Immunogenicity and safety of concomitant administration of a combined hepatitis A/B vaccine and a quadrivalent meningococcal conjugate vaccine in healthy adults.

PubMed

Alberer, Martin; Burchard, Gerd; Jelinek, Tomas; Reisinger, Emil C; Meyer, Seetha; Forleo-Neto, Eduardo; Dagnew, Alemnew F; Arora, Ashwani Kumar

2015-01-01

This phase 3b randomized, open-label study evaluated the immunogenicity and safety of coadministration of a hepatitis A and/or B vaccine with a quadrivalent oligosaccharide meningococcal CRM197 -conjugate vaccine (MenACWY-CRM), in the context of an accelerated hepatitis A and/or B immunization schedule. A total of 252 healthy adult subjects were randomized to three groups to receive hepatitis A/B only (HepA/B), hepatitis A/B coadministered with MenACWY-CRM (HepA/B+MenACWY-CRM), or MenACWY-CRM only (MenACWY-CRM). Hepatitis A and/or B vaccination was administered in the form of a single booster dose or a primary three-dose series, depending on the hepatitis A and/or B vaccination history of subjects. Antibody responses to hepatitis A/B vaccination were assessed 1 month following the last hepatitis A and/or B dose. Serum bactericidal activity with human complement (hSBA) against meningococcal serogroups A, C, W-135, and Y was assessed 1 month post-MenACWY-CRM vaccination. Safety was monitored throughout the study. At 1 month following the final hepatitis A and/or B vaccination, concomitant administration of hepatitis A/B and MenACWY-CRM was non-inferior to administration of hepatitis A/B alone in terms of geometric mean concentrations of antibodies against the hepatitis A and B antigens. One month post-MenACWY-CRM vaccination, the percentages of subjects achieving hSBA titers ≥8 for serogroups A, C, W-135, and Y in the HepA/B+MenACWY-CRM group (76, 87, 99, and 94%, respectively) were comparable to those in the MenACWY-CRM group (67, 82, 96, and 88%, respectively). The percentages of subjects reporting adverse events (AEs) were similar across study groups and a majority of the reported AEs were mild to moderate in nature. There were no study vaccine-related serious AEs. MenACWY-CRM can be administered concomitantly with a hepatitis A and/or B vaccine in the context of an accelerated hepatitis A and/or B immunization schedule without increasing safety concerns

Immunogenicity and safety of a novel quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) in healthy Korean adolescents and adults.

PubMed

Lee, Hoan Jong; Chung, Moon-Hyun; Kim, Woo Joo; Hong, Young Jin; Choi, Kyong Min; Lee, Jina; Oh, Chi Eun; Welsch, Jo Anne; Kim, Kyung-Hyo; Hong, Ki Bae; Dagnew, Alemnew F; Bock, Hans; Dull, Peter M; Odrljin, Tatjana

2014-11-01

This phase III placebo-controlled study evaluated the immunogenicity and safety of MenACWY-CRM vaccination in healthy Korean adolescents and adults. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination against all four meningococcal serogroups. The IgG concentration specific for serogroup W capsular polysaccharide was measured in a subset of subjects in a post-hoc analysis. Adverse reactions were monitored throughout the study. Four hundred and fifty subjects were randomized 2:1 to receive MenACWY-CRM (N=297) or a saline placebo (N=153). MenACWY-CRM induced a good immune response against all four serogroups, with seroprotection rates (hSBA titers ≥8) of 79%, 99%, 98%, and 94% for serogroups A, C, W, and Y, respectively. Seroresponse rates were high for serogroups A, C, and Y, i.e. 76%, 86%, and 69%, respectively; the rate for serogroup W was 28%. MenACWY-CRM vaccine induced serum bactericidal antibodies against all four serogroups in a majority of subjects regardless of their baseline hSBA titers. MenACWY-CRM was generally well tolerated with most reactions being transient and mild to moderate in severity. Findings of this first study of a quadrivalent meningococcal polysaccharide conjugate vaccine in Korean adults and adolescents demonstrated that a single dose of MenACWY-CRM was well tolerated and immunogenic, as indicated by the percentages of subjects with hSBA titers ≥8 (79%, 99%, 98%, and 94% of subjects) and geometric mean titers (48, 231, 147, and 107) against serogroups A, C, W, and Y, respectively, at 1 month post-vaccination.

Evaluating the case for trivalent or quadrivalent influenza vaccines.

PubMed

Baxter, David

2016-10-02

Influenza viruses circulate widely throughout the world and it is estimated that they affect between 5 and 15% of the population annually. Since 1977, four viruses co-circulate - two A Viruses (H1N1 and H3N2) and two B viruses (B Yamagata and B Victoria). Type A viruses generally cause up to two thirds of annual infections, although single country studies have shown that B infections may be the predominant virus in the one year in four. Influenza vaccines have traditionally included the hamagglutinins and neuraminidases from the two circulating A viruses and either B Yamagata or B Victoria - however, selecting the B strain for inclusion in these trivalent vaccines has variable success. The alternative approach is to include both B strains in a quadrivalent vaccine. Immunological studies of such vaccines show non-inferiority with a trivalent vaccine comparator, and significant superiority to the additional B strain. Quadrivalent vaccines are more expensive than trivalent preparations but theoretical evidence would suggest they are likely to be more effective and therefore play a much greater role in national immunisation programmes in the future.

Oral Modeling of an Adenovirus-Based Quadrivalent Influenza Vaccine in Ferrets and Mice.

PubMed

Scallan, Ciaran D; Lindbloom, Jonathan D; Tucker, Sean N

2016-06-01

Oral vaccines delivered as tablets offer a number of advantages over traditional parenteral-based vaccines including the ease of delivery, lack of needles, no need for trained medical personnel, and the ability to formulate into temperature-stable tablets. We have been evaluating an oral vaccine platform based on recombinant adenoviral vectors for the purpose of creating a prophylactic vaccine to prevent influenza, and have demonstrated vaccine efficacy in animal models and substantial immunogenicity in humans. These studies have evaluated monovalent vaccines to date. To protect against the major circulating A and B influenza strains, a multivalent influenza vaccine will be required. In this study, the immunogenicity of orally delivered monovalent, bivalent, trivalent, and quadrivalent vaccines was tested in ferrets and mice. The various vaccine combinations were tested by blending monovalent recombinant adenovirus vaccines, each expressing hemagglutinin from a single strain. Human tablet delivery was modeled in animals by oral gavage in mice and by endoscopic delivery in ferrets. We demonstrated minimal interference between the various vaccine vectors when used in combination and that the oral quadrivalent vaccine compared favorably to an approved trivalent inactivated vaccine. The quadrivalent vaccine presented here produced immune responses that we predict should be capable of providing protection against multiple influenza strains, and the platform should have applications to other multivalent vaccines. Vaxart, Inc.

Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines.

PubMed

Van Damme, Pierre; Bonanni, Paolo; Bosch, F Xavier; Joura, Elmar; Kjaer, Susanne Krüger; Meijer, Chris J L M; Petry, Karl-Ulrich; Soubeyrand, Benoit; Verstraeten, Thomas; Stanley, Margaret

2016-02-03

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Critical appraisal of a quadrivalent CRM(197) conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo) in the context of treatment and prevention of invasive disease.

PubMed

Bröker, Michael; Cooper, Brian; Detora, Lisa M; Stoddard, Jeffrey J

2011-01-01

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo(®)) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need.

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.

Critical appraisal of a quadrivalent CRM197 conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo®) in the context of treatment and prevention of invasive disease

PubMed Central

Bröker, Michael; Cooper, Brian; DeTora, Lisa M; Stoddard, Jeffrey J

2011-01-01

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo®) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need. PMID:21904459

Cost-effectiveness of vaccination with a quadrivalent HPV vaccine in Germany using a dynamic transmission model

PubMed Central

2012-01-01

Introduction Persistent infections with human papillomavirus (HPV) are a necessary cause of cervical cancer and are responsible for important morbidity in men and women. Since 2007, HPV vaccination has been recommended and funded for all girls aged 12 to 17 in Germany. A previously published cost-effectiveness analysis, using a static model, showed that a quadrivalent HPV vaccination programme for 12-year-old girls in Germany would be cost effective. Here we present the results from a dynamic transmission model that can be used to evaluate the impact and cost-effectiveness of different vaccination schemas. Methods We adapted a HPV dynamic transmission model, which has been used in other countries, to the German context. The model was used to compare a cervical cancer screening only strategy with a strategy of combining vaccination of females aged 12–17 years old and cervical cancer screening, based on the current recommendations in Germany. In addition, the impact of increasing vaccination coverage in this cohort of females aged 12–17 years old was evaluated in sensitivity analysis. Results The results from this analysis show that the current quadrivalent HPV vaccination programme of females ages 12 to 17 in Germany is cost-effective with an ICER of 5,525€/QALY (quality adjusted life year). The incremental cost-effectiveness ratio (ICER) increased to 10,293€/QALY when the vaccine effects on HPV6/11 diseases were excluded. At steady state, the model predicted that vaccinating girls aged 12 to 17 could reduce the number of HPV 6/11/16/18-related cervical cancers by 65% and genital warts among women and men by 70% and 48%, respectively. The impact on HPV-related disease incidence and costs avoided would occur relatively soon after initiating the vaccine programme, with much of the early impact being due to the prevention of HPV6/11-related genital warts. Conclusions These results show that the current quadrivalent HPV vaccination and cervical cancer screening

Cost-effectiveness of vaccination with a quadrivalent HPV vaccine in Germany using a dynamic transmission model.

PubMed

Schobert, Deniz; Remy, Vanessa; Schoeffski, Oliver

2012-09-25

Persistent infections with human papillomavirus (HPV) are a necessary cause of cervical cancer and are responsible for important morbidity in men and women. Since 2007, HPV vaccination has been recommended and funded for all girls aged 12 to 17 in Germany. A previously published cost-effectiveness analysis, using a static model, showed that a quadrivalent HPV vaccination programme for 12-year-old girls in Germany would be cost effective. Here we present the results from a dynamic transmission model that can be used to evaluate the impact and cost-effectiveness of different vaccination schemas. We adapted a HPV dynamic transmission model, which has been used in other countries, to the German context. The model was used to compare a cervical cancer screening only strategy with a strategy of combining vaccination of females aged 12-17 years old and cervical cancer screening, based on the current recommendations in Germany. In addition, the impact of increasing vaccination coverage in this cohort of females aged 12-17 years old was evaluated in sensitivity analysis. The results from this analysis show that the current quadrivalent HPV vaccination programme of females ages 12 to 17 in Germany is cost-effective with an ICER of 5,525€/QALY (quality adjusted life year). The incremental cost-effectiveness ratio (ICER) increased to 10,293€/QALY when the vaccine effects on HPV6/11 diseases were excluded. At steady state, the model predicted that vaccinating girls aged 12 to 17 could reduce the number of HPV 6/11/16/18-related cervical cancers by 65% and genital warts among women and men by 70% and 48%, respectively. The impact on HPV-related disease incidence and costs avoided would occur relatively soon after initiating the vaccine programme, with much of the early impact being due to the prevention of HPV6/11-related genital warts. These results show that the current quadrivalent HPV vaccination and cervical cancer screening programmes in Germany will substantially

Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males

PubMed Central

Giuliano, Anna R.; Palefsky, Joel M.; Goldstone, Stephen; Moreira, Edson D.; Penny, Mary E.; Aranda, Carlos; Vardas, Eftyhia; Moi, Harald; Jessen, Heiko; Hillman, Richard; Chang, Yen-Hwa; Ferris, Daron; Rouleau, Danielle; Bryan, Janine; Marshall, J. Brooke; Vuocolo, Scott; Barr, Eliav; Radley, David; Haupt, Richard M.; Guris, Dalya

2012-01-01

BACKGROUND Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. RESULTS In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in

Determination of influenza B identity and potency in quadrivalent inactivated influenza vaccines using lineage-specific monoclonal antibodies

PubMed Central

Verma, Swati; Soto, Jackeline; Vasudevan, Anupama; Schmeisser, Falko; Alvarado-Facundo, Esmeralda; Wang, Wei; Weiss, Carol D.

2017-01-01

Co-circulation of two antigenically and genetically distinct lineages of influenza B virus, represented by prototype viruses B/Victoria/2/1987 and B/Yamagata/16/1988, has led to the development of quadrivalent influenza vaccines that contain two influenza B antigens. The inclusion of two influenza B antigens presents challenges for the production and regulation of inactivated quadrivalent vaccines, including the potential for cross-reactivity of the reagents used in identity and potency assays because of the relative close relatedness of the hemagglutinin (HA) from the two virus lineages. Monoclonal antibodies (mAbs) specific for the two lineages of influenza B HA were generated and characterized and used to set-up simple identity tests that distinguish the influenza B antigens in inactivated trivalent and quadrivalent vaccines. The lineage-specific mAbs bound well to the HA of influenza B strains included in influenza vaccines over a period of more than 10 years, suggesting that identity tests using such lineage-specific mAbs would not necessarily have to be updated with every influenza B vaccine strain change. These lineage-specific mAbs were also used in an antibody capture ELISA format to quantify HA in vaccine samples, including monovalent, trivalent, and quadrivalent vaccine samples from various manufacturers. The results demonstrated correlation with HA values determined by the traditional single radial immunodiffusion (SRID) assay. Further, the antibody-capture ELISA was able to distinguish heat-stressed vaccine from unstressed vaccine, and was similar to the SRID in quantifying the resultant loss of potency. These mAb reagents should be useful for further development of antibody-based alternative influenza B identity and potency assays. PMID:28423025

Determination of influenza B identity and potency in quadrivalent inactivated influenza vaccines using lineage-specific monoclonal antibodies.

PubMed

Verma, Swati; Soto, Jackeline; Vasudevan, Anupama; Schmeisser, Falko; Alvarado-Facundo, Esmeralda; Wang, Wei; Weiss, Carol D; Weir, Jerry P

2017-01-01

Co-circulation of two antigenically and genetically distinct lineages of influenza B virus, represented by prototype viruses B/Victoria/2/1987 and B/Yamagata/16/1988, has led to the development of quadrivalent influenza vaccines that contain two influenza B antigens. The inclusion of two influenza B antigens presents challenges for the production and regulation of inactivated quadrivalent vaccines, including the potential for cross-reactivity of the reagents used in identity and potency assays because of the relative close relatedness of the hemagglutinin (HA) from the two virus lineages. Monoclonal antibodies (mAbs) specific for the two lineages of influenza B HA were generated and characterized and used to set-up simple identity tests that distinguish the influenza B antigens in inactivated trivalent and quadrivalent vaccines. The lineage-specific mAbs bound well to the HA of influenza B strains included in influenza vaccines over a period of more than 10 years, suggesting that identity tests using such lineage-specific mAbs would not necessarily have to be updated with every influenza B vaccine strain change. These lineage-specific mAbs were also used in an antibody capture ELISA format to quantify HA in vaccine samples, including monovalent, trivalent, and quadrivalent vaccine samples from various manufacturers. The results demonstrated correlation with HA values determined by the traditional single radial immunodiffusion (SRID) assay. Further, the antibody-capture ELISA was able to distinguish heat-stressed vaccine from unstressed vaccine, and was similar to the SRID in quantifying the resultant loss of potency. These mAb reagents should be useful for further development of antibody-based alternative influenza B identity and potency assays.

[Conjugated vaccines].

PubMed

Fritzell, Bernard

2005-01-01

Encapsulated bacterial pathogens (e.g. Haemophilus influenzae type b [Hib], Neisseria meningitidis, or Streptococcus pneumoniae) target infants and young children who have lost any protective anti-capsular antibodies supplied maternally and whose immune systems are ineffective against T-independent antigens such as the polysaccharides of the capsule. The polysaccharide-protein conjugate vaccines overcome this limitation by converting the polysaccharide to a T-dependent antigen, which allows a vaccinated infant to mount a protective immune response. Where conjugated vaccines have been introduced into paediatric vaccination schedules, the incidence of invasive diseases caused by Hib, the group C meningococcus, or the pneumococcus has plummeted by at least 80%, a major public health success. Furthermore, surveillance has demonstrated that the conjugate vaccines provide 'herd protection' through their beneficial impact on nasopharyngeal colonisation among vaccinated children. Promising future approaches include enhancement of the number of capsular serogroups targeted by the meningococcal or pneumococcal conjugate vaccines.

Economics of an adolescent meningococcal conjugate vaccination catch-up campaign in the United States.

PubMed

Ortega-Sanchez, Ismael R; Meltzer, Martin I; Shepard, Colin; Zell, Elizabeth; Messonnier, Mark L; Bilukha, Oleg; Zhang, Xinzhi; Stephens, David S; Messonnier, Nancy E

2008-01-01

In June 2005, the Advisory Committee on Immunization Practices recommended the newly licensed quadrivalent meningococcal conjugate vaccine for routine use among all US children aged 11 years. A 1-time catch-up vaccination campaign for children and adolescents aged 11-17 years, followed by routine annual immunization of each child aged 11 years, could generate immediate herd immunity benefits. The objective of our study was to analyze the cost-effectiveness of a catch-up vaccination campaign with quadrivalent meningococcal conjugate vaccine for children and adolescents aged 11-17 years. We built a probabilistic model of disease burden and economic impacts for a 10-year period with and without a program of adolescent catch-up meningococcal vaccination, followed by 9 years of routine immunization of children aged 11 years. We used US age- and serogroup-specific surveillance data on incidence and mortality. Assumptions related to the impact of herd immunity were drawn from experience with routine meningococcal vaccination in the United Kingdom. We estimated costs per case, deaths prevented, life-years saved, and quality-adjusted life-years saved. With herd immunity, the catch-up and routine vaccination program for adolescents would prevent 8251 cases of meningococcal disease in a 10-year period (a 48% decrease). Excluding program costs, this catch-up and routine vaccination program would save US$551 million in direct costs and $920 million in indirect costs, including costs associated with permanent disability and premature death. At $83 per vaccinee, the catch-up vaccination would cost society approximately $223,000 per case averted, approximately $2.6 million per death prevented, approximately $127,000 per life-year saved, and approximately $88,000 per quality-adjusted life-year saved. Targeting counties with a high incidence of disease decreased the cost per life-year saved by two-thirds. Although costly, catch-up and routine vaccination of adolescents can have a

Immunogenicity of a Booster Dose of Quadrivalent Meningococcal Conjugate Vaccine in Previously Immunized HIV-Infected Children and Youth.

PubMed

Warshaw, Meredith G; Siberry, George K; Williams, Paige; Decker, Michael D; Jean-Philippe, Patrick; Lujan-Zilbermann, Jorge

2017-09-01

The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection. The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.5 years after primary MCV4 immunization. Antibody titers were evaluated at the time of the booster vaccine and 1, 4, and 24 weeks after the booster. Immunogenicity was measured by rabbit serum bactericidal antibody (rSBA) against each meningococcal serogroup. Immunologic memory was defined as either seroprotection (rSBA titer ≥1:128) or a ≥4-fold increase 1 week after the booster dose. Primary response was defined as either a ≥4-fold response or seropositivity 4 weeks after the booster in the absence of immunologic memory. Adverse events were assessed for 4 weeks after the booster dose. Of 174 participants with serology results at entry and 1 and 4 weeks later, the percentage with protective antibody levels at entry varied according to serogroup, ranging from a low of 26% for serogroup C to a high of 68% for serogroup A. A memory response to at least 1 serogroup occurred in 98% of the participants: 93% each for serogroups A and Y, 88% for serogroup C, and 94% for serogroup W-135; 83% had a memory response to all 4 serogroups. Overall, rates of any memory or primary response were ≥90% for all serogroups. No serious adverse events were encountered. A booster dose of MCV4 elicited a memory response in 88% to 94% of previously immunized HIV-infected participants depending on serogroup, including those who lacked a protective titer level for that serogroup before booster vaccination. © The Author 2017. Published by the Oxford University Press on behalf of The Journal of the Pediatric

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.

Seropositivity to non-vaccine incorporated genotypes induced by the bivalent and quadrivalent HPV vaccines: A systematic review and meta-analysis.

PubMed

Bissett, Sara L; Godi, Anna; Jit, Mark; Beddows, Simon

2017-07-13

Human papillomavirus vaccines have demonstrated remarkable efficacy against persistent infection and disease associated with vaccine-incorporated genotypes and a degree of efficacy against some genetically related, non-vaccine-incorporated genotypes. The vaccines differ in the extent of cross-protection against these non-vaccine genotypes. Data supporting the role for neutralizing antibodies as a correlate or surrogate of cross-protection are lacking, as is a robust assessment of the seroconversion rates against these non-vaccine genotypes. We performed a systematic review and meta-analysis of available data on vaccine-induced neutralizing antibody seropositivity to non-vaccine incorporated HPV genotypes. Of 304 articles screened, 9 were included in the analysis representing ca. 700 individuals. The pooled estimate for seropositivity against HPV31 for the bivalent vaccine (86%; 95%CI 78-91%) was higher than that for the quadrivalent vaccine (61%; 39-79%; p=0.011). The pooled estimate for seropositivity against HPV45 for the bivalent vaccine (50%; 37-64%) was also higher than that for the quadrivalent vaccine (16%; 6-36%; p=0.007). Seropositivity against HPV33, HPV52 and HPV58 were similar between the vaccines. Mean seropositivity rates across non-vaccine genotypes were positively associated with the corresponding vaccine efficacy data reported from vaccine trials. These data improve our understanding of vaccine-induced functional antibody specificity against non-vaccine incorporated genotypes and may help to parameterize vaccine-impact models and improve patient management in a post-vaccine setting. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Immunogenicity and safety of a quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) administered to adults aged 56 Years and older: results of an open-label, randomized, controlled trial.

PubMed

Dbaibo, Ghassan; El-Ayoubi, Nabil; Ghanem, Soha; Hajar, Farah; Bianco, Veronique; Miller, Jacqueline M; Mesaros, Narcisa

2013-05-01

The burden of invasive meningococcal disease is substantial in older adults in whom the case fatality rate is high. Travelers to regions with high rates of meningococcal disease, such as Hajj pilgrims, are at increased risk of meningococcal infection, and disease transmission from travelers to their close contacts has been documented. In younger individuals, meningococcal conjugate vaccines offer advantages over polysaccharide vaccines in terms of duration of protection and boostability, and induction of herd immune effects through reductions in nasopharyngeal carriage of meningococci. To date, few data are available evaluating meningococcal conjugate vaccine use in adults >55 years of age. To evaluate the immunogenicity and safety of quadrivalent meningococcal serogroups A, C, W-135 and Y vaccine with all serogroups conjugated to tetanus toxoid (MenACWY-TT, Nimenrix™, GlaxoSmithKline, Belgium) and a licensed quadrivalent polysaccharide vaccine (MenPS, Mencevax™ GlaxoSmithKline, Belgium) in adults >55 years of age. This was a phase IIIb, open-label, randomized (3:1), controlled study conducted at one study center in Lebanon. A total of 400 healthy adults between 56 and 103 years of age without previous MenPS or tetanus toxoid vaccination within the previous 5 years or meningococcal conjugate vaccination at any time previously were included. They received a single-dose vaccination with MenACWY-TT or MenPS with blood sampling before and 1 month after vaccination. The main outcome measures were serum bactericidal activity (rabbit complement source: rSBA) vaccine response (VR) rate [rSBA titer of ≥1:32 in initially seronegative subjects (rSBA titer <1:8); ≥4-fold increase in subjects with pre-vaccination rSBA titers between 1:8 and 1:128, and ≥2-fold increase in subjects with pre-vaccination rSBA titers ≥1:128]. The percentages of subjects with rSBA titers ≥1:8 and ≥1:128 and rSBA geometric mean titers (GMTs) were assessed. Solicited adverse events

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.

Cost-effectiveness analysis of adding a quadrivalent HPV vaccine to the cervical cancer screening programme in Switzerland.

PubMed

Szucs, Thomas D; Largeron, Nathalie; Dedes, Konstantin J; Rafia, Rachid; Bénard, Stève

2008-05-01

Based on positive safety and efficacy data, a quadrivalent Human PapillomaVirus (HPV) vaccine has been approved in Switzerland to prevent HPV types 6, 11, 16 and 18 infections. The objective of this study was to explore the cost-effectiveness of an HPV vaccination in Switzerland. A Markov model of the natural history of HPV infection was adapted to the Swiss context and followed a hypothetical cohort of 41,200 girls aged 11 years over their lifetime. Main epidemiological and economic parameters were extracted from the literature. Two strategies were compared: conventional cytological screening only and HPV vaccination followed by conventional cytological screening. A coverage rate of 80% was used and the vaccine was assumed to provide a lifelong protection. Analyses were performed from the direct health care cost perspective including only direct medical costs. Compared to screening only, adding a quadrivalent HPV vaccine could prevent over lifetime 62% of cervical cancers and related deaths, 19% of Cervical Intraepithelial Neoplasia (CIN 1), 43% of CIN 2, 45% of CIN 3 and 66% of genital warts per cohort. Incremental cost-effectiveness ratios (ICER) were estimated to be CHF 45,008 per Life Year Gained (LYG) and CHF 26,005 per Quality Adjusted Life Year (QALY) gained. Sensitivity analyses demonstrated that the ICER was robust to all parameters, but was most sensitive to the need for a booster and discount rates. Compared to commonly accepted standard thresholds in Europe and other vaccination strategies implemented in Switzerland, adding a quadrivalent HPV vaccine alongside the current cervical cancer screening programme is likely to be cost-effective in Switzerland.

Impact of a quadrivalent HPV6/11/16/18 vaccine in Mexican women: public health implications for the region.

PubMed

Lazcano-Ponce, Eduardo; Pérez, Gonzalo; Cruz-Valdez, Aurelio; Zamilpa, Laura; Aranda-Flores, Carlos; Hernández-Nevarez, Pilar; Viramontes, Jose Luis; Salgado-Hernández, Joaquín; James, Margaret; Lu, Shuang; Sattler, Carlos; Haupt, Richard M; Hernández-Avila, Mauricio

2009-08-01

Recognition of human papillomavirus (HPV) as a necessary cause of cervical cancer (CC) led to new perspectives for its control and the demonstration of an effective primary prevention strategy through vaccination. We undertook this study to evaluate the safety, efficacy and immunogenicity of a quadrivalent HPV6/11/16/18 vaccine in Mexican women. A total of 679 Mexican women between 18 and 23 years old participated in two Phase III double-blind, randomized, placebo-controlled clinical trials of a quadrivalent HPV 6/11/16/18 vaccine. Women were enrolled who tested negative for pregnancy and reported having four or less sexual partners during their lifetime. Vaccine or placebo was administered at day 1, month 2 and month 6. Among Mexican women who were naïve to the respective vaccine type at enrollment, the quadrivalent vaccine was highly efficacious, preventing 100% of HPV6/11/16/18-related cervical intraepithelial neoplasia grade 2/3, adenocarcinoma in situ, condyloma and vaginal intraepithelial neoplasia. Statistical significance was not reached for every endpoint due to the limited sample size. Vaccination was generally well tolerated and immunogenic. To widely administer the vaccine, collaborative efforts should be coordinated among public, private and local community sectors. In light of the scarce knowledge of many health professionals with respect to the primary prevention of CC, it will be necessary to educate health providers on the advantages and specific recommendations of HPV vaccines and secondary prevention. Decision making should be based on scientific evidence, allowing health professionals to provide an organized social response that supports the universal right to health.

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

Immunogenicity and safety of Southern Hemisphere inactivated quadrivalent influenza vaccine: a Phase III, open-label study of adults in Brazil.

PubMed

Zerbini, Cristiano A F; Ribeiro Dos Santos, Rodrigo; Jose Nunes, Maria; Soni, Jyoti; Li, Ping; Jain, Varsha K; Ofori-Anyinam, Opokua

The World Health Organization influenza forecast now includes an influenza B strain from each of the influenza B lineages (B/Yamagata and B/Victoria) for inclusion in seasonal influenza vaccines. Traditional trivalent influenza vaccines include an influenza B strain from one lineage, but because two influenza B lineages frequently co-circulate, the effectiveness of trivalent vaccines may be reduced in seasons of influenza B vaccine-mismatch. Thus, quadrivalent vaccines may potentially reduce the burden of influenza compared with trivalent vaccines. In this Phase III, open-label study, we assessed the immunogenicity and safety of Southern Hemisphere inactivated quadrivalent influenza vaccine (Fluarix™ Tetra) in Brazilian adults (NCT02369341). The primary objective was to assess hemagglutination-inhibition antibody responses against each vaccine strain 21 days after vaccination in adults (aged ≥18-60 years) and older adults (aged >60 years). Solicited adverse events for four days post-vaccination, and unsolicited adverse events and serious adverse events for 21 days post-vaccination were also assessed. A total of 63 adults and 57 older adults received one dose of inactivated quadrivalent influenza vaccine at the beginning of the 2015 Southern Hemisphere influenza season. After vaccination, in adults and older adults, the hemagglutination-inhibition titers fulfilled the European licensure criteria for immunogenicity. In adults, the seroprotection rates with HI titer ≥1:40 were 100% (A/H1N1), 98.4% (A/H3N2), 100% (B/Yamagata), and 100% (B/Victoria); in older adults were 94.7% (A/H1N1), 96.5% (A/H3N2), 100% (B/Yamagata), and 100% (B/Victoria). Pain was the most common solicited local adverse events in adults (27/62) and in older adults (13/57), and the most common solicited general adverse events in adults was myalgia (9/62), and in older adults were myalgia and arthralgia (both 2/57). Unsolicited adverse events were reported by 11/63 adults and 10/57 older adults

The clinical and economic benefits of school-based quadrivalent HPV vaccination in Singapore.

PubMed

Tay, Sun Kuie; Hsu, Tun-Ying; Shcheprov, Andrei; Walia, Anuj; Kulkarni, Amit S

2017-05-01

To investigate the clinical and economic impacts of school-based administration of the quadrivalent HPV vaccine. A retrospective health-economic analysis was conducted using data collected in Singapore between 2004 and 2005. A dynamic transmission model was adapted for universal vaccination that provided 80% coverage among students aged 11-12 years. Strategy 1 involved only girls, with a 5-year catch-up vaccination to provide 50% coverage among those aged 13-17 years. Strategy 2 included both girls and boys with no catch-up vaccination. Outcomes included the predicted incidence of HPV-related disease over 100 years. Current coverage was assumed to be 5%. Strategy 1 would reduce cervical intraepithelial neoplasia grade 1 (CIN1) by 63.8%, cervical intraepithelial neoplasia grade 2-3 (CIN2-3) by 62.9%, cervical cancer by 50.9%, and genital warts by 78.0% (female individuals) and 73.6% (male individuals). Strategy 2 would reduce CIN1 by 64.0%, CIN2-3 by 63.1%, cervical cancer by 50.7%, and genital warts by 79.9% (female individuals) and 80.1% (male individuals). The incremental cost-effectiveness ratio was S$12 464 for strategy 1 and $27 837 for Strategy 2. These values decreased to $7477 and $22 574, respectively, if a two-dose regimen was adapted. School-based quadrivalent HPV vaccination offered clinical and economic benefits, and is cost-effective in Singapore. © 2017 International Federation of Gynecology and Obstetrics.

Safety and immunogenicity of one dose of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines.

