccine was 45.9%. Coverage was higher for each vaccine among women who received adequate prenatal care compared with those who received inadequate or intermediate care, based on the initiation of prenatal care and the number of recommended prenatal visits attended. Coverage also varied based on mother's race, country of birth or region, and other demographic characteristics. Further study is needed to better understand the maternal vaccination disparities found in this study and to inform future public health initiatives.

Effect of whole-body irradiation with x rays on the formation of immunity in tetanus toxoid-immunized mice. Part 2. Secondary immunity to tetanus toxin (in Polish)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galazka, A.; Albrycht, H.; Gajewski, A.K.

1972-01-01

White mice were twofold immunized with various doses of adsorbed tetanus toxoid and irradiated with a dose of 500 R at various time intervals before and after the second immunization. The secondary response of the animals was more resistant to irradiation than the primary one. It was found, however, that antibody synthesis was disturbed in mice irradiated 1 to 2 hrs prior to the second immunization. The detrimental effect of irradiation was found to depend to a high extent on antigen dose used for the first, and not the second, immunization. (auth)

Use of synthetic peptides and site-specific antibodies to localize a diphtheria toxin sequence associated with ADP-ribosyltransferase activity.

PubMed Central

Olson, J C

1993-01-01

Diphtheria toxin (DT) and Pseudomonas aeruginosa exotoxin A have the same molecular mechanism of toxicity; both toxins ADP-ribosylate a modified histidine residue in elongation factor 2. To help identify amino acids involved in this reaction, sequences in DT that share homology with P. aeruginosa exotoxin A were synthesized and examined for a role in the ADP-ribosyltransferase reaction. By using this approach, residues 32 to 54 of DT were found to define an epitope associated with antibody-mediated inhibition of DT enzyme activity. This lends further support to the notion that residues in this region of DT are involved in the enzymatic reaction. PMID:8423159

Maternal Tetanus Toxoid Vaccination and Neonatal Mortality in Rural North India

PubMed Central

Singh, Abhishek; Pallikadavath, Saseendran; Ogollah, Reuben; Stones, William

2012-01-01

Objectives Preventable neonatal mortality due to tetanus infection remains common. We aimed to examine antenatal vaccination impact in a context of continuing high neonatal mortality in rural northern India. Methods and Findings Using the third round of the Indian National Family Health Survey (NFHS) 2005–06, mortality of most recent singleton births was analysed in discrete-time logistic model with maternal tetanus vaccination, together with antenatal care utilisation and supplementation with iron and folic acid. 59% of mothers reported receiving antenatal care, 48% reported receiving iron and folic acid supplementation and 68% reported receiving two or more doses of tetanus toxoid (TT) vaccination. The odds of all-cause neonatal death were reduced following one or more antenatal dose of TT with odds ratios (OR) of 0.46 (95% CI 0.26 to 0.78) after one dose and 0.45 (95% CI 0.31 to 0.66) after two or more doses. Reported utilisation of antenatal care and iron-folic acid supplementation did not influence neonatal mortality. In the statistical model, 16% (95% CI 5% to 27%) of neonatal deaths could be attributed to a lack of at least two doses of TT vaccination during pregnancy, representing an estimated 78,632 neonatal deaths in absolute terms. Conclusions Substantial gains in newborn survival could be achieved in rural North India through increased coverage of antenatal TT vaccination. The apparent substantial protective effect of a single antenatal dose of TT requires further study. It may reflect greater population vaccination coverage and indicates that health programming should prioritise universal antenatal coverage with at least one dose. PMID:23152814

Evaluation of a toxoid for protection of rabbits against enterotoxaemia experimentally induced by trypsin-activated supernatant of Clostridium spiroforme.

PubMed

Ellis, T M; Gregory, A R; Logue, G D

1991-06-01

Investigations were conducted into an enterotoxaemia caused by Clostridium spiroforme responsible for significant losses in commercial rabbit farms in Western Australia. Two trials using laboratory and farm bred rabbits were performed to evaluate the protective value of a toxoid prepared from the supernatant of C. spiroforme cultures against intraperitoneal challenge with the trypsin-activated toxin of C. spiroforme. The trials showed clearly that a single vaccination at weaning (four weeks) was protective against toxin but more complete and lasting protection was conferred following a second vaccination administered 14 days after the first. Adults likewise showed similar levels of protective antibodies but did not appear to pass on this protection to their kits although ELISA results indicated levels of antibody in kits from unvaccinated mother to be lower than progeny from vaccinated mothers. However antibody levels in kits from vaccinated mothers were very low and did not protect against challenge with toxin.

Immunogenicity and safety of a booster dose of diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine (Tdap-IPV; Repevax) administered concomitantly versus non-concomitantly with an influenza vaccine (Vaxigrip) to adults aged ≥60 years: an open-label, randomised trial.

PubMed

Zimmermann, Ulrich; Gavazzi, Gaëtan; Richard, Patrick; Eymin, Cécile; Soubeyrand, Benoît; Baudin, Martine

2013-03-01

Annual influenza vaccination provides an opportunity to administer a booster dose of diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine (Tdap-IPV) to the elderly. This study evaluated immune responses to and safety of the two vaccines administered concomitantly or sequentially to elderly individuals in France and Germany. Individuals aged ≥60 years who had received a diphtheria/tetanus booster within 5-15 years were randomised (1:1) to receive either Tdap-IPV and an inactivated influenza vaccine concomitantly (Group 1) or inactivated influenza vaccine then Tdap-IPV 28-35 days later (Group 2). Antibody titres were measured before and 28-35 days after each vaccination. The mean age of randomised individuals (n=954) was 68.8 years. Post-vaccination seroprotection rates (≥0.1 IU/mL for diphtheria/tetanus and ≥8 1/dilution for polio) for Group 1 were non-inferior to Group 2 for diphtheria (85.4% vs. 87.5%), tetanus (both 100%), polio type 1 (99.8% vs. 100%), polio type 2 (both 100%) and polio type 3 (99.3% vs. 99.8%). Similarly, percentages of individuals with pertussis antibodies ≥5 EU/mL for Group 1 were non-inferior to Group 2: pertussis toxin (94.3% vs. 98.1%), filamentous haemagglutinin (99.8% vs. 100%), pertactin (97.3% vs. 96.0%), fimbriae 2 and 3 (91.7% vs. 89.5%). Post-vaccination geometric mean titres of anti-influenza haemagglutinin antibodies for Group 1 were non-inferior to Group 2. Adverse events following administration of Tdap-IPV were similar in both study groups, with no vaccine-related serious adverse events. Tdap-IPV and inactivated influenza vaccine can be administered concomitantly in the elderly without impairing tolerability or the immune response to either vaccine. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development of chitosan-pullulan composite nanoparticles for nasal delivery of vaccines: in vivo studies.

PubMed

Cevher, Erdal; Salomon, Stefan K; Somavarapu, Satyanarayana; Brocchini, Steve; Alpar, H Oya

2015-01-01

Here, we aimed at developing chitosan/pullulan composite nanoparticles and testing their potential as novel systems for the nasal delivery of diphtheria toxoid (DT). All the chitosan derivatives [N-trimethyl (TMC), chloride and glutamate] and carboxymethyl pullulan (CMP) were synthesised and antigen-loaded composites were prepared by polyion complexation of chitosan and pullulan derivatives (particle size: 239-405 nm; surface charge: +18 and +27 mV). Their immunological effects after intranasal administration to mice were compared to intramuscular route. Composite nanoparticles induced higher levels of IgG responses than particles formed with chitosan derivative and antigen. Nasally administered TMC-pullulan composites showed higher DT serum IgG titre when compared with the other composites. Co-encapsulation of CpG ODN within TMC-CMP-DT nanoparticles resulted in a balanced Th1/Th2 response. TMC/pullulan composite nanoparticles also induced highest cytokine levels compared to those of chitosan salts. These findings demonstrated that TMC-CMP-DT composite nanoparticles are promising delivery system for nasal vaccination.

Anchoring antibodies to membranes using a diphtheria toxin T domain-ZZ fusion protein as a pH sensitive membrane anchor.

PubMed

Nizard, P; Liger, D; Gaillard, C; Gillet, D

1998-08-14

We have constructed a fusion protein, T-ZZ, in which the IgG-Fc binding protein ZZ was fused to the C-terminus of the diphtheria toxin transmembrane domain (T domain). While soluble at neutral pH, T-ZZ retained the capacity of the T domain to bind to phospholipid membranes at acidic pH. Once anchored to the membrane, the ZZ part of the protein was capable of binding mouse monoclonal or rabbit polyclonal IgG. Our results show that the T-ZZ protein can function as a pH sensitive membrane anchor for the linkage of IgG to the membrane of lipid vesicles, adherent and non-adherent cells.

Human immune response to botulinum pentavalent (ABCDE) toxoid determined by a neutralization test and by an enzyme-linked immunosorbent assay.

PubMed Central

Siegel, L S

1988-01-01

To determine the immune status of persons receiving botulinum pentavalent (ABCDE) toxoid and to evaluate the effectiveness of the vaccine, we surveyed immunized individuals for neutralizing antibodies to type A and to type B botulinum toxins. After the primary series of three immunizations administered at 0, 2, and 12 weeks, 21 of 23 persons tested (91%) had a titer for type A that was greater than or equal to 0.08 international units (IU)/ml, and 18 (78%) had a titer for type B of greater than or equal to 0.02 IU/ml. (One international unit is defined as the amount of antibody neutralizing 10,000 mouse 50% lethal doses of type A or B botulinum toxin). Just before the first annual booster, 10 of 21 (48%) and 14 of 21 (67%) people lacked a detectable titer for type A and for type B, respectively. After the first booster, all individuals tested had a demonstrable titer to both types A and B. Of 77 persons who had previously received from one to eight boosts of the toxoid, 74 (96%) had an A titer of greater than or equal to 0.25 IU/ml and would not require an additional booster, according to the recommendations of the Centers for disease Control. However, only 44 of 77 (57%) had a B titer of greater than or equal to 0.25 IU/ml. In each group by booster number, even the group having had eight boosts, at least one person would require reimmunization on the basis of B titer. There was a wide range of antibody levels among individuals at the same point in the immunization scheme. Results from an enzyme linked immunosorbent assay, with purified type A or type B neurotoxin as the capture antigen, were compared with neutralization test results on 186 serum samples for type A and 168 samples for type B. Statistically, the correlation coefficients for results from the two assays were high (r = 0.69, P < 0.0001, for type A and r = 0.77, P < 0.0001, for type B). However, due to the wide dispersion of values obtained, using enzyme-linked immunosorbent assay results to predict

Ultraviolet light induction of diphtheria toxin-resistant mutations in normal and DNA repair-deficient human and Chinese hamster fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trosko, J.E.; Schultz, R.S.; Chang, C.C.

1980-01-01

The role on unrepaired DNA lesions in the production of mutations is suspected of contributing to the initiation phase of carcinogenesis. Since the molecular basis of mutagenesis is not understood in eukaryotic cells, development of new genetic markers for quantitative in vitro measurement of mutations for mammalian cells is needed. Furthermore, mammalian cells, genetically deficient for various DNA repair enzymes, will be needed to study the role of unrepaired DNA lesions in mutagenesis. The results in this report relate to preliminary attempts to characterize the diphtheria toxin resistance marker as a useful quantitative genetic marker in human cells and tomore » isolate and characterize various DNA repair-deficient Chinese hamster cells.« less

Tetanus toxoid-pulsed monocyte vaccination for augmentation of collateral vessel growth.

PubMed

Herold, Joerg; Francke, Alexander; Weinert, Soenke; Schmeisser, Alexander; Hebel, Katrin; Schraven, Burkhart; Roehl, Friedich-Wilhelm; Strasser, Ruth H; Braun-Dullaeus, Ruediger C

2014-04-14

The pathogenesis of collateral growth (arteriogenesis) has been linked to both the innate and adaptive immune systems. While therapeutic approaches for the augmentation of arteriogenesis have focused on innate immunity, exploiting both innate and adaptive immune responses has not been examined. We hypothesized that tetanus toxoid (tt) immunization of mice followed by transplantation of monocytes (Mo) exposed ex vivo to tt augments arteriogenesis after ligation of the hind limb. Mo were generated from nonimmunized BALB/c mice, exposed ex vivo to tt for 24 hours and intravenously injected (ttMo, 2.5×10(6)) into the tail veins of tt-immunized syngeneic mice whose hind limbs had been ligated 24 hours prior to transplantation. Laser Doppler perfusion imaging was applied, and a perfusion index (PI) was calculated (ratio ligated/unligated). Twenty-one days after ligation, the arteriogenesis of untreated BALB/c mice was limited (PI=0.49±0.09). Hind limb function was impaired in 80% of animals. Injection of non-engineered Mo insignificantly increased the PI to 0.56±0.07. However, ttMo transplantation resulted in a strong increase of the PI to 0.82±0.08 (n=7; P<0.001), with no (0%) detectable functional impairment. ttMo injected into nonimmunized mice had no effect. The strong arteriogenic response of ttMo transplantation into immunized mice was prevented when mice had been depleted of T-helper cells by CD4-antibody pretreatment (PI=0.50±0.08; n=17; P<0.001), supporting the hypothesis that transplanted cells interact with recipient lymphocytes. Transplantation of ttMo into pre-immunized mice strongly promotes arteriogenesis. This therapeutic approach is feasible and highly attractive for the alleviation of morbidity associated with vascular occlusive disease.

Vaccine antigens modulate the innate response of monocytes to Al(OH)3

PubMed Central

Brummelman, Jolanda; van Els, Cécile A. C. M.; Marino, Fabio; Heck, Albert J. R.; van Riet, Elly; Metz, Bernard; Kersten, Gideon F. A.; Pennings, Jeroen L. A.; Meiring, Hugo D.

2018-01-01

Aluminum-based adjuvants have widely been used in human vaccines since 1926. In the absence of antigens, aluminum-based adjuvants can initiate the inflammatory preparedness of innate cells, yet the impact of antigens on this response has not been investigated so far. In this study, we address the modulating effect of vaccine antigens on the monocyte-derived innate response by comparing processes initiated by Al(OH)3 and by Infanrix, an Al(OH)3-adjuvanted trivalent combination vaccine (DTaP), containing diphtheria toxoid (D), tetanus toxoid (T) and acellular pertussis (aP) vaccine antigens. A systems-wide analysis of stimulated monocytes was performed in which full proteome analysis was combined with targeted transcriptome analysis and cytokine analysis. This comprehensive study revealed four major differences in the monocyte response, between plain Al(OH)3 and DTaP stimulation conditions: (I) DTaP increased the anti-inflammatory cytokine IL-10, whereas Al(OH)3 did not; (II) Al(OH)3 increased the gene expression of IFNγ, IL-2 and IL-17a in contrast to the limited induction or even downregulation by DTaP; (III) increased expression of type I interferons-induced proteins was not observed upon DTaP stimulation, but was observed upon Al(OH)3 stimulation; (IV) opposing regulation of protein localization pathways was observed for Al(OH)3 and DTaP stimulation, related to the induction of exocytosis by Al(OH)3 alone. This study highlights that vaccine antigens can antagonize Al(OH)3-induced programming of the innate immune responses at the monocyte level. PMID:29813132

The impact of administration of conjugate vaccines containing cross reacting material on Haemophilus influenzae type b antibody responses in infants: A systematic review and meta-analysis of randomised controlled trials.

PubMed

Voysey, Merryn; Sadarangani, Manish; Clutterbuck, Elizabeth; Bolgiano, Barbara; Pollard, Andrew J

2016-07-25

Protein-polysaccharide conjugate vaccines such as Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal vaccine, induce immunological memory and longer lasting protection than plain polysaccharide vaccines. The most common proteins used as carriers are tetanus toxoid (TT) and cross reacting material-197 (CRM), a mutant form of diphtheria toxoid. CRM conjugate vaccines have been reported to suppress antibody responses to co-administered Hib-TT vaccine. We conducted a systematic review and meta-analysis of randomised controlled trials in which infants were randomised to receive meningococcal or pneumococcal conjugate vaccines along with Hib-TT. Trials of licensed vaccines with different carrier proteins were included for group C meningococcal (MenC), quadrivalent ACWY meningococcal (MenACWY), and pneumococcal vaccines. Twenty-three trials were included in the meta-analyses. Overall, administration of MenC-CRM in a 2 or 3 dose schedule resulted in a 45% reduction in Hib antibody concentrations (GMR 0.55, 95% CI 0.49-0.62). MenACWY-CRM boosted Hib antibody responses by 22% (GMR 1.22, 95% CI 1.06-1.41) whilst pneumococcal CRM conjugate vaccines had no impact on Hib antibody responses (GMR 0.91, 95% CI 0.68-1.22). The effect of CRM protein-polysaccharide conjugate vaccines on Hib antibody responses varies greatly between vaccines. Co-administration of a CRM conjugate vaccine can produce either positive or negative effects on Hib antibody responses. These inconsistencies suggest that CRM itself may not be the main driver of variability in Hib responses, and challenge current perspectives on this issue. Copyright © 2016 Elsevier Ltd. All rights reserved.