PubMed

Arguedas, A; Soley, C; Loaiza, C; Rincon, G; Guevara, S; Perez, A; Porras, W; Alvarado, O; Aguilar, L; Abdelnour, A; Grunwald, U; Bedell, L; Anemona, A; Dull, P M

2010-04-19

This Phase III study evaluates an investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM (Novartis Vaccines), when administered concomitantly or sequentially with two other recommended adolescent vaccines; combined tetanus, reduced diphtheria and acellular pertussis (Tdap), and human papillomavirus (HPV) vaccine. In this single-centre study, 1620 subjects 11-18 years of age, were randomized to three groups (1:1:1) to receive MenACWY-CRM concomitantly or sequentially with Tdap and HPV. Meningococcal serogroup-specific serum bactericidal assay using human complement (hSBA), and antibodies to Tdap antigens and HPV virus-like particles were determined before and 1 month after study vaccinations. Proportions of subjects with hSBA titres > or =1:8 for all four meningococcal serogroups (A, C, W-135, Y) were non-inferior for both concomitant and sequential administration. Immune responses to Tdap and HPV antigens were comparable when these vaccines were given alone or concomitantly with MenACWY-CRM. All vaccines were well tolerated; concomitant or sequential administration did not increase reactogenicity. MenACWY-CRM was well tolerated and immunogenic in subjects 11-18 years of age, with comparable immune responses to the four serogroups when given alone or concomitantly with Tdap or HPV antigens. This is the first demonstration that these currently recommended adolescent vaccines could be administered concomitantly without causing increased reactogenicity. Copyright 2010 Elsevier Ltd. All rights reserved.

Cost-effectiveness analysis of the introduction of a quadrivalent human papillomavirus vaccine in France.

PubMed

Bergeron, Christine; Largeron, Nathalie; McAllister, Ruth; Mathevet, Patrice; Remy, Vanessa

2008-01-01

A vaccine to prevent diseases due to human papillomavirus (HPV) types 6, 11, 16, and 18 is now available in France. The objective of this study was to assess the health and economic impact in France of implementing a quadrivalent HPV vaccine alongside existing screening practices versus screening alone. A Markov model of the natural history of HPV infection incorporating screening and vaccination, was adapted to the French context. A vaccine that would prevent 100 percent of HPV 6, 11, 16, and 18-associated diseases, with lifetime duration and 80 percent coverage, given to girls at age 14 in conjunction with current screening was compared with screening alone. Results were analyzed from both a direct healthcare cost perspective (DCP) and a third-party payer perspective (TPP). Indirect costs such as productivity loss were not taken into account in this analysis. The incremental cost per life-year gained from vaccination was euro12,429 (TPP) and euro20,455 (DCP). The incremental cost per quality-adjusted life-year (QALY) for the introduction of HPV vaccination alongside the French cervical cancer screening program was euro8,408 (TPP) and euro13,809 (DCP). Sensitivity analyses demonstrated that cost-effectiveness was stable, but was most sensitive to the discount rate used for costs and benefits. Considering the commonly accepted threshold of euro50,000 per QALY, these analyses support the fact that adding a quadrivalent HPV vaccine to the current screening program in France is a cost-effective strategy for reducing the burden of cervical cancer, precancerous lesions, and genital warts caused by HPV types 6, 11, 16, and 18.

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

Baseline demographic characteristics of subjects enrolled in international quadrivalent HPV (types 6/11/16/18) vaccine clinical trials.

PubMed

Paavonen, Jorma

2008-06-01

In Phase II/III trials, administration of quadrivalent human papillomavirus (HPV) (types 6/11/16/18) L1 virus-like-particle vaccine was highly effective in preventing HPV6/11/16/18-related cervical intraepithelial neoplasia and non-invasive cervical cancer in women aged 16-26 years who were naïve to these HPV types at enrollment. However, the makeup and extent of catch-up vaccination programs among young women is unclear, because a proportion of this population will likely already have been exposed to one or more vaccine-HPV-types. Herein we analyze baseline data from the quadrivalent HPV vaccine clinical trial program to investigate variables which may help shape catch-up vaccine implementation policies. Female adolescents and young adults aged 16-26 years were randomized into five clinical trials. Baseline data regarding demographics, sexual history, pregnancy history, and other characteristics were collected at enrollment. At the baseline gynecological examination during enrollment, specimens were obtained for Pap testing. Swabs of external genital, lateral vaginal, and cervical sites for HPV polymerase chain reaction (PCR) testing were taken, and serum samples were obtained for HPV serology testing. Regional analyses of data were conducted. Overall, 72% of subjects enrolled worldwide were naïve by both serology and PCR to all four vaccine HPV types. Few subjects were seropositive and/or PCR positive for more than two vaccine-related HPV types. Of all subjects with HSIL at enrollment, 78% were positive to at least one vaccine-related HPV type at enrollment. Regional differences in HPV and STD prevalence were evident. Study limitations included under-representation of women with >/=4 sexual partners and possible underestimation of prior HPV exposure. Our findings demonstrate that sexually active 16-26 year-old women with

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.

Meningococcal conjugate vaccines: optimizing global impact

PubMed Central

Terranella, Andrew; Cohn, Amanda; Clark, Thomas

2011-01-01

Meningococcal conjugate vaccines have several advantages over polysaccharide vaccines, including the ability to induce greater antibody persistence, avidity, immunologic memory, and herd immunity. Since 1999, meningococcal conjugate vaccine programs have been established across the globe. Many of these vaccination programs have resulted in significant decline in meningococcal disease in several countries. Recent introduction of serogroup A conjugate vaccine in Africa offers the potential to eliminate meningococcal disease as a public health problem in Africa. However, the duration of immune response and the development of widespread herd immunity in the population remain important questions for meningococcal vaccine programs. Because of the unique epidemiology of meningococcal disease around the world, the optimal vaccination strategy for long-term disease prevention will vary by country. PMID:22114508

Guillain–Barre syndrome following quadrivalent human papillomavirus vaccination among vaccine-eligible individuals in the United States

PubMed Central

Ojha, Rohit P; Jackson, Bradford E; Tota, Joseph E; Offutt-Powell, Tabatha N; Singh, Karan P; Bae, Sejong

2014-01-01

Post-marketing surveillance studies provide conflicting evidence about whether Guillain–Barre syndrome occurs more frequently following quadrivalent human papillomavirus (HPV4) vaccination. We aimed to assess whether Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y in the United States. We used adverse event reports received by the United States Vaccine Adverse Event Reporting System (VAERS) between January 1, 2010 and December 31, 2012 to estimate overall, age-, and sex-specific proportional reporting ratios (PRRs) and corresponding Χ2 values for reports of Guillain–Barre syndrome between 5 and 42 d following HPV vaccination. Minimum criteria for a signal using this approach are 3 or more cases, PRR ≥2, and Χ2 ≥ 4. Guillain–Barre syndrome was listed as an adverse event in 45 of 14 822 reports, of which 9 reports followed HPV4 vaccination and 36 reports followed all other vaccines. The overall, age-, and sex-specific PRR estimates were uniformly below 1. In addition, the overall, age-, and sex-specific Χ2 values were uniformly below 3. Our analysis of post-marketing surveillance data does not suggest that Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among vaccine-eligible females or males in the United States. Our findings may be useful when discussing the risks and benefits of HPV4 vaccination. PMID:24013368

Guillain-Barre syndrome following quadrivalent human papillomavirus vaccination among vaccine-eligible individuals in the United States.

PubMed

Ojha, Rohit P; Jackson, Bradford E; Tota, Joseph E; Offutt-Powell, Tabatha N; Singh, Karan P; Bae, Sejong

2014-01-01

Post-marketing surveillance studies provide conflicting evidence about whether Guillain-Barre syndrome occurs more frequently following quadrivalent human papillomavirus (HPV4) vaccination. We aimed to assess whether Guillain-Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y in the United States. We used adverse event reports received by the United States Vaccine Adverse Event Reporting System (VAERS) between January 1, 2010 and December 31, 2012 to estimate overall, age-, and sex-specific proportional reporting ratios (PRRs) and corresponding Χ2 values for reports of Guillain-Barre syndrome between 5 and 42 d following HPV vaccination. Minimum criteria for a signal using this approach are 3 or more cases, PRR≥2, and Χ2≥4. Guillain-Barre syndrome was listed as an adverse event in 45 of 14,822 reports, of which 9 reports followed HPV4 vaccination and 36 reports followed all other vaccines. The overall, age-, and sex-specific PRR estimates were uniformly below 1. In addition, the overall, age-, and sex-specific Χ2 values were uniformly below 3. Our analysis of post-marketing surveillance data does not suggest that Guillain-Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among vaccine-eligible females or males in the United States. Our findings may be useful when discussing the risks and benefits of HPV4 vaccination.

Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like-particle vaccine in Latin American women.

PubMed

Perez, Gonzalo; Lazcano-Ponce, Eduardo; Hernandez-Avila, Mauricio; García, Patricia J; Muñoz, Nubia; Villa, Luisa L; Bryan, Janine; Taddeo, Frank J; Lu, Shuang; Esser, Mark T; Vuocolo, Scott; Sattler, Carlos; Barr, Eliav

2008-03-15

The prevalence of HPV infection in Latin America is among the highest in the world. A quadrivalent (types 6/11/16/18) human papillomavirus L1 virus-like-particle vaccine has been shown to be 95-100% effective in preventing HPV 6/11/16/18-related cervical and genital disease in women naive to vaccine HPV types. A total of 6,004 female subjects aged 9-24 were recruited from Brazil, Mexico, Colombia, Costa Rica, Guatemala and Peru. Subjects were randomized to immunization with intramuscular (deltoid) injections of HPV vaccine or placebo at enrollment (day 1), month 2 and month 6. Among vaccinated subjects in the per-protocol population from Latin America, quadrivalent HPV vaccine was 92.8 and 100% effective in preventing cervical intraepithelial neoplasia and external genital lesions related to vaccine HPV types, respectively. These data support vaccination of adolescents and young adults in the region, which is expected to greatly reduce the burden of cervical and genital cancers, precancers and genital warts. (c) 2007 Wiley-Liss, Inc.

Immunogenicity of the meningococcal polysaccharide conjugate vaccine in pediatric kidney transplant patients.

PubMed

Nelson, Delphine R; Fadrowski, Jeffrey; Neu, Alicia

2018-06-01

Immunosuppressed kidney transplant patients may have suboptimal response to vaccinations. The aim of this study was to determine antibody response to a quadrivalent meningococcal conjugate vaccine (MenACWY-D) in adolescents with a kidney transplant. This was a prospective, single-center, cohort study. Adolescent patients (11-22 years old) with a functioning kidney transplant for at least 3 months and no previous meningococcal vaccination were eligible for enrollment. Antibody levels to all serogroups were measured before vaccination (baseline) and at 4 weeks and 1, 2 and 3 years after vaccination. Seropositivity was defined as a titer ≥ 1:8 at baseline, and seroconversion as a fourfold or greater increase in antibody titer from baseline at 4 weeks post-vaccination. Geometric mean titers (GMTs) were calculated at each time point and compared to published GMTs from vaccinated healthy adolescents. Nineteen patients were enrolled. No patient had seroprotective titers against all four serogroups at baseline. At 4 weeks post-vaccination 41% of patients seroconverted to all four serogroups, with seroconversion rates of 88, 53, 71 and 94% for serogroups A, C, W and Y, respectively. GMTs were significantly lower in adolescents with a kidney transplant than in healthy adolescents at 1 month (p = 0.02) and 3 years (p = 0.04) post-vaccination. There were no significant adverse events, episodes of rejection or death in any patient. Adolescents with a kidney transplant may not respond adequately to MenACWY-D and may experience more rapid declines in antibody titers than healthy adolescents. Further study is needed to determine if alternative dosing schedules can improve antibody response in this population.

Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink.

PubMed

Gee, Julianne; Naleway, Allison; Shui, Irene; Baggs, James; Yin, Ruihua; Li, Rong; Kulldorff, Martin; Lewis, Edwin; Fireman, Bruce; Daley, Matthew F; Klein, Nicola P; Weintraub, Eric S

2011-10-26

In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9-26 year-old female vaccine recipients between August 2006 and October 2009. Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan-Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis. A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9-17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization). In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted. Published by Elsevier Ltd.

Cost–effectiveness analysis of quadrivalent influenza vaccine in Spain

PubMed Central

García, Amos; Ortiz de Lejarazu, Raúl; Reina, Jordi; Callejo, Daniel; Cuervo, Jesús; Morano Larragueta, Raúl

2016-01-01

ABSTRACT Influenza has a major impact on healthcare systems and society, but can be prevented using vaccination. The World Health Organization (WHO) currently recommends that influenza vaccines should include at least two virus A and one virus B lineage (trivalent vaccine; TIV). A new quadrivalent vaccine (QIV), which includes an additional B virus strain, received regulatory approval and is now recommended by several countries. The present study estimates the cost-effectiveness of replacing TIVs with QIV for risk groups and elderly population in Spain. A static, lifetime, multi-cohort Markov model with a one-year cycle time was adapted to assess the costs and health outcomes associated with a switch from TIV to QIV. The model followed a cohort vaccinated each year according to health authority recommendations, for the duration of their lives. National epidemiological data allowed the determination of whether the B strain included in TIVs matched the circulating one. Societal perspective was considered, costs and outcomes were discounted at 3% and one-way and probabilistic sensitivity analyses were performed. Compared to TIVs, QIV reduced more influenza cases and influenza-related complications and deaths during periods of B-mismatch strains in the TIV. The incremental cost-effectiveness ratio (ICER) was 8,748€/quality-adjusted life year (QALY). One-way sensitivity analysis showed mismatch with the B lineage included in the TIV was the main driver for ICER. Probabilistic sensitivity analysis shows ICER below 30,000€/QALY in 96% of simulations. Replacing TIVs with QIV in Spain could improve influenza prevention by avoiding B virus mismatch and provide a cost-effective healthcare intervention. PMID:27184622

Cost-effectiveness analysis of quadrivalent influenza vaccine in Spain.

PubMed

García, Amos; Ortiz de Lejarazu, Raúl; Reina, Jordi; Callejo, Daniel; Cuervo, Jesús; Morano Larragueta, Raúl

2016-09-01

Influenza has a major impact on healthcare systems and society, but can be prevented using vaccination. The World Health Organization (WHO) currently recommends that influenza vaccines should include at least two virus A and one virus B lineage (trivalent vaccine; TIV). A new quadrivalent vaccine (QIV), which includes an additional B virus strain, received regulatory approval and is now recommended by several countries. The present study estimates the cost-effectiveness of replacing TIVs with QIV for risk groups and elderly population in Spain. A static, lifetime, multi-cohort Markov model with a one-year cycle time was adapted to assess the costs and health outcomes associated with a switch from TIV to QIV. The model followed a cohort vaccinated each year according to health authority recommendations, for the duration of their lives. National epidemiological data allowed the determination of whether the B strain included in TIVs matched the circulating one. Societal perspective was considered, costs and outcomes were discounted at 3% and one-way and probabilistic sensitivity analyses were performed. Compared to TIVs, QIV reduced more influenza cases and influenza-related complications and deaths during periods of B-mismatch strains in the TIV. The incremental cost-effectiveness ratio (ICER) was 8,748€/quality-adjusted life year (QALY). One-way sensitivity analysis showed mismatch with the B lineage included in the TIV was the main driver for ICER. Probabilistic sensitivity analysis shows ICER below 30,000€/QALY in 96% of simulations. Replacing TIVs with QIV in Spain could improve influenza prevention by avoiding B virus mismatch and provide a cost-effective healthcare intervention.

Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data.

PubMed

Donovan, Basil; Franklin, Neil; Guy, Rebecca; Grulich, Andrew E; Regan, David G; Ali, Hammad; Wand, Handan; Fairley, Christopher K

2011-01-01

Quadrivalent human papillomavirus (HPV) vaccine has high efficacy in clinical trials but no reports describe its effects at a population level. From July, 2007, Australia was the first country to fund a vaccination programme for all women aged 12-26 years. We established a national surveillance network in Australia and aimed to identify trends in diagnoses of genital warts in 2004-09. We obtained standardised data for demographic factors, frequency of genital warts, HPV vaccination status, and sexual behaviour for new patients attending eight sexual health services in Australia between January, 2004, and December, 2009. We used χ² analysis to identify significant trends in proportions of patients diagnosed with warts in periods before and after vaccination began. Our primary group of interest was female Australian residents who were eligible for free vaccination, although data were assessed for patients ineligible for free vaccination, including women older than 26 years of age, non-resident women, and men. Among 112 083 new patients attending sexual health services, we identified 9867 (9%) cases of genital warts. Before the vaccine programme started, there was no change in proportion of women or heterosexual men diagnosed with genital warts. After vaccination began, a decline in number of diagnoses of genital warts was noted for young female residents (59%, p(trend)<0·0001). No significant decline was noted in female non-residents, women older than 26 years in July, 2007, or in men who have sex with men. However, proportionally fewer heterosexual men were diagnosed with genital warts during the vaccine period (28%, p(trend)<0·0001), and this effect was more pronounced in young men. By 2009, 65·1% of female Australian residents who were eligible for free vaccine reported receipt of quadrivalent or unknown HPV vaccine. The decrease in frequency of genital warts in young Australian women resulting from the high coverage of HPV vaccination might provide

Immunogenicity and safety of the quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) in splenectomized or hyposplenic children and adolescents: Results of a phase III, open, non-randomized study.

PubMed

Klein, Nicola P; Habanec, Tomas; Kosina, Pavel; Shah, Nirmish R; Kolhe, Devayani; Miller, Jacqueline M; Hezareh, Marjan; Van der Wielen, Marie

2018-04-19

Individuals with functional or anatomic asplenia are at high risk for meningococcal disease. We evaluated the immunogenicity and safety of 1 and 2 doses of the quadrivalent meningococcal serogroups A, C, W, Y tetanus toxoid-conjugate vaccine (MenACWY-TT) in this high-risk population. This phase III, open-label, controlled, non-randomized study (NCT01641042) enrolled 1-17-year-olds with impaired splenic activity (high-risk group) and age-matched healthy controls (control group). We measured immune responses to MenACWY-TT by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement and in terms of antibodies against polysaccharides of the 4 vaccine serogroups. We evaluated vaccine response rates (VRRs) as 4-fold increases from pre-vaccination levels or titers ≥1:32 (rSBA)/≥1:8 (hSBA). We recorded solicited and unsolicited adverse events (AEs) during 4 and 31 days post-vaccination, and serious AEs (SAEs) and new onset of chronic illnesses (NOCIs) throughout the study. The according-to-protocol cohort for immunogenicity included 40 participants per group. In both groups, the first MenACWY-TT dose induced rSBA VRRs of 92.5-100% and hSBA VRRs of 55.6-77.1% across vaccine serogroups. Following the second MenACWY-TT dose, all participants had high responses, with rSBA and hSBA VRRs of 73.0-100% across vaccine serogroups. rSBA and hSBA geometric mean titers for each serogroup increased in both groups (with different magnitudes, but ≥13.1-fold) compared with baseline levels. Polysaccharide antibody concentrations ≥2.0 μg/ml were detected in ≥84.4% of participants and were similar between groups. Incidences of solicited and unsolicited AEs were comparable between groups. We recorded SAEs in 4/43 participants in the high-risk group and 1/43 participants in the control group (none vaccine-related). No NOCIs were reported. In this descriptive study, MenACWY-TT induced similar functional and humoral immune responses and had a clinically

Pneumococcal conjugate vaccine: economic issues of the introduction of a new childhood vaccine.

PubMed

Ray, G Thomas

2002-06-01

In February 2000, a pneumococcal conjugate vaccine was licensed for use in the USA. This vaccine has been shown to be effective in reducing pneumococcal disease, and has been recommended for universal use in infants. However, pneumococcal conjugate vaccine is by far the most expensive child vaccine series routinely administered in the USA, alone accounting for over 40% of the total purchase price of vaccines for the recommended childhood schedule. This article reviews the existing efficacy and economic studies of pneumococcal conjugate vaccine and discusses the process by which routine use of pneumococcal conjugate vaccine was introduced and the role economic analysis played in that process. Some of the scientific and funding issues relating to its use in both the industrialized and developing world are also discussed.

Cost-utility of quadrivalent versus trivalent influenza vaccine in Brazil - comparison of outcomes from different static model types.

PubMed

Van Bellinghen, Laure-Anne; Marijam, Alen; Tannus Branco de Araujo, Gabriela; Gomez, Jorge; Van Vlaenderen, Ilse

Influenza burden in Brazil is considerable with 4.2-6.4 million cases in 2008 and influenza-like-illness responsible for 16.9% of hospitalizations. Cost-effectiveness of influenza vaccination may be assessed by different types of models, with limitations due to data availability, assumptions, and modelling approach. To understand the impact of model complexity, the cost-utility of quadrivalent versus trivalent influenza vaccines in Brazil was estimated using three distinct models: a 1-year decision tree population model with three age groups (FLOU); a more detailed 1-year population model with five age groups (FLORA); and a more complex lifetime multi-cohort Markov model with nine age groups (FLORENCE). Analysis 1 (impact of model structure) compared each model using the same data inputs (i.e., best available data for FLOU). Analysis 2 (impact of increasing granularity) compared each model populated with the best available data for that model. Using the best data for each model, the discounted cost-utility ratio of quadrivalent versus trivalent influenza vaccine was R$20,428 with FLOU, R$22,768 with FLORA (versus R$20,428 in Analysis 1), and, R$19,257 with FLORENCE (versus R$22,490 in Analysis 1) using a lifetime horizon. Conceptual differences between FLORA and FLORENCE meant the same assumption regarding increased all-cause mortality in at-risk individuals had an opposite effect on the incremental cost-effectiveness ratio in Analysis 2 versus 1, and a proportionally higher number of vaccinated elderly in FLORENCE reduced this ratio in Analysis 2. FLOU provided adequate cost-effectiveness estimates with data in broad age groups. FLORA increased insights (e.g., in healthy versus at-risk, paediatric, respiratory/non-respiratory complications). FLORENCE provided greater insights and precision (e.g., in elderly, costs and complications, lifetime cost-effectiveness). All three models predicted a cost per quality-adjusted life year gained for quadrivalent versus

The potential health and economic benefits of preventing recurrent respiratory papillomatosis through quadrivalent human papillomavirus vaccination.

PubMed

Chesson, Harrell W; Forhan, Sara E; Gottlieb, Sami L; Markowitz, Lauri E

2008-08-18

We estimated the health and economic benefits of preventing recurrent respiratory papillomatosis (RRP) through quadrivalent human papillomavirus (HPV) vaccination. We applied a simple mathematical model to estimate the averted costs and quality-adjusted life years (QALYs) saved by preventing RRP in children whose mothers had been vaccinated at age 12 years. Under base case assumptions, the prevention of RRP would avert an estimated USD 31 (range: USD 2-178) in medical costs (2006 US dollars) and save 0.00016 QALYs (range: 0.00001-0.00152) per 12-year-old girl vaccinated. Including the benefits of RRP reduced the estimated cost per QALY gained by HPV vaccination by roughly 14-21% in the base case and by <2% to >100% in the sensitivity analyses. More precise estimates of the incidence of RRP are needed, however, to quantify this impact more reliably.

Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults.

PubMed

Pépin, Stéphanie; Donazzolo, Yves; Jambrecina, Alen; Salamand, Camille; Saville, Melanie

2013-11-12

Although two antigenically distinct B strain lineages of influenza have co-circulated globally since the mid-1980s, trivalent influenza vaccines (TIVs) contain only one, resulting in frequent mismatches. This study examined the safety and immunogenicity of an inactivated quadrivalent influenza vaccine (QIV) candidate. This was a phase III, randomized, active-controlled, multicenter trial in adults during the 2011/2012 influenza season. Enrollment was stratified to include equal numbers of subjects 18-60 and >60 years of age. Subjects were randomized 5:1:1 to be vaccinated with the QIV, the licensed TIV, or an investigational TIV containing the alternate B strain lineage. Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination. 1116 subjects were vaccinated with QIV, 226 with the licensed TIV, and 223 with the investigational TIV. For all four vaccine strains, antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains. For both B strains, post-vaccination antibody responses to the QIV were superior to the responses to the TIVs lacking the corresponding B strain. The QIV met all European Medicines Agency criteria for all four vaccine strains. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for the QIV and pooled TIV groups. The most commonly reported solicited reactions were injection-site pain, headache, and myalgia, and most solicited reactions were mild or moderate and appeared and resolved within 3 days of vaccination. No treatment-related serious adverse events or deaths were reported. The inactivated QIV was well tolerated without any safety concerns. For all four vaccine strains, antibody responses to the QIV were superior to the responses to TIV for the unmatched strains and non-inferior for the matched strains. QIV could therefore help address an unmet need due to mismatched B strains in previous influenza vaccines. EudraCT: 2011

Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.

PubMed

Borja-Tabora, Charissa Fay Corazon; Montalban, Cecilia; Memish, Ziad A; Boutriau, Dominique; Kolhe, Devayani; Miller, Jacqueline M; Van der Wielen, Marie

2015-10-06

Long-term protection against meningococcal disease is associated with persistence of post-vaccination antibodies at protective levels. We evaluated the bactericidal antibody persistence and safety of the quadrivalent meningococcal serogroups A, C, W and Y tetanus-toxoid conjugate vaccine (MenACWY-TT) and the meningococcal polysaccharide serogroups A, C, W, and Y vaccine (MenACWY-PS) up to 5 years post-vaccination. This phase IIb, open, randomized, controlled study conducted in the Philippines and Saudi Arabia consisted of a vaccination phase and a long-term persistence phase. Healthy adolescents and adults aged 11-55 years were randomized (3:1) to receive a single dose of MenACWY-TT (ACWY-TT group) or MenACWY-PS (Men-PS group). Primary and persistence results up to 3 years post-vaccination have been previously reported. Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by a serum bactericidal antibody assay using rabbit complement (rSBA, cut-off titers 1:8 and 1:128) at Year 4 and Year 5 post-vaccination. Vaccine-related serious adverse events (SAEs) and cases of meningococcal disease were assessed up to Year 5. Of the 500 vaccinated participants, 404 returned for the Year 5 study visit (Total Cohort Year 5). For the Total Cohort Year 5, 71.6-90.0 and 64.9-86.3 % of MenACWY-TT recipients had rSBA titers ≥1:8 and ≥1:128, respectively, compared to 24.8-74.3 and 21.0-68.6 % of MenACWY-PS recipients. The rSBA geometric mean titers (GMTs) remained above the pre-vaccination levels in both treatment groups. Exploratory analyses suggested that both rSBA GMTs as well as the percentages of participants with rSBA titers above the cut-offs were higher in the ACWY-TT than in the Men-PS group for serogroups A, W and Y, with no apparent difference for MenC. No SAEs related to vaccination or cases of meningococcal disease were reported up to Year 5. These results suggest that a single dose of MenACWY-TT could protect at least 72 % of vaccinated

Modelling the effects of quadrivalent Human Papillomavirus (HPV) vaccination in Puerto Rico.

PubMed

Ortiz, Ana Patricia; Ortiz-Ortiz, Karen J; Ríos, Moraima; Laborde, José; Kulkarni, Amit; Pillsbury, Matthew; Lauschke, Andreas; Monsanto, Homero A; Marques-Goyco, Cecile

2017-01-01

No study has estimated the potential impact of Human Papillomavirus (HPV) vaccination in Puerto Rico, a population with considerable burden of HPV-related morbidities. We evaluated the health and economic impacts of implementing a vaccination strategy for females and males in Puerto Rico, with the quadrivalent HPV (HPV4) vaccine, under different vaccination scenarios. We adapted a mathematical model which estimates the direct and indirect health benefits and costs of HPV4 vaccination in a dynamic population. The model compared three vaccination scenarios against screening only (no-vaccination) for three doses of HPV4 vaccine among individuals aged 11-15 years in Puerto Rico: 1) 34% for females and 13% for males (34%F/13%M), 2) 50% for females and 40% for males (50%F/40%M), and 3) 80% for female and 64% for male (80%F/64%M). Data specific to Puerto Rico was used. When not available, values from the United States were used. Input data consisted of demographic, behavioral, epidemiological, screening, and economic parameters. The model predicted decreases in: 1) HPV infection prevalence for females and males, 2) cervical intraepithelial neoplasia and cervical cancer incidence for females, 3) genital warts incidence for females and males, and 4) cervical cancer deaths among females, when various vaccination program scenarios were considered. In addition, when the vaccination percentage was increased in every scenario, the reduction was greater and began earlier. The analysis also evidenced an incremental cost effectiveness ratio (ICER) of $1,964 per quality-adjusted life year gained for the 80%F/64%M uptake scenario. HPV vaccine can prove its cost effectiveness and substantially reduce the burden and costs associated to various HPV-related conditions when targeted to the adequate population together with an organized HPV vaccination program.

Modelling the effects of quadrivalent Human Papillomavirus (HPV) vaccination in Puerto Rico

PubMed Central

Ortiz, Ana Patricia; Ortiz-Ortiz, Karen J.; Ríos, Moraima; Laborde, José; Kulkarni, Amit; Pillsbury, Matthew; Lauschke, Andreas; Monsanto, Homero A.; Marques-Goyco, Cecile

2017-01-01

Background No study has estimated the potential impact of Human Papillomavirus (HPV) vaccination in Puerto Rico, a population with considerable burden of HPV-related morbidities. We evaluated the health and economic impacts of implementing a vaccination strategy for females and males in Puerto Rico, with the quadrivalent HPV (HPV4) vaccine, under different vaccination scenarios. Methods We adapted a mathematical model which estimates the direct and indirect health benefits and costs of HPV4 vaccination in a dynamic population. The model compared three vaccination scenarios against screening only (no-vaccination) for three doses of HPV4 vaccine among individuals aged 11–15 years in Puerto Rico: 1) 34% for females and 13% for males (34%F/13%M), 2) 50% for females and 40% for males (50%F/40%M), and 3) 80% for female and 64% for male (80%F/64%M). Data specific to Puerto Rico was used. When not available, values from the United States were used. Input data consisted of demographic, behavioral, epidemiological, screening, and economic parameters. Results The model predicted decreases in: 1) HPV infection prevalence for females and males, 2) cervical intraepithelial neoplasia and cervical cancer incidence for females, 3) genital warts incidence for females and males, and 4) cervical cancer deaths among females, when various vaccination program scenarios were considered. In addition, when the vaccination percentage was increased in every scenario, the reduction was greater and began earlier. The analysis also evidenced an incremental cost effectiveness ratio (ICER) of $1,964 per quality–adjusted life year gained for the 80%F/64%M uptake scenario. Conclusions HPV vaccine can prove its cost effectiveness and substantially reduce the burden and costs associated to various HPV-related conditions when targeted to the adequate population together with an organized HPV vaccination program. PMID:29190725

Factors contributing to the immunogenicity of meningococcal conjugate vaccines

PubMed Central

Bröker, Michael; Berti, Francesco; Costantino, Paolo

2016-01-01

ABSTRACT Various glycoprotein conjugate vaccines have been developed for the prevention of invasive meningococcal disease, having significant advantages over pure polysaccharide vaccines. One of the most important features of the conjugate vaccines is the induction of a T-cell dependent immune response, which enables both the induction of immune memory and a booster response after repeated immunization. The nature of the carrier protein to which the polysaccharides are chemically linked, is often regarded as the main component of the vaccine in determining its immunogenicity. However, other factors can have a significant impact on the vaccine's profile. In this review, we explore the physico-chemical properties of meningococcal conjugate vaccines, which can significantly contribute to the vaccine's immunogenicity. We demonstrate that the carrier is not the sole determining factor of the vaccine's profile, but, moreover, that the conjugate vaccine's immunogenicity is the result of multiple physico-chemical structures and characteristics. PMID:26934310

Safety and immunogenicity of a CRM or TT conjugated meningococcal vaccine in healthy toddlers.

PubMed

Bona, Gianni; Castiglia, Paolo; Zoppi, Giorgio; de Martino, Maurizio; Tasciotti, Annaelisa; D'Agostino, Diego; Han, Linda; Smolenov, Igor

2016-06-17

MenACWY-CRM (Menveo(®); GlaxoSmithKline) and MenACWY-TT (Nimenrix(®); Pfizer) are two meningococcal vaccines licensed in the European Union for use in both children and adults. While both vaccines target meningococcal serogroups A, C, W and Y, immunogenicity and reactogenicity of these quadrivalent meningococcal conjugate vaccines may differ due to differences in formulation processes and chemical structure. Yet data on the comparability of these two vaccines are limited. The reactogenicity and immunogenicity of one dose of either MenACWY-CRM or MenACWY-TT were evaluated in healthy toddlers aged 12-15 months. Immunogenicity was assessed using serum bactericidal antibody assays (SBA) with human (hSBA) and rabbit (rSBA) complement. A total of 202 children aged 12-15 months were enrolled to receive one dose of MenACWY-CRM or MenACWY-TT. Similar numbers of subjects reported solicited reactions within 7 days following either vaccination. Tenderness at the injection site was the most common local reaction. Systemic reactions reported were similar for both vaccines and mostly mild to moderate in severity: irritability, sleepiness and change in eating habits were most commonly reported. Immunogenicity at 1 month post-vaccination was generally comparable for both vaccines across serogroups. At 6 months post-vaccination antibody persistence against serogroups C, W, and Y was substantial for both vaccines, as measured by both assay methodologies. For serogroup A, hSBA titers declined in both groups, while rSBA titers remained high. Despite differences in composition, the MenACWY-CRM and MenACWY-TT vaccines have comparable reactogenicity and immunogenicity profiles. Immediate immune responses and short-term antibody persistence were largely similar between groups. Both vaccines were well-tolerated and no safety concerns were identified. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

PubMed Central

Chen, Quanyi; Dintaman, Jay; Lees, Andrew; Sen, Goutam; Schwartz, David; Shirtliff, Mark E.; Park, Saeyoung; Lee, Jean C.; Mond, James J.

2013-01-01

Staphylococcal infections are a major source of global morbidity and mortality. Currently there exists no antistaphylococcal vaccine in clinical use. Previous animal studies suggested a possible role for purified lipoteichoic acid as a vaccine target for eliciting protective IgG to several Gram-positive pathogens. Since the highly conserved (poly)glycerolphosphate backbone of lipoteichoic acid is a major antigenic target of the humoral immune system during staphylococcal infections, we developed a synthetic method for producing glycerol phosphoramidites to create a covalent 10-mer of (poly)glycerolphosphate for potential use in a conjugate vaccine. We initially demonstrated that intact Staphylococcus aureus elicits murine CD4+ T cell-dependent (poly)glycerolphosphate-specific IgM and IgG responses in vivo. Naive mice immunized with a covalent conjugate of (poly)glycerolphosphate and tetanus toxoid in alum plus CpG-oligodeoxynucleotides produced high secondary titers of serum (poly)glycerolphosphate-specific IgG. Sera from immunized mice enhanced opsonophagocytic killing of live Staphylococcus aureus in vitro. Mice actively immunized with the (poly)glycerolphosphate conjugate vaccine showed rapid clearance of staphylococcal bacteremia in vivo relative to mice similarly immunized with an irrelevant conjugate vaccine. In contrast to purified, natural lipoteichoic acid, the (poly)glycerolphosphate conjugate vaccine itself exhibited no detectable inflammatory activity. These data suggest that a synthetic (poly)glycerolphosphate-based conjugate vaccine will contribute to active protection against extracellular Gram-positive pathogens expressing this highly conserved backbone structure in their membrane-associated lipoteichoic acid. PMID:23649092

Immunogenicity, Safety and Antibody Persistence of a Booster Dose of Quadrivalent Meningococcal ACWY-tetanus Toxoid Conjugate Vaccine Compared with Monovalent Meningococcal Serogroup C Vaccine Administered Four Years After Primary Vaccination Using the Same Vaccines.

PubMed

Vesikari, Timo; Forsten, Aino; Bianco, Veronique; Van der Wielen, Marie; Miller, Jacqueline M

2015-12-01

We evaluated safety, immunogenicity and antibody persistence of meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) booster vaccination 4 years after priming of toddlers. This phase III, open-label, controlled study in Finland (NCT00955682) enrolled children previously randomized (3:1) at 12-23 months (NCT00474266) to receive 1 dose of MenACWY-TT or MenC conjugate vaccine (MenC-CRM197). Serum bactericidal antibody titers using rabbit (rSBA, cut-off 1:8) and human complement (hSBA, cut-off 1:8) were assessed at year 3 and 4 after priming and 1 month and 1 year after administration of a booster dose of the same vaccine given for primary vaccination. Reactogenicity and safety were assessed, and vaccination-related serious adverse events were recorded from the time of primary vaccination. Before booster (year 4), 74.1%, 40.4%, 49.3% and 58.2% of MenACWY-TT-recipients retained rSBA titers ≥1:8 for serogroups A, C, W and Y, respectively; 28.8%, 73.2%, 80.6% and 65.4% retained hSBA ≥1:8. Percentages for the MenC-CRM group were 35.6% (rSBA-MenC) and 46.9% (hSBA-MenC). After MenACWY-TT booster, ≥99.5% had rSBA ≥1:8 and hSBA ≥1:8 for each serogroup. After MenC-CRM197 booster, all children had rSBA-MenC ≥1:8 and hSBA-MenC ≥1:8. At year 5, percentages above the cut-off were ≥97.4% (rSBA) and ≥95.5% (hSBA) in MenACWY-TT-vaccinees for each serogroup. The MenACWY-TT booster dose had a clinically acceptable safety profile. No vaccine-related serious adverse events were reported. There was evidence of antibody persistence 4 years after toddlers were primed with MenACWY-TT. Booster vaccination induced robust immune responses for all serogroups with an acceptable safety profile.

Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine.

PubMed

Levin, Myron J; Buchwald, Ulrike K; Gardner, Julie; Martin, Jason; Stek, Jon E; Brown, Elizabeth; Popmihajlov, Zoran

2018-01-02

Randomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults≥50years of age (NCT02519855). Overall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015-2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4. Varicella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay. Injection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study. The adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed. The concomitant administration of ZV and IIV4 to adults≥50years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunogenicity and Safety of the New Inactivated Quadrivalent Influenza Vaccine Vaxigrip Tetra: Preliminary Results in Children ≥6 Months and Older Adults

PubMed Central

Montomoli, Emanuele; Torelli, Alessandro; Gianchecchi, Elena

2018-01-01

Since the mid-1980s, two lineages of influenza B viruses have been distinguished. These can co-circulate, limiting the protection provided by inactivated trivalent influenza vaccines (TIVs). This has prompted efforts to formulate quadrivalent influenza vaccines (QIVs), to enhance protection against circulating influenza B viruses. This review describes the results obtained from seven phase III clinical trials evaluating the immunogenicity, safety, and lot-to-lot consistency of a new quadrivalent split-virion influenza vaccine (Vaxigrip Tetra®) formulated by adding a second B strain to the already licensed TIV. Since Vaxigrip Tetra was developed by means of a manufacturing process strictly related to that used for TIV, the data on the safety profile of TIV are considered supportive of that of Vaxigrip Tetra. The safety and immunogenicity of Vaxigrip Tetra were similar to those of the corresponding licensed TIV. Moreover, the new vaccine elicits a superior immune response towards the additional strain, without affecting immunogenicity towards the other three strains. Vaxigrip Tetra is well tolerated, has aroused no safety concerns, and is recommended for the active immunization of individuals aged ≥6 months. In addition, preliminary data confirm its immunogenicity and safety even in children aged 6–35 months and its immunogenicity in older subjects (aged 66–80 years). PMID:29518013

Safety and immunogenicity of a quadrivalent intradermal influenza vaccine in adults.

PubMed

Gorse, Geoffrey J; Falsey, Ann R; Ozol-Godfrey, Ayca; Landolfi, Victoria; Tsang, Peter H

2015-02-25

An intradermal (ID) trivalent split-virion influenza vaccine (IIV3-ID) (Fluzone(®) Intradermal, Sanofi Pasteur, Swiftwater, PA) has been available in the US since the 2011/2012 influenza season for adults aged 18-64 years. This study examined whether adding a second B-lineage strain affects immunogenicity and safety. This randomized, double-blind, multicentre trial evaluated the immunogenicity and safety of an intradermal quadrivalent split-virion influenza vaccine (IIV4-ID) in adults 18-64 years of age in the US during the 2012-2013 influenza season. Participants were randomized 2:1:1 to receive a single injection of IIV4-ID, licensed IIV3-ID, or an investigational IIV3-ID containing the alternate B-lineage strain. Haemagglutination inhibition antibody titres were assessed in two-thirds of participants before vaccination and 28 days after vaccination. 1672 participants were vaccinated with IIV4-ID, 837 with licensed IIV3-ID, and 846 with an investigational IIV3-ID. For all four vaccine strains, antibody responses to IIV4-ID were statistically non-inferior to the response to the IIV3-ID vaccines containing the matched strains. For both B strains, post-vaccination antibody responses to IIV4-ID were statistically superior to the responses to IIV3-ID lacking the corresponding B strain. Adverse events were similar for IIV4-ID and IIV3-ID. The most commonly reported solicited reactions were pain, pruritus, myalgia, headache, and malaise; and most were grade 1 or 2 and appeared and resolved within 3 days of vaccination. IIV4-ID was statistically non-inferior to the two pooled IIV3-ID vaccines for the proportions of participants with at least one grade 2 or 3 systemic reaction. Antibody responses to the IIV4-ID were non-inferior to IIV3-ID for the A and matched B strains and superior for the unmatched B strains. IIV4-ID was well tolerated without any safety concerns. IIV4-ID may help address an unmet need due to mismatched B strains in previous influenza vaccines

Review of seasonal influenza in Canada: Burden of disease and the cost-effectiveness of quadrivalent inactivated influenza vaccines

PubMed Central

Thommes, Edward W.; Kruse, Morgan; Kohli, Michele; Sharma, Rohita; Noorduyn, Stephen G.

2017-01-01

ABSTRACT In the 2015/16 influenza season, the Canadian National Advisory Committee on Immunization (NACI) recommended vaccination with quadrivalent inactivated influenza vaccine (QIV) for infants aged 6–23 months and trivalent inactivated influenza vaccines (TIVs) or QIVs in adults. The objective of this review (GSK study identifier: HO-13-14054) is to examine the epidemiology and disease burden of influenza in Canada and the economic benefits of vaccination. To inform this review, we performed a systematic literature search of relevant Canadian literature and National surveillance data. Influenza B viruses from phylogenetically-distinct lineages (B/Yamagata and B/Victoria) co-circulate in Canada, and are an important cause of influenza complications. Modeling studies, including those postdating the search suggest that switching from TIV to QIV in Canada reduces the burden of influenza and would likely be cost-effective. However, more robust real-world outcomes data is required to inform health policy decision makers on appropriate influenza vaccination strategies for Canada. PMID:27858509

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

Use of MenACWY-CRM in adolescents in the United States.

PubMed

Black, Steven; Block, Stan L

2013-03-01

Adolescents constitute a high-risk group for invasive meningococcal disease. MenACWY-CRM (Menveo, Novartis Vaccines, Cambridge, MA) is a quadrivalent meningococcal conjugate vaccine indicated to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135, and Y. It has been approved for use in persons age 2-55 years. The tolerability and immunogenicity of MenACWY-CRM in adolescents have been ascertained in phase 2 and 3 trials against MPSV4 (Menomune, sanofi pasteur, Swiftwater, PA), an unconjugated quadrivalent meningococcal vaccine, and MenACWY-D (Menactra, sanofi pasteur), another conjugated quadrivalent meningococcal vaccine. Clinical trials also have demonstrated that MenACWY-CRM is well tolerated and immunogenic when administered to adolescents concomitantly with the combined tetanus, diphtheria, and acellular pertussis vaccine (Boostrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent human papillomavirus vaccine (Gardasil, Merck & Co., Inc., Whitehouse Station, NJ). Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control

PubMed Central

Ray, Riju; Dos Santos, Gaël; Buck, Philip O.; Claeys, Carine; Matias, Gonçalo; Innis, Bruce L.; Bekkat-Berkani, Rafik

2017-01-01

ABSTRACT The contribution of influenza B to the seasonal influenza burden varies from year-to-year. Although 2 antigenically distinct influenza B virus lineages have co-circulated since 2001, trivalent influenza vaccines (TIVs) contain antigens from only one influenza B virus. B-mismatch or co-circulation of both B lineages results in increased morbidity and mortality attributable to the B lineage absent from the vaccine. Quadrivalent vaccines (QIVs) contain both influenza B lineages. We reviewed currently licensed QIVs and their value by focusing on the preventable disease burden. Modeling studies support that QIVs are expected to prevent more influenza cases, hospitalisations and deaths than TIVs, although estimates of the case numbers prevented vary according to local specificities. The value of QIVs is demonstrated by their capacity to broaden the immune response and reduce the likelihood of a B-mismatched season. Some health authorities have preferentially recommended QIVs over TIVs in their influenza prevention programmes. PMID:28532276

Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience

PubMed Central

Garland, Suzanne M.; Kjaer, Susanne K.; Muñoz, Nubia; Block, Stan L.; Brown, Darron R.; DiNubile, Mark J.; Lindsay, Brianna R.; Kuter, Barbara J.; Perez, Gonzalo; Dominiak-Felden, Geraldine; Saah, Alfred J.; Drury, Rosybel; Das, Rituparna; Velicer, Christine

2016-01-01

Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage. PMID:27230391

Immunogenicity and Safety of an Inactivated Quadrivalent Influenza Vaccine in US Children 6-35 Months of Age During 2013-2014: Results From A Phase II Randomized Trial.

PubMed

Wang, Long; Chandrasekaran, Vijayalakshmi; Domachowske, Joseph B; Li, Ping; Innis, Bruce L; Jain, Varsha K

2016-06-01

Viruses from 2 influenza B lineages co-circulate, leading to suboptimal protection with trivalent influenza vaccines (TIV). Quadrivalent influenza vaccines (QIV) containing both lineages offer broader protection. We compared inactivated seasonal QIV versus TIV (15 and 7.5 μg hemagglutinin [HA] for each influenza strain, respectively) in a phase II randomized (1 : 1), observer-blind trial in US children 6-35 months of age (identifier NCT01974895). The primary objective was to evaluate immune responses induced by QIV for the 4 vaccine strains 28 days after completion of vaccination. A secondary objective was to demonstrate superiority of QIV versus TIV for the B/Victoria strain contained in QIV but not TIV. Immunogenicity was evaluated in the per-protocol cohort (N = 280), and safety was evaluated in the intent-to-treat cohort (N = 314). Seroconversion rates (SCRs) for QIV were 80.4% (95% confidence interval [CI], 73.0%-86.6%), 72.0% (95% CI, 63.9%-79.2%), 86.0% (95% CI, 79.2%-91.2%), and 66.4% (95% CI, 58.1%-74.1%) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria, respectively. Quadrivalent influenza vaccines demonstrated immunogenic superiority over TIV for B/Victoria with a geometric mean titer ratio of 4.73 (95% CI, 3.73%-5.99%) and SCR difference of 54.02% (95% CI, 43.88%-62.87%). Safety was similar between the vaccine groups despite the QIV's higher antigen content. No serious adverse events were reported related to vaccination. Quadrivalent influenza vaccine (15 µg HA/strain) was immunogenic with an acceptable safety profile. The next phase of its development in children 6-35 months of age is a phase III trial in countries where it is not yet licensed. In countries where it is already licensed, a switch from TIV to QIV would provide broader protection in this vulnerable group. © The Author 2015. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society.

Hypothesis: conjugate vaccines may predispose children to autism spectrum disorders.

PubMed

Richmand, Brian J

2011-12-01

The first conjugate vaccine was approved for use in the US in 1988 to protect infants and young children against the capsular bacteria Haemophilus influenzae type b (Hib). Since its introduction in the US, this vaccine has been approved in most developed countries, including Denmark and Israel where the vaccine was added to their national vaccine programs in 1993 and 1994, respectively. There have been marked increases in the reported prevalence of autism spectrum disorders (ASDs) among children in the US beginning with birth cohorts in the late 1980s and in Denmark and Israel starting approximately 4-5 years later. Although these increases may partly reflect ascertainment biases, an exogenous trigger could explain a significant portion of the reported increases in ASDs. It is hypothesized here that the introduction of the Hib conjugate vaccine in the US in 1988 and its subsequent introduction in Denmark and Israel could explain a substantial portion of the initial increases in ASDs in those countries. The continuation of the trend toward increased rates of ASDs could be further explained by increased usage of the vaccine, a change in 1990 in the recommended age of vaccination in the US from 15 to 2 months, increased immunogenicity of the vaccine through changes in its carrier protein, and the subsequent introduction of the conjugate vaccine for Streptococcus pneumoniae. Although conjugate vaccines have been highly effective in protecting infants and young children from the significant morbidity and mortality caused by Hib and S. pneumoniae, the potential effects of conjugate vaccines on neural development merit close examination. Conjugate vaccines fundamentally change the manner in which the immune systems of infants and young children function by deviating their immune responses to the targeted carbohydrate antigens from a state of hypo-responsiveness to a robust B2 B cell mediated response. This period of hypo-responsiveness to carbohydrate antigens coincides

[Withdrawal of an advertising campaign to promote the quadrivalent human papilloma virus vaccine in Spain].

PubMed

Martín-Llaguno, Marta; Alvarez-Dardet, Carlos

2010-01-01

The inclusion of the quadrivalent human papilloma virus (HPV) vaccine in the schedule of the Spanish National Health System sparked the debate over Gardasil, which was presented to the public as a "vaccine against cervical cancer". In this context, Sanofi Pasteur MSD was sued for misleading advertising in the campaign "cuentaselo.org". Although the complaint was not admitted, the lawsuit triggered five changes in the ownership of the web domain which, although backed by scientific societies, was not supported by law. Because of the violation of the Law of the Society of Information Services, and prompted by the suspicion that the pharmaceutical company was behind these changes (as it could not advertise the product), the platform for the moratorium on the HPV vaccine filed a complaint against the Spanish Society of Gynecology and Obstetrics (whose logo appeared on the webpage) for breaching the code of advertising self-regulation. Sanofi Pasteur MSD, the advertiser which was not mentioned, "accepted the complaint and removed the webpage", thus corroborating its involvement. Copyright 2009 SESPAS. Published by Elsevier Espana. All rights reserved.

Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults.

PubMed

Greenberg, David P; Robertson, Corwin A; Noss, Michael J; Blatter, Mark M; Biedenbender, Rex; Decker, Michael D

2013-01-21

To evaluate the safety and immunogenicity of a prototype quadrivalent inactivated influenza vaccine (QIV) containing two influenza B strains, one of each lineage, compared with licensed trivalent inactivated influenza vaccines (TIVs) containing either a Victoria B-lineage strain (2009-2010 TIV) or a Yamagata B-lineage strain (2008-2009 TIV). Healthy adults ≥18 years of age were eligible to participate in this phase II, open-label, randomized, controlled, multicenter study conducted in the US. Participants received a single dose of 2009-2010 TIV, 2008-2009 TIV, or QIV. Sera were collected before and 21 days after vaccine administration to test for hemagglutination inhibition (HAI) antibodies to each of the four influenza strains. Immunogenicity endpoints included geometric mean HAI antibody titers (GMTs) and rates of seroprotection (titer ≥1:40) and seroconversion (4-fold rise pre- to post-vaccination). Safety endpoints included frequency of solicited injection-site and systemic reactions occurring within 3 days of vaccination, and unsolicited non-serious adverse events (AEs) and serious AEs (SAEs) within 21 days of vaccination. One hundred and ninety participants were enrolled to each vaccine group. QIV induced GMTs to each A and B strain that were noninferior to those induced by the 2009-2010 and 2008-2009 TIVs (i.e., lower limit of the two-sided 95% confidence interval of the ratio of GMT(QIV)/GMT(TIV)>0.66 for each strain). Rates of seroprotection and seroconversion were similar in all groups. Incidence and severity of solicited injection-site and systemic reactions, AEs, and SAEs were similar among groups. QIV, containing two B strains (one from each B lineage), was as safe and immunogenic as licensed TIV. QIV has the potential to be a useful alternative to TIV and offer protection against both B lineages. Copyright © 2012 Elsevier Ltd. All rights reserved.

Antibody persistence and booster response 68 months after vaccination at 2-10 years of age with one dose of MenACWY-TT conjugate vaccine.

PubMed

Knuf, Markus; Helm, Klaus; Kolhe, Devayani; Van Der Wielen, Marie; Baine, Yaela

2018-05-31

We evaluated antibody persistence up to 68 months (M) post-vaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) or a licensed monovalent MenC conjugate vaccine (MenC-CRM 197 ) and subsequent booster responses to MenACWY-TT in healthy European children. In the initial study (NCT00674583), healthy children, 2-10 years of age, were randomized to receive a single dose of either MenACWY-TT or MenC-CRM 197 . In the follow-up study, we present the persistence at 32, 44, 56, and 68 M post-vaccination, overall and stratified by age (2-5 and 6-10 years), and the immunogenicity and safety of MenACWY-TT administered to all study participants at M68 post-primary vaccination. At M68, 33.3% (age group 2-5 years) and 47.1% (age group 6-10 years) of the children vaccinated with MenACWY-TT, and 50.0% (age group 2-5 years) and 75.9% (age group 6-10 years) vaccinated with MenC-CRM 197 retained titers ≥1:8 for MenC, as assessed by a serum bactericidal assay using rabbit complement (rSBA). In the MenACWY-TT recipients, the percentages of children retaining rSBA titers ≥1:8 for MenA, MenW, and MenY were 81.7%, 47.3% and 66.7% in age group 2-5 years and 91.8%, 58,8% and 76.5% in age group 6-10 years, respectively. The booster dose induced robust responses (100% for all serogroups) and was well-tolerated. Antibody persistence (rSBA titers ≥ 1:8) for serogroups A, W and Y was observed in more than 50.0% of the children 68 M after receiving one dose of MenACWY-TT; for MenC, antibody persistence was observed in more than one third of MenACWY-TT and more than half of MenC-CRM 197 recipients. Vaccination with a booster dose of MenACWY-TT induced robust immune responses for all serogroups. Copyright © 2018. Published by Elsevier Ltd.

A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years.

PubMed

Domachowske, Joseph B; Pankow-Culot, Heidemarie; Bautista, Milagros; Feng, Yang; Claeys, Carine; Peeters, Mathieu; Innis, Bruce L; Jain, Varsha

2013-06-15

Two antigenically distinct influenza B lineages have cocirculated since 2001, yet trivalent influenza vaccines (TIVs) contain 1 influenza B antigen, meaning lineage mismatch with the vaccine is frequent. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages vs TIV in healthy children aged 3-17 years. Children were randomized 1:1:1 to receive QIV or 1 of 2 TIVs (either B/Victoria or B/Yamagata lineage; N = 2738). Hemagglutination-inhibition assays were performed 28 days after 1 or 2 doses in primed and unprimed children, respectively. Immunological noninferiority of QIV vs TIV against shared strains, and superiority against alternate-lineage B strains was based on geometric mean titers (GMTs) and seroconversion rates. Reactogenicity and safety were also assessed (Clinicaltrials.gov NCT01196988). Noninferiority against shared strains and superiority against alternate-lineage B strains was demonstrated for QIV vs TIV. QIV was highly immunogenic; seroconversion rates were 91.4%, 72.3%, 70.0%, and 72.5% against A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, respectively. Reactogenicity and safety of QIV was consistent with TIV. QIV vs TIV showed superior immunogenicity for the additional B strain without interfering with immune responses to shared strains. QIV may offer improved protection against influenza B in children compared with current trivalent vaccines.

Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study.

PubMed

Liu, Erin Y; Smith, Leah M; Ellis, Anne K; Whitaker, Heather; Law, Barbara; Kwong, Jeffrey C; Farrington, Paddy; Lévesque, Linda E

2018-05-28

Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario's school-based HPV vaccination program. We undertook a population-based retrospective cohort study using Ontario's administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7-60 post-vaccination ("exposed" follow-up) to that at any other time ("unexposed"). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections. The study cohort consisted of 290 939 girls aged 12-17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination ( n = 681; rate ratio 1.12, 95% CI 0.85-1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy ( n = 65; rate ratio 1.73, 95% CI 0.77-3.89), optic neuritis ( n = 67; rate ratio 1.57, 95% CI 0.74-3.33) and Graves disease ( n = 47; rate ratio 1.55, 95% CI 0.92-2.63). We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers. © 2018 Joule Inc. or its licensors.

Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study

PubMed Central

Liu, Erin Y.; Smith, Leah M.; Ellis, Anne K.; Whitaker, Heather; Law, Barbara; Kwong, Jeffrey C.; Farrington, Paddy

2018-01-01

BACKGROUND: Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario’s school-based HPV vaccination program. METHODS: We undertook a population-based retrospective cohort study using Ontario’s administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7–60 post-vaccination (“exposed” follow-up) to that at any other time (“unexposed”). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections. RESULTS: The study cohort consisted of 290 939 girls aged 12–17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination (n = 681; rate ratio 1.12, 95% CI 0.85–1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy (n = 65; rate ratio 1.73, 95% CI 0.77–3.89), optic neuritis (n = 67; rate ratio 1.57, 95% CI 0.74–3.33) and Graves disease (n = 47; rate ratio 1.55, 95% CI 0.92–2.63). INTERPRETATION: We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers. PMID:29807937

Trends in genital warts diagnoses in New Zealand five years following the quadrivalent human papillomavirus vaccine introduction.

PubMed

Oliphant, Jeannie; Stewart, Joanna; Saxton, Peter; Lo, Min; Perkins, Nicky; Ward, Daniel

2017-03-24

To investigate whether changes in rates of genital warts diagnosis at Auckland Sexual Health Service (ASHS), pre and post the quadrivalent human papillomavirus (4vHPV) vaccine introduction in late 2008, differed between clients vaccine-eligible and not eligible. All new clients attending ASHS from 2007 to 2013 were categorised as having genital warts or not. Generalised linear mixed models were used to compare differences in rates of change in diagnoses. Overall, 43,480 were seen with genital warts diagnosed in 13.1%. The difference in rate of change over time in diagnosis pre- to post-vaccine differed in females vaccine-eligible to not (p=0.004). The relative risk of diagnosis per year pre-vaccine was 0.98 (0.84, 1.13) and post-vaccine 0.77 (0.74, 0.81) in those eligible compared to 0.87 (0.80, 0.95) and 0.95 (0.91, 0.98), respectively, in those not eligible. This difference in change, between vaccine eligible or not, differed between males and females (p=0.02), with males considered eligible if the same aged female would have been. In males, no difference in rate change pre- to post-vaccine could be shown in those eligible or not (p=0.53). In this study a population effect for women of the 4vHPV vaccine was demonstrated.

Safety and immunogenicity of meningococcal ACWY CRM197-conjugate vaccine in children, adolescents and adults in Russia.

PubMed

Ilyina, Natalia; Kharit, Susanna; Namazova-Baranova, Leila; Asatryan, Asmik; Benashvili, Mayya; Tkhostova, Elmira; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2014-01-01

Neisseria meningitidis is the leading cause of bacterial invasive infections in people aged <15 years in the Russian Federation. The aim of this phase III, multicenter, open-label study was to assess the immunogenicity and safety of the quadrivalent meningococcal CRM197-conjugate vaccine MenACWY when administered to healthy Russian subjects aged 2 years and above. A total of 197 subjects were immunized with a single dose of the vaccine, and serogroup-specific serum bactericidal activity was measured pre and 1-month post-vaccination with human complement (hSBA) serum titers. Regardless of baseline serostatus, 1 month after a single dose of MenACWY-CRM197 85% (95%CI, 79-90%) of subjects showed serologic response against serogroup A, 74% (67-80%) against serogroup C, 60% (53-67%) against serogroup W, and 83% (77-88%) against serogroup Y. The percentage of subjects with hSBA titers ≥ 1:8 1 month after vaccination was 89% (83-93%) against serogroup A, 84% (78-89%) against serogroup C, 97% (93-99%) against serogroup W, and 88% (82-92%) against serogroup Y. Comparable results were obtained across all subjects: children (2 to 10 years), adolescents (11 to 17 years), and adults (≥18 years). The MenACWY-CRM197 vaccine showed an acceptable safety profile and was well tolerated across all age groups, with no serious adverse events or deaths reported during the study. In conclusion, a single dose of meningococcal MenACWY-CRM197 vaccine is immunogenic and has an acceptable safety profile, provides a broad protection against the most frequent epidemic serogroups, and is a suitable alternative to currently available unconjugated monovalent or bivalent polysaccharide vaccines in Russia.

Cost-Effectiveness Evaluation of Quadrivalent Human Papilloma Virus Vaccine for HPV-Related Disease in Iran

PubMed Central

Khatibi, Mohsen; Rasekh, Hamid Reza; Shahverdi, Zohreh; jamshidi, Hamid Reza

2014-01-01

Human Papilloma Virus (HPV) vaccine has been added recently to the Iran Drug List. So, decision makers need information beyond that available from RCTs to recommend funding for this vaccination program to add it to the National Immunization program in Iran. Modeling and economic studies have addressed some of those information needs in foreign countries. In order to determine the long term benefit of this vaccine and impact of vaccine program on the future rate of cervical cancer in Iran, we described a model, based on the available economic and health effects of human papilloma virus (HPV), to estimate the cost-effectiveness of HPV vaccination of 15-year-old girls in Iran. Our objective is to estimate the cost-effectiveness of HPV vaccination in Iran against cervical cancer based on available data; incremental cost-effectiveness ratio (ICER) calculations were based on a model comparing a cohort of 15-year-old girls with and without vaccination. We developed a static model based on available data in Iran on the epidemiology of HPV related health outcome. The model compared the cohort of all 15-year old girls alive in the year 2013 with and without vaccination. The cost per QALY, which was found based on our assumption for the vaccination of 15-years old girl to current situation was 439,000,000 Iranian Rial rate (IRR). By considering the key parameters in our sensitivity analysis, value varied from 251,000,000 IRR to 842,000,000 IRR. In conclusion, quadrivalent HPV vaccine (Gardasil) is not cost-effective in Iran based on the base-case parameters value. PMID:24711850

Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia.