Corynebacterium diphtheriae employs specific minor pilins to target human pharyngeal epithelial cells

PubMed Central

Mandlik, Anjali; Swierczynski, Arlene; Das, Asis; Ton-That, Hung

2010-01-01

Summary Adherence to host tissues mediated by pili is pivotal in the establishment of infection by many bacterial pathogens. Corynebacterium diphtheriae assembles on its surface three distinct pilus structures. The function and the mechanism of how various pili mediate adherence, however, have remained poorly understood. Here we show that the SpaA-type pilus is sufficient for the specific adherence of corynebacteria to human pharyngeal epithelial cells. The deletion of the spaA gene, which encodes the major pilin forming the pilus shaft, abolishes pilus assembly but not adherence to pharyngeal cells. In contrast, adherence is greatly diminished when either minor pilin SpaB or SpaC is absent. Antibodies directed against either SpaB or SpaC block bacterial adherence. Consistent with a direct role of the minor pilins, latex beads coated with SpaB or SpaC protein bind specifically to pharyngeal cells. Therefore, tissue tropism of corynebacteria for pharyngeal cells is governed by specific minor pilins. Importantly, immunoelectron microscopy and immunofluorescence studies reveal clusters of minor pilins that are anchored to cell surface in the absence of a pilus shaft. Thus, the minor pilins may also be cell wall anchored in addition to their incorporation into pilus structures that could facilitate tight binding to host cells during bacterial infection. PMID:17376076

Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine for infants and toddlers.

PubMed

Bryant, Kristina A; Marshall, Gary S

2011-07-01

The highest rates of invasive meningococcal disease occur in children under 2 years of age, yet as of early 2011 no vaccine was licensed for the youngest infants. However, a novel vaccine consisting of capsular polysaccharides from Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroups C and Y conjugated to tetanus toxoid (HibMenCY-TT; MenHibrix, GlaxoSmithKline) is in the late stages of development. In clinical trials involving more than 7800 children, HibMenCY-TT was shown to be safe and immunogenic when administered at 2, 4, 6 and 12-15 months of age. Anti-polyribosylribitol phosphate antibody responses were noninferior to those elicited by licensed monovalent Hib vaccines, and most vaccinees developed bactericidal antibodies against N. meningitidis serogroups C and Y. The majority of subjects retained antibody responses as far as 3 years after vaccination. If licensed, HibMenCY-TT not only represents an incremental option for protection against invasive Hib, but also has the potential to prevent invasive meningococcal disease without increasing the number of injections.

Transcutaneous immunization with tetanus toxoid and mutants of Escherichia coli heat-labile enterotoxin as adjuvants elicits strong protective antibody responses.

PubMed

Tierney, Rob; Beignon, Anne-Sophie; Rappuoli, Rino; Muller, Sylviane; Sesardic, Dorothea; Partidos, Charalambos D

2003-09-01

In this study, the adjuvanticity of 2 nontoxic derivatives (LTK63 and LTR72) of heat-labile enterotoxin of Escherichia coli (LT) was evaluated and was compared with that of a cytosine phosphodiester-guanine (CpG) motif, after transcutaneous immunization with tetanus toxoid (TT). TT plus LTR72 elicited the strongest antibody responses, compared with those elicited by the other vaccines (TT, TT plus LTK63, TT plus CpG, and TT plus LTK63 plus CpG); it neutralized the toxin and conferred full protection after passive transfer in mice. Preexisting immunity to LT mutants did not adversely affect their adjuvant potency. Both LTK63 and LTR72 promoted the induction of IgG1 antibodies. In contrast, mice receiving either CpG motif alone or CpG motif plus LTK63 produced strong IgG2a anti-TT antibody responses. Overall, these findings demonstrate that mutants of enterotoxins with reduced toxicity are effective adjuvants for transcutaneous immunization.

Adjuvant dependence of APS pathology-related low-affinity antibodies during secondary immune response to tetanus toxoid in BALB/c mice.

PubMed

Zivković, Irena; Petrušić, Vladimir; Dimitrijević, Rajna; Stojanović, Marijana; Dimitrijević, Ljiljana

2013-05-01

One of the established animal models for autoimmune disease antiphospholipid syndrome (APS) is TTd hyperimmunization of mice. Tetanus toxoid (TTd) and plasma protein β2GPI share structural homology so that immunization with TTd induces appearance of cross-reactive antibodies. In this paper, we have investigated the presence and dynamic of fluctuation of specific (anti-TTd) and auto (anti-β2GPI) antibodies induced in BALB/c mice during secondary immune response after TTd immunization with alhydrogel or glycerol as adjuvants. In addition, we followed the induced reproductive pathology as a sign of autoimmune outcome. We show undoubtedly adjuvant dependance of (1) level of induced anti-TTd IgG antibodies, (2) changes in levels of low-affinity anti-β2GPI IgG antibodies, and (3) change in fecundity and fertility during secondary immune response. These findings once more indicate the importance of chosen adjuvants used for successful immunization and eventual autoantibody outcome, this time associated with the processes involving low affinity, natural antibodies.

Transcriptomic Response of Porcine PBMCs to Vaccination with Tetanus Toxoid as a Model Antigen

PubMed Central

Adler, Marcel; Murani, Eduard; Brunner, Ronald; Ponsuksili, Siriluck; Wimmers, Klaus

2013-01-01

The aim of the present study was to characterize in vivo genome-wide transcriptional responses to immune stimulation in order to get insight into the resulting changes of allocation of resources. Vaccination with tetanus toxoid was used as a model for a mixed Th1 and Th2 immune response in pig. Expression profiles of PBMCs (peripheral blood mononuclear cells) before and at 12 time points over a period of four weeks after initial and booster vaccination at day 14 were studied by use of Affymetrix GeneChip microarrays and Ingenuity Pathway Analysis (IPA). The transcriptome data in total comprised more than 5000 genes with different transcript abundances (DE-genes). Within the single time stages the numbers of DE-genes were between several hundred and more than 1000. Ingenuity Pathway Analysis mainly revealed canonical pathways of cellular immune response and cytokine signaling as well as a broad range of processes in cellular and organismal growth, proliferation and development, cell signaling, biosynthesis and metabolism. Significant changes in the expression profiles of PBMCs already occurred very early after immune stimulation. At two hours after the first vaccination 679 DE-genes corresponding to 110 canonical pathways of cytokine signaling, cellular immune response and other multiple cellular functions were found. Immune competence and global disease resistance are heritable but difficult to measure and to address by breeding. Besides QTL mapping of immune traits gene expression profiling facilitates the detection of functional gene networks and thus functional candidate genes. PMID:23536793

Transcriptomic response of porcine PBMCs to vaccination with tetanus toxoid as a model antigen.

PubMed

Adler, Marcel; Murani, Eduard; Brunner, Ronald; Ponsuksili, Siriluck; Wimmers, Klaus

2013-01-01

The aim of the present study was to characterize in vivo genome-wide transcriptional responses to immune stimulation in order to get insight into the resulting changes of allocation of resources. Vaccination with tetanus toxoid was used as a model for a mixed Th1 and Th2 immune response in pig. Expression profiles of PBMCs (peripheral blood mononuclear cells) before and at 12 time points over a period of four weeks after initial and booster vaccination at day 14 were studied by use of Affymetrix GeneChip microarrays and Ingenuity Pathway Analysis (IPA). The transcriptome data in total comprised more than 5000 genes with different transcript abundances (DE-genes). Within the single time stages the numbers of DE-genes were between several hundred and more than 1000. Ingenuity Pathway Analysis mainly revealed canonical pathways of cellular immune response and cytokine signaling as well as a broad range of processes in cellular and organismal growth, proliferation and development, cell signaling, biosynthesis and metabolism. Significant changes in the expression profiles of PBMCs already occurred very early after immune stimulation. At two hours after the first vaccination 679 DE-genes corresponding to 110 canonical pathways of cytokine signaling, cellular immune response and other multiple cellular functions were found. Immune competence and global disease resistance are heritable but difficult to measure and to address by breeding. Besides QTL mapping of immune traits gene expression profiling facilitates the detection of functional gene networks and thus functional candidate genes.

Autoradiographic detection of diphtheria toxin resistant mutants in human diploid fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta, R.S.; Singh, B.

1985-01-01

An autoradiographic procedure for the detection of diphtheria toxin (DT) resistant (Dip/sub R/) mutants in human diploid fibroblast (HDF) cells has been developed. The assay is based on the observation that when HDFs from confluent cultures are seeded in medium containing 0.01 flocculating units/ml or higher concentration of DT, protein synthesis in sensitive cells is severely inhibited by 4-6 hr. If at this or later time, a radiolabeled protein precursor (eg, /sup 3/H-leucine) is added to the culture, it is almost exclusively incorporated into the resistant cells, which are then readily identified by autoradiography. These studies provide strong evidence thatmore » the labeled cells identified by autoradiography are bona fide Dip/sub R/ mutants. The detection of Dip/sub R/ cells by autoradiography is apparently not affected by the presence of the sensitive cells in the mixtures. The spontaneous frequency of Dip/sub R/ cells in HDFs has been found to be in the range of 1-5 x 10/sup -6/, and this increases in a dose dependent manner upon treatment with the mutagen ethyl methanesulfonate. These results indicate that the autoradiographic assay could be used for quantitative mutagenesis. Since the autoradiographic assay does not depend on cell division, it may prove useful in estimating the incidence of pre-existing mutations in cell populations that either do not divide or have very limited growth potential (eg, lymphocytes, muscle cells, neurons, senescent fibroblasts, etc.).« less

Multidisciplinary approach to the management of a case of classical respiratory diphtheria requiring percutaneous endoscopic gastrostomy feeding.

PubMed

Haywood, Matthew James; Vijendren, Ananth; Acharya, Vikas; Mulla, Rohinton; Panesar, Miss Jaan

2017-03-06

We present a case of a Caucasian woman aged 67 years referred with a 4-day history of sore throat, dysphagia, fever and nasal blockage. Examination revealed a swollen neck and pharyngeal pseudomembrane. A throat swab was positive on culture for Corynebacterium ulcerans , with toxin expression confirmed on PCR and Elek testing. A diagnosis of classical respiratory diphtheria was made, with subsequent confirmation of the patient's domesticated dog as the source of infection. The dog had recently been attacked by a wild badger and was being treated for an ear infection. The patient made a good recovery with intravenous antimicrobial and supportive therapy; however, she subsequently developed a diphtheritic polyneuropathy in the form of a severe bulbar palsy with frank aspiration necessitating percutaneous endoscopic gastrostomy feeding. A mild sensorimotor peripheral neuropathy was also diagnosed. The patient eventually made an almost complete recovery. 2017 BMJ Publishing Group Ltd.

Tetanus toxoid vaccine: Elimination of neonatal tetanus in selected states of India

PubMed Central

Verma, Ramesh; Khanna, Pardeep

2012-01-01

Tetanus is caused by a neurotoxin produced by Clostridium tetani (C. tetani), a spore-forming bacterium. Infection begins when tetanus spores are introduced into damaged tissue. Tetanus is characterized by muscle rigidity and painful muscle spasms caused by tetanus toxin’s blockade of inhibitory neurons that normally oppose and modulate the action of excitatory motor neurons. Maternal and neonatal tetanus (MNT) are caused by unhygienic methods of delivery, abortion, or umbilical-cord care. Maternal and neonatal tetanus are both forms of generalized tetanus and have similar clinical courses. About 90% of neonates with tetanus develop symptoms in the first 3–14 d of life, mostly on days 6–8, distinguishing neonatal tetanus from other causes of neonatal mortality which typically occur during the first two days of life. Overall case fatality rates for patients admitted to the hospital with neonatal tetanus in developing countries are 8–50%, while the fatality rate can be as high as 100% without hospital care. Tetanus toxoid (TT) vaccination of pregnant women to prevent neonatal tetanus was included in WHO’s Expanded Program on Immunization (EPI) a few years after its inception in 1974. In 2000, WHO, UNICEF, and UNFPA formed a partnership to relaunch efforts toward this goal, adding the elimination of maternal tetanus as a program objective, and setting a new target date of 2005. By February 2007, 40 countries had implemented tetanus vaccination campaigns in high-risk areas, targeting more than 94 million women, and protecting more than 70 million subjects with at least two doses of TT. In 2011, 653 NT cases were reported in India compared with 9313 in 1990. As of February 2012, 25 countries and 15 States and Union Territories of India, all of Ethiopia except Somaliland, and almost 29 of 34 provinces in Indonesia have been validated to have eliminated MNT. PMID:22894950

Tetanus toxoid vaccine: elimination of neonatal tetanus in selected states of India.

PubMed

Verma, Ramesh; Khanna, Pardeep

2012-10-01

Tetanus is caused by a neurotoxin produced by Clostridium tetani (C. tetani), a spore-forming bacterium. Infection begins when tetanus spores are introduced into damaged tissue. Tetanus is characterized by muscle rigidity and painful muscle spasms caused by tetanus toxin's blockade of inhibitory neurons that normally oppose and modulate the action of excitatory motor neurons. Maternal and neonatal tetanus (MNT) are caused by unhygienic methods of delivery, abortion, or umbilical-cord care. Maternal and neonatal tetanus are both forms of generalized tetanus and have similar clinical courses. About 90% of neonates with tetanus develop symptoms in the first 3-14 d of life, mostly on days 6-8, distinguishing neonatal tetanus from other causes of neonatal mortality which typically occur during the first two days of life. Overall case fatality rates for patients admitted to the hospital with neonatal tetanus in developing countries are 8-50%, while the fatality rate can be as high as 100% without hospital care. Tetanus toxoid (TT) vaccination of pregnant women to prevent neonatal tetanus was included in WHO's Expanded Program on Immunization (EPI) a few years after its inception in 1974. In 2000, WHO, UNICEF, and UNFPA formed a partnership to relaunch efforts toward this goal, adding the elimination of maternal tetanus as a program objective, and setting a new target date of 2005. By February 2007, 40 countries had implemented tetanus vaccination campaigns in high-risk areas, targeting more than 94 million women, and protecting more than 70 million subjects with at least two doses of TT. In 2011, 653 NT cases were reported in India compared with 9313 in 1990. As of February 2012, 25 countries and 15 States and Union Territories of India, all of Ethiopia except Somaliland, and almost 29 of 34 provinces in Indonesia have been validated to have eliminated MNT.

Synthesis of IgM and IgG antibodies in mice irradiated with x rays and immunized with tetanus toxoid (in Polish)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galazka, A.; Albrycht, H.; Aleksandrowicz, J.

1972-01-01

White mice were immunized with adsorbed tetanus toxoid 1 to 2 hrs following irradiation with a dose of 300 R. The antibody response was tested in whole sera 7, 14, 28, and 42 days after immunization; it was found to be delayed and repressed compared with controls. In tests for antibody activity of different classes of immunoglobulins, isolated on Sephadex G-200, the IgM- producing mechanisms were found to be highly radiosensitive; peak of the response was greatly delayed (28 days); and peak titers were threefold lower than in controls. IgG antibody production also was delayed and in the initial periodmore » it was repressed. Six weeks after irradiation, IgG antibody levels were equal in the irradiated and control mice. The present results concerning radiosensitivity of IgM-producing mechanisms are discordant with data of other authors, who immunized animals with other antigens or investigated the metabolism of immunoglobulins in irradiated but nonimmunized animals. (auth)« less

Comparison of inflation of third dose diphtheria tetanus pertussis (DTP3) administrative coverage to other vaccine antigens.

PubMed

Dolan, Samantha B; MacNeil, Adam

2017-06-14

Third dose diphtheria tetanus pertussis (DTP3) administrative coverage is a commonly used indicator for immunization program performance, although studies have demonstrated data quality issues with administrative DTP3 coverage. It is possible that administrative coverage for DTP3 may be inflated more than for other antigens. To examine this, theory, we compiled immunization coverage estimates from recent country surveys (n=71) and paired these with corresponding administrative coverage estimates, by country and cohort year, for DTP3 and 4 other antigens. Median administrative coverage was higher than survey estimates of coverage for all antigens (median differences from 26 to 30%), however this difference was similar for DTP3 as for all other antigens. These findings were consistent when countries were stratified by income level and eligibility for Gavi funding. Our findings demonstrate that while country administrative coverage estimates tend to be higher than survey estimates, DTP3 administrative coverage is not inflated more than other antigens. Published by Elsevier Ltd.