PubMed

Crowe, Elizabeth; Pandeya, Nirmala; Brotherton, Julia M L; Dobson, Annette J; Kisely, Stephen; Lambert, Stephen B; Whiteman, David C

2014-03-04

To measure the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine against cervical abnormalities four years after implementation of a nationally funded vaccination programme in Queensland, Australia. Case-control analysis of linked administrative health datasets. Queensland, Australia. Women eligible for free vaccination (aged 12-26 years in 2007) and attending for their first cervical smear test between April 2007 and March 2011. High grade cases were women with histologically confirmed high grade cervical abnormalities (n = 1062) and "other cases" were women with any other abnormality at cytology or histology (n = 10,887). Controls were women with normal cytology (n = 96,404). Exposure odds ratio (ratio of odds of antecedent vaccination (one, two, or three vaccine doses compared with no doses) among cases compared with controls), vaccine effectiveness ((1-adjusted odds ratio) × 100), and number needed to vaccinate to prevent one cervical abnormality at first screening round. We stratified by four age groups adjusted for follow-up time, year of birth, and measures of socioeconomic status and remoteness. The primary analysis concerned women whose first ever smear test defined their status as a case or a control. The adjusted odds ratio for exposure to three doses of HPV vaccine compared with no vaccine was 0.54 (95% confidence interval 0.43 to 0.67) for high grade cases and 0.66 (0.62 to 0.70) for other cases compared with controls with normal cytology, equating to vaccine effectiveness of 46% and 34%, respectively. The adjusted numbers needed to vaccinate were 125 (95% confidence interval 97 to 174) and 22 (19 to 25), respectively. The adjusted exposure odds ratios for two vaccine doses were 0.79 (95% confidence interval 0.64 to 0.98) for high grade cases and 0.79 (0.74 to 0.85) for other cases, equating to vaccine effectiveness of 21%. The quadrivalent HPV vaccine conferred statistically significant protection against cervical abnormalities in

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

Comparative cost effectiveness of varicella, hepatitis A, and pneumococcal conjugate vaccines.

PubMed

Jacobs, R J; Meyerhoff, A S

2001-12-01

Several state and local U.S. governments are considering making varicella, hepatitis A, and/or pneumococcal conjugate vaccination conditions of day care or school entry. These requirements will likely be issued sequentially, because simultaneous mandates exacerbate budget constraints and complicate communication with parents and providers. Cost-effectiveness assessments should aid the establishment of vaccination priorities, but comparing results of published studies is confounded by their dissimilar methods. We reviewed U.S. cost-effectiveness studies of childhood varicella, hepatitis A, and pneumococcal conjugate vaccines and identified four providing data required to standardize methods. Vaccination, disease treatment, and work-loss costs were estimated from original study results and current prices. Estimated life-years saved were derived from original study results, epidemiological evidence, and alternative procedures for discounting to present values. Hepatitis A vaccine would have the lowest health system costs per life-year saved. Varicella vaccine would provide the greatest reduction in societal costs, mainly through reduced parent work loss. Pneumococcal conjugate vaccine would cost twice the amount of varicella and hepatitis A vaccines combined and be less cost effective than the other vaccines. Hepatitis A and varicella vaccines, but not pneumococcal conjugate vaccine, meet or exceed conventional standards of cost effectiveness. Copyright 2001 American Health Foundation and Elsevier Science.

Autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus vaccination in Colombians: a call for personalised medicine.

PubMed

Anaya, Juan-Manuel; Reyes, Benjamin; Perdomo-Arciniegas, Ana M; Camacho-Rodríguez, Bernardo; Rojas-Villarraga, Adriana

2015-01-01

This was a case study in which 3 patients with autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus vaccination (HPV) were evaluated and described. All the patients were women. Diagnosis consisted of HLA-B27 enthesitis related arthritis, rheumatoid arthritis and systemic lupus erythematous, respectively. Our results highlight the risk of developing ASIA after HPV vaccination and may serve to increase the awareness of such a complication. Factors that are predictive of developing autoimmune diseases should be examined at the population level in order to establish preventive measures in at-risk individuals for whom healthcare should be personalized and participatory.

Immunogenicity and Safety of an Inactivated Quadrivalent Influenza Vaccine in US Children 6–35 Months of Age During 2013–2014: Results From A Phase II Randomized Trial

PubMed Central

Wang, Long; Chandrasekaran, Vijayalakshmi; Domachowske, Joseph B.; Li, Ping; Innis, Bruce L.; Jain, Varsha K.

2016-01-01

Background Viruses from 2 influenza B lineages co-circulate, leading to suboptimal protection with trivalent influenza vaccines (TIV). Quadrivalent influenza vaccines (QIV) containing both lineages offer broader protection. Methods We compared inactivated seasonal QIV versus TIV (15 and 7.5 μg hemagglutinin [HA] for each influenza strain, respectively) in a phase II randomized (1 : 1), observer-blind trial in US children 6–35 months of age (identifier NCT01974895). The primary objective was to evaluate immune responses induced by QIV for the 4 vaccine strains 28 days after completion of vaccination. A secondary objective was to demonstrate superiority of QIV versus TIV for the B/Victoria strain contained in QIV but not TIV. Immunogenicity was evaluated in the per-protocol cohort (N = 280), and safety was evaluated in the intent-to-treat cohort (N = 314). Results Seroconversion rates (SCRs) for QIV were 80.4% (95% confidence interval [CI], 73.0%–86.6%), 72.0% (95% CI, 63.9%–79.2%), 86.0% (95% CI, 79.2%–91.2%), and 66.4% (95% CI, 58.1%–74.1%) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria, respectively. Quadrivalent influenza vaccines demonstrated immunogenic superiority over TIV for B/Victoria with a geometric mean titer ratio of 4.73 (95% CI, 3.73%–5.99%) and SCR difference of 54.02% (95% CI, 43.88%–62.87%). Safety was similar between the vaccine groups despite the QIV's higher antigen content. No serious adverse events were reported related to vaccination. Conclusions Quadrivalent influenza vaccine (15 µg HA/strain) was immunogenic with an acceptable safety profile. The next phase of its development in children 6–35 months of age is a phase III trial in countries where it is not yet licensed. In countries where it is already licensed, a switch from TIV to QIV would provide broader protection in this vulnerable group. PMID:26407273

Conjugate-like immunogens produced as protein capsular matrix vaccines.

PubMed

Thanawastien, Ann; Cartee, Robert T; Griffin, Thomas J; Killeen, Kevin P; Mekalanos, John J

2015-03-10

Capsular polysaccharides are the primary antigenic components involved in protective immunity against encapsulated bacterial pathogens. Although immunization of adolescents and adults with polysaccharide antigens has reduced pathogen disease burden, pure polysaccharide vaccines have proved ineffective at conferring protective immunity to infants and the elderly, age cohorts that are deficient in their adaptive immune responses to such antigens. However, T-cell-independent polysaccharide antigens can be converted into more potent immunogens by chemically coupling to a "carrier protein" antigen. Such "conjugate vaccines" efficiently induce antibody avidity maturation, isotype switching, and immunological memory in immunized neonates. These immune responses have been attributed to T-cell recognition of peptides derived from the coupled carrier protein. The covalent attachment of polysaccharide antigens to the carrier protein is thought to be imperative to the immunological properties of conjugate vaccines. Here we provide evidence that covalent attachment to carrier proteins is not required for conversion of T-independent antigens into T-dependent immunogens. Simple entrapment of polysaccharides or a d-amino acid polymer antigen in a cross-linked protein matrix was shown to be sufficient to produce potent immunogens that possess the key characteristics of conventional conjugate vaccines. The versatility and ease of manufacture of these antigen preparations, termed protein capsular matrix vaccines (PCMVs), will likely provide improvements in the manufacture of vaccines designed to protect against encapsulated microorganisms. This in turn could improve the availability of such vaccines to the developing world, which has shown only a limited capacity to afford the cost of conventional conjugate vaccines.

Public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines compared to trivalent influenza vaccines in Europe.

PubMed

Uhart, Mathieu; Bricout, Hélène; Clay, Emilie; Largeron, Nathalie

2016-09-01

Influenza B strains represent on average 23% of all circulating strains in Europe and when there is a vaccine mismatch on B strains, additional influenza-related hospitalizations and deaths as well as substantial additional costs are observed. The objective was to estimate the public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines (QIV) compared to trivalent influenza vaccines (TIV) in Europe (EU). Based on data from 5 EU countries (France, Germany, Italy, Spain and UK) during 10 influenza seasons from 2002 to 2013, epidemiological and associated economic outcomes were estimated for each season for the actual scenario where the TIV was used, and for a hypothetical scenario where QIV could have been used instead. By using QIV, this study estimated that for the 5 EU countries, an additional 1.03 million (327.9/100,000 inhabitants) influenza cases, 453,000 (143.9/100,000) general practitioners consultations, 672,000 (213.1/100,000) workdays lost, 24,000 (7.7/100,000) hospitalizations and 10,000 (3.1/100,000) deaths could have been avoided compared to the use of TIV over the 10-seasons-period. This study estimates that QIV can be of economic value since from a societal perspective 15 million Euros would have been saved on general practitioners consultations (14 million Euros from third-party payer perspective), 77 million on hospitalizations (74 million Euros from third-party payer perspective) and 150 million Euros on workdays lost, across the 5 EU countries. In conclusion, the present study estimates that, compared to TIV, QIV may result in a substantial decrease in epidemiological burden and in influenza-related costs.

Cost-effectiveness analysis of quadrivalent influenza vaccine versus trivalent influenza vaccine for elderly in Hong Kong.

PubMed

You, Joyce H S; Ming, Wai-kit; Chan, Paul K S

2014-11-25

Cost and quality-adjusted life-years (QALYs) gained by quadrivalent influenza vaccine (QIV) versus trivalent influenza vaccine (TIV) in Hong Kong elderly were estimated over 9 seasons. TIV-unmatched influenza B infection rates with QIV versus TIV were estimated by an epidemiology model. Model parameters included percentages of influenza B lineages in circulation, influenza B-associated hospital admission, age-specific population, vaccine coverage and effectiveness. Incremental cost per QALY gained (ICER) by QIV versus TIV were estimated from Hong Kong's societal perspective. Mean reduction in influenza B infection rate was 191.3 (95%CI 45.1-337.5) per 100,000 population aged ≥65 years. Highest cost savings and QALYs gained by QIV occurred in 2007 with high percentage of TIV-unmatched strain (92.9%) for age groups 65-79 years (USD266,473 and 22.8 QALYs) and ≥80 years (USD483,461 and 27.3 QALYs). ICERs of QIV were below willingness-to-pay for age group 65-79 years in 6, 5 and 3 years when QIV cost + USD1 + USD2 and + USD5 more than TIV, respectively. For age group ≥80 years, ICERs of QIV were below willingness-to-pay in 7 and 5 years when QIV cost + USD1 and + USD5, correspondingly. Acceptance of QIV to be cost-effective in Hong Kong elderly was subject to QIV unit cost and percentage of circulating TIV-unmatched influenza B lineages.

Modeling the cost-effectiveness of infant vaccination with pneumococcal conjugate vaccines in Germany.

PubMed

Kuhlmann, Alexander; von der Schulenburg, J-Matthias Graf

2017-04-01

In 2009, the European Medicines Agency granted approval for two higher-valent pneumococcal conjugate vaccines. This study aims to evaluate the cost-effectiveness of universal infant (<2 years old) vaccination with a 13-valent pneumococcal conjugate vaccine (PCV13) in comparison with a 10-valent pneumococcal conjugate vaccine (PCV10) for the prevention of pneumococcal disease in Germany. A population-based Markov model was developed to estimate the impact of PCV13 and PCV10 on invasive pneumococcal disease (IPD), non-invasive pneumonia (PNE), and acute otitis media (AOM) over a time horizon of 50 years. The model included the effects of the historical vaccination scheme in infants as well as indirect herd effects and replacement disease. We used German epidemiological data to calculate episodes of IPD, PNE, and AOM, as well as direct and indirect effects of the vaccination. Parameter uncertainty was tested in univariate and probabilistic sensitivity analyses. In the base-case analysis, the ICER of PCV13 versus PCV10 infant vaccination was EUR 9826 per quality-adjusted life-year (QALY) gained or EUR 5490 per life-year (LY) gained from the societal perspective and EUR 3368 per QALY gained or EUR 1882 per LY gained from the perspective of the German statutory health insurance. The results were particularly sensitive to the magnitude of indirect effects of both vaccines. Universal infant vaccination with PCV13 is likely to be a cost-effective intervention compared with PCV10 within the German health care system, if additional net indirect effects of PCV13 vaccination are significant.

Human papillomavirus vaccines and vaccine implementation.

PubMed

de Sanjosé, Silvia; Alemany, Laia; Castellsagué, Xavier; Bosch, F Xavier

2008-11-01

Countries are now challenged by the rapid development of vaccines aimed at the primary prevention of infections. In the years to come, several vaccines will need to be considered as potential candidates in routine immunization programs. Recently, two new vaccines against two/four types of human papillomavirus (HPV) have been commercialized. Bivalent HPV 16 and 18 (Cervarix) and quadrivalent HPV 6, 11, 16 and 18 (Gardasil) vaccines are now extensively used in some countries. These vaccines will prevent infection and long-running complications, such as cervical cancer, other HPV-related cancers and genital warts (for the quadrivalent vaccine). The beneficial effect of these vaccines will be largely observed in women. This article summarizes the burden of HPV preventable disease worldwide and briefly describes the impact of secondary prevention and the most relevant aspects of the current available vaccines, their efficacy and safety. Finally, some major aspects that are likely to impact the introduction of these vaccines around the world are outlined, with particular emphasis on developing countries.

Cost-effectiveness of different human papillomavirus vaccines in Singapore.

PubMed

Lee, Vernon J; Tay, Sun Kuie; Teoh, Yee Leong; Tok, Mei Yin

2011-03-31

Human papillomavirus (HPV) vaccines are widely available and there have been studies exploring their potential clinical impact and cost-effectiveness. However, few studies have compared the cost-effectiveness among the 2 main vaccines available - a bivalent vaccine against HPV 16/18, and a quadrivalent vaccine against 6/11/16/18. We explore the cost-effectiveness of these two HPV vaccines in tropical Singapore. We developed a Markov state-transition model to represent the natural history of cervical cancer to predict HPV infection, cancer incidence, mortality, and costs. Cytologic screening and treatment of different outcomes of HPV infection were incorporated. Vaccination was provided to a cohort of 12-year old females in Singapore, followed up until death. Based on available vaccines on the market, the bivalent vaccine had increased effectiveness against a wider range of HPV types, while the quadrivalent vaccine had effectiveness against genital warts. Incremental cost-effectiveness ratios (ICER) compared vaccination to no-vaccination, and between the two vaccines. Sensitivity analyses explored differences in vaccine effectiveness and uptake, and other key input parameters. For the no vaccination scenario, 229 cervical cancer cases occurred over the cohort's lifetime. The total discounted cost per individual due to HPV infection was SGD$275 with 28.54 discounted life-years. With 100% vaccine coverage, the quadrivalent vaccine reduced cancers by 176, and had an ICER of SGD$12,866 per life-year saved. For the bivalent vaccine, 197 cancers were prevented with an ICER of $12,827 per life-year saved. Comparing the bivalent to the quadrivalent vaccine, the ICER was $12,488 per life-year saved. However, the cost per QALY saved for the quadrivalent vaccine compared to no vaccine was $9,071, while it was $10,392 for the bivalent vaccine, with the quadrivalent vaccine dominating the bivalent vaccine due to the additional QALY effect from reduction in genital warts. The

[Pneumococcal vaccines. New conjugate vaccines for adults].

PubMed

Campins Martí, Magda

2015-11-01

Pneumococcal infections are a significant cause of morbidity and mortality, and are one of the 10 leading causes of death worldwide. Children under 2 years have a higher incidence rate, followed by adults over 64 years. The main risk group are individuals with immunodeficiency, and those with anatomical or functional asplenia, but can also affect immunocompetent persons with certain chronic diseases. Significant progress has been made in the last 10 years in the prevention of these infections. Until a few years ago, only the 23-valent non-conjugate pneumococcal vaccine was available. Its results were controversial in terms of efficacy and effectiveness, and with serious limitations on the type of immune response induced. The current possibility of using the 13-valent conjugate vaccine in adults has led to greater expectations in improving the prevention of pneumococcal disease in these age groups. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Cost-effectiveness analysis of the bivalent compared with the quadrivalent human papillomavirus vaccines in Taiwan.

PubMed

Demarteau, Nadia; Tang, Chao-Hsiun; Chen, Hui-Chi; Chen, Chien-Jen; Van Kriekinge, Georges

2012-01-01

To compare the epidemiological and economic impact of additional cross-protection against oncogenic human papillomavirus (HPV) types beyond 16/18 of the bivalent vaccine (BV) versus protection against nononcogenic HPV types 6/11 of the quadrivalent vaccine (QV) in Taiwan. A lifetime Markov model calibrated to the Taiwanese setting simulated the natural history of low-risk (engendering cervical intraepithelial neoplasia [CIN] 1 and genital warts) and high-risk HPV (engendering CIN1, CIN2/3, and cervical cancer [CC]) infections, screening, and vaccination (100% coverage) for a cohort of 12-year-old girls (N = 153,000). Transition probabilities, costs, and utilities were estimated from published data and expert opinion. Vaccine efficacy was obtained from each vaccine's respective clinical trials. Price-parity and lifelong protection was assumed for both vaccines. The number of CIN lesions, CC cases, CC deaths and genital wart (GW) cases, and quality-adjusted life-years were estimated. Costs and outcomes (discounted at 3% and 1.5%, respectively) were compared from a payer's perspective. The model estimated that the BV led to an additional, undiscounted, 11,484 CIN1, 1,779 (+34.3% vs. QV) CIN2/3, 188 (+29.0% vs. QV) CC, and 69 (+29.0% vs. QV) CC deaths prevented compared with the QV, while the QV prevented 4,150 GW (+71%). This resulted in an additional 768 quality-adjusted life-years (QALY) and 11.6 million new Taiwan dollars costs saved for the BV versus the QV after discounting. Both vaccines have a different epidemiological impact with an increased number of CC-related lesions potentially prevented for the BV because of additional cross-protection. In the Taiwanese setting, HPV mass vaccination using the BV was estimated to dominate vaccination using the QV. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Conjugation, characterization and toxicity of lipophosphoglycan-polyacrylic acid conjugate for vaccination against leishmaniasis.

PubMed

Topuzogullari, Murat; Cakir Koc, Rabia; Dincer Isoglu, Sevil; Bagirova, Melahat; Akdeste, Zeynep; Elcicek, Serhat; Oztel, Olga N; Yesilkir Baydar, Serap; Canim Ates, Sezen; Allahverdiyev, Adil M

2013-06-03

Research on the conjugates of synthetic polyelectrolytes with antigenic molecules, such as proteins, peptides, or carbohydrates, is an attractive area due to their highly immunogenic character in comparison to classical adjuvants. For example, polyacrylic acid (PAA) is a weak polyelectrolyte and has been used in several biomedical applications such as immunological studies, drug delivery, and enzyme immobilization. However, to our knowledge, there are no studies that document immune-stimulant properties of PAA in Leishmania infection. Therefore, we aimed to develop a potential vaccine candidate against leishmaniasis by covalently conjugating PAA with an immunologically vital molecule of lipophosphoglycan (LPG) found in Leishmania parasites. In the study, LPG and PAA were conjugated by a multi-step procedure, and final products were analyzed with GPC and MALDI-TOF MS techniques. In cytotoxicity experiments, LPG-PAA conjugates did not indicate toxic effects on L929 and J774 murine macrophage cells. We assume that LPG-PAA conjugate can be a potential vaccine candidate, and will be immunologically characterized in further studies to prove its potential.

Safety and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected and HIV-negative adolescents and young adults.

PubMed

Giacomet, Vania; Penagini, Francesca; Trabattoni, Daria; Viganò, Alessandra; Rainone, Veronica; Bernazzani, Giada; Bonardi, Claudia Maria; Clerici, Mario; Bedogni, Giorgio; Zuccotti, Gian Vincenzo

2014-09-29

Human papillomavirus (HPV) infection is highly prevalent and can lead to cancer; the development of safe and efficacious vaccines for HPV is a major public health concern. The two licensed HPV vaccines contain recombinant virus-like particles of HPV 16 and 18; one of such vaccines also protects against HPV types 6 and 11 which cause genital warts. We determined safety and immunogenicity of quadrivalent HPV vaccine in HIV-infected and HIV-negative adolescents and young adults, aged 13-27 years. The seroconversion rate, assessed by antibody titers, 1 month after the administration of the third vaccine dose was 0.85 (95% CI 0.75-0.95) in the HIV-infected group and 0.91 (0.83-0.99) in the HIV-negative subjects (p=0.52). The vaccine was generally safe and well tolerated; the most common side effect was local pain and the most frequent systemic side effect was headache. This is the first report on response to HPV vaccination in both female and male HIV-infected adolescents and young adults and highlights that this population may benefit from HPV immunoprophylaxis. Further studies are needed to examine the long term efficacy of this vaccine in HIV-infected individuals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lessons learned during the development and transfer of technology related to a new Hib conjugate vaccine to emerging vaccine manufacturers.

PubMed

Hamidi, A; Boog, C; Jadhav, S; Kreeftenberg, H

2014-07-16

The incidence of Haemophilus Influenzae type b (Hib) disease in developed countries has decreased since the introduction of Hib conjugate vaccines in their National Immunization Programs (NIP). In countries where Hib vaccination is not applied routinely, due to limited availability and high cost of the vaccines, invasive Hib disease is still a cause of mortality. Through the development of a production process for a Hib conjugate vaccine and related quality control tests and the transfer of this technology to emerging vaccine manufacturers in developing countries, a substantial contribution was made to the availability and affordability of Hib conjugate vaccines in these countries. Technology transfer is considered to be one of the fastest ways to get access to the technology needed for the production of vaccines. The first Hib conjugate vaccine based on the transferred technology was licensed in 2007, since then more Hib vaccines based on this technology were licensed. This paper describes the successful development and transfer of Hib conjugate vaccine technology to vaccine manufacturers in India, China and Indonesia. By describing the lessons learned in this process, it is hoped that other technology transfer projects can benefit from the knowledge and experience gained. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cost-effectiveness analysis of the bivalent and quadrivalent human papillomavirus vaccines from a societal perspective in Colombia.

PubMed

Aponte-González, Johanna; Fajardo-Bernal, Luisa; Diaz, Jorge; Eslava-Schmalbach, Javier; Gamboa, Oscar; Hay, Joel W

2013-01-01

To compare costs and effectiveness of three strategies used against cervical cancer (CC) and genital warts: (i) Screening for CC; (ii) Bivalent Human Papillomavirus (HPV) 16/18 vaccine added to screening; (iii) Quadrivalent HPV 6/11/16/18 vaccine added to screening. A Markov model was designed in order to simulate the natural history of the disease from 12 years of age (vaccination) until death. Transition probabilities were selected or adjusted to match the HPV infection profile in Colombia. A systematic review was undertaken in order to derive efficacy values for the two vaccines as well as for the operational characteristics of the cytology test. The societal perspective was used. Effectiveness was measured in number of averted Disability Adjusted Life Years (DALYS). At commercial prices reported for 2010 the two vaccines were shown to be non-cost-effective alternatives when compared with the existing screening strategy. Sensitivity analyses showed that results are affected by the cost of vaccines and their efficacy values, making it difficult to determine with certainty which of the two vaccines has the best cost-effectiveness profile. To be 'cost-effective' vaccines should cost between 141 and 147 USD (Unite States Dollars) per vaccinated girl at the most. But at lower prices such as those recommended by WHO or the price of other vaccines in Colombia, HPV vaccination could be considered very cost-effective. HPV vaccination could be a convenient alternative for the prevention of CC in Colombia. However, the price of the vaccine should be lower for this vaccination strategy to be cost-effective. It is also important to take into consideration the willingness to pay, budgetary impact, and program implications, in order to determine the relevance of a vaccination program in this country, as well as which vaccine should be selected for use in the program.

Cost-Effectiveness Analysis of the Bivalent and Quadrivalent Human Papillomavirus Vaccines from a Societal Perspective in Colombia

PubMed Central

Aponte-González, Johanna; Fajardo-Bernal, Luisa; Diaz, Jorge; Eslava-Schmalbach, Javier; Gamboa, Oscar; Hay, Joel W.

2013-01-01

Objective To compare costs and effectiveness of three strategies used against cervical cancer (CC) and genital warts: (i) Screening for CC; (ii) Bivalent Human Papillomavirus (HPV) 16/18 vaccine added to screening; (iii) Quadrivalent HPV 6/11/16/18 vaccine added to screening. Methods A Markov model was designed in order to simulate the natural history of the disease from 12 years of age (vaccination) until death. Transition probabilities were selected or adjusted to match the HPV infection profile in Colombia. A systematic review was undertaken in order to derive efficacy values for the two vaccines as well as for the operational characteristics of the cytology test. The societal perspective was used. Effectiveness was measured in number of averted Disability Adjusted Life Years (DALYS). Results At commercial prices reported for 2010 the two vaccines were shown to be non-cost-effective alternatives when compared with the existing screening strategy. Sensitivity analyses showed that results are affected by the cost of vaccines and their efficacy values, making it difficult to determine with certainty which of the two vaccines has the best cost-effectiveness profile. To be ‘cost-effective’ vaccines should cost between 141 and 147 USD (Unite States Dollars) per vaccinated girl at the most. But at lower prices such as those recommended by WHO or the price of other vaccines in Colombia, HPV vaccination could be considered very cost-effective. Conclusions HPV vaccination could be a convenient alternative for the prevention of CC in Colombia. However, the price of the vaccine should be lower for this vaccination strategy to be cost-effective. It is also important to take into consideration the willingness to pay, budgetary impact, and program implications, in order to determine the relevance of a vaccination program in this country, as well as which vaccine should be selected for use in the program. PMID:24260441

Safety and immunogenicity of typhoid fever and yellow fever vaccines when administered concomitantly with quadrivalent meningococcal ACWY glycoconjugate vaccine in healthy adults.

PubMed

Alberer, Martin; Burchard, Gerd; Jelinek, Tomas; Reisinger, Emil; Beran, Jiri; Hlavata, Lucie Cerna; Forleo-Neto, Eduardo; Dagnew, Alemnew F; Arora, Ashwani K

2015-01-01

Compact and short pre-travel immunization schedules, which include several vaccinations in a single visit, are desirable for many travelers. However, concomitant vaccination could potentially compromise immunogenicity and/or safety of the individual vaccines and, therefore, possible vaccine interferences should be carefully assessed. This article discusses the immunogenicity and safety of travel vaccines for typhoid fever (TF) and yellow fever (YF), when administered with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine (MenACWY-CRM). Healthy adults (18-≤60 years) were randomized to one of three vaccine regimens: TF + YF + MenACWY-CRM (group I; n = 100), TF + YF (group II; n = 101), or MenACWY-CRM (group III; n = 100). Immunogenicity at baseline and 4 weeks post-vaccination (day 29) was assessed by serum bactericidal assay using human complement (hSBA), enzyme-linked immunosorbent assay (ELISA), or a neutralization test. Adverse events (AEs) and serious adverse events (SAEs) were collected throughout the study period. Non-inferiority of post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) was established for TF and YF vaccines, respectively, when given concomitantly with MenACWY-CRM vaccine versus when given alone. The percentages of subjects with seroprotective neutralizing titers against YF on day 29 were similar in groups I and II. The antibody responses to meningococcal serogroups A, C, W-135, and Y were within the same range when MenACWY-CRM was given separately or together with TF and YF vaccines. The percentage of subjects reporting AEs was the same for TF and YF vaccines with or without MenACWY-CRM vaccine. There were no reports of SAEs or AEs leading to study withdrawals. These data provide evidence that MenACWY-CRM can be administered with typhoid Vi polysaccharide vaccine and live attenuated YF vaccine without compromising antibody responses stimulated by the

Antibody persistence up to 5 years after vaccination of toddlers and children between 12 months and 10 years of age with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine.

PubMed

Vesikari, Timo; Forsten, Aino; Bianco, Veronique; Van der Wielen, Marie; Miller, Jacqueline M

2016-01-01

We studied the persistence of serum bactericidal antibody using rabbit and human complement (rSBA/hSBA, cut-offs 1:8) 5 y after a single dose of meningococcal serogroups A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT) compared with age-appropriate control vaccines in toddlers and children (NCT00427908). Children were previously randomized (3:1) to receive either MenACWY-TT or control vaccine (MenC-CRM197 in 1-<2 y olds; MenACWY-polysaccharide vaccine [Men-PS] in 2-<11 y olds). Subjects with rSBA-MenC titers <1:8 at any time point were revaccinated with MenC conjugate vaccine and discontinued from the study. A repeated measurement statistical model assessed potential selection effects due to drop-outs. At year 5 in MenACWY-TT-vaccinated-toddlers for serogroups A, C, W, and Y respectively, percentages with rSBA titers ≥1:8 were 73.5%, 77.6%, 34.7%, and 42.9%, hSBA ≥1:8 were 35.6%, 91.7%, 82.6% and 80.0%. For MenC-CRM197 recipients, 63.6% had persisting rSBA-MenC titers ≥1:8 and 90.9% had hSBA-MenC ≥1:8 (not significantly different versus MenACWY-TT for either assay: exploratory analyses). In 2-<11 y olds rSBA titers ≥1:8 in MenACWY-TT-vaccinees were 90.8%, 90.8%, 78.6%, and 78.6% and 15.4%, 100%, 0.0%, 7.7% in Men-PS-vaccinees (significantly different for serogroups A, W and Y, exploratory analyses). Serogroups A, W and Y rSBA GMTs were ≥ 26-fold higher in MenACWY-TT-vaccinees. As expected, GMTs modeled at year 5 to assess the impact of subject drop out (mainly for revaccination), appeared lower for serogroup C. No vaccine-related SAEs were reported. Antibody persistence was observed for all serogroups up to 5 y after MenACWY-TT vaccination.

Safety and immunogenicity of an investigational meningococcal ACWY conjugate vaccine (MenACWY-CRM) in healthy Indian subjects aged 2 to 75 years.

PubMed

Lalwani, Sanjay; Agarkhedkar, Sharad; Gogtay, Nithya; Palkar, Sonali; Agarkhedkar, Shalaka; Thatte, Urmila; Vakil, Hoshang; Jonnalagedda, Rekha; Pedotti, Paola; Hoyle, Margaret; Bhusal, Chiranjiwi; Arora, Ashwani

2015-09-01

This phase 3, multi-center, open-label study evaluated the immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM, Menveo(®); Novartis Vaccines and Diagnostics S.r.l., Siena, Italy) in healthy Indian subjects aged 2-75 years, to provide data for licensure in India. A total of 180 subjects were enrolled (60 subjects 2-10 years, 60 subjects 11-18 years, and 60 subjects 19-75 years) and received one dose of MenACWY-CRM. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination. Adverse events were collected throughout the 29-day study period. Percentages of subjects with post-vaccination hSBA ≥8 were 72%, 95%, 94%, and 90% for serogroups A, C, W, and Y, respectively. Geometric mean titers rose 7-fold to 42-fold against the four serogroups. Similar immune responses were observed for the age subgroups 2-10 years, 11-18 years, and 19-75 years. Seroresponse rates at 1 month following vaccination were 72%, 88%, 55%, and 71% for serogroups A, C, W, and Y, respectively. The vaccine was well tolerated with no safety concerns. A single dose of MenACWY-CRM induced a robust immune response against all four meningococcal serogroups and was well tolerated in an Indian population 2-75 years of age. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

The Australian funding debate on quadrivalent HPV vaccine: a case study for the national pharmaceutical policy.

PubMed

Roughead, Elizabeth Ellen; Gilbert, Andrew L; Vitry, Agnes I

2008-12-01

To analyse the media and political reactions to the initial decision of the Pharmaceutical Benefits Advisory Committee (PBAC) to reject funding of the quadrivalent human papilloma virus (HPV) vaccine in Australia. A case study, informed by media reports and government documents, was utilised to examine the reactions of key stakeholders; PBAC, consumers, consumer organisations, pharmaceutical industry, politicians, health professionals and the media to the initial decision to reject funding of HPV vaccine. The initial decision to reject funding of the HPV vaccine led to unprecedented public response with over 300 newspaper articles and calls by consumers, health professionals and politicians to intervene in the decision making process. Misunderstanding of the decision making process, particularly cost-effectiveness assessments, the need for an independent process, the legislated inability of a timely and transparent response from policy makers and the lack of a risk mitigation strategy all played a role in the public outcry. Despite 15 years of implementation of cost-effectiveness assessments there is still a need for improving stakeholder understanding of the decision making process and for timely transfer of complete information. Risk mitigation strategies should be considered as part of the communication plan for all decisions.

Assessment of potential public health impact of a quadrivalent inactivated influenza vaccine in Thailand.

PubMed

Kittikraisak, Wanitchaya; Chittaganpitch, Malinee; Gregory, Christopher J; Laosiritaworn, Yongjua; Thantithaveewat, Thanawadee; Dawood, Fatimah S; Lindblade, Kim A

2016-05-01

Each year, an influenza B strain representing only one influenza B lineage is included in the trivalent inactivated influenza vaccine (IIV3); a mismatch between the selected lineage and circulating viruses can result in suboptimal vaccine effectiveness. We modeled the added potential public health impact of a quadrivalent inactivated influenza vaccine (IIV4) that includes strains from both influenza B lineages compared to IIV3 on influenza-associated morbidity and mortality in Thailand. Using data on the incidence of influenza-associated hospitalizations and deaths, vaccine effectiveness, and vaccine coverage from the 2007-2012 influenza seasons in Thailand, we estimated rates of influenza-associated outcomes that might be averted using IIV4 instead of IIV3. We then applied these rates to national population estimates to calculate averted illnesses, hospitalizations, and deaths for each season. We assumed that the influenza B lineage included in IIV3 would provide a relative vaccine effectiveness of 75% against the other B lineage. Compared to use of IIV3, use of IIV4 might have led to an additional reduction ranging from 0·4 to 14·3 influenza-associated illnesses per 100 000 population/year, <0·1 to 0·5 hospitalizations per 100 000/year, and <0·1 to 0·4 deaths per 1000/year. Based on extrapolation to national population estimates, replacement of IIV3 with IIV4 might have averted an additional 267-9784 influenza-associated illnesses, 9-320 hospitalizations, and 0-3 deaths. Compared to use of IIV3, IIV4 has the potential to further reduce the burden of influenza-associated morbidity and mortality in Thailand. © 2015 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

A plant-derived quadrivalent virus like particle influenza vaccine induces cross-reactive antibody and T cell response in healthy adults.

PubMed

Pillet, Stéphane; Aubin, Éric; Trépanier, Sonia; Bussière, Diane; Dargis, Michèle; Poulin, Jean-François; Yassine-Diab, Bader; Ward, Brian J; Landry, Nathalie

2016-07-01

Recent issues regarding efficacy of influenza vaccines have re-emphasized the need of new approaches to face this major public health issue. In a phase 1-2 clinical trial, healthy adults received one intramuscular dose of a seasonal influenza plant-based quadrivalent virus-like particle (QVLP) vaccine or placebo. The hemagglutination inhibition (HI) titers met all the European licensure criteria for the type A influenza strains at the 3μg/strain dose and for all four strains at the higher dosages 21days after immunization. High HI titers were maintained for most of the strains 6months after vaccination. QVLP vaccine induced a substantial and sustained increase of hemagglutinin-specific polyfunctional CD4 T cells, mainly transitional memory and TEMRA effector IFN-γ(+) CD4 T cells. A T cells cross-reactive response was also observed against A/Hong-Kong/1/1968 H3N2 and B/Massachusetts/2/2012. Plant-based QVLP offers an attractive alternative manufacturing method for producing effective and HA-strain matching seasonal influenza vaccines. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Humoral, Mucosal, and Cell-Mediated Immunity Against Vaccine and Nonvaccine Genotypes After Administration of Quadrivalent Human Papillomavirus Vaccine to HIV-Infected Children

PubMed Central

Weinberg, Adriana; Song, Lin-Ye; Saah, Alfred; Brown, Martha; Moscicki, Anna B.; Meyer, William A.; Bryan, Janine; Levin, Myron J.

2012-01-01

Objectives. To characterize the immunogenicity of a quadrivalent human papillomavirus vaccine (QHPV) in human immunodeficiency virus (HIV)–infected children, we studied their immune responses to 3 or 4 doses. Methods. HIV-infected children aged 7–12 years with a CD4 cell percentage of ≥15% of lymphocytes, received 3 doses of QHPV with or without a fourth dose after 72 weeks. Type-specific and cross-reactive antibodies and cell-mediated immunity were measured. Results. Type-specific antibodies to HPV6, 11, and 16 were detected in 100% and ≥94% of children at 4 and 72 weeks, respectively, after the third QHPV dose. Corresponding numbers for HPV18 were 97% and 76%, respectively. A fourth QHPV dose increased seropositivity to ≥96% for all vaccine genotypes. Four weeks after the third QHPV dose, 67% of vaccinees seroconverted to HPV31, an HPV16-related genotype not in the vaccine; 69% and 39% of vaccinees developed mucosal HPV16 and 18 immunoglobulin G antibodies, respectively; and 60% and 52% of vaccinees developed cytotoxic T lymphocytes (CTLs) for HPV16 and 31, respectively. Conclusions. Three QHPV doses generated robust and persistent antibodies to HPV6, 11, and 16 but comparatively weaker responses to HPV18. A fourth dose increased antibodies against all vaccine genotypes in an anamnestic fashion. CTLs and mucosal antibodies against vaccine genotypes, as well as cross-reactive antibodies and CTL against nonvaccine genotypes, were detected. PMID:22859825

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.

2010 FIFA world cup South Africa: travel health issues and new options for protection against meningococcal disease.

PubMed

Zuckerman, Jane N; Bröker, Michael; Worth, Christopher

2010-03-01

The public health implications of large crowds gathering at a range of key global events should never be underestimated. This is especially the case with the upcoming 2010 FIFA World Cup South Africa programme where thousands of local and travelling spectators, players and officials from all over the world will be present. Although meningococcal disease contracted whilst actually travelling is relatively rare, any travel health risk assessment should involve consideration of potential exposure to and transmission of this disease where crowding occurs. In South Africa, for reasons not completely understood, the incidence of meningococcal disease is higher than in most European countries. Whilst the currently available polysaccharide vaccines can help protect travellers against meningococcal disease there are some well recognised limitations of such vaccines. These can, however, be overcome with the use of newly developed conjugated quadrivalent meningococcal vaccines. A quadrivalent conjugate vaccine should be the first choice for travellers to areas in which the risk of exposure to meningococcal disease is significant. The conjugated quadrivalent meningococcal vaccine should be recommended for all those attending or playing in the 2010 FIFA World Cup South Africa as well as similar global and regional events.

Self-Adjuvanting Glycopeptide Conjugate Vaccine against Disseminated Candidiasis

PubMed Central

Xin, Hong; Cartmell, Jonathan; Bailey, Justin J.; Dziadek, Sebastian; Bundle, David R.; Cutler, Jim E.

2012-01-01

Our research on pathogenesis of disseminated candidiasis led to the discovery that antibodies specific for Candida albicans cell surface β-1, 2–mannotriose [β-(Man)3] protect mice. A 14 mer peptide Fba, which derived from the N-terminal portion of the C. albicans cytosolic/cell surface protein fructose-bisphosphate aldolase, was used as the glycan carrier and resulted in a novel synthetic glycopeptide vaccine β-(Man)3-Fba. By a dendritic cell-based immunization approach, this conjugate induced protective antibody responses against both the glycan and peptide parts of the vaccine. In this report, we modified the β-(Man)3-Fba conjugate by coupling it to tetanus toxoid (TT) in order to improve immunogenicity and allow for use of an adjuvant suitable for human use. By new immunization procedures entirely compatible with human use, the modified β-(Man)3-Fba-TT was administered either alone or as a mixture made with alum or monophosphoryl lipid A (MPL) adjuvants and given to mice by a subcutaneous (s.c.) route. Mice vaccinated with or, surprisingly, without adjuvant responded well by making robust antibody responses. The immunized groups showed a high degree of protection against a lethal challenge with C. albicans as evidenced by increased survival times and reduced kidney fungal burden as compared to control groups that received only adjuvant or DPBS buffer prior to challenge. To confirm that induced antibodies were protective, sera from mice immunized against the β-(Man)3-Fba-TT conjugate transferred protection against disseminated candidiasis to naïve mice, whereas C. albicans-absorbed immune sera did not. Similar antibody responses and protection induced by the β-(Man)3-Fba-TT vaccine was observed in inbred BALB/c and outbred Swiss Webster mice. We conclude that addition of TT to the glycopeptide conjugate results in a self-adjuvanting vaccine that promotes robust antibody responses without the need for additional adjuvant, which is novel and represents a

Preclinical evaluation of a Haemophilus influenzae type b conjugate vaccine process intended for technology transfer.

PubMed

Hamidi, Ahd; Verdijk, Pauline; Kreeftenberg, Hans

2014-01-01

Introduction of Haemophilus influenzae type b (Hib) vaccine in low- and middle-income countries has been limited by cost and availability of Hib conjugate vaccines for a long time. It was previously recognized by the Institute for Translational Vaccinology (Intravacc, originating from the former Vaccinology Unit of the National Institute of Public Health [RIVM] and the Netherlands Vaccine Institute [NVI]) that local production of a Hib conjugate vaccine would increase the affordability and sustainability of the vaccine and thereby help to speed up Hib introduction in these countries. A new affordable and a non-infringing production process for a Hib conjugate vaccine was developed, including relevant quality control tests, and the technology was transferred to a number of vaccine manufacturers in India, Indonesia, and China. As part of the Hib technology transfer project managed by Intravacc, a preclinical toxicity study was conducted in the Netherlands to test the safety and immunogenicity of this new Hib conjugate vaccine. The data generated by this study were used by the technology transfer partners to accelerate the clinical development of the new Hib conjugate vaccine. A repeated dose toxicity and local tolerance study in rats was performed to assess the reactogenicity and immunogenicity of a new Hib conjugate vaccine compared to a licensed vaccine. The results showed that the vaccine was well tolerated and immunogenic in rats, no major differences in both safety and immunogenicity in rats were found between the vaccine produced according to the production process developed by Intravacc and the licensed one. Rats may be useful to verify the immunogenicity of Hib conjugate vaccines and for preclinical evaluation. In general, nonclinical evaluation of the new Hib conjugate vaccine, including this proof of concept (safety and immunogenicity study in rats), made it possible for technology transfer partners, having implemented the original process with no changes

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

Post-marketing surveillance of adverse events following immunization with inactivated quadrivalent and trivalent influenza vaccine in health care providers in Western Australia.

PubMed

Regan, Annette K; Tracey, Lauren; Gibbs, Robyn

2015-11-17

In 2015, inactivated quadrivalent influenza vaccine (QIV) was first introduced into the Australian market. A routine vaccine safety surveillance system in Western Australia was used to conduct post-licensure surveillance of adverse events following immunization with inactivated QIV and trivalent influenza vaccines (TIV) in a sample of 1685 healthcare providers (HCPs). A similar percentage of HCPs who received QIV reported having any reaction seven days post-vaccination as HCPs who received TIV (13.6 vs. 12.8%, respectively; p=0.66). However, a slightly higher percentage of HCPs who received QIV reported pain or swelling at the injection site as compared to HCPs who received TIV (6.9% vs. 4.2%, respectively; p=0.02). No serious vaccine-associated adverse events were detected during follow-up of either vaccine. Acknowledging the study limitations, the results of this post-marketing surveillance support the safety of QIV, suggesting there is little difference in the reactogenicity of QIV as compared to TIV. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015.

PubMed

Arana, Jorge E; Harrington, Theresa; Cano, Maria; Lewis, Paige; Mba-Jonas, Adamma; Rongxia, Li; Stewart, Brock; Markowitz, Lauri E; Shimabukuro, Tom T

2018-03-20

The Food and Drug Administration (FDA) approved quadrivalent human papillomavirus vaccine (4vHPV) for use in females and males aged 9-26 years, since 2006 and 2009 respectively. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS), a US spontaneous reporting system, in females and males who received 4vHPV vaccination. We searched VAERS for US reports of adverse events (AEs) following 4vHPV from January 2009 through December 2015. Signs and symptoms were coded using Medical Dictionary for Regulatory Activities (MedDRA). We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reports. Clinicians reviewed available information, including medical records, and reports of selected pre-specified conditions. VAERS received 19,760 reports following 4vHPV; 60.2% in females, 17.2% in males, and in 22.6% sex was missing. Overall, 94.2% of reports were non-serious; dizziness, syncope and injection site reactions were commonly reported in both males and females. Headache, fatigue and nausea were commonly reported serious AEs. More than 60 million 4vHPV doses were distributed during the study period. Crude AE reporting rates were 327 reports per million 4vHPV doses distributed for all reports, and 19 per million for serious reports. Among 29 verified reports of death, there was no pattern of clustering of deaths by diagnosis, co-morbidities, age, or interval from vaccination to death. No new or unexpected safety concerns or reporting patterns of 4vHPV with clinically important AEs were detected. Safety profile of 4vHPV is consistent with data from pre-licensure trials and postmarketing safety data. Published by Elsevier Ltd.

Focal epithelial hyperplasia by human papillomavirus (HPV)-32 misdiagnosed as HPV-16 and treated with combination of retinoids, imiquimod and quadrivalent HPV vaccine.

PubMed

Gemigniani, Franco; Hernández-Losa, Javier; Ferrer, Berta; García-Patos, Vicente

2015-12-01

Focal epithelial hyperplasia (FEH) or Heck's disease is a rare, benign and asymptomatic mucosal proliferation associated with human papillomavirus (HPV) infection, mainly with genotypes 13 and 32. We report a florid case of FEH in an 11-year-old Haitian girl with systemic lupus erythematosus receiving immunosuppressive therapy. Cryotherapy was previously performed on numerous occasions with no results. We decided to prescribe a non-invasive and more comfortable treatment. A combination of topical retinoid and imiquimod cream was well tolerated and led to an important improvement. The evidence of infection by HPV-16 detected by polymerase chain reaction (PCR) technique, prompted us to prescribe the quadrivalent HPV vaccine (types 6, 11,16 and 18). Subsequent PCR sequencing with generic primers GP5-GP6 and further BLAST comparative analysis confirmed that genomic viral sequence in our case truly corresponded with HPV-32. This molecular misdiagnosis can be explained by the similarity between genomic sequences of both HPV-16 and -32 genotypes. At the 1-year follow up, we observed total clinical improvement and no recurrences of the disease. Complete healing in this case may correspond to a potential action of topical retinoid, imiquimod and the cross-protection mechanism of the quadrivalent HPV vaccine. © 2015 Japanese Dermatological Association.

Antibody persistence of two pentavalent DTwP-HB-Hib vaccines to the age of 15-18 months, and response to the booster dose of quadrivalent DTwP-Hib vaccine.

PubMed

Sharma, Hitt; Yadav, Sangeeta; Lalwani, Sanjay; Kapre, Subhash; Jadhav, Suresh; Parekh, Sameer; Palkar, Sonali; Ravetkar, Satish; Bahl, Sunil; Kumar, Rakesh; Shewale, Sunil

2013-01-07

Antibody persistence in children following three doses of primary vaccination with diphtheria, tetanus, whole-cell-pertussis (DTwP), hepatitis B, and Haemophilus influenzae type b (Hib) vaccines (SIIL Pentavac vaccine vs. Easyfive(®) of Panacea Biotec), and response to the booster dose of DTwP-Hib (Quadrovax(®)) vaccine. Children who completed their primary immunization were assessed for antibodies at 15-18 months of age, and then given a booster dose of DTwP-Hib vaccine. Reactogenicity and safety of the booster dose was evaluated. Both pentavalent vaccines demonstrated a good immune response at 15-18 months. Following the booster dose, all vaccinated subjects achieved protective titers against diphtheria, tetanus and Hib, whereas the response to pertussis antigen was ~78%. Fever and irritability was noted in 24%, local pain in 51%, and swelling in 36% of the children following booster dose. Primary immunization with either pentavalent vaccine induced an excellent immunity lasting till the second year of life. A booster dose with DTwP-Hib (Quadrovax(®)) vaccine effectuated a good anamnestic response to all vaccine components, being specially strong for Hib in children previously vaccinated with SIIL liquid pentavalent vaccine (Pentavac(®)). Also, the safety profile of SIIL quadrivalent vaccine (Quadrovax(®)) administered as booster dose was acceptable. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluating the Early Benefit of Quadrivalent HPV Vaccine on Genital Warts in Belgium: A Cohort Study.

PubMed

Dominiak-Felden, Geraldine; Gobbo, Corrado; Simondon, François

2015-01-01

Genital warts (GWs) are common, with about 5% to 10% of people having at least one episode in their lifetime. They develop about 2-3 months after infection with human papillomavirus (HPV) genotypes 6 and 11. The prophylactic quadrivalent HPV vaccine (qHPV), protects against HPV6/11 infections and diseases. In Belgium, HPV vaccines started to be reimbursed in 2007 and have been fully reimbursed since December 2008 for women 12 to 18 years old. This study aimed at evaluating the real-life benefit of qHPV vaccine introduction in Belgium on GWs by measuring both vaccine impact (VI) at a population level and the direct effect of the qHPV vaccine at an individual level (vaccine effectiveness (VE)), using data from a large sick-fund (MLOZ) reimbursement database. A first reimbursement for imiquimod (most common first-line GWs treatment in Belgium) was used as a surrogate for a first GWs episode; reimbursement of qHPV vaccine was used as surrogate for vaccination. VI was estimated by comparing the incidence of GWs before and after qHPV vaccine introduction in Belgium (ecologic evaluation). VE was assessed by comparing GWs incidences in vaccinated vs. unvaccinated women, among women eligible for HPV vaccination. VI was evaluated in 9,223,384 person-years. Overall, GWs incidence rates decreased significantly between the pre- and post-vaccination periods (-8.1% (95% CI: -15.3; -0.3) for men and women aged 18-59 years. This decrease was highest in women targeted by the HPV vaccination programme (-72.1% (95% CI: -77.9; -64.7) in women aged 16-22 years, with a 43% vaccine uptake in 2013). A significant decrease was also observed in men aged 16-22 years (-51.1%, 95%CI: -67.6; -26.2), suggesting herd-protection. VE was evaluated in 369,881 person-years. Age-adjusted VE for fully vaccinated women was 88.0% (95% CI: 79.4; 93.0). VE was higher when the first dose was given younger and remained high for over 4 years post-vaccination in all ages. High VI and VE of the qHPV vaccine were

Evaluating the Early Benefit of Quadrivalent HPV Vaccine on Genital Warts in Belgium: A Cohort Study

PubMed Central

Dominiak-Felden, Geraldine; Gobbo, Corrado; Simondon, François

2015-01-01

Genital warts (GWs) are common, with about 5% to 10% of people having at least one episode in their lifetime. They develop about 2–3 months after infection with human papillomavirus (HPV) genotypes 6 and 11. The prophylactic quadrivalent HPV vaccine (qHPV), protects against HPV6/11 infections and diseases. In Belgium, HPV vaccines started to be reimbursed in 2007 and have been fully reimbursed since December 2008 for women 12 to 18 years old. This study aimed at evaluating the real-life benefit of qHPV vaccine introduction in Belgium on GWs by measuring both vaccine impact (VI) at a population level and the direct effect of the qHPV vaccine at an individual level (vaccine effectiveness (VE)), using data from a large sick-fund (MLOZ) reimbursement database. A first reimbursement for imiquimod (most common first-line GWs treatment in Belgium) was used as a surrogate for a first GWs episode; reimbursement of qHPV vaccine was used as surrogate for vaccination. VI was estimated by comparing the incidence of GWs before and after qHPV vaccine introduction in Belgium (ecologic evaluation). VE was assessed by comparing GWs incidences in vaccinated vs. unvaccinated women, among women eligible for HPV vaccination. VI was evaluated in 9,223,384 person-years. Overall, GWs incidence rates decreased significantly between the pre- and post-vaccination periods (-8.1% (95% CI: -15.3; -0.3) for men and women aged 18–59 years. This decrease was highest in women targeted by the HPV vaccination programme (-72.1% (95% CI: -77.9; -64.7) in women aged 16–22 years, with a 43% vaccine uptake in 2013). A significant decrease was also observed in men aged 16-22 years (-51.1%, 95%CI: -67.6; -26.2), suggesting herd-protection. VE was evaluated in 369,881 person-years. Age-adjusted VE for fully vaccinated women was 88.0% (95% CI: 79.4; 93.0). VE was higher when the first dose was given younger and remained high for over 4 years post-vaccination in all ages. High VI and VE of the q

Development and technology transfer of Haemophilus influenzae type b conjugate vaccines for developing countries.

PubMed

Beurret, Michel; Hamidi, Ahd; Kreeftenberg, Hans

2012-07-13

This paper describes the development of a Haemophilus influenzae type b (Hib) conjugate vaccine at the National Institute for Public Health and the Environment/Netherlands Vaccine Institute (RIVM/NVI, Bilthoven, The Netherlands), and the subsequent transfer of its production process to manufacturers in developing countries. In 1998, at the outset of the project, the majority of the world's children were not immunized against Hib because of the high price and limited supply of the conjugate vaccines, due partly to the fact that local manufacturers in developing countries did not master the Hib conjugate production technology. To address this problem, the RIVM/NVI has developed a robust Hib conjugate vaccine production process based on a proven model, and transferred this technology to several partners in India, Indonesia, Korea and China. As a result, emerging manufacturers in developing countries acquired modern technologies previously unavailable to them. This has in turn facilitated their approach to producing other conjugate vaccines. As an additional spin-off from the project, a World Health Organization (WHO) Hib quality control (QC) course was designed and conducted at the RIVM/NVI, resulting in an increased regulatory capacity for conjugate vaccines in developing countries at the National Regulatory Authority (NRA) level. For the local populations, this has translated into an increased and sustainable supply of affordable Hib conjugate-containing combination vaccines. During the course of this project, developing countries have demonstrated their ability to produce large quantities of high-quality modern vaccines after a successful transfer of the technology. Copyright © 2012 Elsevier Ltd. All rights reserved.

Safety of quadrivalent live attenuated influenza vaccine in subjects aged 2-49years.

PubMed

Baxter, Roger; Eaton, Abigail; Hansen, John; Aukes, Laurie; Caspard, Herve; Ambrose, Christopher S

2017-03-01

Quadrivalent live attenuated influenza vaccine (Q/LAIV) was licensed in 2012 and replaced trivalent live attenuated influenza vaccine in the United States during the 2013-2014 influenza season. This study assessed the safety of Q/LAIV in children and adults aged 2-49years. This was a prospective observational cohort study using data collected from Kaiser Permanente Northern California. Post-vaccination events of interest were any hospitalization, hospitalization for lower respiratory tract infection, and the following medically attended events: hypersensitivity, seizures/convulsions, lower respiratory tract infection, wheezing, Guillain-Barré syndrome, Bell's palsy, encephalitis, neuritis, vasculitis, and narcolepsy/cataplexy. The rates of these events during the risk interval post-vaccination were compared with rates observed during reference periods later in the follow-up (within-cohort analysis) and with rates observed in frequency-matched unvaccinated controls and inactivated influenza vaccine (IIV) recipients. A total of 62,040 eligible Q/LAIV recipients were identified during the 2013-2014 influenza season. Within-cohort comparisons of all Q/LAIV recipients as well as comparisons between Q/LAIV recipients and unvaccinated controls or IIV recipients did not show any significantly higher risk of hospitalizations or medically attended events following administration of Q/LAIV. Additional analyses by setting (clinic visits, emergency department visits, and hospital admissions) and age group (2-4, 5-8, 9-17, and 18-49years) also did not reveal clinically consistent findings that suggested any increased risk after administration of Q/LAIV. In this large population study of individuals aged 2-49years, no safety signals associated with the administration of Q/LAIV were observed. A much larger study population would be needed to confidently reject any association between Q/LAIV and very rare events, specifically those with an incidence of <1 event/10,000 person

Development of a bivalent conjugate vaccine candidate against malaria transmission and typhoid fever.

PubMed

An, So Jung; Scaria, Puthupparampil V; Chen, Beth; Barnafo, Emma; Muratova, Olga; Anderson, Charles; Lambert, Lynn; Chae, Myung Hwa; Yang, Jae Seung; Duffy, Patrick E

2018-05-17

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials. Vi-Pfs25 conjugates induced strong immune responses against both Vi and Pfs25 in mice, whereas the unconjugated antigens are poorly immunogenic. Functional assays of immune sera revealed potent transmission blocking activity mediated by anti-Pfs25 antibody and serum bactericidal activity due to anti-Vi antibody. Pfs25 conjugation to Vi modified the IgG isotype distribution of antisera, inducing a Th2 polarized immune response against Vi antigen. This conjugate may be further developed as a bivalent vaccine to concurrently target malaria and typhoid fever. Copyright © 2018. Published by Elsevier Ltd.

Characteristics of memory B cells elicited by a highly efficacious HPV vaccine in subjects with no pre-existing immunity.

PubMed

Scherer, Erin M; Smith, Robin A; Simonich, Cassandra A; Niyonzima, Nixon; Carter, Joseph J; Galloway, Denise A

2014-10-01

Licensed human papillomavirus (HPV) vaccines provide near complete protection against the types of HPV that most commonly cause anogenital and oropharyngeal cancers (HPV 16 and 18) when administered to individuals naive to these types. These vaccines, like most other prophylactic vaccines, appear to protect by generating antibodies. However, almost nothing is known about the immunological memory that forms following HPV vaccination, which is required for long-term immunity. Here, we have identified and isolated HPV 16-specific memory B cells from female adolescents and young women who received the quadrivalent HPV vaccine in the absence of pre-existing immunity, using fluorescently conjugated HPV 16 pseudoviruses to label antigen receptors on the surface of memory B cells. Antibodies cloned and expressed from these singly sorted HPV 16-pseudovirus labeled memory B cells were predominantly IgG (>IgA>IgM), utilized diverse variable genes, and potently neutralized HPV 16 pseudoviruses in vitro despite possessing only average levels of somatic mutation. These findings suggest that the quadrivalent HPV vaccine provides an excellent model for studying the development of B cell memory; and, in the context of what is known about memory B cells elicited by influenza vaccination/infection, HIV-1 infection, or tetanus toxoid vaccination, indicates that extensive somatic hypermutation is not required to achieve potent vaccine-specific neutralizing antibody responses.

Cost-effectiveness of quadrivalent influenza vaccine in Hong Kong - A decision analysis.

PubMed

You, Joyce H S; Ming, Wai-Kit; Chan, Paul K S

2015-01-01

Trivalent influenza vaccine (TIV) selects one of the 2 co-circulating influenza B lineages whereas quadrivalent influenza vaccine (QIV) includes both lineages. We examined potential cost-effectiveness of QIV versus TIV from perspectives of healthcare provider and society of Hong Kong. A decision tree was designed to simulate the outcomes of QIV vs. TIV in 6 age groups: 0-4 years, 5-9 years, 10-14 years, 15-64 years, 65-79 y and ≥80 years. Direct cost alone, direct and indirect costs, and quality-adjusted life-years (QALYs) loss due to TIV-unmatched influenza B infection were simulated for each study arm. Outcome measure was incremental cost per QALY (ICER). In base-case analysis, QIV was more effective than TIV in all-age population with additional direct cost per QALY (ICER-direct cost) and additional total cost per QALY (ICER-total cost) of USD 22,603 and USD 12,558, respectively. Age-stratified analysis showed that QIV was cost-effective in age groups 6 months to 9 y and ≥80 years from provider's perspective, and it was cost-effective in all age group except 15-64 y from societal perspective. Percentage of TIV-unmatched influenza B in circulation and additional vaccine cost of QIV were key influential factors. From perspectives of healthcare provider and society, QIV was the preferred option in 52.77% and 66.94% of 10,000 Monte Carlo simulations, respectively. QIV appears to be cost-effective in Hong Kong population, except for age group 15-64 years, from societal perspective. From healthcare provider's perspective, QIV seems to be cost-effective in very young (6 months-9 years) and older (≥80 years) age groups.

Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children.

PubMed

Weinberg, Adriana; Huang, Sharon; Moscicki, Anna-Barbara; Saah, Afred; Levin, Myron J

2018-04-24

To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNγ and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. HPV16 and HPV18 T-cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation.

Consensus recommendation for meningococcal disease prevention for Hajj and Umra pilgrimage/travel medicine.

PubMed

Shibl, A; Tufenkeji, H; Khalil, M; Memish, Z

2013-04-01

The Islamic Hajj to Makkah (Mecca) has been associated with outbreaks of invasive meningococcal disease and the global spread of Neisseria meningitidis serogroup W-135. For Hajj pilgrims the quadrivalent vaccination against serogroups A, C, W-135 and Y is a mandatory requirement. Novel conjugate vaccines may provide benefits for the community by reduction of carriage. With the introduction of the new generation of quadrivalent meningococcal conjugate vaccines (Menveo, Menactra, and others pending license) and their recent implementation in Saudi Arabia, experts from 11 countries in the Middle East region met at a Meningococcal Leadership Forum (MLF), in Dubai in May 2010 to exchange opinions on meningococcal disease and prevention strategies. These experts discussed the importance of introducing conjugate vaccines for pilgrims and travellers, and elaborated a consensus recommendation to support healthcare professionals and decision-makers.