A physico-chemical assessment of the thermal stability of pneumococcal conjugate vaccine components

PubMed Central

Gao, Fang; Lockyer, Kay; Burkin, Karena; Crane, Dennis T; Bolgiano, Barbara

2014-01-01

Physico-chemical analysis of pneumococcal polysaccharide (PS)-protein conjugate vaccine components used for two commercially licensed vaccines was performed to compare the serotype- and carrier protein-specific stabilities of these vaccines. Nineteen different monovalent pneumococcal conjugates from commercial vaccines utilizing CRM197, diphtheria toxoid (DT), Protein D (PD) or tetanus toxoid (TT) as carrier proteins were incubated at temperatures up to 56°C for up to eight weeks or were subjected to freeze-thawing (F/T). Structural stability was evaluated by monitoring their size, integrity and carrier protein conformation. The molecular size of the vaccine components was well maintained for Protein D, TT and DT conjugates at -20°C, 4°C and F/T, and for CRM197 conjugates at 4°C and F/T. It was observed that four of the eight serotypes of Protein D conjugates tended to form high molecular weight complexes at 37°C or above. The other conjugated carrier proteins also appeared to form oligomers or ‘aggregates’ at elevated temperatures, but rarely when frozen and thawed. There was evidence of degradation in some of the conjugates as evidenced by the formation of lower molecular weight materials which correlated with measured free saccharide. In conclusion, pneumococcal-Protein D/TT/DT and most CRM197 bulk conjugate vaccines were stable when stored at 2–8°C, the recommended temperature. In common between the conjugates produced by the two manufacturers, serotypes 1, 5, and 19F were relatively less stable and 6B was the most stable, with types 7F and 23F also showing good stability. PMID:25483488

Safety and Immunogenicity of 3 Formulations of an Investigational Respiratory Syncytial Virus Vaccine in Nonpregnant Women: Results From 2 Phase 2 Trials

PubMed Central

Beran, Jiři; Lickliter, Jason D; Schwarz, Tino F; Johnson, Casey; Chu, Laurence; Domachowske, Joseph B; Van Damme, Pierre; Withanage, Kanchanamala; Fissette, Laurence A; David, Marie-Pierre; Maleux, Koen; Schmidt, Alexander C; Picciolato, Marta; Dieussaert, Ilse

2018-01-01

Abstract Background Respiratory syncytial virus (RSV) causes bronchiolitis and pneumonia in neonates and infants. RSV vaccination during pregnancy could boost preexisting neutralizing antibody titers, providing passive protection to newborns. Methods Two observer-blinded, controlled studies (RSV F-020 [clinical trials registration NCT02360475] and RSV F-024 [NCT02753413]) evaluated immunogenicity and safety of an investigational RSV vaccine in healthy, nonpregnant 18–45-year-old women. Both studies used a licensed adult formulation of combined tetanus toxoid-diphtheria toxoid-acellular pertussis (Tdap) vaccine as a control. RSV F-020 evaluated immunogenicity and safety: participants were randomized (1:1:1:1) to receive 1 dose of RSV–prefusion F protein (PreF) vaccine containing 30 µg or 60 µg of nonadjuvanted RSV-PreF, 60 µg of aluminum-adjuvanted RSV-PreF, or Tdap. RSV F-024 evaluated safety: participants were randomized 1:1 to receive 1 dose of 60 µg of nonadjuvanted RSV-PreF or Tdap. Results Both studies showed similar reactogenicity profiles for RSV-PreF and Tdap. No serious adverse events were considered vaccine related. In RSV F-020, geometric mean ratios of RSV-A neutralizing antibody levels at day 30 versus prevaccination were 3.1–3.9 in RSV-PreF recipients and 0.9 in controls. Palivizumab-competing antibody concentrations increased >14-fold in RSV-PreF recipients on day 30. RSV antibody titers waned after day 30 but remained well above baseline through day 90. Conclusions All formulations of RSV-PreF boosted preexisting immune responses in 18–45-year old women with comparable immunogenicity. The RSV-PreF safety profile was similar to that of Tdap vaccine. PMID:29401325

Increasing Tdap Coverage Among Postpartum Women: A Quality Improvement Intervention.

PubMed

Bernstein, Henry H; Monty, Mikhaela; Yang, Patriot; Cohen, Amy

2017-03-01

Infants are at greatest risk for severe disease and death from pertussis; most acquire it from household contacts. Centers for Disease Control and Prevention guidelines recommend tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap) vaccination for infant caregivers, especially postpartum women who did not receive it during pregnancy. Our objective was to increase the percentage of women receiving Tdap vaccine before postpartum discharge. An interdisciplinary workgroup identified barriers to improvement of postpartum Tdap vaccination from which a 5-step intervention was created: (1) provide education on Tdap and pertussis; (2) offer Tdap throughout hospitalization; (3) create a Tdap standing order; (4) keep Tdap as floor stock; and (5) document administration. Pre- and postintervention data were collected from monthly chart reviews. Our main outcome measures were the proportion of postpartum women eligible for Tdap and the proportion of those eligible who received Tdap. Preintervention baseline data (202 charts) described 166 postpartum women eligible to receive Tdap. Of the eligible women, 91 (55%) received the Tdap vaccine. During the 9-month postintervention period, 844 charts were reviewed (average, 93 per month; range, 82-104). Of the 632 women eligible to receive the Tdap vaccine, 462 (73% overall [range, 67%-79%]) received it. Thirty-three percent more postpartum mothers received the Tdap vaccine before discharge in the postintervention period ( P < .01). The percentage of women eligible decreased from 82% to 75%. This quality improvement initiative substantially increased Tdap immunization in the immediate postpartum period. Efforts to increase immunization during pregnancy for passive transfer of maternal antibodies remain preferable. Copyright © 2017 by the American Academy of Pediatrics.

An Assessment of the Cocooning Strategy for Preventing Infant Pertussis—United States, 2011

PubMed Central

Blain, Amy E.; Lewis, Melissa; Banerjee, Emily; Kudish, Kathy; Liko, Juventila; McGuire, Suzanne; Selvage, David; Watt, James; Martin, Stacey W.; Skoff, Tami H.

2017-01-01

Background Infants are at greatest risk for severe pertussis. In 2006, the Advisory Committee on Immunization Practices recommended that adolescents and adults, especially those with infant contact, receive a single dose of Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine). To assess the effectiveness of cocooning, we conducted a case-control evaluation of infant close contacts. Methods Pertussis cases aged <2 months with onset between 1 January 2011 and 31 December 2011 were identified in Emerging Infections Program Network sites. For each case, we recruited 3 controls from birth certificates and interviewed identified adult close contacts (CCs) or parents of CCs aged <18 years. Pertussis vaccination was verified through medical providers and/or immunization registries. Results Forty-two cases were enrolled, with 154 matched controls. Around enrolled infants, 859 CCs were identified (600 adult and 259 nonadult). An average of 5.4 CCs was identified per case and 4.1 CCs per control. Five hundred fifty-four (64.5%) CCs were enrolled (371 adult and 183 non-adult CCs); 119 (32.1% of enrolled) adult CCs had received Tdap. The proportion of Tdap-vaccinated adult CCs was similar between cases and controls (P = .89). The 600 identified adult CCs comprised 172 potential cocoons; 71 (41.3%) potential cocoons had all identified adult CCs enrolled. Of these, 9 were fully vaccinated and 43.7% contained no Tdap-vaccinated adults. The proportion of fully vaccinated case (4.8%) and control (10.0%) cocoons was similar (P = .43). Conclusions Low Tdap coverage among adult CCs reinforces the difficulty of implementing the cocooning strategy and the importance of vaccination during pregnancy to prevent infant pertussis. PMID:27838676

Refined structure of dimeric diphtheria toxin at 2.0 A resolution.

PubMed Central

Bennett, M. J.; Choe, S.; Eisenberg, D.

1994-01-01

The refined structure of dimeric diphtheria toxin (DT) at 2.0 A resolution, based on 37,727 unique reflections (F > 1 sigma (F)), yields a final R factor of 19.5% with a model obeying standard geometry. The refined model consists of 523 amino acid residues, 1 molecule of the bound dinucleotide inhibitor adenylyl 3'-5' uridine 3' monophosphate (ApUp), and 405 well-ordered water molecules. The 2.0-A refined model reveals that the binding motif for ApUp includes residues in the catalytic and receptor-binding domains and is different from the Rossmann dinucleotide-binding fold. ApUp is bound in part by a long loop (residues 34-52) that crosses the active site. Several residues in the active site were previously identified as NAD-binding residues. Glu 148, previously identified as playing a catalytic role in ADP-ribosylation of elongation factor 2 by DT, is about 5 A from uracil in ApUp. The trigger for insertion of the transmembrane domain of DT into the endosomal membrane at low pH may involve 3 intradomain and 4 interdomain salt bridges that will be weakened at low pH by protonation of their acidic residues. The refined model also reveals that each molecule in dimeric DT has an "open" structure unlike most globular proteins, which we call an open monomer. Two open monomers interact by "domain swapping" to form a compact, globular dimeric DT structure. The possibility that the open monomer resembles a membrane insertion intermediate is discussed. PMID:7833807

Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine.

PubMed

Haile, Colin N; Kosten, Therese A; Shen, Xiaoyun Y; O'Malley, Patrick W; Winoske, Kevin J; Kinsey, Berma M; Wu, Yan; Huang, Zhen; Lykissa, Ernest D; Naidu, Naga; Cox, Joseph A; Arora, Reetakshi; Kosten, Thomas R; Orson, Frank M

2015-12-01

We previously reported that an anti-methamphetamine (MA) vaccine attenuated drug-conditioned effects in mice, but it used a carrier protein and adjuvant not available for clinical use. Here we produced a vaccine with the same hapten (succinyl-methamphetamine, SMA) but attached to tetanus toxoid (SMA-TT) and adsorbed to aluminum hydroxide, components approved for use in humans. We then assessed the vaccine's ability to generate anti-MA antibodies, alter acquisition and reinstatement of MA place conditioning, and prevent MA brain penetration. Mice were administered SMA-TT at weeks 0 and 3 and non-vaccinated mice received saline. Anti-MA antibody concentrations were determined at 8 and 12 weeks. Place conditioning began during week 9 in which vaccinated and non-vaccinated mice were divided into groups and conditioned with .5, or 2.0 mg/kg MA. Following acquisition training, mice were extinguished and then a reinstatement test was performed in which mice were administered their original training dose of MA. Separate groups of non-vaccinated and vaccinated mice were administered .5 and 2.0 mg/kg MA and brain MA levels determined. Anti-MA antibody levels were elevated at week 8 and remained so through week 12. The SMA-TT vaccine attenuated acquisition and reinstatement of MA place conditioning. Significantly greater proportions of vaccinated mice during acquisition and reinstatement tests showed conditioned place aversion. Moreover, MA brain levels were decreased in vaccinated mice following administration of both doses of MA. Results support further development of anti-MA vaccines using components approved for use in humans. © American Academy of Addiction Psychiatry.

Elevated Immune Response Among Children 4 Years of Age With Pronounced Local Adverse Events After the Fifth Diphtheria, Tetanus, Acellular Pertussis Vaccination.

PubMed

van der Lee, Saskia; Kemmeren, Jeanet M; de Rond, Lia G H; Öztürk, Kemal; Westerhof, Anneke; de Melker, Hester E; Sanders, Elisabeth A M; Berbers, Guy A M; van der Maas, Nicoline A T; Rümke, Hans C; Buisman, Anne-Marie

2017-09-01

In the Netherlands, acellular pertussis vaccines replaced the more reactogenic whole-cell pertussis vaccines. This replacement in the primary immunization schedule of infants coincided with a significant increase in pronounced local adverse events (AEs) in 4 years old children shortly after the administration of a fifth diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV) vaccine. The objective of this study was to investigate possible differences in vaccine antigen-specific immune responses between children with and without a pronounced local AE after the fifth DTaP-IPV vaccination. Blood was sampled in 2 groups of 4-year-olds: a case group reporting pronounced local swelling and/or erythema up to extensive limb swelling at the injection site (n = 30) and a control group (n = 30). Peripheral blood mononuclear cells were stimulated with individual vaccine antigens. Plasma antigen-specific IgG, IgG subclass and total IgE concentrations and T-cell cytokine [interferon-gamma, interleukin (IL)-13, IL-17 and IL-10] production by stimulated peripheral blood mononuclear cells were determined by multiplex bead-based fluorescent multiplex immunoassays. In children with AEs, significantly higher total IgE and vaccine antigen-specific IgG and IgG4 responses as well as levels of the T-helper 2 (Th2) cytokine IL-13 were found after pertussis, tetanus and diphtheria stimulation compared with controls. Children with pronounced local reactions show higher humoral and cellular immune responses. Acellular vaccines are known to skew toward more Th2 responses. The pronounced local AEs may be associated with more Th2 skewing after the fifth DTaP-IPV vaccination, but other biologic factors may also impact the occurrence of these pronounced local reactions.

Immunity against measles, mumps, rubella, varicella, diphtheria, tetanus, polio, hepatitis A and hepatitis B among adult asylum seekers in the Netherlands, 2016.

PubMed

Freidl, Gudrun S; Tostmann, Alma; Curvers, Moud; Ruijs, Wilhelmina L M; Smits, Gaby; Schepp, Rutger; Duizer, Erwin; Boland, Greet; de Melker, Hester; van der Klis, Fiona R M; Hautvast, Jeannine L A; Veldhuijzen, Irene K

2018-03-14

Asylum seekers are a vulnerable population for contracting infectious diseases. Outbreaks occur among children and adults. In the Netherlands, asylum seeker children are offered vaccination according to the National Immunization Program. Little is known about protection against vaccine-preventable diseases (VPD) in adult asylum seekers. In this 2016 study, we assessed the immunity of adult asylum seekers against nine VPD to identify groups that might benefit from additional vaccinations. We invited asylum seekers from Syria, Iran, Iraq, Afghanistan, Eritrea and Ethiopia to participate in a serosurvey. Participants provided informed consent and a blood sample, and completed a questionnaire. We measured prevalence of protective antibodies to measles, mumps, rubella, varicella, diphtheria, tetanus, polio type 1-3 and hepatitis A and B, stratified them by country of origin and age groups. The median age of the 622 participants was 28 years (interquartile range: 23-35), 81% were male and 48% originated from Syria. Overall, seroprotection was 88% for measles (range between countries: 83-93%), 91% for mumps (81-95%), 94% for rubella (84-98%), 96% for varicella (92-98%), 82% for diphtheria (65-88%), 98% for tetanus (86-100%), 91% (88-94%) for polio type 1, 95% (90-98%) for polio type 2, 82% (76-86%) for polio type 3, 84% (54-100%) for hepatitis A and 27% for hepatitis B (anti-HBs; 8-42%). Our results indicate insufficient protection against certain VPD in some subgroups. For all countries except Eritrea, measles seroprotection was below the 95% threshold required for elimination. Measles seroprevalence was lowest among adults younger than 25 years. In comparison, seroprevalence in the Dutch general population was 96% in 2006/07. The results of this study can help prioritizing vaccination of susceptible subgroups of adult asylum seekers, in general and in outbreak situations. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

PubMed

Li, Pan; Asokanathan, Catpagavalli; Liu, Fang; Khaing, Kyi Kyi; Kmiec, Dorota; Wei, Xiaoqing; Song, Bing; Xing, Dorothy; Kong, Deling

2016-11-20

Poly(lactic-co-glycolic acid) (PLGA) based nano/micro particles were investigated as a potential vaccine platform for pertussis antigen. Presentation of pertussis toxoid as nano/micro particles (NP/MP) gave similar antigen-specific IgG responses in mice compared to soluble antigen. Notably, in cell line based assays, it was found that PLGA based nano/micro particles enhanced the phagocytosis of fluorescent antigen-nano/micro particles by J774.2 murine monocyte/macrophage cells compared to soluble antigen. More importantly, when mice were immunised with the antigen-nano/micro particles they significantly increased antigen-specific Th1 cytokines INF-γ and IL-17 secretion in splenocytes after in vitro re-stimulation with heat killed Bordetalla pertussis, indicating the induction of a Th1/Th17 response. Also, presentation of pertussis antigen in a NP/MP formulation is able to provide protection against respiratory infection in a murine model. Thus, the NP/MP formulation may provide an alternative to conventional acellular vaccines to achieve a more balanced Th1/Th2 immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B.