A universal polysaccharide conjugated vaccine against O111 E. coli

PubMed Central

Andrade, Gabrielle R; New, Roger R C; Sant’Anna, Osvaldo A; Williams, Neil A; Alves, Rosely C B; Pimenta, Daniel C; Vigerelli, Hugo; Melo, Bruna S; Rocha, Letícia B; Piazza, Roxane M F; Mendonça-Previato, Lucia; Domingos, Marta O

2014-01-01

E. coli O111 strains are responsible for outbreaks of blood diarrhea and hemolytic uremic syndrome throughout the world. Because of their phenotypic variability, the development of a vaccine against these strains which targets an antigen that is common to all of them is quite a challenge. Previous results have indicated, however, that O111 LPS is such a candidate, but its toxicity makes LPS forbidden for human use. To overcome this problem, O111 polysaccharides were conjugated either to cytochrome C or to EtxB (a recombinant B subunit of LT) as carrier proteins. The O111-cytochrome C conjugate was incorporated in silica SBA-15 nanoparticles and administered subcutaneously in rabbits, while the O111-EtxB conjugate was incorporated in VaxcineTM, an oil-based delivery system, and administered orally in mice. The results showed that one year post-vaccination, the conjugate incorporated in silica SBA-15 generated antibodies in rabbits able to inhibit the adhesion of all categories of O111 E. coli to epithelial cells. Importantly, mice immunized orally with the O111-EtxB conjugate in VaxcineTM generated systemic and mucosal humoral responses against all categories of O111 E. coli as well as antibodies able to inhibit the toxic effect of LT in vitro. In summary, the results obtained by using 2 different approaches indicate that a vaccine that targets the O111 antigen has the potential to prevent diarrhea induced by O111 E. coli strains regardless their mechanism of virulence. They also suggest that a conjugated vaccine that uses EtxB as a carrier protein has potential to combat diarrhea induced by ETEC. PMID:25483465

Maleimide conjugation markedly enhances the immunogenicity of both human and murine idiotype-KLH vaccines

PubMed Central

Kafi, Kamran; Betting, David J.; Yamada, Reiko E.; Bacica, Michael; Steward, Kristopher K.; Timmerman, John M.

2009-01-01

The collection of epitopes present within the variable regions of the tumor-specific clonal immunoglobulin expressed by B cell lymphomas (idiotype, Id) can serve as a target for active immunotherapy. Traditionally, tumor-derived Id protein is chemically-conjugated to the immunogenic foreign carrier protein keyhole limpet hemocyanin (KLH) using glutaraldehyde to serve as a therapeutic vaccine. While this approach offered promising results for some patients treated in early clinical trials, glutaraldehyde Id-KLH vaccines have failed to induce immune and clinical responses in many vaccinated subjects. We recently described an alternative conjugation method employing maleimide-sulfhydryl chemistry that significantly increased the therapeutic efficacy of Id-KLH vaccines in three different murine B cell lymphoma models, with protection mediated by either CD8+ T cells or antibodies. We now define in detail the methods and parameters critical for enhancing the in vivo immunogenicity of human as well as murine Id-KLH conjugate vaccines. Optimal conditions for Id sulfhydryl pre-reduction were determined, and maleimide Id-KLH conjugates maintained stability and potency even after prolonged storage. Field flow fractionation analysis of Id-KLH particle size revealed that maleimide conjugates were far more uniform in size than glutaraldehyde conjugates. Under increasingly stringent conditions, maleimide Id-KLH vaccines maintained superior efficacy over glutaraldehyde Id-KLH in treating established, disseminated murine lymphoma. More importantly, human maleimide Id-KLH conjugates were consistently superior to glutaraldehyde Id-KLH conjugates in inducing Id-specific antibody and T cell responses. The described methods should be easily adaptable to the production of clinical grade vaccines for human trials in B cell malignancies. PMID:19046770

Cost-effectiveness of 13-valent pneumococcal conjugate vaccine in Switzerland.

PubMed

Blank, Patricia R; Szucs, Thomas D

2012-06-13

The 7-valent pneumococcal conjugate vaccine (PCV7) has been shown to be highly cost-effective. The 13-valent pneumococcal conjugate vaccine (PCV13) offers seroprotection against six additional serotypes. A decision-analytic model was constructed to estimate direct medical costs and clinical effectiveness of PCV13 vaccination on invasive pneumococcal disease (IPD), pneumonia, and otitis media relative to PCV7 vaccination. The option with an one-dose catch-up vaccination in children of 15-59 months was also considered. Assuming 83% vaccination coverage and considering indirect effects, 1808 IPD, 5558 pneumonia and 74,136 otitis media cases could be eliminated from the entire population during a 10-year modelling period. The PCV13 vaccination programme would lead to additional costs (+€26.2 Mio), but saved medical costs of -€77.1 Mio due to cases averted and deaths avoided, overcompensate these costs (total cost savings -€50.9 Mio). The national immunisation programmes with PCV13 can be assumed cost saving when compared with the current vaccine PCV7 in Switzerland. Copyright © 2012 Elsevier Ltd. All rights reserved.

Update on the use of meningococcal serogroup C CRM₁₉₇-conjugate vaccine (Meningitec) against meningitis.

PubMed

Badahdah, Al-Mamoon; Rashid, Harunor; Khatami, Ameneh

2016-01-01

Meningitec is a CRM197-conjugated meningococcal serogroup C (MenC) vaccine, first licensed in 1999. It has been used as a primary and booster vaccine in infants, toddlers, older children and adults, and has been shown to be immunogenic and well-tolerated in all age groups, including premature infants. Vaccine effectiveness has been demonstrated using combined data on all three licensed MenC conjugate vaccines. Evidence from clinical trials, however, suggests that the different MenC conjugate vaccines behave differently with respect to the induction and persistence of bactericidal antibody and generation of immune memory. It appears that Meningitec has a less favorable immunologic profile compared particularly to tetanus toxoid (TT) MenC conjugate vaccines. Data from comparative trials have raised interesting questions on priming of the immune system by conjugate vaccines, particularly in infants. The results from these and other studies are reviewed here with specific focus on Meningitec.

Cost-effectiveness evaluation of quadrivalent influenza vaccines for seasonal influenza prevention: a dynamic modeling study of Canada and the United Kingdom.

PubMed

Thommes, Edward W; Ismaila, Afisi; Chit, Ayman; Meier, Genevieve; Bauch, Christopher T

2015-10-27

The adoption of quadrivalent influenza vaccine (QIV) to replace trivalent influenza vaccine (TIV) in immunization programs is growing worldwide, thus helping to address the problem of influenza B lineage mismatch. However, the price per dose of QIV is higher than that of TIV. In such circumstances, cost-effectiveness analyses provide important and relevant information to inform national health recommendations and implementation decisions. This analysis assessed potential vaccine impacts and cost-effectiveness of a country-wide switch from TIV to QIV, in Canada and the UK, from a third-party payer perspective. An age-stratified, dynamic four-strain transmission model which incorporates strain interaction, transmission-rate seasonality and age-specific mixing in the population was used. Model input data were obtained from published literature and online databases. In Canada, we evaluated a switch from TIV to QIV in the entire population. For the UK, we considered two strategies: Children aged 2-17 years who receive the live-attenuated influenza vaccine (LAIV) switch to the quadrivalent formulation (QLAIV), while individuals aged > 18 years switch from TIV to QIV. Two different vaccination uptake scenarios in children (UK1 and UK2, which differ in the vaccine uptake level) were considered. Health and cost outcomes for both vaccination strategies, and the cost-effectiveness of switching from TIV/LAIV to QIV/QLAIV, were estimated from the payer perspective. For Canada and the UK, cost and outcomes were discounted using 5 % and 3.5 % per year, respectively. Overall, in an average influenza season, our model predicts that a nationwide switch from TIV to QIV would prevent 4.6 % influenza cases, 4.9 % general practitioner (GP) visits, 5.7 % each of emergency room (ER) visits and hospitalizations, and 6.8 % deaths in Canada. In the UK (UK1/UK2), implementing QIV would prevent 1.4 %/1.8 % of influenza cases, 1.6 %/2.0 % each of GP and ER visits, 1.5 %/1.9 % of

An improved conjugate vaccine technology; induction of antibody responses to the tumor vasculature.

PubMed

Huijbers, Elisabeth J M; van Beijnum, Judy R; Lê, Chung T; Langman, Sofya; Nowak-Sliwinska, Patrycja; Mayo, Kevin H; Griffioen, Arjan W

2018-05-17

The induction of an antibody response against self-antigens requires a conjugate vaccine technology, where the self-antigen is conjugated to a foreign protein sequence, and the co-application of a potent adjuvant. The choice of this foreign sequence is crucial as a very strong antibody response towards it may compromise the anti-self immune response. Here, we aimed to optimize the conjugate design for application of vaccination against the tumor vasculature, using two different approaches. First, the immunogenicity of the previously employed bacterial thioredoxin (TRX) was reduced by using a truncated from (TRXtr). Second, the Escherichia coli proteome was scrutinized to identify alternative proteins, based on immunogenicity and potency to increase solubility, suitable for use in a conjugate vaccine. This technology was used for vaccination against a marker of the tumor vasculature, the well-known extra domain B (EDB) of fibronectin. We demonstrate that engineering of the foreign sequence of a conjugate vaccine can significantly improve antibody production. The TRXtr construct outperformed the one containing full-length TRX, for the production of anti-self antibodies to EDB. In addition, efficient tumor growth inhibition was observed with the new TRXtr-EDB vaccine. Microvessel density was decreased and enhanced leukocyte infiltration was observed, indicative of an active immune response directed against the tumor vasculature. Summarizing, we have identified a truncated form of the foreign antigen TRX that can improve conjugate vaccine technology for induction of anti-self antibody titers. This technology was named Immuno-Boost (I-Boost). Our findings are important for the clinical development of cancer vaccines directed against self antigens, e.g. the ones selectively found in the tumor vasculature. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Anti-Group B Streptococcus Glycan-Conjugate Vaccines Using Pilus Protein GBS80 As Carrier and Antigen: Comparing Lysine and Tyrosine-directed Conjugation.

PubMed

Nilo, Alberto; Morelli, Laura; Passalacqua, Irene; Brogioni, Barbara; Allan, Martin; Carboni, Filippo; Pezzicoli, Alfredo; Zerbini, Francesca; Maione, Domenico; Fabbrini, Monica; Romano, Maria Rosaria; Hu, Qi-Ying; Margarit, Immaculada; Berti, Francesco; Adamo, Roberto

2015-07-17

Gram-positive Streptococcus agalactiae or group B Streptococcus (GBS) is a leading cause of invasive infections in pregnant women, newborns, and elderly people. Vaccination of pregnant women represents the best strategy for prevention of neonatal disease, and GBS polysaccharide-based conjugate vaccines are currently under clinical testing. The potential of GBS pilus proteins selected by genome-based reverse vaccinology as protective antigens for anti-streptococcal vaccines has also been demonstrated. Dressing pilus proteins with surface glycan antigens could be an attractive approach to extend vaccine coverage. We have recently developed an efficient method for tyrosine-directed ligation of large glycans to proteins via copper-free azide-alkyne [3 + 2] cycloaddition. This method enables targeting of predetermined sites of the protein, ensuring that protein epitopes are preserved prior to glycan coupling and a higher consistency in glycoconjugate batches. Herein, we compared conjugates of the GBS type II polysaccharide (PSII) and the GBS80 pilus protein obtained by classic lysine random conjugation and by the recently developed tyrosine-directed ligation. PSII conjugated to CRM197, a carrier protein used for vaccines in the market, was used as a control. We found that the constructs made from PSII and GBS80 were able to elicit murine antibodies recognizing individually the glycan and protein epitopes on the bacterial surface. The generated antibodies were efficacious in mediating opsonophagocytic killing of strains expressing exclusively PSII or GBS80 proteins. The two glycoconjugates were also effective in protecting newborn mice against GBS infection following vaccination of the dams. Altogether, these results demonstrated that polysaccharide-conjugated GBS80 pilus protein functions as a carrier comparably to CRM197, while maintaining its properties of protective protein antigen. Glycoconjugation and reverse vaccinology can, therefore, be combined to design

Early direct and indirect impact of quadrivalent HPV (4HPV) vaccine on genital warts: a systematic review.

PubMed

Mariani, Luciano; Vici, Patrizia; Suligoi, Barbara; Checcucci-Lisi, Giovanni; Drury, Rosybel

2015-01-01

Since 2007, many countries have implemented national human papillomavirus (HPV) vaccination programs with the quadrivalent HPV (4HPV) vaccine that has been shown to be efficacious in clinical trials involving 25,000 subjects. Two vaccine serotypes, HPV16 and 18, are responsible for cervical cancer and other HPV-related cancers, but the impact of the 4HPV vaccine on these cancers cannot be seen immediately as there is a considerable lag between infection with HPV and cancer development. The other two serotypes, HPV6 and 11, are responsible for genital warts (GWs), which develop within a few months after infection, making GWs an early clinical endpoint for the assessment of the impact of 4HPV vaccination. We performed a systematic literature search in PubMed to identify all published studies on 4HPV vaccination, including those that assessed the impact of 4HPV vaccination programs on the incidence of GWs at a population level around the world. A total of 354 records were identified in the PubMed search. After screening and obtaining full papers for 56 publications, 16 publications presenting data on the impact or effectiveness of 4HPV vaccination on GWs were identified. These reported data on the impact or effectiveness of 4HPV in six countries [Australia (n = 6), New Zealand (n = 2), United States (n = 3), Denmark (n = 2), Germany (n = 1), and Sweden (n = 2)]. In Australia, no GWs were diagnosed in women aged <21 years who reported being vaccinated. A 92.6% reduction in GWs incidence was reported for all women in this age group, where the vaccine uptake rate (VUR) was 70% for 3 doses. The highest reductions were reported in countries with high VURs, mostly through school-based vaccination programs, although high VURs were obtained with some non-school-based programs. The results are coherent with the GWs incidence reduction reported in clinical trials and are an early indicator of what can be expected for the long-term clinical impact on vaccine-type HPV

Trends in Meningococcal Disease Occurrences in the United States Military, 1971-2010

DTIC Science & Technology

2012-09-01

1982, a quadrivalent polysaccharide vaccine (MPSV-4; Menomune, Sanofi Pasteur, Bridgewater, NJ, USA) was introduced; this vaccine targets serogroups...regarding the performance of current vaccines. Of particular interest is the performance of the newer conjugate vaccine, MCV-4 (Menactra; Sanofi

Safety and immunogenicity of a novel quadrivalent meningococcal CRM-conjugate vaccine given concomitantly with routine vaccinations in infants.

PubMed

Klein, Nicola P; Reisinger, Keith S; Johnston, William; Odrljin, Tatjana; Gill, Christopher J; Bedell, Lisa; Dull, Peter

2012-01-01

In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.

[Pneumococcal vaccine: protection of adults and reduction of antibiotic resistence by vaccination of children with a conjugated vaccine].

PubMed

Pletz, Mathias W

2011-06-01

Pneumococcal infections (pneumonia, otitis media, sinusitis, meningitis) are common and usually involve toddlers, immunocompromised and the elderly. Main reservoir of pneumococci is the nasopharyngeal zone of healthy carriers, especially of toddlers. Currently, two types of pneumococcal vaccines are in clinical use, which induce production of antibodies against capsular polysaccharides. The older vaccine consists of pure capsular polysaccharides. It induces a limited immunity, because polysaccharides are poor antigens that stimulate mainly B-cells. In children under two years of age this vaccine is not used, because it does not induce a sufficient immunologic response, presumably because of the immaturity of their immune system. In 2000, a vaccination program with a novel pneumococcal vaccine was launched in the USA. This vaccine contains capsular polysaccharides, that are conjugated with a highly immunogenic protein. It induces both a T cell and B cell response that results in specific humoral and mucosal immunity. U.S. data demonstrate, that serotypes covered by the conjugated vaccine can be reduced in the whole population by vaccination of children being the main reservoir of pneumococci. This so called ,,herd protection" results in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as in a reduction of antibiotic resistance rates by reducing resistant pneumococcal cones.

Immunology Update: New Vaccines.

PubMed

Starr, S Paul

2016-11-01

A new 9-valent human papillomavirus (HPV) vaccine is effective against more cancer-causing HPV types than previous vaccines. HPV vaccine series started with previous vaccines can be completed with the 9-valent vaccine. Two new influenza vaccines are available for adults 65 years and older: a high-dose vaccine and an enhanced adjuvant vaccine. These elicit stronger antibody responses than standard-dose vaccines. Current guidelines specify no preference for the new versus standard-dose vaccines. Two new group B meningococcal vaccines are intended for use during outbreaks and for patients with asplenia, complement deficiencies, frequent occupational meningococcus exposure, or for patients who desire protection from type B meningococcus. These are not substitutes for the quadrivalent vaccine already in use. For pneumococcus, new recommendations state that 13-valent pneumococcal conjugate vaccine (PCV13) should be administered to patients 65 years and older, followed at least 1 year later by the polyvalent pneumococcal polysaccharide vaccine (PPSV23). For patients ages 19 to 64 years with immunocompromise and not previously vaccinated against pneumococcus, administration of these two vaccines should be separated by at least 8 weeks. Rotavirus vaccine is standard for infants at age 2 months. Also, there is a new cholera vaccine approved for use in the United States. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Should I or shouldn't I: decision making, knowledge and behavioral effects of quadrivalent HPV vaccination in men who have sex with men.

PubMed

Thomas, Emily A; Goldstone, Stephen E

2011-01-10

Prior to FDA licensure in men, a surgical practice (SG) offered the quadrivalent HPV vaccine (qHPV) off-label to men who have sex with men (MSM). We administered a written or telephone survey to MSM to elicit drivers and barriers to vaccination, sexual behavior changes post-vaccination, and knowledge. 191 subjects enrolled: 68 refused qHPV, 71 received qHPV <1 year ago, and 52 received qHPV >1 year ago. History of HPV infection (86%, n=164) and level of HPV and qHPV knowledge were high, with a mean of 10.8 of 13 knowledge questions correct. Ninety-seven percent of participants understood that qHPV does not cure present infection or disease. MSM refused qHPV for reasons including cost and not FDA approved; prevention of future HPV infection was the paramount driver for immunization. Vaccination did not affect sexual behavior. Copyright © 2010 Elsevier Ltd. All rights reserved.

Comparing health outcomes and costs of general vaccination with pneumococcal conjugate vaccines in Sweden: a Markov model.

PubMed

By, Asa; Sobocki, Patrik; Forsgren, Arne; Silfverdal, Sven-Arne

2012-01-01

Two new pneumococcal conjugate vaccines were licensed to immunize infants and young children against pneumococcal disease. The objective of this study was to estimate the expected health benefits, costs, and incremental cost-effectiveness of routine vaccination with the 10-valent pneumococcal nontypeable hemophilus influenza protein-D conjugate vaccine (PHiD-CV) compared with the 13-valent pneumococcal conjugate vaccine (PCV13) in Sweden. A Markov cohort model was used to estimate the effect of vaccination at vaccine steady state, taking a societal perspective and using a 2+1 vaccination schedule. Price parity was assumed between the vaccines. Outcomes were measured by reduction in disease burden, costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio. The results predicted that PCV13 would prevent 3 additional cases of invasive pneumococcal disease and 34 additional cases of pneumonia, whereas PHiD-CV would avoid 3 additional cases of mastoiditis, 1010 tube insertions, and 10,420 cases of ambulatory acute otitis media compared with PCV13. By combining morbidity and mortality benefits of all clinical outcomes, PHiD-CV would generate 45.3 additional QALYs compared with PCV13 and generate savings of an estimated 62 million Swedish kronors. The present study predicted lower costs and better health outcome (QALYs) gained by introducing PHiD-CV compared with PCV13 in routine vaccination. Our results indicated that PHiD-CV is cost-effective compared with PCV13 in Sweden. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Impact and cost-effectiveness of Haemophilus influenzae type b conjugate vaccination in India.

PubMed

Clark, Andrew D; Griffiths, Ulla K; Abbas, Syed Shahid; Rao, Krishna D; Privor-Dumm, Lois; Hajjeh, Rana; Johnson, Hope; Sanderson, Colin; Santosham, Mathuram

2013-07-01

To estimate the potential health impact and cost-effectiveness of nationwide Haemophilus influenzae type b (Hib) vaccination in India. A decision support model was used, bringing together estimates of demography, epidemiology, Hib vaccine effectiveness, Hib vaccine costs, and health care costs. Scenarios favorable and unfavorable to the vaccine were evaluated. State-level analyses indicate where the vaccine might have the greatest impact and value. Between 2012 and 2031, Hib conjugate vaccination is estimated to prevent over 200 000 child deaths (∼1% of deaths in children <5 years of age) in India at an incremental cost of US$127 million per year. From a government perspective, state-level cost-effectiveness ranged from US$192 to US$1033 per discounted disability adjusted life years averted. With the inclusion of household health care costs, cost-effectiveness ranged from US$155-US$939 per discounted disability adjusted life year averted. These values are below the World Health Organization thresholds for cost effectiveness of public health interventions. Hib conjugate vaccination is a cost-effective intervention in all States of India. This conclusion does not alter with plausible changes in key parameters. Although investment in Hib conjugate vaccination would significantly increase the cost of the Universal Immunization Program, about 15% of the incremental cost would be offset by health care cost savings. Efforts should be made to expedite the nationwide introduction of Hib conjugate vaccination in India. Copyright © 2013. Published by Mosby, Inc.

Impact and Cost-Effectiveness of Haemophilus influenzae Type b Conjugate Vaccination in India

PubMed Central

Clark, Andrew D.; Griffiths, Ulla K.; Abbas, Syed Shahid; Rao, Krishna D.; Privor-Dumm, Lois; Hajjeh, Rana; Johnson, Hope; Sanderson, Colin; Santosham, Mathuram

2017-01-01

Objective To estimate the potential health impact and cost-effectiveness of nationwide Haemophilus influenzae type b (Hib) vaccination in India. Study design A decision support model was used, bringing together estimates of demography, epidemiology, Hib vaccine effectiveness, Hib vaccine costs, and health care costs. Scenarios favorable and unfavorable to the vaccine were evaluated. State-level analyses indicate where the vaccine might have the greatest impact and value. Results Between 2012 and 2031, Hib conjugate vaccination is estimated to prevent over 200 000 child deaths (~1% of deaths in children <5 years of age) in India at an incremental cost of US$127 million per year. From a government perspective, state-level cost-effectiveness ranged from US$192 to US$1033 per discounted disability adjusted life years averted. With the inclusion of household health care costs, cost-effectiveness ranged from US$155-US$939 per discounted disability adjusted life year averted. These values are below the World Health Organization thresholds for cost effectiveness of public health interventions. Conclusions Hib conjugate vaccination is a cost-effective intervention in all States of India. This conclusion does not alter with plausible changes in key parameters. Although investment in Hib conjugate vaccination would significantly increase the cost of the Universal Immunization Program, about 15% of the incremental cost would be offset by health care cost savings. Efforts should be made to expedite the nationwide introduction of Hib conjugate vaccination in India. PMID:23773596

Meningococcal serogroup C immunogenicity, antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial.

PubMed

van Ravenhorst, Mariëtte B; van der Klis, Fiona R M; van Rooijen, Debbie M; Knol, Mirjam J; Stoof, Susanne P; Sanders, Elisabeth A M; Berbers, Guy A M

2017-08-24

Adolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster. Healthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year. Of 501 participants, 464 (92.6%) were included in the 'according to protocol' cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds. Both MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease

Public health impact and economic benefits of quadrivalent influenza vaccine in Latin America

PubMed Central

Jamotte, Aurélien; Clay, Emilie; Macabeo, Bérengère; Caicedo, Andrès; Lopez, Juan Guillermo; Bricks, Lucia; Romero Prada, Martín; Marrugo, Rubén; Alfonso, Pamela; Moreno Arévalo, Brechla; Franco, Danilo; Garcia Diaz, Lourdes; Isaza de Molto, Yadira

2017-01-01

ABSTRACT Annual trivalent influenza vaccines (TIV) containing 2 A strains and one B lineage have been recommended for the prevention of influenza in most of Latin American countries. However, the circulation of 2 B lineages (Victoria and Yamagata) and difficulties in predicting the predominating lineage have led to the development of quadrivalent influenza vaccines (QIV), including both B lineages. Thus, the objective was to estimate the public health impact and influenza-related costs if QIV would have been used instead of TIV in 3 Latin American countries. We used a static model over the seasons 2010–2014 in Brazil, 2007–2014 in Colombia and 2006–2014 in Panama, focusing on population groups targeted by local vaccination recommendations: young children, adults with risk factors and the elderly. In Brazil, between 2010 and 2014, using QIV instead of TIV would have avoided US$ 6,200 per 100,000 person-years in societal costs, based on 168 influenza cases, 89 consultations, 3.2 hospitalizations and 0.38 deaths per 100,000 person-years. In Colombia and Panama, these would have ranged from US$ 1,000 to 12,700 (based on 34 cases, 13–25 consultations, 0.6–8.9 hospitalizations and 0.04–1.74 deaths) and from US$ 3,000 to 33,700 (based on 113 cases, 55–82 consultations, 0.5–27.8 hospitalizations and 0.08–6.87 deaths) per 100,000 person-years, respectively. Overall, the broader protection offered by QIV would have reduced the influenza humanistic and economic burden in the 3 countries. Despite the lack of local data leading to several extrapolations, this study is the first to give quantitative estimates of the potential benefits of QIV in Latin America. PMID:28118092

Cost of Preventing, Managing, and Treating Human Papillomavirus (HPV)-Related Diseases in Sweden before the Introduction of Quadrivalent HPV Vaccination

PubMed Central

Östensson, Ellinor; Fröberg, Maria; Leval, Amy; Hellström, Ann-Cathrin; Bäcklund, Magnus; Zethraeus, Niklas; Andersson, Sonia

2015-01-01

Objective Costs associated with HPV-related diseases such as cervical dysplasia, cervical cancer, and genital warts have not been evaluated in Sweden. These costs must be estimated in order to determine the potential savings if these diseases were eradicated and to assess the combined cost-effectiveness of HPV vaccination and cervical cancer screening. The present study aimed to estimate prevention, management, and treatment costs associated with cervical dysplasia, cervical cancer, and genital warts from a societal perspective in Sweden in 2009, 1 year before the quadrivalent HPV vaccination program was implemented. Methods and Materials Data from the Swedish cervical cancer screening program was used to calculate the costs associated with prevention (cytological cervical cancer screening), management (colposcopy and biopsy following inadequate/abnormal cytological results), and treatment of CIN. Swedish official statistics were used to estimate treatment costs associated with cervical cancer. Published epidemiological data were used to estimate the number of incident, recurrent, and persistent cases of genital warts; a clinical expert panel assessed management and treatment procedures. Estimated visits, procedures, and use of medications were used to calculate the annual cost associated with genital warts. Results From a societal perspective, total estimated costs associated with cervical cancer and genital warts in 2009 were €106.6 million, of which €81.4 million (76%) were direct medical costs. Costs associated with prevention, management, and treatment of CIN were €74 million; screening and management costs for women with normal and inadequate cytology alone accounted for 76% of this sum. The treatment costs associated with incident and prevalent cervical cancer and palliative care were €23 million. Estimated costs for incident, recurrent and persistent cases of genital warts were €9.8 million. Conclusion Prevention, management, and treatment costs

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.

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery.

PubMed

Bahadoran, Azadeh; Moeini, Hassan; Bejo, Mohd Hair; Hussein, Mohd Zobir; Omar, Abdul Rahman

In order to enhance cellular uptake and to facilitate transdermal delivery of DNA vaccine, polyamidoamine (PAMAM) dendrimers conjugated with HIV transactivator of transcription (TAT) was developed. First, the plasmid DNA (pIRES-H5/GFP) nanoparticle was formulated using PAMAM dendrimer and TAT peptide and then characterized for surface charge, particle size, DNA encapsulation and protection of the pIRES-H5/GFP DNA plasmid to enzymatic digestion. Subsequently, the potency of the TAT-conjugated dendrimer for gene delivery was evaluated through in vitro transfection into Vero cells followed by gene expression analysis including western blotting, fluorescent microscopy and PCR. The effect of the TAT peptide on cellular uptake of DNA vaccine was studied by qRT-PCR and flow cytometry. Finally, the ability of TAT-conjugated PAMAM dendrimer for transdermal delivery of the DNA plasmid was assessed through artificial membranes followed by qRT-PCR and flow cytometry. TAT-conjugated PAMAM dendrimer showed the ability to form a compact and nanometre-sized polyplexes with the plasmid DNA, having the size range of 105 to 115 nm and a positive charge of +42 to +45 mV over the N/P ratio of 6:1(+/-).  In vitro transfection analysis into Vero cells confirms the high potency of TAT-conjugated PAMAM dendrimer to enhance the cellular uptake of DNA vaccine.  The permeability value assay through artificial membranes reveals that TAT-conjugated PAMAM has more capacity for transdermal delivery of the DNA compared to unmodified PAMAM dendrimer (P<0.05). The findings of this study suggest that TAT-conjugated PAMAM dendrimer is a promising non-viral vector for transdermal use.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Safety and immunogenicity of coadministering a combined meningococcal serogroup C and Haemophilus influenzae type b conjugate vaccine with 7-valent pneumococcal conjugate vaccine and measles, mumps, and rubella vaccine at 12 months of age.

PubMed

Miller, Elizabeth; Andrews, Nick; Waight, Pauline; Findlow, Helen; Ashton, Lindsey; England, Anna; Stanford, Elaine; Matheson, Mary; Southern, Joanna; Sheasby, Elizabeth; Goldblatt, David; Borrow, Ray

2011-03-01

The coadministration of the combined meningococcal serogroup C conjugate (MCC)/Haemophilus influenzae type b (Hib) vaccine with pneumococcal conjugate vaccine (PCV7) and measles, mumps, and rubella (MMR) vaccine at 12 months of age was investigated to assess the safety and immunogenicity of this regimen compared with separate administration of the conjugate vaccines. Children were randomized to receive MCC/Hib vaccine alone followed 1 month later by PCV7 with MMR vaccine or to receive all three vaccines concomitantly. Immunogenicity endpoints were MCC serum bactericidal antibody (SBA) titers of ≥8, Hib-polyribosylribitol phosphate (PRP) IgG antibody concentrations of ≥0.15 μg/ml, PCV serotype-specific IgG concentrations of ≥0.35 μg/ml, measles and mumps IgG concentrations of >120 arbitrary units (AU)/ml, and rubella IgG concentrations of ≥11 AU/ml. For safety assessment, the proportions of children with erythema, swelling, or tenderness at site of injection or fever or other systemic symptoms for 7 days after immunization were compared between regimens. No adverse consequences for either safety or immunogenicity were demonstrated when MCC/Hib vaccine was given concomitantly with PCV and MMR vaccine at 12 months of age or separately at 12 and 13 months of age. Any small differences in immunogenicity were largely in the direction of a higher response when all three vaccines were given concomitantly. For systemic symptoms, there was no evidence of an additive effect; rather, any differences between schedules showed benefit from the concomitant administration of all three vaccines, such as lower overall proportions with postvaccination fevers. The United Kingdom infant immunization schedule now recommends that these three vaccines may be offered at one visit at between 12 and 13 months of age.

Impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in children.

PubMed

Ruiz-Contreras, Jesus; Picazo, Juan; Casado-Flores, Juan; Baquero-Artigao, Fernando; Hernández-Sampelayo, Teresa; Otheo, Enrique; Méndez, Cristina; Del Amo, María; Balseiro, César

2017-08-16

To evaluate the impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in children. Children younger than 15years of age attending 27 hospitals in the Region of Madrid with confirmed pneumococcal meningitis were identified in a prospective surveillance study, from 2007 to 2015. Clinical data, neurological sequelae, pneumococcal vaccination status, serotyping and antibiotic susceptibility were recorded. One hundred and four cases of pneumococcal meningitis were identified, 63 during the period of routine 7-valent pneumococcal conjugate vaccine immunisation (May 2007-April 2010) and 41 during the period of 13-valent pneumococcal conjugate vaccine immunisation (May 2010-April 2015). When both periods were compared, a 62% (95% CI: 45-75%) decrease in the incidence of pneumococcal meningitis was observed, from 2.19 cases per 100,000 inhabitants in the PCV7 period to 0.81 per 100,000 inhabitants in the PCV13 period (p=0.0001), mainly due to an 83% (95% CI: 30-96%) reduction in cases caused by serotype 19A. Isolates not susceptible to cefotaxime (MIC>0.5μg/L) decreased from 27% to 8%, (p=0.02). Mean patient ages rose from 28.7months to 38.5months (p<0.05). Case fatality rate across both periods was 5%. An unfavourable outcome (death or neurological sequelae) occurred in 27% of patients, while the rate was similar in both periods. There was no increase in meningitis caused by pneumococcal serotypes not included in 13-valent pneumococcal conjugate vaccine throughout the years of the study. Immunisation with 13-valent pneumococcal conjugate vaccine has reduced the rate of pneumococcal meningitis in children less than 15years, with a near-elimination of cefotaxime-resistant isolates, but morbidity has remained unchanged. A shift of pneumococcal meningitis towards slightly higher age groups was also observed. Copyright © 2017. Published by Elsevier Ltd.

Preclinical immunogenicity and functional activity studies of an A+W meningococcal outer membrane vesicle (OMV) vaccine and comparisons with existing meningococcal conjugate- and polysaccharide vaccines.

PubMed

Tunheim, G; Arnemo, M; Næss, L M; Fjeldheim, Å K; Nome, L; Bolstad, K; Aase, A; Mandiarote, A; González, H; González, D; García, L; Cardoso, D; Norheim, G; Rosenqvist, E

2013-12-09

Meningococci of serogroups A and W (MenA and MenW) are the main causes of epidemic bacterial meningitis outbreaks in sub-Saharan Africa. In this study we prepared a detergent extracted outer membrane vesicle (dOMV) vaccine from representative African MenA and MenW strains, and compared the immunogenicity of this vaccine with existing meningococcal conjugate and polysaccharide (PS) vaccines in mice. NMRI mice were immunized with preclinical batches of the A+W dOMV vaccine, or with commercially available vaccines; a MenA conjugate vaccine (MenAfriVac(®), Serum Institute of India), ACYW conjugate vaccine (Menveo(®), Novartis) or ACYW PS vaccine (Mencevax(®), GlaxoSmithKline). The mice received 2 doses of 1/10 or 1/50 of a human dose with a three week interval. Immune responses were tested in ELISA, serum bactericidal activity (SBA) and opsonophagocytic activity (OPA) assays. High levels of IgG antibodies against both A and W dOMV were detected in mice receiving the A+W dOMV vaccine. High SBA titers against both MenA and MenW vaccine strains were detected after only one dose of the A+W dOMV vaccine, and the titers were further increased after the second dose. The SBA and OPA titers in mice immunized with dOMV vaccine were significantly higher than in mice immunized with the ACYW-conjugate vaccine or the PS vaccine. Furthermore, the A+W dOMV vaccine was shown to induce SBA and OPA titers against MenA of the same magnitude as the titers induced by the A-conjugate vaccine. In conclusion, the A+W dOMV vaccine induced high levels of functional antibodies to both MenA and MenW strains, levels that were shown to be higher or equal to the levels induced by licensed meningococcal vaccines. Thus, an A+W dOMV vaccine could potentially serve as an alternative or a supplement to existing conjugate and PS vaccines in the African meningitis belt. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

Impact of Haemophilus influenzae Type b conjugate vaccine in Mongolia: prospective population-based surveillance, 2002-2010.

PubMed

Scott, Susana; Altanseseg, Dorjpurev; Sodbayer, Demberelsuren; Nymadawa, Pagvajav; Bulgan, Davaadash; Mendsaikhan, Jamsran; Watt, James P; Slack, Mary P E; Carvalho, Maria G; Hajjeh, Rana; Edmond, Karen M

2013-07-01

Bacterial meningitis is associated with high mortality and long-term complications. This study assessed the impact of Haemophilus influenzae type b (Hib) conjugate vaccine on childhood bacterial meningitis in Ulaanbaatar, Mongolia. Prospective, active, population-based surveillance for suspected meningitis in children aged 2-59 months was conducted (February 2002-January 2011) in 6 hospitals. Clinical data, blood, and cerebrospinal fluid were collected. The impact of Hib conjugate vaccine was assessed by comparing Hib and all cause meningitis data in the 3 years preceding pentavalent conjugate vaccine implementation (2002-2004) with 3 years postimplementation (2008-2010). Five hundred eleven cases of suspected meningitis were identified from 2002-2011. Pentavalent conjugate vaccine coverage in December 2005 in Ulaanbaatar city was 97%. The proportion of suspected cases confirmed as Hib meningitis decreased from 25% (50/201) in the prevaccination era to 2% (4/193) in the postvaccination era (P < .0001). The annual incidence of Hib decreased from 28 cases per 100,000 children in 2002-2005 to 2 per 100,000 in 2008-2010 (P < .0001). This article demonstrates the marked impact of Hib conjugate vaccine introduction on meningitis in Mongolia. It is important to sustain this surveillance system to monitor the long-term impact of Hib conjugate vaccine, as well as other interventions such as pneumococcal and meningococcal vaccines. Copyright © 2013. Published by Mosby, Inc.

Dismantling the Taboo against Vaccines in Pregnancy

PubMed Central

de Martino, Maurizio

2016-01-01

Vaccinating pregnant women in order to protect them, the fetus, and the child has become universal in no way at all. Prejudice in health professionals add to fears of women and their families. Both these feelings are not supported by even the smallest scientific data. Harmlessness for the mother and the child has been observed for seasonal, pandemic, or quadrivalent influenza, mono, combined polysaccharide or conjugated meningococcal or pneumococcal, tetanus toxoid, acellular pertussis, human papillomavirus, cholera, hepatitis A, Japanese encephalitis, rabies, anthrax, smallpox, yellow fever, mumps, measles and rubella combined, typhoid fever, inactivated or attenuated polio vaccines, and Bacillus Calmétte Guerin vaccines. Instead, the beneficial effects of influenza vaccine for the mother and the child as well as of pertussis vaccine for the child have been demonstrated. Obstetrician-gynecologists, general practitioners, and midwives must incorporate vaccination into their standard clinical care. Strong communication strategies effective at reducing parental vaccine hesitancy and approval of regulatory agencies for use of vaccines during pregnancy are needed. It must be clear that the lack of pre-licensure studies in pregnant women and, consequently, the lack of a statement about the use of the vaccine in pregnant women does not preclude its use in pregnancy. PMID:27338346

Dismantling the Taboo against Vaccines in Pregnancy.

PubMed

de Martino, Maurizio

2016-06-07

Vaccinating pregnant women in order to protect them, the fetus, and the child has become universal in no way at all. Prejudice in health professionals add to fears of women and their families. Both these feelings are not supported by even the smallest scientific data. Harmlessness for the mother and the child has been observed for seasonal, pandemic, or quadrivalent influenza, mono, combined polysaccharide or conjugated meningococcal or pneumococcal, tetanus toxoid, acellular pertussis, human papillomavirus, cholera, hepatitis A, Japanese encephalitis, rabies, anthrax, smallpox, yellow fever, mumps, measles and rubella combined, typhoid fever, inactivated or attenuated polio vaccines, and Bacillus Calmétte Guerin vaccines. Instead, the beneficial effects of influenza vaccine for the mother and the child as well as of pertussis vaccine for the child have been demonstrated. Obstetrician-gynecologists, general practitioners, and midwives must incorporate vaccination into their standard clinical care. Strong communication strategies effective at reducing parental vaccine hesitancy and approval of regulatory agencies for use of vaccines during pregnancy are needed. It must be clear that the lack of pre-licensure studies in pregnant women and, consequently, the lack of a statement about the use of the vaccine in pregnant women does not preclude its use in pregnancy.

Effectiveness of HPV vaccines against genital warts in women from Valencia, Spain.

PubMed

Navarro-Illana, Esther; López-Lacort, Mónica; Navarro-Illana, Pedro; Vilata, Juan José; Diez-Domingo, Javier

2017-06-05

To assess the effectiveness of the HPV vaccines in preventing genital warts in young women. Population-based study using health databases. Valencian Community (Spain). All girls and women aged 14-19years who were registered in the Valencian Community between January 2009 and December 2014 (n=279,787). Incident cases of genital warts were defined as the first activation of diagnosis code ICD-9-CM 078.11 (Condyloma acuminatum) in primary care and outpatient clinics during the study period. There were 612 cases of genital warts. The overall incidence rate was 75.8/100,000 person-years (95% CrI 69.7-81.8). There was a decrease in genital warts when female candidates to be vaccinated with quadrivalent HPV vaccine reached the age of 18 (in 2012), compared to previous years. Incidence of genital warts in unvaccinated women and those who received the bivalent vaccine was higher than in girls and women who received the quadrivalent HPV vaccine. The effectiveness of a three-dose regimen of the quadrivalent HPV vaccine was 77% (95 CrI: 66-85%), whereas that of a single dose was 61% (95 CrI: 20-87%). No effectiveness was seen with a full vaccination course with the bivalent HPV vaccine. Three doses of the quadrivalent HPV vaccine were effective against genital warts in our population. Moreover, with low vaccine coverage the incidence of genital warts decreased only in the vaccinated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

PubMed

McVernon, J; Johnson, P D R; Pollard, A J; Slack, M P E; Moxon, E R

2003-05-01

To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.

Post-licensure surveillance of quadrivalent live attenuated influenza vaccine United States, Vaccine Adverse Event Reporting System (VAERS), July 2013-June 2014.

PubMed

Haber, Penina; Moro, Pedro L; Cano, Maria; Lewis, Paige; Stewart, Brock; Shimabukuro, Tom T

2015-04-15

Quadrivalent live attenuated influenza vaccine (LAIV4) was approved in 2012 for healthy persons aged 2-49 years. Beginning with the 2013-2014 influenza season, LAIV4 replaced trivalent live attenuated influenza vaccine (LAIV3). We analyzed LAIV4 reports to VAERS, a national spontaneous reporting system. LAIV4 reports in 2013-2014 were compared to LAIV3 reports from the previous three influenza seasons. Medical records were reviewed for non-manufacturer serious reports (i.e., death, hospitalization, prolonged hospitalization, life-threatening illness, permanent disability) and reports of selected conditions of interest. We conducted Empirical Bayesian data mining to identify disproportional reporting for LAIV4. In 2013-2014, 12.7 million doses of LAIV4 were distributed and VAERS received 779 reports in individuals aged 2-49 years; 95% were non-serious. Expired drug administered (42%), fever (13%) and cough (8%) were most commonly reported in children aged 2-17 years when LAIV4 was administered alone, while headache (18%), expired drug administered (15%) and exposure during pregnancy (12%) were most common in adults aged 18-49 years. We identified one death report in a child who died from complications of cerebellar vascular tumors. Among non-death serious reports, neurologic conditions were common in children and adults. In children, seizures (3) and Guillain-Barré syndrome (2) were the most common serious neurologic outcomes. We identified three serious reports of asthma/wheezing following LAIV4 in children. Data mining detected disproportional reporting for vaccine administration errors and for influenza illness in children. Our analysis of VAERS reports for LAIV4 did not identify any concerning patterns. The data mining finding for reports of influenza illness is consistent with low LAIV4 vaccine effectiveness observed for influenza A disease in children in 2013-2014. Reports of LAIV4 administration to persons in whom the vaccine is not recommended (e

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.

Priming for immunologic memory in adults by meningococcal group C conjugate vaccination.

PubMed

Vu, David M; de Boer, Alberdina W; Danzig, Lisa; Santos, George; Canty, Bridget; Flores, Betty M; Granoff, Dan M

2006-06-01

Meningococcal group C polysaccharide-protein conjugate vaccines (MCV) prime infants and children for memory anticapsular responses upon subsequent exposure to unconjugated polysaccharide. The objective of this study was to determine whether MCV primes vaccine-naïve adults and adults previously vaccinated with meningococcal polysaccharide vaccine (MPSV) for memory antibody responses. Meningococcal vaccine-naïve adults were randomized to receive either MCV (MCV/naïve group) (n = 35) or pneumococcal conjugate vaccine (PCV) (PCV/naïve group) (n = 34). Participants with a history of receiving MPSV were given MCV (MCV/MPSV group) (n = 26). All subjects were challenged 10 months later with one-fifth of the usual dose of MPSV (10 mug of each polysaccharide). Sera were obtained before the conjugate vaccination and before and 7 days after the MPSV challenge and assayed for immunoglobulin G (IgG) anticapsular antibody concentrations and bactericidal titers. The MCV/naïve group had 7- to 10-fold-higher serum IgG and bactericidal responses after the MPSV challenge than the PCV/naïve group (P < 0.001). The increases (n-fold) in anticapsular antibody concentrations in the MCV/naïve group were greatest in subjects with antibody concentrations of 2 microg/ml before the challenge; P < 0.0001). Only 3 of 11 MCV-vaccinated subjects who had received MPSV before enrollment and who had antibody concentrations of vaccination of meningococcal vaccine-naïve adults primes for robust memory antibody responses. There was no evidence of induction of memory by MCV in adults previously vaccinated with MPSV.

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 design of a capsule polysaccharide conjugate vaccine against Campylobacter jejuni serotype HS15.

PubMed

Bertolo, Lisa; Ewing, Cheryl P; Maue, Alexander; Poly, Frederic; Guerry, Patricia; Monteiro, Mario A

2013-01-25

Campylobacter jejuni infection is now the main cause of diarrhea-related illnesses in humans. An efficacious vaccine for the traveler and developing world market would be welcomed. We are engaged in the discovery and characterization of serotype-specific C. jejuni capsule polysaccharides (CPSs) to study their role in virulence and as protective vaccine antigens. Our prototype conjugate vaccine with serotype HS23 CPS (strain 81-176) has been shown to fully protect non-human primates against diarrhea inflicted by C. jejuni HS23, but ultimately, a useful CPS-based vaccine will have to be multivalent. To this end, we describe here the creation of a CPS-conjugate vaccine against C. jejuni serotype HS15. Structural analysis revealed that a repeating block consisting of L-α-arabinofuranose (Ara) and 6-deoxy-L-α-gulo-heptopyranose (6d-gulo-Hep) comprised the CPS of serotype HS15 type strain ATCC 43442 [→3)-α-L-Araf-(1→3)-6d-L-α-gulo-Hepp(1→](n). Strategically, the non-reducing end of the CPS was activated and used in the attachment of CPS to CRM₁₉₇ to yield a conjugate vaccine. A serological assessment of the CPS(HS15)-CRM₁₉₇ conjugate with an anti-HS15 polyclonal antibody confirmed the conservation of antigenic epitopes, and subsequent inoculation of mice with CPS(HS15)-CRM₁₉₇ revealed that this conjugate was indeed capable of raising anti-CPS(HS15) antibodies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure

PubMed Central

McVernon, J; Johnson, P; Pollard, A; Slack, M; Moxon, E

2003-01-01

Aims: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Methods: Unmatched case-control study in the UK and Eire 1992–2001 and Victoria, Australia 1988–1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Results: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 µg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 µg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 µg/ml (2.78 to 5.15); unvaccinated GMC 1.48 µg/ml (0.90 to 2.21); p = 0.003). Conclusions: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear. PMID:12716702

Quadrivalent human papillomavirus vaccine and autoimmune adverse events: a case-control assessment of the vaccine adverse event reporting system (VAERS) database.

PubMed

Geier, David A; Geier, Mark R

2017-02-01

Gardasil is a quadrivalent human papillomavirus (HPV4) vaccine that was approved for use by the US Food and Drug Administration in June 2006. HPV4 vaccine is routinely recommended for administration to women in the USA who are 11-12 years old by the Advisory Committee on Immunization Practices. Previous studies suggest HPV4 vaccine administration was associated with autoimmune diseases. As a consequence, an epidemiological assessment of the vaccine adverse event reporting system database was undertaken for adverse event reports associated with vaccines administered from 2006 to 2014 to 6-39 year-old recipients with a listed US residence and a specified female gender. Cases with the serious autoimmune adverse event (SAAE) outcomes of gastroenteritis (odds ratio (OR) 4.627, 95 % confidence interval (CI) 1.892-12.389), rheumatoid arthritis (OR 5.629, 95 % CI 2.809-12.039), thrombocytopenia (OR 2.178, 95 % CI 1.222-3.885), systemic lupus erythematosus (OR 7.626, 95 % CI 3.385-19.366), vasculitis (OR 3.420, 95 % CI 1.211-10.408), alopecia (OR 8.894, 95 % CI 6.255-12.914), CNS demyelinating conditions (OR 1.585, 95 % CI 1.129-2.213), ovarian damage (OR 14.961, 95 % CI 6.728-39.199), or irritable bowel syndrome (OR 10.021, 95 % CI 3.725-33.749) were significantly more likely than controls to have received HPV4 vaccine (median onset of initial symptoms ranged from 3 to 37 days post-HPV4 vaccination). Cases with the outcome of Guillain-Barre syndrome (OR 0.839, 95 % CI 0.601-1.145) were no more likely than controls to have received HPV4 vaccine. In addition, cases with the known HPV4-related outcome of syncope were significantly more likely than controls to have received HPV4 vaccine (OR 5.342, 95 % CI 4.942-5.777). Cases with the general health outcomes of infection (OR 0.765, 95 % CI 0.428-1.312), conjunctivitis (OR 1.010, 95 % CI 0.480-2.016), diarrhea (OR 0.927, 95 % CI 0.809-1.059), or pneumonia (OR 0.785, 95 % CI 0.481-1.246) were no more likely

Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine.

PubMed

Chabot, Donald J; Ribot, Wilson J; Joyce, Joseph; Cook, James; Hepler, Robert; Nahas, Debbie; Chua, Jennifer; Friedlander, Arthur M

2016-07-25

The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines. Published by Elsevier Ltd.

Pneumococcal conjugate vaccine introduction in Latin America and the Caribbean: progress and lessons learned.

PubMed

de Oliveira, Lucia Helena; Trumbo, Silas Pierson; Ruiz Matus, Cuauhtémoc; Sanwogou, N Jennifer; Toscano, Cristiana M

2016-10-01

In Latin America and the Caribbean, pneumococcus has been estimated to cause 12,000-28,000 deaths, 182,000 hospitalizations, and 1.4 million clinic visits annually. Countries in the Americas have been among the first developing nations to introduce pneumococcal conjugate vaccines into their Expanded Programs on Immunization, with 34 countries and territories having introduced these vaccines as of September 2015. Lessons learned for successful vaccine introduction include the importance of coordination between political and technical decision makers, adjustments to the cold chain prior to vaccine introduction, and the need for detailed plans addressing the financial and technical sustainability of introduction. Though many questions on the Pneumococcal Conjugate Vaccine remain unanswered, the experience of the Americas suggests that the vaccines can be introduced quickly and effectively.

Cost effectiveness of pneumococcal conjugate vaccination against acute otitis media in children: a review.

PubMed

Boonacker, Chantal W B; Broos, Pieter H; Sanders, Elisabeth A M; Schilder, Anne G M; Rovers, Maroeska M

2011-03-01

While pneumococcal conjugate vaccines have shown to be highly effective against invasive pneumococcal disease, their potential effectiveness against acute otitis media (AOM) might become a major economic driver for implementing these vaccines in national immunization programmes. However, the relationship between the costs and benefits of available vaccines remains a controversial topic. Our objective is to systematically review the literature on the cost effectiveness of pneumococcal conjugate vaccination against AOM in children. We searched PubMed, Cochrane and the Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects [DARE], NHS Economic Evaluation Database [NHS EED] and Health Technology Assessment database [HTA]) from inception until 18 February 2010. We used the following keywords with their synonyms: 'otitis media', 'children', 'cost-effectiveness', 'costs' and 'vaccine'. Costs per AOM episode averted were calculated based on the information in this literature. A total of 21 studies evaluating the cost effectiveness of pneumococcal conjugate vaccines were included. The quality of the included studies was moderate to good. The cost per AOM episode averted varied from &U20AC;168 to &U20AC;4214, and assumed incidence rates varied from 20,952 to 118,000 per 100,000 children aged 0-10 years. Assumptions regarding direct and indirect costs varied between studies. The assumed vaccine efficacy of the 7-valent pneumococcal CRM197-conjugate vaccine was mainly adopted from two trials, which reported 6-8% efficacy. However, some studies assumed additional effects such as herd immunity or only took into account AOM episodes caused by serotypes included in the vaccine, which resulted in efficacy rates varying from 12% to 57%. Costs per AOM episode averted were inversely related to the assumed incidence rates of AOM and to the estimated costs per AOM episode. The median costs per AOM episode averted tended to be lower in industry

Siderophore vaccine conjugates protect against uropathogenic Escherichia coli urinary tract infection

PubMed Central

Mike, Laura A.; Smith, Sara N.; Sumner, Christopher A.; Eaton, Kathryn A.; Mobley, Harry L. T.

2016-01-01

Uropathogenic Escherichia coli (UPEC) is the primary cause of uncomplicated urinary tract infections (UTIs). Whereas most infections are isolated cases, 1 in 40 women experience recurrent UTIs. The rise in antibiotic resistance has complicated the management of chronic UTIs and necessitates new preventative strategies. Currently, no UTI vaccines are approved for use in the United States, and the development of a highly effective vaccine remains elusive. Here, we have pursued a strategy for eliciting protective immunity by vaccinating with small molecules required for pathogenesis, rather than proteins or peptides. Small iron-chelating molecules called siderophores were selected as antigens to vaccinate against UTI for this vaccine strategy. These pathogen-associated stealth siderophores evade host immune defenses and enhance bacterial virulence. Previous animal studies revealed that vaccination with siderophore receptor proteins protects against UTI. The poor solubility of these integral outer-membrane proteins in aqueous solutions limits their practical utility. Because their cognate siderophores are water soluble, we hypothesized that these bacterial-derived small molecules are prime vaccine candidates. To test this hypothesis, we immunized mice with siderophores conjugated to an immunogenic carrier protein. The siderophore–protein conjugates elicited an adaptive immune response that targeted bacterial stealth siderophores and protected against UTI. Our study has identified additional antigens suitable for a multicomponent UTI vaccine and highlights the potential use of bacterial-derived small molecules as antigens in vaccine therapies. PMID:27821778

Siderophore vaccine conjugates protect against uropathogenic Escherichia coli urinary tract infection.

PubMed

Mike, Laura A; Smith, Sara N; Sumner, Christopher A; Eaton, Kathryn A; Mobley, Harry L T

2016-11-22

Uropathogenic Escherichia coli (UPEC) is the primary cause of uncomplicated urinary tract infections (UTIs). Whereas most infections are isolated cases, 1 in 40 women experience recurrent UTIs. The rise in antibiotic resistance has complicated the management of chronic UTIs and necessitates new preventative strategies. Currently, no UTI vaccines are approved for use in the United States, and the development of a highly effective vaccine remains elusive. Here, we have pursued a strategy for eliciting protective immunity by vaccinating with small molecules required for pathogenesis, rather than proteins or peptides. Small iron-chelating molecules called siderophores were selected as antigens to vaccinate against UTI for this vaccine strategy. These pathogen-associated stealth siderophores evade host immune defenses and enhance bacterial virulence. Previous animal studies revealed that vaccination with siderophore receptor proteins protects against UTI. The poor solubility of these integral outer-membrane proteins in aqueous solutions limits their practical utility. Because their cognate siderophores are water soluble, we hypothesized that these bacterial-derived small molecules are prime vaccine candidates. To test this hypothesis, we immunized mice with siderophores conjugated to an immunogenic carrier protein. The siderophore-protein conjugates elicited an adaptive immune response that targeted bacterial stealth siderophores and protected against UTI. Our study has identified additional antigens suitable for a multicomponent UTI vaccine and highlights the potential use of bacterial-derived small molecules as antigens in vaccine therapies.

Quadrivalent human papillomavirus vaccine uptake in adolescent boys and maternal utilization of preventive care and history of sexually transmitted infections.

PubMed

Hechter, Rulin C; Chao, Chun; Sy, Lina S; Ackerson, Bradley K; Slezak, Jeff M; Sidell, Margo A; Jacobsen, Steven J

2013-09-01

We examined whether maternal utilization of preventive care and history of sexually transmitted infections (STIs) predicted quadrivalent human papillomavirus vaccine (HPV4) uptake among adolescent boys 1 year following the recommendation for permissive use of HPV4 for males. We linked maternal information with electronic health records of 254 489 boys aged 9 to 17 years who enrolled in Kaiser Permanente Southern California health plan from October 21, 2009, through December 21, 2010. We used multivariable Poisson regression with robust error variance to examine whether HPV4 initiation was associated with maternal uptake of influenza vaccine, Papanicolaou (Pap) screening, and history of STIs. We identified a modest but statistically significant association between initiation of HPV4 series and maternal receipt of influenza vaccine (rate ratio [RR] = 1.16; 95% confidence interval [CI] = 1.07, 1.26) and Pap screening (RR = 1.13; 95% CI = 1.01, 1.26). Boys whose mothers had a history of genital warts were more likely to initiate HPV4 (RR = 1.47; 95% CI = 0.93, 2.34), although the association did not reach statistical significance (P = .1). Maternal utilization of preventive care and history of genital warts may influence HPV4 uptake among adolescent boys. The important role of maternal health characteristics and health behaviors needs be considered in intervention efforts to increase vaccine uptake among boys.

Quadrivalent influenza vaccines in low and middle income countries: Cost-effectiveness, affordability and availability.

PubMed

Hendriks, Jan; Hutubessy, Raymond C W; Grohmann, Gary; Torelli, Guido; Friede, Martin; Kieny, Marie-Paule

2018-06-27

In high-income countries, there is an increased tendency to replace inactivated seasonal trivalent influenza (TIV) vaccines with quadrivalent (QIV) vaccines as these are considered to give a greater public health benefit. In addition, several recent studies from the USA and Europe indicate that replacement with QIV might also be cost-effective; however, the situation in low- and middle-income countries (LMIC) is less clear as few studies have investigated this aspect. The paper by de Boer et al. (2008) describes a dynamic modelling study commissioned by WHO that suggests that in LMICs, under certain conditions, QIV might also be more cost-effective than TIV. In this commentary, we discuss some important aspects that policymakers in LMICs might wish to take into account when considering replacing TIV by QIV. Indeed, from the data presented in the paper by de Boer et al. it can be inferred that replacing QIV for TIV would mean a 25-29% budget increase for seasonal influenza vaccination in South Africa and Vietnam, resulting in an incremental influenza-related health impact reduction of only 7-8% when a 10% symptomatic attack rate is assumed. We argue that national health budget considerations in LMIC might lead decision-makers to choose other investments with higher health impact for a budget equivalent to roughly a quarter of the yearly TIV immunization costs. In addition to an increased annual cost that would be associated with a decision to replace TIV with QIV, there would be an increased pressure on manufacturers to produce QIV in time for the influenza season requiring manufacturers to produce some components of the seasonal vaccine at risk prior to the WHO recommendations for influenza vaccines. Unless the current uncertainties, impracticalities and increased costs associated with QIVs are resolved, TIVs are likely to remain the more attractive option for many LMICs. Each country should establish its context-specific process for decision-making based on

Pain in adolescent girls receiving human papillomavirus vaccine with concomitantly administered vaccines.

PubMed

Walter, Emmanuel B; Kemper, Alex R; Dolor, Rowena J; Dunne, Eileen F

2015-02-01

Using the Faces Pain Scale - Revised, we assessed injection site pain 10 minutes after vaccination in young females randomized to receive either quadrivalent human papillomavirus vaccine (HPV4) before or after concomitantly administered vaccines. Although pain was modestly more after HPV4 injection than after other vaccines, the pain intensity after HPV4 injection was significantly less in those who received HPV4 before receiving other concomitant vaccines.

Vi-CRM 197 as a new conjugate vaccine against Salmonella Typhi.

PubMed

Micoli, F; Rondini, S; Pisoni, I; Proietti, D; Berti, F; Costantino, P; Rappuoli, R; Szu, S; Saul, A; Martin, L B

2011-01-17

An efficacious, low cost vaccine against typhoid fever, especially for young children, would make a major impact on disease burden in developing countries. The virulence capsular polysaccharide of Salmonella Typhi (Vi) coupled to recombinant mutant Pseudomonas aeruginosa exoprotein A (Vi-rEPA) has been shown to be highly efficacious. We investigated the use of carrier proteins included in infant vaccines, standardized the conjugation process and developed key assays required for routine lot release at production scale. Vi from a BSL1 organism, Citrobacter freundii, strain WR7011, was used as an alternative to Vi from S. Typhi. We showed that Vi conjugated to CRM(197), a non-toxic mutant of diphtheria toxin, widely used in commercial vaccines, was produced at high yield. Vi-CRM(197) proved immunogenic in animal studies, even without adjuvant. Thus, Vi-CRM(197) appears to be a suitable candidate for the development of a commercially viable, effective typhoid vaccine for developing countries. Copyright © 2010 Elsevier Ltd. All rights reserved.

A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men.

PubMed

Van Damme, Pierre; Meijer, Chris J L M; Kieninger, Dorothee; Schuyleman, Anne; Thomas, Stephane; Luxembourg, Alain; Baudin, Martine

2016-07-29

A nine-valent human papilloma virus (9vHPV) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 (as per the licensed quadrivalent HPV (qHPV) vaccine) as well as to five additional oncogenic HPV types (HPV 31/33/45/52/58). The 9vHPV vaccine has the potential to prevent 90% of cervical cancers, HPV-related anal, vaginal and vulval cancers and anogenital warts. We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 16-26-year-old men. Participants (N=500) were randomised to receive 9vHPV or qHPV vaccines on day 1, month 2 and month 6. Serology testing was performed on day 1 and month 7. HPV type-specific antibody titres (anti-HPV 6/11/16/18/31/33/45/52/58) were determined by competitive Luminex immunoassay and expressed as geometric mean titres and seroconversion rates. Vaccine safety was also assessed. The HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine. All participants receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58. The 9vHPV and qHPV vaccines showed comparable safety profiles. In addition to immune responses to HPV 31/33/45/52/58, a three-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in men aged 16-26years. The safety profile was also similar for the two vaccines. The results from this study support extending the efficacy findings with qHPV vaccine to 9vHPV vaccine in men aged 16-26years. NCT02114385. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pneumococcal conjugate vaccines: proceedings from an interactive symposium at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy.

PubMed

Pelton, Stephen I; Dagan, Ron; Gaines, Beverly M; Klugman, Keith P; Laufer, Dagna; O'Brien, Katherine; Schmitt, Heinz J

2003-04-02

Globally, Streptococcus pneumoniae is a leading cause of invasive and noninvasive disease in infants and young children. The emergence of antibiotic-resistant strains has increased interest in prevention through immunization. Currently, the only available conjugate pneumococcal vaccine is a seven-valent formulation, PNCRM7. This paper presents excerpts from a symposium that provided an update of ongoing surveillance data and clinical trials evaluating pneumococcal conjugate vaccines. The topics addressed included: (1) PNCRM7 postmarketing safety data; (2) the impact of PNCRM7 in premature infants; (3) the direct and indirect effect of pneumococcal conjugate vaccines on colonization; (4) the effect of pneumococcal conjugate vaccines on replacement disease and the rate of resistance among replacement serotypes; (5) the current recommendations for the use of PNCRM7; and (6) the potential impact of conjugate vaccines in Europe and the Asia-Pacific region.