PubMed

Sun, Yuelian; Christensen, Jakob; Hviid, Anders; Li, Jiong; Vedsted, Peter; Olsen, Jørn; Vestergaard, Mogens

2012-02-22

Vaccination with whole-cell pertussis vaccine carries an increased risk of febrile seizures, but whether this risk applies to the acellular pertussis vaccine is not known. In Denmark, acellular pertussis vaccine has been included in the combined diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine since September 2002. To estimate the risk of febrile seizures and epilepsy after DTaP-IPV-Hib vaccination given at 3, 5, and 12 months. A population-based cohort study of 378,834 children who were born in Denmark between January 1, 2003, and December 31, 2008, and followed up through December 31, 2009; and a self-controlled case series (SCCS) study based on children with febrile seizures during follow-up of the cohort. Hazard ratio (HR) of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination and HR of epilepsy after first vaccination in the cohort study. Relative incidence of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination in the SCCS study. A total of 7811 children were diagnosed with febrile seizures before 18 months, of whom 17 were diagnosed within 0 to 7 days after the first (incidence rate, 0.8 per 100,000 person-days), 32 children after the second (1.3 per 100,000 person-days), and 201 children after the third (8.5 per 100,000 person-days) vaccinations. Overall, children did not have higher risks of febrile seizures during the 0 to 7 days after the 3 vaccinations vs a reference cohort of children who were not within 0 to 7 days of vaccination. However, a higher risk of febrile seizures was found on the day of the first (HR, 6.02; 95% CI, 2.86-12.65) and on the day of the second (HR, 3.94; 95% CI, 2.18-7.10), but not on the day of the third vaccination (HR, 1.07; 95% CI, 0.73-1.57) vs the reference cohort. On the day of vaccination, 9 children were diagnosed with febrile seizures after the first (5.5 per 100,000 person-days), 12

Clinician awareness of tetanus-diphtheria vaccination in trauma patients: a questionnaire study

PubMed Central

2012-01-01

Background Most trauma patients visit the hospital via the emergency department. They are at high risk for tetanus infection because many trauma patients are wounded. Tetanus immunity in the Korean population has been revealed to be decreased in age groups over 20 years old. It is important for emergency physicians to vaccinate patients with the tetanus booster in wound management. Methods Questionnaires were sent to the directors of the emergency departments of resident training hospitals certified by the Korean Society of Emergency Medicine. Results Two thirds of the emergency department directors surveyed reported applying tetanus prophylaxis guidelines to more than 80% of wounded patients. However, about 45% of clinicians in the emergency departments considered giving less than half of the wounded patient tetanus booster vaccinations, and there were no distinct differences in tetanus booster vaccination rates among different age groups. Most emergency physicians are familiar with tetanus prophylaxis guidelines for wound management. However, more than half of the emergency department directors reported that the major reason for not considering tetanus-diphtheria vaccination was due to assumptions that patients already had tetanus immunity. Conclusion Attitude changes should be encouraged among emergency physicians regarding tetanus prophylaxis. As emergency physicians are frequently confronted with patients that are at a high risk for tetanus infection in emergency situations, they need to be more informed regarding tetanus immunity epidemiology and encouraged to administer tetanus booster vaccines. PMID:22587533

Killing of cultured hepatocytes by conjugates of asialofetuin and EGF linked to the A chains of ricin or diphtheria toxin.

PubMed

Simpson, D L; Cawley, D B; Herschman, H R

1982-06-01

A disulfide-linked conjugate between asialofetuin (ASF) and the toxic A chain (RTA) of ricin is as potent a toxin for cultured rat hepatocytes as our previously described conjugate between ASF and fragment A of diphtheria toxin (DTA). An RTA conjugate of epidermal growth factor (EGF) was a potent toxin for 3T3 cells. In contrast, EGF-DTA was essentially nontoxic for 3T3 cells. We have now examined the toxicity of EGF-RTA and EGF-DTA on cultured hepatocytes. The EGF-DTA conjugate, nontoxic to 3T3 cells, is also a potent toxin for hepatocytes. We also observed a decrease with time of culture in the sensitivity of hepatocytes to the ASF and EGF conjugates. This decrease is not a result of a decrease in EGF or asialoglycoprotein receptors.

Tetanus toxoid immunization campaign in West Nusa Tenggara, Indonesia.

PubMed

1985-01-01

A tetanus toxoid (TT) immunization campaign was carried out in Central Lombok district of Indonesia in the province of West Nusa Tenggara (NTB) from January to April 1985. A coverage rate of 93% for 2 doses was obtained among women of childbearing age. This paper summarizes the major components of the activity, discussing some of the strengths and weaknesses of the campaign. The major objective of this crash campaign was to raise the tetanus immunity level throughout the fertile age group and thus to achieve a marked reduction in the incidence of neonatal tetanus. A draft protocol for the campaign was developed by national and provincial health staff. The governor of NTB pledged the full support of the provincial administrative apparatus, and funds, equipment, and vaccine were guaranteed at the national level. Commitments of support were received from all relevant sectoral departments at provincial and district levels. About 2 weeks before the vaccination activities began, PKK cadres -- about 6000 women in Central Lombok district -- were provided with forms to take a census of all fertile women in their respective areas. This information was consolidated at the village level, where a serial number was assigned to each name. The enumeration forms were later used as vaccination registers. The number of women identified in each village was reported to the appropriate health center for use in planning vaccine requirements and the deployment of manpower. 2 or 3 days prior to the scheduled vaccination session, PKK cadres again visited all women on their census list to inform them of the place and time of the vaccinator's visit and to distribute appointment cards which carried serial numbers matching those on the census list. The 31 vaccinators were newly qualified nursing school graduates awaiting their 1st government postings. They were given a 2-day orientation course on campaign strategy and methods, and their work schedule was explained. First-line technical

Antibody response to booster vaccination with tetanus and diphtheria in adults exposed to perfluorinated alkylates.

PubMed

Kielsen, Katrine; Shamim, Zaiba; Ryder, Lars P; Nielsen, Flemming; Grandjean, Philippe; Budtz-Jørgensen, Esben; Heilmann, Carsten

2016-01-01

Recent studies suggest that exposure to perfluorinated alkylate substances (PFASs) may induce immunosuppression in humans and animal models. In this exploratory study, 12 healthy adult volunteers were recruited. With each subject, serum-PFAS concentrations were measured and their antibody responses prospectively followed for 30 days after a booster vaccination with diphtheria and tetanus. The results indicated that serum-PFAS concentrations were positively correlated and positively associated with age and male sex. The specific antibody concentrations in serum were increased from Day 4 to Day 10 post-booster, after which a constant concentration was reached. Serum PFAS concentrations showed significant negative associations with the rate of increase in the antibody responses. Interestingly, this effect was particularly strong for the longer-chain PFASs. All significant associations remained significant after adjustment for sex and age. Although the study involved a small number of subjects, these findings of a PFAS-associated reduction of the early humoral immune response to booster vaccination in healthy adults supported previous findings of PFAS immunosuppression in larger cohorts. Furthermore, the results suggested that cellular mechanisms right after antigen exposure should be investigated more closely to identify possible mechanisms of immunosuppression from PFAS.

Corynebacterium diphtheriae methionine sulfoxide reductase a exploits a unique mycothiol redox relay mechanism.

PubMed

Tossounian, Maria-Armineh; Pedre, Brandán; Wahni, Khadija; Erdogan, Huriye; Vertommen, Didier; Van Molle, Inge; Messens, Joris

2015-05-01

Methionine sulfoxide reductases are conserved enzymes that reduce oxidized methionines in proteins and play a pivotal role in cellular redox signaling. We have unraveled the redox relay mechanisms of methionine sulfoxide reductase A of the pathogen Corynebacterium diphtheriae (Cd-MsrA) and shown that this enzyme is coupled to two independent redox relay pathways. Steady-state kinetics combined with mass spectrometry of Cd-MsrA mutants give a view of the essential cysteine residues for catalysis. Cd-MsrA combines a nucleophilic cysteine sulfenylation reaction with an intramolecular disulfide bond cascade linked to the thioredoxin pathway. Within this cascade, the oxidative equivalents are transferred to the surface of the protein while releasing the reduced substrate. Alternatively, MsrA catalyzes methionine sulfoxide reduction linked to the mycothiol/mycoredoxin-1 pathway. After the nucleophilic cysteine sulfenylation reaction, MsrA forms a mixed disulfide with mycothiol, which is transferred via a thiol disulfide relay mechanism to a second cysteine for reduction by mycoredoxin-1. With x-ray crystallography, we visualize two essential intermediates of the thioredoxin relay mechanism and a cacodylate molecule mimicking the substrate interactions in the active site. The interplay of both redox pathways in redox signaling regulation forms the basis for further research into the oxidative stress response of this pathogen. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Seroprevalence of tetanus toxoid antibody and booster vaccination efficacy in Japanese travelers.

PubMed

Mizuno, Yasutaka; Yamamoto, Akihiko; Komiya, Takako; Takeshita, Nozomi; Takahashi, Motohide

2014-01-01

Tetanus can be prevented by vaccination, which is especially important for overseas travelers. However, despite booster vaccination every 10 years being recommended, most Japanese adults do not receive it in the absence of physical injury or overseas travel. We aimed to investigate the level of protective immunity against tetanus among Japanese travelers, which may provide valuable information for formulating booster vaccination recommendations. 113 Japanese travelers given tetanus toxoid were recruited. The collected samples included paired samples prior to and 3-5 weeks after receiving the booster vaccination. Travelers who did not return and those lacking sample collection at the second visit were excluded. Finally, 96 paired blood samples were collected. History of immunization against tetanus, including DPT and DT vaccines, was determined from interviews or immunization records. The pre-vaccination geometric mean titer for the 96 participants was 1.07 IU/mL; 76% had a protective antitoxin level (>0.1 IU/mL), and 50% had a long-term protective antitoxin level (>1.0 IU/mL). Most participants <40 years old had protective immunity without receiving booster vaccination, whereas only 30.8% of those >50 years of age had protective immunity. Among the 23 participants without protective antitoxin levels (<0.1 IU/mL), booster vaccination was efficient in 100% of those <40 years but in only 28.6% of those >50 years of age. Although the tetanus antitoxin level decreases with age, booster vaccination helped to achieve an adequate protective antitoxin levels in Japanese travelers <40 years of age. Furthermore, the individuals who have never been vaccinated against tetanus especially in those >50 years old need to obtain protective immunity against tetanus according to a basic immunization schedule to prevent tetanus in travelers and residents of Japan. Copyright © 2013 Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases. Published by

Sero-efficacy of Vi-polysaccharide tetanus-toxoid typhoid conjugate vaccine (Typbar-TCV).

PubMed

Voysey, Merryn; Pollard, Andrew J

2018-01-17

Salmonella Typhi is the major cause of enteric fever in lower income countries. New conjugate vaccines show promise as public health interventions, however there are no efficacy data available from endemic areas. Data were obtained from a previously published phase 3 randomised controlled trial comparing Vi-polysaccharide tetanus-toxoid conjugate vaccine (Typbar-TCV; Bharat Biotech Intl Ltd, India): (Vi-TT) with Vi-polysaccharide (Typbar; Bharat Biotech Intl Ltd, India): (Vi-PS) in participants aged 2- 45 years. An additional open-label arm administered Vi-TT to children aged 6 months to 23 months. The proportion of participants with presumed clinical or subclinical infection ('seroincidence'), was determined using mixture models and compared using relative risks. 81/387 (21%) participants were classified as having presumed typhoid infection during the 2 year period post-vaccination. Seroincidence was lower in those randomised to Vi-TT than Vi-PS in those aged 2-45 years; 21/155 (13.5%) vs 47/129 (36.4%); RR 0.372 (95%CI 0.235-0.588), p<0.0001 and in those aged 2-15 years RR 0.424 (95%CI 0.231-0.778), p=0.0039. There was no difference in seroincidence in those receiving Vi-TT aged 2-45 years and those aged 6-23 months; 21/155 (13.5%) vs 13/103 (12.6%); RR 1.073 (0.563, 2.046), p=0.8293. Vaccine seroefficacy was 85% (95%CI 80-88%). This is the first field estimate of the seroefficacy of a Vi-TT vaccine and shows that Typbar TCV substantially reduces the number of serologically defined (sub)clinical infections in infants, children and adults. These results support the recent World Health Organisation recommendations for deployment of typhoid conjugate vaccines in high burden areas. © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Vascular Endothelial Growth Factor-A165b Restores Normal Glomerular Water Permeability in a Diphtheria-Toxin Mouse Model of Glomerular Injury.

PubMed

Stevens, Megan; Neal, Christopher R; Salmon, Andrew H J; Bates, David O; Harper, Steven J; Oltean, Sebastian

2018-01-01

Genetic cell ablation using the human diphtheria toxin receptor (hDTR) is a new strategy used for analysing cellular function. Diphtheria toxin (DT) is a cytotoxic protein that leaves mouse cells relatively unaffected, but upon binding to hDTR it ultimately leads to cell death. We used a podocyte-specific hDTR expressing (Pod-DTR) mouse to assess the anti-permeability and cyto-protective effects of the splice isoform vascular endothelial growth factor (VEGF-A165b). The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A165b specifically in the podocytes (Neph-VEGF-A165b). Wild type (WT), Pod-DTR, Neph-VEGF-A165b and Pod-DTR X Neph-VEGF-A165b mice were treated with several doses of DT (1, 5, 100, and 1,000 ng/g bodyweight). Urine was collected and the glomerular water permeability (LpA/Vi) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. Pod-DTR mice developed an increased glomerular LpA/Vi 14 days after administration of DT (all doses), which was prevented when the mice over-expressed VEGF-A165b. No major structural abnormalities, podocyte ablation or albuminuria was observed in Pod-DTR mice, indicating this to be a mild model of podocyte disease. However, a change in expression and localisation of nephrin within the podocytes was observed, indicating disruption of the slit diaphragm in the Pod-DTR mice. This was prevented in the Pod-DTR X Neph-VEGF-A165b mice. Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A165b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A165b in glomerular disease. © 2018 The Author(s) Published by S. Karger AG, Basel.

Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa.

PubMed

Vesikari, Timo; Rivera, Luis; Korhonen, Tiina; Ahonen, Anitta; Cheuvart, Brigitte; Hezareh, Marjan; Janssens, Winnie; Mesaros, Narcisa

2017-07-03

Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (D A T A Pa-HBV-IPV/Hib), or B (D B T B Pa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12-15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1-3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued.

Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa

PubMed Central

Vesikari, Timo; Rivera, Luis; Korhonen, Tiina; Ahonen, Anitta; Cheuvart, Brigitte; Hezareh, Marjan; Janssens, Winnie; Mesaros, Narcisa

2017-01-01

ABSTRACT Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV-IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12–15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1–3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued. PMID:28340322

Subnormal and waning immunity to tetanus toxoid in previously vaccinated HIV-infected children and response to booster doses of the vaccine.

PubMed

Choudhury, Shahana A; Matin, Fazle

2013-12-01

Little is known regarding waning immunity to tetanus toxoid (TT) in HIV-infected children and the need for booster doses before the recommended interval of 5-10 years. Anti-tetanus antibodies were assessed by ELISA in 24 HIV-infected and 24 control children. A protective level (>0.1 IU/ml) of TT antibodies was observed in 62% of HIV-infected children and in 100% of controls. HIV-infected children with five doses had a significantly (p=0.01) lower prevalence of protective immunity compared to controls. Follow-up anti-TT antibody levels in nine HIV-infected children declined from 1.27 to 0.26 IU/ml, but levels did not decline in the seven controls; five of the seven (71%) children with a non-protective level of antibodies responded with a level>0.16 IU/ml following one booster dose of the vaccine. HIV-infected children may need TT boosters before the recommended 5-10 years. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Use of a tetanus toxoid marker to allow differentiation of infected from vaccinated poultry without affecting the efficacy of a H5N1 avian influenza virus vaccine.

PubMed

James-Berry, C M; Middleton, D; Mansfield, J P; Fenwick, S G; Ellis, T M

2010-10-30

Tetanus toxoid (TT) was assessed as a positive marker for avian influenza (AI) virus vaccination in chickens, in a vaccination and challenge study. Chickens were vaccinated twice with inactivated AI H5N2 virus vaccine, and then challenged three weeks later with highly pathogenic AI H5N1 virus. Vaccinated chickens were compared with other groups that were either sham-vaccinated or vaccinated with virus with the TT marker. All sham-vaccinated chickens died by 36 hours postinfection, whereas all vaccinated chickens, with or without the TT marker, were protected from morbidity and mortality following exposure to the challenge virus. Serological testing for H5-specific antibodies identified anamnestic responses to H5 in some of the vaccinated birds, indicating active virus infection.

Determinants of utilization of sufficient tetanus toxoid immunization during pregnancy: evidence from the Kenya Demographic and Health Survey, 2008-2009.

PubMed

Haile, Zelalem T; Chertok, Ilana R Azulay; Teweldeberhan, Asli K

2013-06-01

Although the effectiveness of tetanus toxoid (TT) immunization during pregnancy in preventing maternal and neonatal tetanus is well established, in many developing countries, TT immunization programs are underutilized. The objective of this study was to examine factors associated with sufficient TT immunization among postpartum women in Kenya. Population based secondary data analysis was conducted using de-identified data from the 2008-2009 Kenyan Demographic and Health Survey (KDHS) for 1,370 female participants who had a live birth during or within 12 months of the cross-sectional survey. Chi-square test and independent sample t test were conducted to assess bivariate associations and a multivariable logistic regression analysis was conducted to examine associations before and after adjustment for demographic, socioeconomic, cultural, and access to care factors. The main factors contributing to having been sufficiently immunized against tetanus were lower birth order, higher household wealth index, women's employment, making joint health-related decisions with a partner, and higher number of antenatal care visits. Implications for health care providers and other professionals involved in development of strategies and interventions aimed at improving immunization rates are discussed.

A comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, M.P.

1988-01-01

The mechanism by which tumor necrosis factor-alpha (TNF) initiates tumor cell destruction is unknown. We have approached this problem by comparing the biological properties of TNF with diphtheria toxin (DTx), a well-characterized cytotoxin. Initial studies with human U937 cells revealed that a transient exposure to low pH enhances the cytotoxic activity of TNF. Detailed studies on the interaction of TNF with pure lipid vesicles revealed that the acid-enhanced cytolytic activity of this cytokine is correlated with the acquisition of membrane binding and insertion properties. Significantly, an increase in target membrane stabilization was observed in the presence of TNF; hence, TNFmore » is not directly lytic for membranes. In susceptible target cells, DTx induces the release of {sup 51}Cr- and {sup 75}Se-labeled proteins within 7 h. Although DTx-triggered cell death has generally been accepted as a straightforward effect of translation inhibition, little or no cell lysis was observed over a 20-30 h period when target cells were exposed to cycloheximide, amino acid deficient medium or metabolic poisons even though protein synthesis was inhibited to levels observed with DTx. The protein synthesis inhibition and cytolytic activities of DTx showed similar dose-dependencies, target cell specificities, and sensitivities to NH{sub 4}Cl inhibition. DTx-induced DNA fragmentation preceded cells lysis and did not occur in cells that were treated with the other protein synthesis inhibitors.« less

Characterization of a human antigen specific helper factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richardson, B.

1986-03-01

While antigen (Ag) specific helper factors have been characterized in mice, similar molecules have not been identified in humans. To characterize human antigen specific helper molecules, an IL-2 dependent tetanus toxoid (T.T.) reactive T cell line was fused with a 6-thioguanine resistant CEM line, and hybrids selected in medium containing hypoxanthine and azaserine. Hybrids were screened by culturing the cells with /sup 35/S-Met then reacting the supernatants with T.T. or hepatitis vaccine immobilized on nitrocellulose. One hybrid, TT6BA-O, was identified which secreted a Met-containing molecule which bound T.T. but not hepatitis vaccine. Supernatants from TT6BA-O, but not the parent CEMmore » line, when added to autologous peripheral blood mononuclear cells (PBMC's) stimulated secretion of T.T. specific antibodies (Abs). Specificity controls demonstrated that TT6BA-O supernatant did not induce antibodies to diphtheria toxoid, hepatitis vaccine or pneumococcal polysaccharide, and total immunoglobulin (lg) synthesis was minimally increased. In contrast, pokeweed mitogen stimulated significant lg synthesis as well as Ab's to pneumococcal polysaccharide and T.T. TT6BA-O supernatant induced anti-T.T.Ab's in autologous PBMC's but not PBMC's from 3 unrelated donors, suggesting that the activity of the helper factor is restricted, possibly by the MHC. The molecular weight of the helper factor was estimated at 100,000-150,000 by Sephacryl S-300 chromatography. Finally, the helper factor could be demonstrated to bind and elute from sephorose-immobilized T.T. and anti-DR antisera, but not anti-lg antisera or the T40/25 monoclonal antibody, which binds a nonpolymorphic determinant on the human T cell receptor. These results demonstrate that human Ag specific helper factors exist, bind antigen and bear class II MHC determinants.« less

Evaluation of two vaccine education interventions to improve pertussis vaccination among pregnant African American women: A randomized controlled trial.

PubMed

Kriss, Jennifer L; Frew, Paula M; Cortes, Marielysse; Malik, Fauzia A; Chamberlain, Allison T; Seib, Katherine; Flowers, Lisa; Ault, Kevin A; Howards, Penelope P; Orenstein, Walter A; Omer, Saad B

2017-03-13

Vaccination coverage with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in pregnancy or immediately postpartum has been low. Limited data exist on rigorously evaluated interventions to increase maternal vaccination, including Tdap. Tailored messaging based on the Elaboration Likelihood Model (ELM) framework has been successful in improving uptake of some public health interventions. We evaluated the effect of two ELM-based vaccine educational interventions on Tdap vaccination among pregnant African American women, a group of women who tend to have lower vaccine uptake compared with other groups. We conducted a prospective randomized controlled trial to pilot test two interventions - an affective messaging video and a cognitive messaging iBook - among pregnant African American women recruited during routine prenatal care visits. We measured Tdap vaccination during the perinatal period (during pregnancy and immediately postpartum), reasons for non-vaccination, and intention to receive Tdap in the next pregnancy. Among the enrolled women (n=106), 90% completed follow-up. Tdap vaccination in the perinatal period was 18% in the control group; 50% in the iBook group (Risk Ratio [vs. control group]: 2.83; 95% CI, 1.26-6.37), and 29% in the video group (RR: 1.65; 95% CI, 0.66-4.09). From baseline to follow-up, women's reported intention to receive Tdap during the next pregnancy improved in all three groups. Among unvaccinated women, the most common reason reported for non-vaccination was lack of a recommendation for Tdap by the woman's physician. Education interventions that provide targeted information for pregnant women in an interactive manner may be useful to improve Tdap vaccination during the perinatal period. However, larger studies including multiple racial and ethnic groups are needed to evaluate robustness of our findings. clinicaltrials.gov Identifier: NCT01740310. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assessment of Tdap Vaccination Effectiveness in Adolescents in Integrated Health-Care Systems.

PubMed

Briere, Elizabeth C; Pondo, Tracy; Schmidt, Mark; Skoff, Tami; Shang, Nong; Naleway, Alison; Martin, Stacey; Jackson, Michael L

2018-06-01

Despite high national vaccination coverage with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines among U.S. adolescents, rates of adolescent pertussis disease are increasing. We estimated the duration of protection after Tdap vaccination and the possible effects of the change from whole-cell to acellular childhood pertussis vaccines in the United States during the 1990s. We conducted a retrospective cohort analysis among 11- to 18-year-olds enrolled in two integrated health-care delivery systems during 2005-2012. Cases met the Council of State and Territorial Epidemiologists' confirmed or probable definition or a polymerase chain reaction-positive suspect definition. We estimated vaccine effectiveness (VE) overall and by time since Tdap receipt. We stratified VE estimates by primary series pertussis vaccine received (based on birth year): mixed-vaccine cohort (1987-1997) and acellular vaccine cohort (1998-2001). The overall Tdap VE was 57% (95% confidence interval [CI]: 42%-68%); the VE in the mixed-vaccine and acellular cohorts was 65% (95% CI: 44%-78%) and 52% (95% CI: 30%-68%), respectively. Tdap VE within <2 years post vaccination (69%, 95% CI: 54%-79%) was significantly different from VE ≥2 years post vaccination (34%, 95% CI: 1%-55%, p value < .01). VE was significantly higher <2 years post vaccination compared with ≥2 years post vaccination in both mixed-vaccine (87%, 95% CI: 58%-96%, and 52%, 95% CI: 13%-73%; p value = .04) and acellular cohorts (62%, 95% CI: 41%-76%, and 21%, 95% CI: -30% to 52%; p value = .01). Although Tdap vaccination remains the best pertussis prevention method for adolescents, protection wanes within 2 years regardless of the type of childhood primary vaccine. Vaccines with longer duration of protection could decrease pertussis burden. Copyright © 2018 The Society for Adolescent Health and Medicine. All rights reserved.

Travel Characteristics and Pretravel Health Care Among Pregnant or Breastfeeding U.S. Women Preparing for International Travel.

PubMed

Hagmann, Stefan H F; Rao, Sowmya R; LaRocque, Regina C; Erskine, Stefanie; Jentes, Emily S; Walker, Allison T; Barnett, Elizabeth D; Chen, Lin H; Hamer, Davidson H; Ryan, Edward T

2017-12-01

To study characteristics and preventive interventions of adult pregnant and breastfeeding travelers seeking pretravel health care in the United States. This cross-sectional study analyzed data (2009-2014) of pregnant and breastfeeding travelers seen at U.S. travel clinics participating in Global TravEpiNet. Nonpregnant, nonbreastfeeding adult female travelers of childbearing age were used for comparison. We evaluated the prescription of malaria chemoprophylaxis and antibiotics for this population as well as the administration of three travel-related vaccines: hepatitis A, typhoid, and yellow fever. We also evaluated use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis and influenza vaccines, because these are widely recommended in pregnancy. Of 21,138 female travelers of childbearing age in Global TravEpiNet, 170 (0.8%) were pregnant and 139 (0.7%) were breastfeeding. Many traveled to destinations endemic for mosquito-borne illnesses, including malaria (pregnant: 95%; breastfeeding: 94%), dengue (pregnant: 87%; breastfeeding: 81%), or yellow fever (pregnant: 35%; breastfeeding: 50%). Compared with nonpregnant, nonbreastfeeding adult female travelers, eligible pregnant travelers were less likely to be vaccinated against hepatitis A (28% compared with 51%, P<.001) and typhoid (35% compared with 74%, P<.001). More than 20% of eligible pregnant travelers did not receive influenza vaccination. Yellow fever vaccine was occasionally provided to pregnant and breastfeeding travelers traveling to countries entirely endemic for yellow fever (6 [20%] of 30 pregnant travelers and 18 [46%] of 39 breastfeeding travelers). Half of pregnant travelers and two thirds of breastfeeding travelers preparing to travel to malaria-holoendemic countries received a prescription for malaria prophylaxis. Most pregnant and breastfeeding travelers seen for pretravel health consultations traveled to destinations with high risk for vector-borne or other travel-related diseases

Travel Characteristics and Pretravel Health Care Among Pregnant or Breastfeeding U.S. Women Preparing for International Travel

PubMed Central

Hagmann, Stefan H. F.; Rao, Sowmya R.; LaRocque, Regina C.; Erskine, Stefanie; Jentes, Emily S.; Walker, Allison T.; Barnett, Elizabeth D.; Chen, Lin H.; Hamer, Davidson H.; Ryan, Edward T.

2018-01-01

OBJECTIVE To study characteristics and preventive interventions of adult pregnant and breastfeeding travelers seeking pretravel health care in the United States. METHODS This cross-sectional study analyzed data (2009–2014) of pregnant and breastfeeding travelers seen at U.S. travel clinics participating in Global TravEpiNet. Nonpregnant, nonbreastfeeding adult female travelers of childbearing age were used for comparison. We evaluated the prescription of malaria chemoprophylaxis and antibiotics for this population as well as the administration of three travel-related vaccines: hepatitis A, typhoid, and yellow fever. We also evaluated use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis and influenza vaccines, because these are widely recommended in pregnancy. RESULTS Of 21,138 female travelers of childbearing age in Global TravEpiNet, 170 (0.8%) were pregnant and 139 (0.7%) were breastfeeding. Many traveled to destinations endemic for mosquito-borne illnesses, including malaria (pregnant: 95%; breastfeeding: 94%), dengue (pregnant: 87%; breastfeeding: 81%), or yellow fever (pregnant: 35%; breastfeeding: 50%). Compared with nonpregnant, nonbreastfeeding adult female travelers, eligible pregnant travelers were less likely to be vaccinated against hepatitis A (28% compared with 51%, P<.001) and typhoid (35% compared with 74%, P<.001). More than 20% of eligible pregnant travelers did not receive influenza vaccination. Yellow fever vaccine was occasionally provided to pregnant and breastfeeding travelers traveling to countries entirely endemic for yellow fever (6 [20%] of 30 pregnant travelers and 18 [46%] of 39 breastfeeding travelers). Half of pregnant travelers and two thirds of breastfeeding travelers preparing to travel to malaria-holoendemic countries received a prescription for malaria prophylaxis. CONCLUSION Most pregnant and breastfeeding travelers seen for pretravel health consultations traveled to destinations with high risk for vector

[The microbial pattern of the catheter exit-site infection in peritoneal dialysis: A non-diphtheria Corynebacteria emergence?].

PubMed

Teixidó, J; Arias, N; Tarrats, L; Romero, R

2007-01-01

.008) throughout the three periods. One half of the Corynebacteria in each period could be considered colonisers. The other half caused true infections, but not one of those episodes required catheter intervention. The non-diphtheria Corynebacteria increase was found related with the continuous cycling Peritoneal Dialysis treatment in multiple factor analysis (p=0.0023) and in the proportion analysis (P=0.039, c2). The progressive protocol applied obtained good results, without the continued use of local antiseptics or antibiotics at the exit-site. However, the non-diphtheria Corynebacteria sp. infection increment favours the consideration of an antiseptic agent for the exit-site care.

Impairment of the humoral and CD4+ T cell responses in HTLV-1-infected individuals immunized with tetanus toxoid

PubMed Central

Souza, Anselmo; Santos, Silvane; Carvalho, Lucas P.; Grassi, Maria Fernanda R.; Carvalho, Edgar M.

2016-01-01

T cells from HTLV-1-infected individuals have a decreased ability to proliferate after stimulation with recall antigens. This abnormality may be due to the production of regulatory cytokine or a dysfunctional antigen presentation. The aims of this study were to evaluate the antibody production and cytokine expression by lymphocytes before and after immunization with tetanus toxoid (TT) and to evaluate the immune response of monocytes after stimulation with TT and frequency of dendritic cells (DC) subsets. HTLV-1 carriers (HC) and uninfected controls with negative serology for TT were immunized with TT, and the antibody titers were determined by ELISA as well as the cell activation markers expression by monocytes. The frequencies of DC subsets were determined by flow cytometry. Following immunization, the IgG anti-TT titers and the frequency of CD4+ T cells expressing IFN-γ, TNF and IL-10 in response to TT were lower in the (HC) than in the controls. Additionally, monocytes from HC did not exhibit increased HLA-DR expression after stimulation with TT, and presented low numbers of DC subsets, therefore, it’s necessary to perform functional studies with antigen-presenting cells. Collectively, our finding suggests that HC present an impairment of the humoral and CD4+ T cell immune responses after vaccination. PMID:27282836

Thermodynamics of membrane insertion and refolding of the diphtheria toxin T-domain

PubMed Central

Vargas-Uribe, Mauricio; Rodnin, Mykola V.; Öjemalm, Karin; Holgado, Aurora; Kyrychenko, Alexander; Nilsson, IngMarie; Posokhov, Yevgen O.; Makhatadze, George; von Heijne, Gunnar; Ladokhin, Alexey S.

2014-01-01

The diphtheria toxin translocation (T) domain inserts into the endosomal membrane in response to the endosomal acidification and enables the delivery of the catalytic domain into the cell. The insertion pathway consists of a series of conformational changes that occur in solution and in the membrane and leads to the conversion of a water-soluble state into a transmembrane state. In this work, we utilize various biophysical techniques to characterize the insertion pathway from the thermodynamic perspective. Thermal and chemical unfolding measured by differential scanning calorimetry, circular dichroism and tryptophan fluorescence reveal that the free energy of unfolding of the T-domain at neutral and mildly acidic pH differ by 3–5 kcal/mol, depending on the experimental conditions. Fluorescence correlation spectroscopy measurements show that the free energy change from the membrane-competent state to the interfacial state is approximately −8 kcal/mol and is pH-independent, while that from the membrane-competent state to the transmembrane state ranges between −9.5 to −12 kcal/mol, depending on the membrane lipid composition and pH. Finally, the thermodynamics of transmembrane insertion of individual helices was tested using an in vitro assay that measures the translocon-assisted integration of test sequences into the microsomal membrane. These experiments suggest that even the most hydrophobic helix TH8 has only a small favorable free energy of insertion. The free energy for the insertion of the consensus insertion unit TH8-TH9 is slightly more favorable, yet less favorable than that measured for the entire protein, suggesting a cooperative effect for the membrane insertion of the helices of the T-domain. PMID:25281329

The economic value of increasing geospatial access to tetanus toxoid immunization in Mozambique.

PubMed

Haidari, Leila A; Brown, Shawn T; Constenla, Dagna; Zenkov, Eli; Ferguson, Marie; de Broucker, Gatien; Ozawa, Sachiko; Clark, Samantha; Lee, Bruce Y

2016-07-29

With tetanus being a leading cause of maternal and neonatal morbidity and mortality in low and middle income countries, ensuring that pregnant women have geographic access to tetanus toxoid (TT) immunization can be important. However, immunization locations in many systems may not be placed to optimize access across the population. Issues of access must be addressed for vaccines such as TT to reach their full potential. To assess how TT immunization locations meet population demand in Mozambique, our team developed and utilized SIGMA (Strategic Integrated Geo-temporal Mapping Application) to quantify how many pregnant women are reachable by existing TT immunization locations, how many cannot access these locations, and the potential costs and disease burden of not covering geographically harder-to-reach populations. Sensitivity analyses covered a range of catchment area sizes to include realistic travel distances and to determine the area some locations would need to cover in order for the existing system to reach at least 99% of the target population. For 99% of the population to reach health centers, people would be required to travel up to 35km. Limiting this distance to 15km would result in 5450 (3033-7108) annual cases of neonatal tetanus that could be prevented by TT, 144,240 (79,878-192,866) DALYs, and $110,691,979 ($56,180,326-$159,516,629) in treatment costs and productivity losses. A catchment area radius of 5km would lead to 17,841 (9929-23,271) annual cases of neonatal tetanus that could be prevented by TT, resulting in 472,234 (261,517-631,432) DALYs and $362,399,320 ($183,931,229-$522,248,480) in treatment costs and productivity losses. TT immunization locations are not geographically accessible by a significant proportion of pregnant women, resulting in substantial healthcare and productivity costs that could potentially be averted by adding or reconfiguring TT immunization locations. The resulting cost savings of covering these harder to reach

Risk of bursitis and other injuries and dysfunctions of the shoulder following vaccinations.

PubMed

Martín Arias, L H; Sanz Fadrique, R; Sáinz Gil, M; Salgueiro-Vazquez, M E

2017-09-05

While vaccination injection site adverse reactions are usually mild and transient in nature, several cases of bursitis and other shoulder injuries have been reported in the medical literature. However, these lesions are not included in vaccine label inserts. To identify the characteristics of post-vaccination shoulder injuries and those of patients and involved vaccines, as well as their potential causes, a systematic review of the cases of vaccination-related bursitis and other shoulder injuries reported in the literature and notified to the Spanish Pharmacovigilance System database (FEDRA) have been conducted. We found 45 cases of bursitis and other shoulder injuries that appeared following the vaccine intramuscular injection given into the deltoid muscle (37 from the systematic review of the literature, and 8 from the scrutiny in the Spanish Pharmacovigilance System database, FEDRA). All the patients were adult, 71.1% females, with a mean and median age of 53.6years (range: 22-89). The most frequently involved vaccines were influenza and pneumococcal vaccines, respectively; followed by diphtheria-tetanus-pertussis, diphtheria-tetanus toxoid, human papillomavirus, and hepatitis A vaccines. The most frequent shoulder lesion was bursitis. Most of patients required medical care due to severe local pain and arm mobility restriction. In a majority of cases, symptoms started 48h post vaccination. Subdeltoid or subacromial bursitis and other shoulder lesions may be more common than suspected. Such lesions predominantly affect women. The cause may be related to antigens or adjuvants contained in the vaccines that would trigger an immune or inflammatory response. However, they are more likely to be the consequence of a poor injection technique (site, angle, needle size, and failure to take into account patient's characteristics, i. e., sex, body weight, and physical constitution). Therefore, vaccination-related shoulder injuries would be amenable to prevention. Copyright

Immunogenicity and reactogenicity of the human rotavirus vaccine, RIX4414 oral suspension, when co-administered with routine childhood vaccines in Chinese infants.

PubMed

Li, Rong-Cheng; Huang, Teng; Li, Yanping; Wang, Lao-Hong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhaojun; Liao, XueYan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay

2016-03-03

This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6-16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9-79.9) and 64.2% (95% CI: 55.4-72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5-77.1) and 50.0% (95% CI: 40.9-59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines.

Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice.

PubMed

Petrušić, Vladimir; Todorović, Nevena; Živković, Irena; Dimitrijević, Rajna; Muhandes, Lina; Rajnpreht, Irena; Dimitrijević, Ljiljana

2015-03-01

Recent data concerning antiphospholipid syndrome (APS) induction have shown that β2-glycoprotein I (β2GPI) binds lipopolysaccharide (LPS), which results in conformational changes, exposition of a cryptic epitope and possible pathological anti-β2GPI antibody production. In order to investigate the effects of LPS on the induction of APS-related pathology, we performed hyperimmunization of BALB/c and C57BL/6 mice with LPS, alone or in combination with tetanus toxoid (TTd), a protein structurally similar to β2GPI. We report that, although high affinity pathological anti-β2GPI antibodies were produced in all groups of animals, the reproductive pathology was recorded only in mice that received both LPS and TTd, implying on the important roles of both infections and molecular mimicry in APS pathogenesis. Moreover, APS-related reproductive pathology was more pronounced in BALB/c (lowered fertility and fecundity) than C57BL/6 mice (lowered fecundity), which correlated well with the disruption in natural antibody network observed in BALB/c mouse strain.

Mutated form (G52E) of inactive diphtheria toxin CRM197: molecular simulations clearly display effect of the mutation to NAD binding.

PubMed

Salmas, Ramin Ekhteiari; Mestanoglu, Mert; Unlu, Ayhan; Yurtsever, Mine; Durdagi, Serdar

2016-11-01

Mutated form (G52E) of diphtheria toxin (DT) CRM197 is an inactive and nontoxic enzyme. Here, we provided a molecular insight using comparative molecular dynamics (MD) simulations to clarify the influence of a single point mutation on overall protein and active-site loop. Post-processing MD analysis (i.e. stability, principal component analysis, hydrogen-bond occupancy, etc.) is carried out on both wild and mutated targets to investigate and to better understand the mechanistic differences of structural and dynamical properties on an atomic scale especially at nicotinamide adenine dinucleotide (NAD) binding site when a single mutation (G52E) happens at the DT. In addition, a docking simulation is performed for wild and mutated forms. The docking scoring analysis and docking poses results revealed that mutant form is not able to properly accommodate the NAD molecule.

Immunogenicity and safety of measles-mumps-rubella and varicella vaccines coadministered with a fourth dose of Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine in toddlers: a pooled analysis of randomized trials.

PubMed

Bryant, Kristina; McVernon, Jodie; Marchant, Colin; Nolan, Terry; Marshall, Gary; Richmond, Peter; Marshall, Helen; Nissen, Michael; Lambert, Stephen; Aris, Emmanuel; Mesaros, Narcisa; Miller, Jacqueline

2012-08-01

A pooled analysis was conducted of 1257 toddlers who received a fourth dose of Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) or Hib conjugate vaccine (Hib polysaccharide conjugated to N. meningitidis outer membrane protein) coadministered with measles-mumps-rubella (MMR) and varicella (VAR) vaccines (NCT00134719/NCT00289783). Noninferiority of immunological responses to MMR and VAR was demonstrated between groups and incidences of MMR- and VAR-specific solicited symptoms were similar, indicating that HibMenCY-TT can be coadministered with MMR and VAR.

Concomitant administration of diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) with pentavalent rotavirus vaccine in Japanese infants.

PubMed

Tanaka, Yoshiyuki; Yokokawa, Ruriko; Rong, Han Shi; Kishino, Hiroyuki; Stek, Jon E; Nelson, Margaret; Lawrence, Jody

2017-06-03

Rotavirus is the leading cause of severe acute gastroenteritis in infants and young children. Most children are infected with rotavirus, and the health and economic burdens of rotavirus gastroenteritis on healthcare systems and families are considerable. In 2012 pentavalent rotavirus vaccine (RV5) and diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) were licensed in Japan. We examined the immunogenicity and safety of DTaP-sIPV when administrated concomitantly with RV5 in Japanese infants. A total of 192 infants 6 to 11 weeks of age randomized to Group 1 (N = 96) received DTaP-sIPV and RV5 concomitantly, and Group 2 (N = 96) received DTaP-sIPV and RV5 separately. Antibody titer to diphtheria toxin, pertussis antigens (PT and FHA), tetanus toxin, and poliovirus type 1, 2, and 3 were measured at 4 to 6 weeks following 3-doses of DTaP-sIPV. Seroprotection rates for all components of DTaP-sIPV were 100% in both groups, and the geometric mean titers for DTaP-sIPV in Group 1 were comparable to Group 2. Incidence of systemic AEs (including diarrhea, vomiting, fever, and nasopharyngitis) were lower in Group 1 than in Group 2. All vaccine-related AEs were mild or moderate in intensity. There were no vaccine-related serious AEs, no deaths, and no cases of intussusception during the study. Concomitant administration of DTaP-sIPV and RV5 induced satisfactory immune responses to DTaP-sIPV and acceptable safety profile. The administration of DTaP-sIPV given concomitantly with RV5 is expected to facilitate compliance with the vaccination schedule and improve vaccine coverage in Japanese infants.

Maternal Vaccination With a Monocomponent Pertussis Toxoid Vaccine Is Sufficient to Protect Infants in a Baboon Model of Whooping Cough.

PubMed

Kapil, Parul; Papin, James F; Wolf, Roman F; Zimmerman, Lindsey I; Wagner, Leslie D; Merkel, Tod J

2018-03-28

Bordetella pertussis is a human pathogen responsible for serious respiratory illness. The disease is most severe in infants too young to be vaccinated with most hospitalizations and deaths occurring within this age group. The Advisory Committee on Immunization Practices recommended immunization of pregnant women to protect infants from birth until their first vaccination at 6-8 weeks of age. We previously demonstrated that maternal vaccination with licensed acellular pertussis vaccines protected newborn baboons from disease. We hypothesized that protection was due to toxin-neutralizing, maternal anti-pertussis toxin antibodies and predicted that maternal vaccination with a pertussis toxoid (PTx)-only vaccine would protect newborns from disease. Infant baboons born to unvaccinated mothers or mothers vaccinated with a PTx-only vaccine were challenged with B. pertussis at 5 weeks of age and followed for infection and signs of disease. Although all challenged infants were heavily colonized, the infant baboons born to mothers vaccinated with PTx-only vaccine were free from clinical disease following exposure to B. pertussis. In contrast, disease was observed in infants born to unvaccinated mothers. Our results demonstrated that maternal vaccination with a PTx-only vaccine is sufficient to protect newborn baboons from disease following exposure to pertussis.

Immunogenicity, Safety, and Antibody Persistence at 3, 5, and 10 Years Postvaccination in Adolescents Randomized to Booster Immunization with a Combined Tetanus, Diphtheria, 5-Component Acellular Pertussis, and Inactivated Poliomyelitis Vaccine Administered with a Hepatitis B Virus Vaccine Concurrently or 1 Month Apart

PubMed Central

Embree, Joanne; Law, Barbara; Voloshen, Tim

2014-01-01

An understanding of the antibody persistence elicited by a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliovirus vaccine (Tdap-IPV) after adolescent vaccination is important to optimize booster dosing intervals. Our objectives were to compare the safety and immunogenicity of Tdap-IPV coadministered with hepatitis B vaccine (HepB) and sequential administration and evaluate humoral immunity at 3, 5, and 10 years after Tdap-IPV vaccination in adolescents. This phase II randomized, controlled, and open-label study enrolled 280 11- to 14-year-old adolescents with up to 10 years postvaccination follow-up. Group 1 (n = 145) received Tdap-IPV, followed by a HepB dose 1 month later, and group 2 (n = 135) received both vaccines simultaneously. No consistent increases in solicited reactions or unsolicited adverse events occurred with coadministration. All vaccinees attained seroprotective antibody levels at ≥0.01 IU/ml for diphtheria and tetanus, at a ≥1:8 dilution for poliovirus (serotypes 1, 2, and 3), and ≥10 mIU/ml for hepatitis B at 1 month postvaccination. Clinically relevant immunologic interactions did not occur with coadministration. For pertussis, all participants achieved seropositivity levels (at or above the lower limit of quantitation), and 72.7% to 95.8% had 4-fold increases in pertussis antibodies at 1 month postvaccination. At 10 years postvaccination, the remaining participants (62.8% of the original cohort) maintained seroprotective levels of ≥0.01 IU/ml for diphtheria and tetanus, a ≥1:8 dilution for all 3 poliovirus serotypes, and 74.1% to 98.2% maintained pertussis seropositivity levels depending on the antigen tested. There were no differences between the groups. These results support the coadministration of Tdap-IPV and HepB to adolescents and suggest that vaccination with Tdap-IPV can offer protection for 10 years after an adolescent booster vaccination. PMID:25540274

[Modification of pertussis vaccination schedule in Chile, immunization of special groups and control strategies: Commentary from the Consultive Committee of Immunizations of The Chilean Society of Infectious Diseases].

PubMed

Potin, Marcela; Cerda, Jaime; Contreras, Lily; Muñoz, Alma; Ripoll, Erna; Vergara, Rodrigo

2012-06-01

In Chile, an increased number of notifications of cases of whooping cough was detected at the beginning of October 2010, and maintained through 2012. Accumulated cases during 2011 were 2,581 (15.0 per 100,000), which is greater than the number of cases registered during the period 2008-2010 (2,460 cases). On the other hand, the local sanitary authority introduced a modification of pertussis vaccination schedule (starting 2012), which consists in the replacement of the second booster of pertussis vaccine (DTwP, administered to 4-year-old children) as well as diphtheria-tetanus toxoid (dT, administered to second grade scholars) for an acellular pertussis vaccine with reduced antigenic content (dTpa), which will be administrated to first grade scholars. The Consultive Committee of Immunizations considers that the modification is adequate, since it extends the age of protection, reducing at least in theory the infection in older scholars and adolescents -who are significant sources of transmission of Bordetella pertussis to infants- using an adequate vaccine formulation (acellular pertussis vaccine). The available evidence regarding vaccination in special groups (adolescents and adults, health-care workers and pregnant women) and cocooning strategy are commented.

Menjugate (Chiron).

PubMed

Jones, D H

2001-01-01

Chiron has developed and launched Menjugate, a vaccine for the treatment for meningococcus C infections caused by the pathogen Neisseria meningitidis [177064]. In August 1999, Chiron filed with the UK MCA for a license to market Menjugate. The licence was granted in March 2000 [339082], [344773], [357897] and as of April 2000, a vaccination program was underway in the UK [362152]. Menjugate is indicated for children of 12 months and older, but Chiron was expecting approval in the US for infants younger than 12 months by the end of 2000. The company will also pursue mutual recognition in Europe [376204]. In August 2000, Chiron received marketing clearance for Menjugate from the Irish Medicines Board as a conjugate against meningococcal C disease [378353]. The vaccine employs CRM-conjugate technology, whereby a diphtheria toxoid is used as a carrier protein for the meningitis C-specific antigens. The vaccine is being developed for its potential to provide protection against meningitis in both adults and infants. In July 2000, Chiron entered into a comarketing and co-promotion agreement with Aventis Pasteur under which Aventis will assist Chiron in marketing and sales efforts for Menjugate in the UK [374760].

Immunization coverage in India for areas served by the Integrated Child Development Services programme. The Integrated Child Development Services Consultants.

PubMed

Tandon, B N; Gandhi, N

1992-01-01

The Integrated Child Development Services (ICDS) programme was launched by the Indian government in October 1975 to provide a package of health, nutrition and informal educational services to mothers and children. In 1988 we studied the impact of ICDS on the immunization coverage of children aged 12-24 months and of mothers of infants in 19 rural, 8 tribal, and 9 urban ICDS projects that had been operational for more than 5 years. Complete coverage with BCG, diphtheria-pertussis-tetanus (DPT) and poliomyelitis vaccines was recorded for 65%, 63%, and 64% of children, respectively, in the ICDS population. By comparison, the coverage in the non-ICDS group was only 22% for BCG, 28% for DPT, and 27% for poliomyelitis. Complete immunization with tetanus toxoid was recorded for 68% of the mothers in the ICDS group and for 40% in the non-ICDS group. Coverage was greater in the urban and lower in the tribal projects. Scheduled castes, scheduled tribes, backward communities, and minorities (groups that have a high priority for social services) had immunization coverages in ICDS projects that were similar to those of higher castes.

CD4 T-helper cell cytokine phenotypes and antibody response following tetanus toxoid booster immunization.

PubMed

Livingston, Kimberly A; Jiang, Xiaowen; Stephensen, Charles B

2013-04-30

Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify tetanus toxoid- (TT) specific Th1, Th2, Th17 and IL10(+) cells. Eight healthy subjects were given a TT booster vaccination. Blood was drawn before, 3, 7, 14, and 28days after vaccination and peripheral blood mononuclear cells (PBMC) were cultured for 7days with TT, negative control (diluent), and a positive control (Staphylococcus enterotoxin B [SEB]). Activation markers (CD25 and CD69) were measured after 44h (n=8), cytokines in supernatant after 3 and 7days, and intracellular cytokine staining (ICS) of proliferated cells (identified by dye dilution) after 7days (n=6). Vaccination increased TT-specific expression of CD25 and CD69 on CD3(+)CD4(+) lymphocytes, and TT-specific proliferation at 7, 14 and 28days post vaccination. Vaccination induced TT-specific Th1 (IFN-γ, TNF-α, and IL-2) Th2 (IL-13, IL-5, and IL-4), Th17 (IL-17A) and IL-10(+) cells as measured by ICS. TT-specific Th1 cells were the most abundant (12-15% of all TT-specific CD4(+) T-cells) while IL10(+) (1.8%) Th17 (1.1%) and Th2 cells (0.2-0.6%) were less abundant. TT-specific cytokine concentrations in PBMC supernatants followed the same pattern where a TT-specific IL-9 response was also seen. In conclusion, TT booster vaccination induced a broad T-helper cell response. This method of evaluating cytokine phenotypes may be useful in examining the impact of nutrition and environmental conditions on the plasticity of T-helper cell memory responses. Published by Elsevier B.V.

Impairment of the humoral and CD4(+) T cell responses in HTLV-1-infected individuals immunized with tetanus toxoid.

PubMed

Souza, Anselmo; Santos, Silvane; Carvalho, Lucas P; Grassi, Maria Fernanda R; Carvalho, Edgar M

2016-08-01

T cells from HTLV-1-infected individuals have a decreased ability to proliferate after stimulation with recall antigens. This abnormality may be due to the production of regulatory cytokine or a dysfunctional antigen presentation. The aims of this study were to evaluate the antibody production and cytokine expression by lymphocytes before and after immunization with tetanus toxoid (TT) and to evaluate the immune response of monocytes after stimulation with TT and frequency of dendritic cells (DC) subsets. HTLV-1 carriers (HC) and uninfected controls (UC) with negative serology for TT were immunized with TT, and the antibody titers were determined by ELISA as well as the cell activation markers expression by monocytes. The frequencies of DC subsets were determined by flow cytometry. Following immunization, the IgG anti-TT titers and the frequency of CD4(+) T cells expressing IFN-γ, TNF-α and IL-10 in response to TT were lower in the HC than in the UC. Additionally, monocytes from HC did not exhibit increased HLA-DR expression after stimulation with TT, and presented low numbers of DC subsets, therefore, it's necessary to perform functional studies with antigen-presenting cells. Collectively, our finding suggests that HC present an impairment of the humoral and CD4(+) T cell immune responses after vaccination. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Tetanus toxoid-loaded layer-by-layer nanoassemblies for efficient systemic, mucosal, and cellular immunostimulatory response following oral administration.

PubMed

Harde, Harshad; Agrawal, Ashish Kumar; Jain, Sanyog

2015-10-01

The present study reports the tetanus toxoid (TT)-loaded layer-by-layer nanoassemblies (layersomes) with enhanced protection, permeation, and presentation for comprehensive oral immunization. The stable and lyophilized TT-loaded layersomes were prepared by a thin-film hydration method followed by alternate layer-by-layer coating of an electrolyte. The developed system was assessed for in vitro stability of antigen and formulation, cellular uptake, ex vivo intestinal uptake, and immunostimulatory response using a suitable experimental protocol. Layersomes improved the stability in simulated biological media as well as protected the integrity/conformation and native 3D structure of TT as confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence spectroscopy, respectively. The cell culture studies demonstrated a 3.8-fold higher permeation of layersomes in Caco-2 cells and an 8.5-fold higher uptake by antigen-presenting cells (RAW 264.7). The TT-loaded layersomes elicited a complete immunostimulatory profile consisting of higher systemic (serum IgG titer), mucosal (sIgA titer), and cellular (interleukin-2 (IL-2) and interferon-γ (IFN-γ) levels) immune response after peroral administration in mice. The modified TT inhibition assay further confirmed the elicitation of complete protective levels of anti-TT antibody (>0.1 IU/mL) by layersomes. In conclusion, the proposed strategy is expected to contribute significantly in the field of stable liposome technology for mass immunization through the oral route.

Supplementation with Natural Forms of Vitamin E Augments Antigen-Specific TH1-Type Immune Response to Tetanus Toxoid

PubMed Central

Radhakrishnan, Ammu Kutty; Mahalingam, Dashayini; Selvaduray, Kanga Rani; Nesaretnam, Kalanithi

2013-01-01

This study compared the ability of three forms of vitamin E [tocotrienol-rich fraction (TRF), alpha-tocopherol (α-T), and delta-tocotrienol (δ-T3)] to enhance immune response to tetanus toxoid (TT) immunisation in a mouse model. Twenty BALB/c mice were divided into four groups of five mice each. The mice were fed with the different forms of vitamin E (1 mg) or vehicle daily for two weeks before they were given the TT vaccine [4 Lf] intramuscularly (i.m.). Booster vaccinations were given on days 28 and 42. Serum was collected (days 0, 28, and 56) to quantify anti-TT levels. At autopsy, splenocytes harvested were cultured with TT or mitogens. The production of anti-TT antibodies was augmented (P < 0.05) in mice that were fed with δ-T3 or TRF compared to controls. The production of IFN-γ and IL-4 by splenocytes from the vitamin E treated mice was significantly (P < 0.05) higher than that from controls. The IFN-γ production was the highest in animals supplemented with δ-T3 followed by TRF and finally α-T. Production of TNF-α was suppressed in the vitamin E treated group compared to vehicle-supplemented controls. Supplementation with δ-T3 or TRF can enhance immune response to TT immunisation and production of cytokines that promote cell-mediated (TH1) immune response. PMID:23936847

Meningococcal quadrivalent (serogroups A, C, W135 and Y) tetanus toxoid conjugate vaccine (Nimenrix™).

PubMed

Croxtall, Jamie D; Dhillon, Sohita

2012-12-24

Nimenrix™ (MenACWY-TT) is a quadrivalent meningococcal conjugate vaccine, comprising the polysaccharide serogroups A, C, W135 and Y, and tetanus toxoid (TT) as carrier protein. It is the first quadrivalent vaccine (administered as a single dose) to be approved in Europe for active immunization of individuals aged ≥ 12 months against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W135 and Y. Administration of a single dose of Nimenrix™ elicited a strong immune response against all four vaccine serogroups in healthy toddlers aged 12-23 months, children and adolescents aged 2-17 years and adults aged 18-55 years in randomized, multicentre, phase III trials. In toddlers, Nimenrix™ was noninferior to Meningitec® in terms of seroresponse rates against meningococcal serogroup C 42 days post-vaccination. In children, adolescents and adults, Nimenrix™ was noninferior to Mencevax™ in terms of vaccination response rates against all four serogroups 1 month post-vaccination. Furthermore, several phase II studies and a phase III trial showed that the immune response elicited by Nimenrix™ in all age groups persisted for 7-42 months after the primary vaccination (when evaluated by rabbit serum bactericidal activity), with the vaccine also inducing immune memory in toddlers. In addition, several randomized, multicentre, phase III, noninferiority trials showed that when coadministered with other childhood vaccines or a seasonal flu vaccine, the immunogenicity of Nimenrix™ or that of the coadministered vaccine was generally not altered. Nimenrix® was generally well tolerated in all age groups whether administered as a single vaccine or coadministered with other routine vaccines. The incidence of grade 3 local or systemic solicited adverse events during the first 4 days following vaccination and of serious adverse events over an extended follow-up period of up to 6 months was low (<4.5%). Although protective effectiveness and longer

An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age.

PubMed

Kosalaraksa, Pope; Mehlsen, Jesper; Vesikari, Timo; Forstén, Aino; Helm, Klaus; Van Damme, Pierre; Joura, Elmar A; Ciprero, Karen; Maansson, Roger; Luxembourg, Alain; Sobanjo-ter Meulen, Ajoke

2015-06-01

A 9-valent human papillomavirus (9vHPV) vaccine has recently been reported to be safe and highly efficacious against infection and disease related to HPV6/11/16/18/31/33/45/52/58. We evaluated the immunogenicity and safety of the 9vHPV vaccine administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine). This open-label, randomized, multicenter study enrolled 1054 males and females ages 11-15 years. Subjects were randomly assigned to each group in a 1:1 ratio. Subjects received a 0.5 mL dose of 9vHPV vaccine intramuscularly at day 1, months 2 and 6 and a 0.5 mL dose of REPEVAX either on day 1 (concomitant vaccination group; n = 526) or at month 1 (nonconcomitant vaccination group, n = 528). Serologic responses for each vaccine component were tested by 1-sided tests of noninferiority between groups. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. Noninferiority of anti-HPV geometric mean titers and seroconversion rates for all 9vHPV antigens were demonstrated for the concomitant group compared with the nonconcomitant group. Seroconversion rates for the 9vHPV vaccine types were ≥99.8% in both groups at month 7. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, all polio and pertussis antigens for both groups. There were no vaccine-related serious AEs. Overall, concomitant administration of 9vHPV vaccine and REPEVAX was generally well tolerated and did not interfere with the immune response to either vaccine. This strategy would minimize the number of visits required to deliver each vaccine individually.

The Economic Value of Increasing Geospatial Access to Tetanus Toxoid Immunization in Mozambique

PubMed Central

Haidari, Leila A.; Brown, Shawn T.; Constenla, Dagna; Zenkov, Eli; Ferguson, Marie; de Broucker, Gatien; Ozawa, Sachiko; Clark, Samantha; Lee, Bruce Y.

2016-01-01

Background With tetanus being a leading cause of maternal and neonatal morbidity and mortality in low and middle income countries, ensuring that pregnant women have geographic access to tetanus toxoid (TT) immunization can be important. However, immunization locations in many systems may not be placed to optimize access across the population. Issues of access must be addressed for vaccines such as TT to reach their full potential. Methods To assess how TT immunization locations meet population demand in Mozambique, our team developed and utilized SIGMA (Strategic Integrated Geo-temporal Mapping Application) to quantify how many pregnant women are reachable by existing TT immunization locations, how many cannot access these locations, and the potential costs and disease burden of not covering geographically harder-to-reach populations. Sensitivity analyses covered a range of catchment area sizes to include realistic travel distances and to determine the area some locations would need to cover in order for the existing system to reach at least 99% of the target population. Results For 99% of the population to reach health centers, people would be required to travel up to 35km. Limiting this distance to 15km would result in 5,450 (3,033–7,108) annual cases of neonatal tetanus that could be prevented by TT, 144,240 (79,878–192,866) DALYs, and $110,691,979 ($56,180,326–$159,516,629) in treatment costs and productivity losses. A catchment area radius of 5km would lead to 17,841 (9,929–23,271) annual cases of neonatal tetanus that could be prevented by TT, resulting in 472,234 (261,517–631,432) DALYs and $362,399,320 ($183,931,229–$522,248,480) in treatment costs and productivity losses. Conclusion TT immunization locations are not geographically accessible by a significant proportion of pregnant women, resulting in substantial healthcare and productivity costs that could potentially be averted by adding or reconfiguring TT immunization locations. The

Non-specific effects of diphtheria tetanus pertussis vaccination on child mortality in Cebu, The Philippines.

PubMed

Chan, Grace J; Moulton, Lawrence H; Becker, Stan; Muñoz, Alvaro; Black, Robert E

2007-10-01

To determine the non-specific effects of diphtheria, tetanus and pertussis (DTP) vaccination and sex on mortality before 30 months of age among those who received Bacille Calmette Guerin (BCG) vaccine in a high mortality area. This analysis used a longitudinal study of child survival monitoring the use of primary care services, morbidity and mortality in Metro Cebu, The Philippines. Participants included 14 537 children under 30 months of age who received a BCG vaccination from July 1988 to January 1991. The main outcome measure was all-cause mortality. Mortality before 30 months of age was 57% lower among BCG-vaccinated children who received DTP vaccination than BCG-vaccinated children who did not receive DTP vaccination {hazard ratio (HR) for vaccinated vs unvaccinated 0.43 [95% confidence interval (CI) 0.21-0.88]}. Females had lower mortality rates [HR = 0.19 (0.04-0.86), P = 0.03] than males among DTP-unvaccinated children. The protective effect of DTP vaccination was more pronounced in males [HR 0.32 (0.14-0.73)] than in females [HR 0.86 (0.18-4.23)]. DTP vaccination increased (interaction term P = 0.08) the female-to-male mortality ratio to 0.76 (0.52-1.12). Among BCG-vaccinated children under 30 months of age, DTP vaccination is associated with improved survival. The increased female-male mortality ratio is associated with reduced mortality among males following DTP vaccination rather than increased mortality among female children.

Coverage and factors associated with tetanus toxoid vaccination among married women of reproductive age: a cross sectional study in Peshawar.

PubMed

Naeem, Mohammad; Khan, Muhammad Zia-ul-Islam; Abbas, Syed Hussain; Adil, Muhammad; Khan, Ayasha; Naz, Syeda Maria; Khan, Muhammad Usman

2010-01-01

Pakistan has one of the highest maternal mortality rates in the world, with widely prevalent maternal and neonatal tetanus. The purpose of this study was to estimate the coverage and determine the factors associated with tetanus toxoid vaccination status among females of reproductive age in Peshawar. A Cross-sectional study was conducted in Peshawar, Pakistan, from 9 June to 19 June 2010. A total of 304 females of reproductive age (17 45) years were selected from both urban and rural areas of Peshawar through random sampling. A pre-tested structured questionnaire was administered to females. Questions about demographics, income, education of husband, occupation, accessibility to health centres and frequency of visits from health workers was inquired. Knowledge and views on immunization were also asked. Overall 55.6% were vaccinated. Urban population was 54.3% while rural population was 45.7%. Reasons for not vaccinating were: No awareness (38.4%), being busy (18.1%), centre too far (18.1%), misconceptions (10.86%), and fear of reactions (4.3%). Most of the females thought immunization was effective (89.5%). Husband education, females' knowledge and views on immunization, income, distance, frequency of health visits were the main factors associated with immunization status. Majority of females are not vaccinated. Effective media campaigns on maternal tetanus vaccination should be carried. Lady health workers should be mobilised effectively to increase the vaccination coverage.

A Chimeric protein of CFA/I, CS6 subunits and LTB/STa toxoid protects immunized mice against enterotoxigenic Escherichia coli.

PubMed

Zeinalzadeh, Narges; Salmanian, Ali Hatef; Goujani, Goli; Amani, Jafar; Ahangari, Ghasem; Akhavian, Asal; Jafari, Mahyat

2017-07-01

Enterotoxigenic Escherichia Coli (ETEC) strains are the commonest bacteria causing diarrhea in children in developing countries and travelers to these areas. Colonization factors (CFs) and enterotoxins are the main virulence determinants in ETEC pathogenesis. Heterogeneity of CFs is commonly considered the bottleneck to developing an effective vaccine. It is believed that broad spectrum protection against ETEC would be achieved by induced anti-CF and anti-enterotoxin immunity simultaneously. Here, a fusion antigen strategy was used to construct a quadrivalent recombinant protein called 3CL and composed of CfaB, a structural subunit of CFA/I, and CS6 structural subunits, LTB and STa toxoid of ETEC. Its anti-CF and antitoxin immunogenicity was then assessed. To achieve high-level expression, the 3CL gene was synthesized using E. coli codon bias. Female BALB/C mice were immunized with purified recombinant 3CL. Immunized mice developed antibodies that were capable of detecting each recombinant subunit in addition to native CS6 protein and also protected the mice against ETEC challenge. Moreover, sera from immunized mice also neutralized STa toxin in a suckling mouse assay. These results indicate that 3CL can induce anti-CF and neutralizing antitoxin antibodies along with introducing CFA/I as a platform for epitope insertion. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

The diphtheria toxin transmembrane domain as a pH sensitive membrane anchor for human interleukin-2 and murine interleukin-3.

PubMed

Liger, D; Nizard, P; Gaillard, C; vanderSpek, J C; Murphy, J R; Pitard, B; Gillet, D

1998-11-01

We have constructed two fusion proteins T-hIL-2 and T-mIL-3 in which human interleukin-2 (hIL-2) or murine interleukin-3 (mIL-3) are fused to the C-terminus of the diphtheria toxin transmembrane domain (T domain). Two additional fusion proteins, T-(Gly4-Ser)2-hIL-2 and T-(Gly4-Ser)2-mIL-3, were derived by introduction of the (Gly4-Ser)2 spacer between the T domain and cytokine components. Recognition of the hIL-2 receptor or the mIL-3 receptor by the corresponding recombinant proteins was demonstrated by their capacity to stimulate cytokine-dependent cell lines. All proteins retained the capacity of the T domain to insert into phospholipid membranes at acidic pH. Finally, anchoring of both cytokines to the membrane of lipid vesicles or living cells was assessed by specific antibody recognition. Our results show that the T domain fused to the N-terminus of a given protein can function as a pH sensitive membrane anchor for that protein.

Men with Low Vitamin A Stores Respond Adequately to Primary Yellow Fever and Secondary Tetanus Toxoid Vaccination12

PubMed Central

Ahmad, Shaikh M.; Haskell, Marjorie J.; Raqib, Rubhana; Stephensen, Charles B.

2008-01-01

Current recommendations for vitamin A intake and liver stores (0.07 μmol/g) are based on maintaining normal vision. Higher levels may be required for maintaining normal immune function. The objective of this study was to assess the relationship between total body vitamin A stores in adult men and measures of adaptive immune function. We conducted an 8-wk residential study among 36 healthy Bangladeshi men with low vitamin A stores. Subjects received a standard diet and were randomized in a double-blind fashion to receive vitamin A (240 mg) or placebo during wk 2 and 3. Subjects received Yellow Fever Virus (YFV) and tetanus toxoid (TT) vaccines during wk 5. Vitamin A stores were estimated by isotopic dilution during wk 8. Vaccine-specific lymphocyte proliferation, cytokine production, and serum antibody responses were evaluated before and after vaccination. Vitamin A supplementation increased YFV- and TT-specific lymphocyte proliferation and YFV-specific interleukin (IL)-5, IL-10, and tumor necrosis factor-α production but inhibited development of a TT-specific IL-10 response. Both groups developed protective antibody responses to both vaccines. Some responses correlated positively with vitamin A stores. These findings indicate that the currently recommended vitamin A intake is sufficient to sustain a protective response to YFV and TT vaccination. However, YFV-specific lymphocyte proliferation, some cytokine responses, and neutralizing antibody were positively associated with liver vitamin A stores > 0.084 μmol/g. Such increases may enhance vaccine protection but raise the question of whether immune-mediated chronic diseases may by exacerbated by high-level dietary vitamin A. PMID:18936231

Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine.

PubMed

Daley, Matthew F; Yih, W Katherine; Glanz, Jason M; Hambidge, Simon J; Narwaney, Komal J; Yin, Ruihua; Li, Lingling; Nelson, Jennifer C; Nordin, James D; Klein, Nicola P; Jacobsen, Steven J; Weintraub, Eric

2014-05-23

In 2008, a diphtheria, tetanus, acellular pertussis, and inactivated poliovirus combined vaccine (DTaP-IPV) was licensed for use in children 4 through 6 years of age. While pre-licensure studies did not demonstrate significant safety concerns, the number vaccinated in these studies was not sufficient to examine the risk of uncommon but serious adverse events. To assess the risk of serious adverse events following DTaP-IPV vaccination. The study was conducted from January 2009 through September 2012 in the Vaccine Safety Datalink (VSD) project. In the VSD, electronic vaccination and encounter data are updated and aggregated weekly as part of ongoing surveillance activities. Based on previous reports and biologic plausibility, eight potential adverse events were monitored: meningitis/encephalitis; seizures; stroke; Guillain-Barré syndrome; Stevens-Johnson syndrome; anaphylaxis; serious allergic reactions other than anaphylaxis; and serious local reactions. Adverse event rates in DTaP-IPV recipients were compared to historical incidence rates in the VSD population prior to 2009. Sequential probability ratio testing was used to analyze the data on a weekly basis. During the study period, 201,116 children received DTaP-IPV vaccine. Ninety-seven percent of DTaP-IPV recipients also received other vaccines on the same day, typically measles-mumps-rubella and varicella vaccines. There was no statistically significant increased risk of any of the eight pre-specified adverse events among DTaP-IPV recipients when compared to historical incidence rates. In this safety surveillance study of more than 200,000 DTaP-IPV vaccine recipients, there was no evidence of increased risk for any of the pre-specified adverse events monitored. Continued surveillance of DTaP-IPV vaccine safety may be warranted to monitor for rare adverse events, such as Guillain-Barré syndrome. Copyright © 2014 Elsevier Ltd. All rights reserved.

Association between sudden infant death syndrome and diphtheria-tetanus-pertussis immunisation: an ecological study.

PubMed

Müller-Nordhorn, Jacqueline; Hettler-Chen, Chih-Mei; Keil, Thomas; Muckelbauer, Rebecca

2015-01-28

Sudden infant death syndrome (SIDS) continues to be one of the main causes of infant mortality in the United States. The objective of this study was to analyse the association between diphtheria-tetanus-pertussis (DTP) immunisation and SIDS over time. The Centers for Disease Control and Prevention provided the number of cases of SIDS and live births per year (1968-2009), allowing the calculation of SIDS mortality rates. Immunisation coverage was based on (1) the United States Immunization Survey (1968-1985), (2) the National Health Interview Survey (1991-1993), and (3) the National Immunization Survey (1994-2009). We used sleep position data from the National Infant Sleep Position Survey. To determine the time points at which significant changes occurred and to estimate the annual percentage change in mortality rates, we performed joinpoint regression analyses. We fitted a Poisson regression model to determine the association between SIDS mortality rates and DTP immunisation coverage (1975-2009). SIDS mortality rates increased significantly from 1968 to 1971 (+27% annually), from 1971 to 1974 (+47%), and from 1974 to 1979 (+3%). They decreased from 1979 to 1991 (-1%) and from 1991 to 2001 (-8%). After 2001, mortality rates remained constant. DTP immunisation coverage was inversely associated with SIDS mortality rates. We observed an incidence rate ratio of 0.92 (95% confidence interval: 0.87 to 0.97) per 10% increase in DTP immunisation coverage after adjusting for infant sleep position. Increased DTP immunisation coverage is associated with decreased SIDS mortality. Current recommendations on timely DTP immunisation should be emphasised to prevent not only specific infectious diseases but also potentially SIDS.

IgE sensitization to gelatin: the probable role of gelatin-containing diphtheria-tetanus-acellular pertussis (DTaP) vaccines.

PubMed

Sakaguchi, M; Inouye, S

2000-04-03

We recently found that most events of anaphylaxis to live attenuated viral vaccines containing gelatin as a stabilizer might be caused by the gelatin. However, the mechanism that the children were sensitized to gelatin was unclear. In Japan, both diphtheria-tetanus-acellular pertussis (DTaP) vaccines with and without gelatin are available. We explored the possibility that gelatin-containing DTaP vaccines before live viral vaccines sensitize children to gelatin. We received the serum samples of 87 children who had systemic immediate-type reactions including anaphylaxis to the vaccines from both physicians and vaccine manufacturers throughout Japan. We then surveyed the DTaP vaccination histories of the children who demonstrated anti-gelatin IgE. Of the above 87 children, 79 (91%) had anti-gelatin IgE. We successfully collected DTaP vaccination histories including the manufacturers' names and numbers of doses on 55 children. Only one child had not received any DTaP vaccine, the other 54 had received gelatin-containing DTaP vaccines and none received gelatin-free DTaP vaccines. We concluded that there was a strong causal relationship between gelatin-containing DTaP vaccination, anti-gelatin IgE production, and risk of anaphylaxis following subsequent immunization with live viral vaccines which contain a larger amount of gelatin.

[Immunogenicity of sabin inactivated poliovirus vaccine induced by diphtheria-tetanus-acellular pertussis and Sabin inactivated poliovirus combined vaccine].

PubMed

Ma, Yan; Qin, Min; Hu, Hui-Qiong; Ji, Guang; Feng, Ling; Gao, Na; Gu, Jie; Xie, Bing-Feng; He, Ji-Hong; Sun, Ming-Bo

2011-06-01

In order to search the preparation process and optimazing dosage ratio of adsorbed diphtheria-tetanus-acellular pertussis and sabin inactivated poliovirus combined vaccine (DTaP-sIPV), the neutralizing antibody titers of IPV induced by different concentration of DTaP-sIPV were investigated on rats. Two batches of DTaP-sLPV were produced using different concentration of sIPV and the quality control was carried. Together with sabin-IPV and DTaP-wIPV ( boostrix-polio, GSK, Belgium) as control group, the DTaP-sIPV were administrated on three-dose schedule at 0, 1, 2 month on rats. Serum sample were collected 30 days after each dose and neutralizing antibody titers against three types poliovirus were determined using micro-neutralization test. Two batches of prepared DTaP-sIPV and control sLPV were according to the requirement of Chinese Pharmacopoeia (Volume III, 2005 edition) and showed good stability. The seropositivity rates were 100% for sabin inactivated poliovirus antigen in all groups. The GMTs (Geometric mean titers) of neutralizing antibodies against three types poliovirus increased. The prepared DTaP-sIPV was safe, stable and effective and could induced high level neutralizing antibody against poliovirus on rats.

Assessment of safety and efficacy against Bordetella pertussis of a new tetanus-reduced dose diphtheria-acellular pertussis vaccine in a murine model.

PubMed

Kwon, Hyo Jin; Han, Seung Beom; Kim, Bo Ram; Kang, Kyu Ri; Huh, Dong Ho; Choi, Gi Sub; Ahn, Dong Ho; Kang, Jin Han

2017-04-04

Tetanus-reduced dose diphtheria-acellular pertussis (Tdap) vaccination during adolescence was introduced in response to the resurgence of pertussis in various countries. A new Tdap vaccine was manufactured in Korea as a countermeasure against a predicted Tdap vaccine shortage. This study was performed to evaluate the immunogenicity, safety, and protection efficacy against Bordetella pertussis of the new Tdap vaccine in a murine model. Four-week-old BABL/c mice were used for assessment of immunogenicity and protection efficacy. A single dose of primary diphtheria-tetanus-acellular pertussis (DTaP) vaccine was administered, followed by a single dose of Tdap booster vaccine after a 12-week interval. Anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA), and anti-pertactin (PRN) IgG titers were measured before primary vaccination, and before and after booster vaccination. An intranasal challenge test was performed after booster vaccination to determine protection efficacy. To assess safety, mouse weight gain test and leukocytosis promotion test were performed using 4-week-old ddY female mice. Anti-PT and anti-FHA IgG titers after booster vaccination were significantly higher than those before booster vaccination with either the new vaccine or a commercially available Tdap vaccine (P = 0.01 for all occasions). After booster vaccination, no significant difference was observed between the two vaccines in antibody titers against pertussis antigens (P = 0.53 for anti-PT IgG, P = 0.91 for anti-FHA IgG, P = 0.39 for anti-PRN IgG). In the intranasal challenge test, inoculated B. pertussis was eradicated 7 days after infection. On days 4 and 7 after infection, colony counts of B. pertussis were not significantly different between the new and positive control vaccine groups (P = 1.00). Mean body weight changes and leukocyte counts of the new vaccine, positive control, and negative control groups were not significantly different 7 days after vaccination (P�

The administrative stabilization of vaccines: Regulating the diphtheria antitoxin in France and Germany, 1894-1900.

PubMed

Hess, Volker

2008-06-01

It is well known that the development of a diphtheria anti-toxin serum evolved in a competitive race between two groups of researchers, one affiliated with Emil Behring in Berlin and Marburg, and another affiliated with Emile Roux in Paris. Proceeding on the basis of different theoretical assumptions and experimental practices, the two groups developed a therapeutic serum almost simultaneously. But the standardized substance they developed took on very different forms in the two countries. In Germany the new serum was marketed in the private sphere and subjected to state regulations, becoming a kind ofprototype of industrial medications. In France, however, the same substance was marketed as a gift of science to humanity and distributed through the communal health care system. This article demonstrates how a new medication emerged from the efforts to produce, market, regulate, distribute, and apply it in the two respective countries. It attributes the difference to the negotiations between the respective actors (scientists, industrialists, politicians, officers, and the public) and institutions (firms, academies, private and public institutes, legislative bodies, professional corporations). I develop this argument on three different levels: First, I stress the importance of the institutional foundations of serum production; second, I illustrate the decisive role played by existing "ways of regulating" in the rapid development of new legal statutes; and third, I describe the consequences that flowed from the respective administrative organization of marketing and dissemination. In sum, I explore how an experimental object was transformed into an object of the public health system and stabilized by administrative means.

Egg yolk antibodies for detection and neutralization of Clostridium botulinum type A neurotoxin.

PubMed

Trott, D L; Yang, M; Gonzalez, J; Larson, A E; Tepp, W H; Johnson, E A; Cook, M E

2009-05-01

The objective of this research project was to determine the usefulness of an egg antibody platform for producing materials for the detection and neutralization of botulinum type A neurotoxin. Yield estimates for detection and neutralizing antibodies produced using methods described were calculated. Antibody specific to botulinum toxoid A (aToxoid) and toxin A (aBoNT/A) was produced by immunizing hens with botulinum toxoid A (toxoid) followed by increasing amounts of botulinum neurotoxin A (BoNT/A) in Freund incomplete adjuvant. Egg yolks were extracted with polyethylene glycol (PEG) for antibody detection and neutralization experiments. A model aToxoid/toxoid immunoassay using only egg yolk antibody was developed and had a detection limit of 1 pg/ml of toxoid. In an indirect enzyme-linked immunosorbent assay of BoNT/A-specific antibody, the aBoNT/A contained more BoNT/A-specific antibody than did the aToxoid, and aBoNT/A was as effective as commercial rabbit antibody. The aToxoid provided no protection against BoNT/A in a standard mouse neutralization assay; however, 1 mg of PEG-extracted aBoNT/A neutralized 4,000 lethal doses of BoNT/A injected intraperitoneally. Based on these results, we calculated that in 1 month one hen could produce more than 100 liters of antibody detection reagents or enough antibody to neutralize approximately 11.6 million mouse lethal doses of botulinum toxin. Utilization of an egg antibody platform is potentially rapid (28 to 70 days) and scalable to kilogram quantities using current egg production facilities with as few as 1,000 hens.

Ablation of breast cancer cells using trastuzumab-functionalized multi-walled carbon nanotubes and trastuzumab-diphtheria toxin conjugate.

PubMed

Oraki Kohshour, Mojtaba; Mirzaie, Sako; Zeinali, Majid; Amin, Mansour; Said Hakhamaneshi, Mohammad; Jalili, Ali; Mosaveri, Nader; Jamalan, Mostafa

2014-03-01

Trastuzumab (Herceptin(®) ) is a monoclonal antibody (mAb) for specific ablation of HER2-overexpressing malignant breast cancer cells. Intensification of antiproliferative activity of trastuzumab through construction of immunotoxins and nano-immunoconjugates is a promising approach for treatment of cancer. In this study, trastuzumab was directly conjugated to diphtheria toxin (DT). Also, conjugates of trastuzumab and multiwalled carbon nanotubes (MWCNT) were constructed by covalent immobilization of trastuzumab onto MWCNTs. Then, antiproliferative activity of the fusion constructs against HER2-overexpressing SK-BR-3 and also HER2-negative MCF-7 cancer cell lines were examined. Cells treated with trastuzumab-MWCNT conjugates were irradiated with near-infrared (NIR) light. Efficient absorption of NIR radiation and its conversion to heat by MWCNTs can be resulted to thermal ablation of cancerous cells. Our results strongly showed that both trastuzumab-MWCNT and trastuzumab-DT conjugates were significantly efficient in the specific killing of SK-BR-3 cells. Targeting of MWCNTs to cancerous cells using trastuzumab followed by exposure of cells to NIR radiation was more efficient in repression of cell proliferation than treatment for cancer cells with trastuzumab-DT. Our results also showed that conjugation linkers can significantly affect the cytotoxicity of MWCNT-immunoconjugates. In conclusion, our data demonstrated that trastuzumab-MWCNT is a promising nano-immunoconjugate for killing of HER2-overexpressing cancerous cells. © 2013 John Wiley & Sons A/S.

Antibody responses to tetanus toxoid and Haemophilus influenzae type b conjugate vaccines following autologous peripheral blood stem cell transplantation (PBSCT).

PubMed

Chan, C Y; Molrine, D C; Antin, J H; Wheeler, C; Guinan, E C; Weinstein, H J; Phillips, N R; McGarigle, C; Harvey, S; Schnipper, C; Ambrosino, D M

1997-07-01

Accelerated granulocyte and platelet recovery following peripheral blood stem cell transplantation (PBSCT) are well documented. We hypothesize that functional immunity may also be enhanced in PBSCT and performed a phase II trial of immunizations in patients with lymphoma undergoing autologous transplantation with peripheral blood stem cells or bone marrow. Seventeen BMT and 10 PBSCT recipients were immunized at 3, 6, 12, and 24-months post-transplantation with Haemophilus influenzae type b (HIB)-conjugate and tetanus toxoid (TT) vaccines. IgG anti-HIB and anti-TT antibody concentrations were measured and compared between the two groups. Geometric mean IgG anti-HIB antibody concentrations were significantly higher for PBSCT recipients compared to BMT recipients at 24 months post-transplantation (11.3 micrograms/ml vs 0.93 microgram/ml, P = 0.051) and following the 24 month immunization (66.2 micrograms/ml vs 1.30 micrograms/ml, P = 0.006). Similar results were noted for IgG anti-TT antibody with significantly higher geometric mean antibody concentrations in the PBSCT group at 24 months post-transplantation (182 micrograms/ml vs 21.6 micrograms/ml, P = 0.039). Protective levels of total anti-HIB antibody were achieved earlier in PBSCT recipients compared with those of BMT recipients. PBSCT recipients had higher antigen-specific antibody concentrations following HIB and TT immunizations. These results suggest enhanced recovery of humoral immunity in PBSCT recipients and earlier protection against HIB with immunization.