Outer membrane protein complex of Meningococcus enhances the antipolysaccharide antibody response to pneumococcal polysaccharide-CRM₁₉₇ conjugate vaccine.

PubMed

Lai, Zengzu; Schreiber, John R

2011-05-01

Bacterial polysaccharides (PS) are T cell-independent antigens that do not induce immunologic memory and are poor immunogens in infants. Conjugate vaccines in which the PS is covalently linked to a carrier protein have enhanced immunogenicity that resembles that of T cell-dependent antigens. The Haemophilus influenzae type b (Hib) conjugate vaccine, which uses the outer membrane protein complex (OMPC) from meningococcus as a carrier protein, elicits protective levels of anti-capsular PS antibody (Ab) after a single dose, in contrast to other conjugate vaccines, which require multiple doses. We have previously shown that OMPC robustly engages Toll-like receptor 2 (TLR2) and enhances the early anti-Hib PS Ab titer associated with an increase in TLR2-mediated induction of cytokines. We now show that the addition of OMPC to the 7-valent pneumococcal PS-CRM₁₉₇ conjugate vaccine during immunization significantly increases the anti-PS IgG and IgM responses to most serotypes of pneumococcus contained in the vaccine. The addition of OMPC also increased the likelihood of anti-PS IgG3 production against serotypes 4, 6B, 9V, 18C, 19F, and 23F. Splenocytes from mice who had received OMPC with the pneumococcal conjugate vaccine produced significantly more interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) than splenocytes from mice who received phosphate-buffered saline (PBS) plus the conjugate vaccine. We conclude that OMPC enhances the anti-PS Ab response to pneumococcal PS-CRM₁₉₇ conjugate vaccine, an effect associated with a distinct change in cytokine profile. It may be possible to reduce the number of conjugate vaccine doses required to achieve protective Ab levels by priming with adjuvants that are TLR2 ligands.

Economic evaluation of second generation pneumococcal conjugate vaccines in Norway.

PubMed

Robberstad, Bjarne; Frostad, Carl R; Akselsen, Per E; Kværner, Kari J; Berstad, Aud K H

2011-11-03

A seven valent pneumococcal conjugate vaccine (PCV7) was introduced in the Norwegian childhood immunization programme in 2006, and since then the incidence of invasive pneumococcal disease has declined substantially. Recently, two new second generation pneumococcal conjugate vaccines have become available, and an update of the economic evidence is needed. The aim of this study was to estimate incremental costs, health effects and cost-effectiveness of the pneumococcal conjugate vaccines PCV7, PCV13 and PHiD-CV in Norway. We used a Markov model to estimate costs and epidemiological burden of pneumococcal- and NTHi-related diseases (invasive pneumococcal disease (IPD), Community Acquired Pneumonia (CAP) and acute otitis media (AOM)) for a specific birth cohort. Using the most relevant evidence and assumptions for a Norwegian setting, we calculated incremental costs, health effects and cost-effectiveness for different vaccination strategies. In addition we performed sensitivity analyses for key parameters, tested key assumptions in scenario analyses and explored overall model uncertainty using probabilistic sensitivity analysis. The model predicts that both PCV13 and PHiD-CV provide more health gains at a lower cost than PCV7. Differences in health gains between the two second generation vaccines are small for invasive pneumococcal disease but larger for acute otitis media and myringotomy procedures. Consequently, PHiD-CV saves more disease treatment costs and indirect costs than PCV13. This study predicts that, compared to PVC13, PHiD-CV entails lower costs and greater benefits if the latter is measured in terms of quality adjusted life years. PVC13 entails more life years gained than PHiD-CV, but those come at a cost of NOK 3.1 million (∼€0.4 million) per life year. The results indicate that PHiD-CV is cost-effective compared to PCV13 in the Norwegian setting. Copyright © 2011 Elsevier Ltd. All rights reserved.

Inclusion of the benefits of enhanced cross-protection against cervical cancer and prevention of genital warts in the cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands.

PubMed

Westra, Tjalke A; Stirbu-Wagner, Irina; Dorsman, Sara; Tutuhatunewa, Eric D; de Vrij, Edwin L; Nijman, Hans W; Daemen, Toos; Wilschut, Jan C; Postma, Maarten J

2013-02-07

Infection with HPV 16 and 18, the major causative agents of cervical cancer, can be prevented through vaccination with a bivalent or quadrivalent vaccine. Both vaccines provide cross-protection against HPV-types not included in the vaccines. In particular, the bivalent vaccine provides additional protection against HPV 31, 33, and 45 and the quadrivalent vaccine against HPV31. The quadrivalent vaccine additionally protects against low-risk HPV type 6 and 11, responsible for most cases of genital warts. In this study, we made an analytical comparison of the two vaccines in terms of cost-effectiveness including the additional benefits of cross-protection and protection against genital warts in comparison with a screening-only strategy. We used a Markov model, simulating the progression from HPV infection to cervical cancer or genital warts. The model was used to estimate the difference in future costs and health effects of both HPV-vaccines separately. In a cohort of 100,000 women, use of the bivalent or quadrivalent vaccine (both at 50% vaccination coverage) reduces the cervical cancer incidence by 221 and 207 cases, corresponding to ICERs of €17,600/QALY and €18,900/QALY, respectively. It was estimated that the quadrivalent vaccine additionally prevents 4390 cases of genital warts, reducing the ICER to €16,300/QALY. Assuming a comparable willingness to pay for cancer and genital warts prevention, the difference in ICERs could justify a slightly higher price (~7% per dose) in favor of the quadrivalent vaccine. Clearly, HPV vaccination has been implemented for the prevention of cervical cancer. From this perspective, use of the bivalent HPV vaccine appears to be most effective and cost-effective. Including the benefits of prevention against genital warts, the ICER of the quadrivalent HPV vaccine was found to be slightly more favourable. However, current decision-making on the introduction of HPV is driven by the primary cervical cancer outcome. New vaccine

Inclusion of the benefits of enhanced cross-protection against cervical cancer and prevention of genital warts in the cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands

PubMed Central

2013-01-01

Background Infection with HPV 16 and 18, the major causative agents of cervical cancer, can be prevented through vaccination with a bivalent or quadrivalent vaccine. Both vaccines provide cross-protection against HPV-types not included in the vaccines. In particular, the bivalent vaccine provides additional protection against HPV 31, 33, and 45 and the quadrivalent vaccine against HPV31. The quadrivalent vaccine additionally protects against low-risk HPV type 6 and 11, responsible for most cases of genital warts. In this study, we made an analytical comparison of the two vaccines in terms of cost-effectiveness including the additional benefits of cross-protection and protection against genital warts in comparison with a screening-only strategy. Methods We used a Markov model, simulating the progression from HPV infection to cervical cancer or genital warts. The model was used to estimate the difference in future costs and health effects of both HPV-vaccines separately. Results In a cohort of 100,000 women, use of the bivalent or quadrivalent vaccine (both at 50% vaccination coverage) reduces the cervical cancer incidence by 221 and 207 cases, corresponding to ICERs of €17,600/QALY and €18,900/QALY, respectively. It was estimated that the quadrivalent vaccine additionally prevents 4390 cases of genital warts, reducing the ICER to €16,300/QALY. Assuming a comparable willingness to pay for cancer and genital warts prevention, the difference in ICERs could justify a slightly higher price (~7% per dose) in favor of the quadrivalent vaccine. Conclusions Clearly, HPV vaccination has been implemented for the prevention of cervical cancer. From this perspective, use of the bivalent HPV vaccine appears to be most effective and cost-effective. Including the benefits of prevention against genital warts, the ICER of the quadrivalent HPV vaccine was found to be slightly more favourable. However, current decision-making on the introduction of HPV is driven by the primary

Dendrimer-conjugated peptide vaccine enhances clearance of Chlamydia trachomatis genital infection.

PubMed

Ganda, Ingrid S; Zhong, Qian; Hali, Mirabela; Albuquerque, Ricardo L C; Padilha, Francine F; da Rocha, Sandro R P; Whittum-Hudson, Judith A

2017-07-15

Peptide-based vaccines have emerged in recent years as promising candidates in the prevention of infectious diseases. However, there are many challenges to maintaining in vivo peptide stability and enhancement of peptide immunogenicity to generate protective immunity which enhances clearance of infections. Here, a dendrimer-based carrier system is proposed for peptide-based vaccine delivery, and shows its anti-microbial feasibility in a mouse model of Chlamydia trachomatis. Chlamydiae are the most prevalent sexually transmitted bacteria worldwide, and also the causal agent of trachoma, the leading cause of preventable infectious blindness. In spite of the prevalence of this infectious agent and the many previous vaccine-related studies, there is no vaccine commercially available. The carrier system proposed consists of generation 4, hydroxyl-terminated, polyamidoamine (PAMAM) dendrimers (G4OH), to which a peptide mimic of a chlamydial glycolipid antigen-Peptide 4 (Pep4, AFPQFRSATLLL) was conjugated through an ester bond. The ester bond between G4OH and Pep4 is expected to break down mainly in the intracellular environment for antigen presentation. Pep4 conjugated to dendrimer induced Chlamydia-specific serum antibodies after subcutaneous immunizations. Further, this new vaccine formulation significantly protected immunized animals from vaginal challenge with infectious Chlamydia trachomatis, and it reduced infectious loads and tissue (genital tract) damage. Pep4 conjugated to G4OH or only mixed with peptide provided enhanced protection compared to Pep4 and adjuvant (i.e. alum), suggesting a potential adjuvant effect of the PAMAM dendrimer. Combined, these results demonstrate that hydroxyl-terminated PAMAM dendrimer is a promising polymeric nanocarrier platform for the delivery of peptide vaccines and this approach has potential to be expanded to other infectious intracellular bacteria and viruses of public health significance. Copyright © 2017 Elsevier B.V. All

Immunogenicity and safety of a quadrivalent inactivated influenza virus vaccine compared with a comparator quadrivalent inactivated influenza vaccine in a pediatric population: A phase 3, randomized noninferiority study.

PubMed

Airey, Jolanta; Albano, Frank R; Sawlwin, Daphne C; Jones, Alison Graves; Formica, Neil; Matassa, Vince; Leong, Jane

2017-05-09

Seqirus 2010 Southern Hemisphere split-virion trivalent inactivated influenza vaccine (IIV3) was associated with increased febrile reactions in children. Studies in vitro concluded that increasing concentrations of splitting agent decreased residual lipids and attenuated proinflammatory cytokine signals associated with fever. We assessed immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4; produced using higher concentration of splitting agent) versus a United States-licensed comparator IIV4 in healthy children aged 5-17years. Participants (N=2278) were randomized 3:1 and stratified by age (5-8years; 9-17years) to receive IIV4 (n=1709) or comparator IIV4 (n=569). Primary objective was to demonstrate noninferiority of IIV4 versus comparator IIV4 as assessed by hemagglutination inhibition (HI) geometric mean titer (GMT) ratio (upper bound of two-sided 95% confidence interval [CI]≤1.5) and difference in seroconversion rate (upper bound of two-sided 95% CI≤10%) for all four vaccine strains. HI antibody titers were assessed at baseline and 28days postvaccination. Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period, respectively. IIV4 met immunogenicity criteria for noninferiority. Adjusted GMT ratios (comparator IIV4/IIV4) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.01 (95% CI; 0.93, 1.09), 1.05 (0.96, 1.15), 0.89 (0.81, 0.98), and 0.92 (0.83, 1.02), respectively. Corresponding values for differences (95% CI) in seroconversion rates (comparator IIV4 minus IIV4) were -3.1 (-8.0, 1.8), 0.4 (-4.5, 5.3), -3.4 (-8.3, 1.5), and -2.0 (-6.9, 2.9). Fever rates were numerically higher, but not statistically different, with IIV4 versus comparator IIV4. No new safety signals were reported. IIV4 demonstrated immunological noninferiority to the comparator IIV4 with a clinically acceptable safety profile in children aged 5-17years. Increased levels of virus splitting agent seem to

Impact of Pneumococcal Conjugate Vaccination on Otitis Media: A Systematic Review

PubMed Central

Taylor, Sylvia; Marchisio, Paola; Vergison, Anne; Harriague, Julie; Hausdorff, William P.; Haggard, Mark

2012-01-01

Acute otitis media (AOM) is a leading cause of visits to physicians and of antibiotic prescriptions for young children. We systematically reviewed studies on all-cause AOM episodes and physician visits in which impact was attributed to pneumococcal conjugate vaccines, either as efficacy or effectiveness. Of 18 relevant publications found, most used the 7-valent pneumococcal conjugate vaccine (7vCRM). The efficacy of 7vCRM against all-cause AOM episodes or visits was 0%–9% in randomized trials and 17%–23% in nonrandomized trials. In observational database studies, physician visits for AOM were already declining in the 3–5 years before 7vCRM introduction (mean change, −15%; range, +14% to −24%) and continued to decline afterward (mean, −19%; range, +7% to −48%). This vaccine provides some protection against OM, but other factors have also contributed to the recent decline in OM incidence. Future effectiveness studies should thus use better-controlled methods to estimate the true impact of vaccination on AOM. PMID:22423134

Quadrivalent Human Papillomavirus Vaccine Uptake in Adolescent Boys and Maternal Utilization of Preventive Care and History of Sexually Transmitted Infections

PubMed Central

Chao, Chun; Sy, Lina S.; Ackerson, Bradley K.; Slezak, Jeff M.; Sidell, Margo A.; Jacobsen, Steven J.

2013-01-01

Objectives. We examined whether maternal utilization of preventive care and history of sexually transmitted infections (STIs) predicted quadrivalent human papillomavirus vaccine (HPV4) uptake among adolescent boys 1 year following the recommendation for permissive use of HPV4 for males. Methods. We linked maternal information with electronic health records of 254 489 boys aged 9 to 17 years who enrolled in Kaiser Permanente Southern California health plan from October 21, 2009, through December 21, 2010. We used multivariable Poisson regression with robust error variance to examine whether HPV4 initiation was associated with maternal uptake of influenza vaccine, Papanicolaou (Pap) screening, and history of STIs. Results. We identified a modest but statistically significant association between initiation of HPV4 series and maternal receipt of influenza vaccine (rate ratio [RR] = 1.16; 95% confidence interval [CI] = 1.07, 1.26) and Pap screening (RR = 1.13; 95% CI = 1.01, 1.26). Boys whose mothers had a history of genital warts were more likely to initiate HPV4 (RR = 1.47; 95% CI = 0.93, 2.34), although the association did not reach statistical significance (P = .1). Conclusions. Maternal utilization of preventive care and history of genital warts may influence HPV4 uptake among adolescent boys. The important role of maternal health characteristics and health behaviors needs be considered in intervention efforts to increase vaccine uptake among boys. PMID:23865707

Preparation and testing of a Haemophilus influenzae Type b/Hepatitis B surface antigen conjugate vaccine.

PubMed

An, So Jung; Woo, Joo Sung; Chae, Myung Hwa; Kothari, Sudeep; Carbis, Rodney

2015-03-24

The majority of conjugate vaccines focus on inducing an antibody response to the polysaccharide antigen and the carrier protein is present primarily to induce a T-cell dependent response. In this study conjugates consisting of poly(ribosylribitolphosphate) (PRP) purified from Haemophilus influenzae Type b bound to Hepatitis B virus surface antigen (HBsAg) virus like particles were prepared with the aim of inducing an antibody response to not only the PRP but also the HBsAg. A conjugate consisting of PRP bound to HBsAg via an adipic acid dihydrazide (ADH) spacer induced strong IgG antibodies to both the PRP and HBsAg. When conjugation was performed without the ADH spacer the induction of an anti-PRP response was equivalent to that seen by conjugate with the ADH spacer, however, a negligible anti-HBsAg response was induced. For comparison, PRP was conjugated to diphtheria toxoid (DT) and Vi polysaccharide purified from Salmonella Typhi conjugated to HBsAg both using an ADH spacer. The PRPAH-DT conjugate induced strong anti-PRP and anti-DT responses, the Vi-AHHBsAg conjugate induced a good anti-HBsAg response but not as strong as that induced by the PRPAH-HBsAg conjugate. This study demonstrated that in mice it was possible to induce robust antibody responses to both polysaccharide and carrier protein provided the conjugate has certain physico-chemical properties. A PRPAH-HBsAg conjugate with the capacity to induce anti-PRP and anti-HBsAg responses could be incorporated into a multivalent pediatric vaccine and simplify formulation of such a vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Health Economic Impact of Universal Infant Vaccination with the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine as Compared with 13-Valent Pneumococcal Conjugate Vaccine in Hong Kong.

PubMed

Lee, Kenneth K C; Chia Wu, David Bin; Topachevskyi, Oleksandr; Delgleize, Emmanuelle; DeAntonio, Rodrigo

2013-05-01

Pneumococcal universal vaccination in Hong Kong was introduced in 2009. We assessed the health and economic impact of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PCV-10) compared with the current 13-valent pneumococcal conjugate vaccine (PCV-13) recommended for Hong Kong in 2011, providing new elements to be considered by public health authorities in the future decision-making process for pneumococcal vaccines in this country. An analytical model was used to estimate the annual economic and health outcomes of invasive pneumococcal disease (IPD), community-acquired pneumonia, and acute otitis media (AOM), including nontypeable H. influenzae-related AOM, for a birth cohort in Hong Kong from the payer perspective with a 10-year horizon. Clinical impact including morbidity-mortality, quality-adjusted life-years (QALYs), incremental costs, and cost-effectiveness comparing PCV-10 and PCV-13 were estimated. Probabilistic sensitivity analyses by using alternate scenarios were performed. Model projections indicate that PCV-13 and PCV-10 have approximately equivalent impact on the prevention of deaths caused by IPD and pneumonia. PCV-13 is projected to prevent 6 additional cases of IPD, whereas PCV-10 is projected to prevent 13,229 additional AOM cases and 101 additional QALYs. For the base case, PCV-10 vaccination is estimated to save 44.6 million Hong Kong dollars (34.1 million Hong Kong dollars discounted). Sensitivity analysis indicated that PCV-10 would generate more QALYs and save costs as compared with PCV-13. Universal infant vaccination with new available pneumococcal vaccines is expected to generate a significant additional impact on reducing the burden of pneumococcal diseases in Hong Kong. PCV-10 vaccination would be potentially a cost-saving strategy compared with PCV-13 vaccination, generating better cost offsets and higher QALY gains. Copyright © 2013 International Society for Pharmacoeconomics and Outcomes

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

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.

The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen.

PubMed

Salehen, Nur'ain; Stover, Cordula

2008-01-24

The complement system, a well-characterised arm of the innate immune system, significantly influences the adaptive immune response via direct cell-cell interaction and maintenance of lymphoid organ architecture. Development of vaccines is a major advance in modern health care. In this review, we highlight the importance of the marginal zone in response to both, polysaccharide and conjugated vaccines, and discuss the relevance of complement herein, based on findings obtained from animal models with specific deletions of certain complement components and from vaccination reports of complement-deficient individuals. We conclude that both, intactness of the complement system and maturity of expression of its components, are relatively more important to aid in the immune response to polysaccharide vaccine than to conjugated vaccines.

Impact of introduction of the Haemophilus influenzae type b conjugate vaccine into childhood immunization on meningitis in Bangladeshi infants.

PubMed

Sultana, Nadira K; Saha, Samir K; Al-Emran, Hassan M; Modak, Joyanta K; Sharker, M A Yushuf; El-Arifeen, Shams; Cohen, Adam L; Baqui, Abdullah H; Luby, Stephen P

2013-07-01

Some Asian countries have been reluctant to adopt Haemophilus influenzae type b (Hib) conjugate vaccination because of uncertainty over disease burden. We assessed the impact of introduction of Hib conjugate vaccine into the Expanded Program on Immunization in Bangladesh on purulent and laboratory-confirmed H influenzae meningitis. Within a well-defined catchment area around 2 surveillance hospitals in Dhaka, Bangladesh, we compared the incidence of Hib meningitis confirmed by culture, latex agglutination, and polymerase chain reaction assay among infants 1 year before and 1 year after introduction of Hib conjugate vaccine. We adjusted the incidence rate for the proportion of children who sought care at the surveillance hospitals. Among infants, the incidence of confirmed Hib meningitis decreased from 92-16 cases per 100,000 within 1 year of vaccine introduction (vaccine preventable incidence = 76; 95% CI 18, 135 per 100,000). The incidence of purulent meningitis decreased from 1659-1159 per 100,000 (vaccine preventable incidence = 500; 95% CI: 203, 799 per 100,000). During the same time period, there was no significant difference in the incidence of meningitis due to Streptococcus pneumoniae. Introduction of conjugate Hib conjugate vaccine into Bangladesh Expanded Program on Immunization markedly reduced the burden of Hib and purulent meningitis. Copyright © 2013. Published by Mosby, Inc.

Assessment of Quadrivalent Human Papillomavirus Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic Signal-Detection Method in the Sentinel System.

PubMed

Yih, W Katherine; Maro, Judith C; Nguyen, Michael; Baker, Meghan A; Balsbaugh, Carolyn; Cole, David V; Dashevsky, Inna; Mba-Jonas, Adamma; Kulldorff, Martin

2018-06-01

The self-controlled tree-temporal scan statistic-a new signal-detection method-can evaluate whether any of a wide variety of health outcomes are temporally associated with receipt of a specific vaccine, while adjusting for multiple testing. Neither health outcomes nor postvaccination potential periods of increased risk need be prespecified. Using US medical claims data in the Food and Drug Administration's Sentinel system, we employed the method to evaluate adverse events occurring after receipt of quadrivalent human papillomavirus vaccine (4vHPV). Incident outcomes recorded in emergency department or inpatient settings within 56 days after first doses of 4vHPV received by 9- through 26.9-year-olds in 2006-2014 were identified using International Classification of Diseases, Ninth Revision, diagnosis codes and analyzed by pairing the new method with a standard hierarchical classification of diagnoses. On scanning diagnoses of 1.9 million 4vHPV recipients, 2 statistically significant categories of adverse events were found: cellulitis on days 2-3 after vaccination and "other complications of surgical and medical procedures" on days 1-3 after vaccination. Cellulitis is a known adverse event. Clinically informed investigation of electronic claims records of the patients with "other complications" did not suggest any previously unknown vaccine safety problem. Considering that thousands of potential short-term adverse events and hundreds of potential risk intervals were evaluated, these findings add significantly to the growing safety record of 4vHPV.

Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010-2015.

PubMed

Myers, Tanya R; McNeil, Michael M; Ng, Carmen S; Li, Rongxia; Lewis, Paige W; Cano, Maria V

2017-03-27

Limited data are available describing the post-licensure safety of meningococcal vaccines, including Menveo®. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in all age groups. VAERS is a national spontaneous vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adverse events in persons who received Menveo from 1 January 2010 through 31 December 2015. We clinically reviewed reports and available medical records for serious AEs, selected pre-specified outcomes, and vaccination during pregnancy. We used empirical Bayesian data mining to identify AEs that were disproportionately reported after receipt of Menveo. During the study period, VAERS received 2614 US reports after receipt of Menveo. Of these, 67 were classified as serious, including 1 report of death. Adolescents (aged 11-18years) accounted for 74% of reports. Most of the reported AEs were non-serious and described AEs consistent with data from pre-licensure studies. Anaphylaxis and syncope were the two most common events in the serious reports. We did not identify any new safety concerns after review of AEs that exceeded the data mining threshold, although we did observe disproportionate reporting for terms that were not associated with an adverse event (e.g., "incorrect drug dosage form administered", "wrong technique in drug usage process"). Although reports were limited, we did not find any evidence for concern regarding the use of Menveo during pregnancy. In our review of VAERS reports, findings of AEs were consistent with the data from pre-licensure studies. Vaccine providers should continue to emphasize and adhere to proper administration of the vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.

A comparative analysis of the epidemiological impact and disease cost-savings of HPV vaccines in France.

PubMed

Bresse, Xavier; Adam, Marjorie; Largeron, Nathalie; Roze, Stephane; Marty, Rémi

2013-04-01

The aim was to compare the epidemiological and economic impact of 16/18 bivalent and 6/11/16/18 quadrivalent HPV vaccination in France, considering differences in licensed outcomes, protection against non-vaccine HPV types and prevention of HPV-6/11-related diseases. The differential impact of the two vaccines was evaluated using a published model adapted to the French setting. The target population was females aged 14-23 y and the time horizon was 100 y. A total of eight different scenarios compared vaccination impact in terms of reduction in HPV-16/18-associated carcinomas (cervical, vulvar, vaginal, anal, penile and head and neck), HPV-6/11-related genital warts and recurrent respiratory papillomatosis, and incremental reduction in cervical cancer due to potential cross-protection. Quadrivalent vaccine was associated with total discounted cost savings ranging from EUR 544-1,020 million vs. EUR 177-538 million with the bivalent vaccination (100-y time horizon). Genital wart prevention thanks to quadrivalent HPV vaccination accounted for EUR 306-380 million savings (37-56% of costs saved). In contrast, the maximal assumed cross-protection against cervical cancer resulted in EUR 13-33 million savings (4%). Prevention of vulvar, vaginal and anal cancers accounted for additional EUR 71-89 million savings (13%). In France, the quadrivalent HPV vaccination would result in significant incremental epidemiological and economic benefits vs. the bivalent vaccination, driven primarily by prevention of genital. The present analysis is the first in the French setting to consider the impact of HPV vaccination on all HPV diseases and non-vaccine types.

Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial

PubMed Central

Jain, Varsha K.; Domachowske, Joseph B.; Wang, Long; Ofori-Anyinam, Opokua; Rodríguez-Weber, Miguel A.; Leonardi, Michael L.; Klein, Nicola P.; Schlichter, Gary; Jeanfreau, Robert; Haney, Byron L.; Chu, Laurence; Harris, Jo-Ann S.; Sarpong, Kwabena O.; Micucio, Amanda C.; Soni, Jyoti; Chandrasekaran, Vijayalakshmi; Li, Ping

2017-01-01

Abstract Background. Children under 3 years of age may benefit from a double-dose of inactivated quadrivalent influenza vaccine (IIV4) instead of the standard-dose. Methods. We compared the only United States-licensed standard-dose IIV4 (0.25 mL, 7.5 µg hemagglutinin per influenza strain) versus double-dose IIV4 manufactured by a different process (0.5 mL, 15 µg per strain) in a phase III, randomized, observer-blind trial in children 6–35 months of age (NCT02242643). The primary objective was to demonstrate immunogenic noninferiority of the double-dose for all vaccine strains 28 days after last vaccination. Immunogenic superiority of the double-dose was evaluated post hoc. Immunogenicity was assessed in the per-protocol cohort (N = 2041), and safety was assessed in the intent-to-treat cohort (N = 2424). Results. Immunogenic noninferiority of double-dose versus standard-dose IIV4 was demonstrated in terms of geometric mean titer (GMT) ratio and seroconversion rate difference. Superior immunogenicity against both vaccine B strains was observed with double-dose IIV4 in children 6–17 months of age (GMT ratio = 1.89, 95% confidence interval [CI] = 1.64–2.17, B/Yamagata; GMT ratio = 2.13, 95% CI = 1.82–2.50, B/Victoria) and in unprimed children of any age (GMT ratio = 1.85, 95% CI = 1.59–2.13, B/Yamagata; GMT ratio = 2.04, 95% CI = 1.79–2.33, B/Victoria). Safety and reactogenicity, including fever, were similar despite the higher antigen content and volume of the double-dose IIV4. There were no attributable serious adverse events. Conclusions. Double-dose IIV4 may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults. PMID:28062552

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.

Post-licensure surveillance of quadrivalent inactivated influenza (IIV4) vaccine in the United States, Vaccine Adverse Event Reporting System (VAERS), July 1, 2013-May 31, 2015.

PubMed

Haber, Penina; Moro, Pedro L; Lewis, Paige; Woo, Emily Jane; Jankosky, Christopher; Cano, Maria

2016-05-11

Quadrivalent inactivated influenza vaccines (IIV4) were first available for use during 2013-14 influenza season for individuals aged ≥6 months. IIV4 is designed to protect against four different flu viruses; two influenza A viruses and two influenza B viruses. We searched the Vaccine Adverse Event Reporting System (VAERS) for US reports after IIV4 and trivalent inactivated influenza vaccine (IIV3) from 7/1/2013-5/31/2015. Medical records were requested for non-manufacturer reports classified as serious (i.e. death, hospitalization, prolonged hospitalization, life-threatening illness, permanent disability). The review included automated data analysis, clinical review of all serious reports, reports of special interest, and empirical Bayesian data mining. VAERS received 1,838 IIV4 reports; 512 (28%) in persons aged 6 months-17 years of which 42 (8.2%) were serious reports; 1,265 (69%) in persons aged >18 years of which 84 (6.6%) were serious reports; two in children <6 months and 59 in persons of unknown age. Injection site erythema (24%), fever (14%) and injection site swelling (17%) were the most frequent adverse events among persons aged 6 months-17 years, while injection site pain (16%), pain (15%) and pain in extremity (13%) were the most frequent among persons aged 18-64 years given the vaccine alone. Among non-death serious reports, injection site reactions, constitutional symptoms, Guillain-Barré syndrome, seizures, and anaphylaxis were the most frequently reported adverse events. Data mining detected disproportional reporting for incorrect vaccine administration with no associated adverse events. Adverse events following IIV4 reported to VAERS were similar to those following IIV3. In our review of VAERS reports, IIV4 had a similar safety profile to IIV3. Most of the reported AEs were non-serious. Our findings are consistent with data from pre-licensure studies of IIV4. Published by Elsevier Ltd.

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.

Impact of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in a sexually active population of North American women.

PubMed

Barr, Eliav; Gause, Christine K; Bautista, Oliver M; Railkar, Radha A; Lupinacci, Lisa C; Insinga, Ralph P; Sings, Heather L; Haupt, Richard M

2008-03-01

The purpose of this study was to inform policy regarding human papillomavirus (HPV) vaccination in North America. We measured the clinical impact of HPV-6/-11/-16/-18 vaccination in North American women. The study enrolled 21,954 women, the majority aged 16-25, across 5 studies of a quadrivalent HPV vaccine or its HPV-16 vaccine prototype. The North American subjects (n = 5996) were pooled from these trials, and the prevalence of HPV-6/-11/-16/-18 exposure was measured. The impact of vaccination on the burden of anogenital HPV lesions in an intention-to-treat population (regardless of enrollment HPV status) was calculated. At enrollment, the median age was 20 years; 13% of the women had had a Papanicolaou test abnormality, and 76% of the women had negative tests results for all 4 vaccine HPV types. With approximately 3 years of follow-up evaluations in the intention-to-treat population (regardless of enrollment HPV status), vaccination reduced the rate of HPV-16- and -18-related precancers and HPV-6/-11/-16/-18-related genital lesions by 66.4% (95% CI, 42.7%-81.1%) and 57.7% (95% CI, 27.3%-76.3%), respectively. The administration of HPV vaccine to sexually active North American women reduced the burden of HPV-6/-11/-16/-18-related disease. Catch-up vaccination programs in this population are warranted.

Efficacy of a capsule conjugate vaccine against inhalational anthrax in rabbits and monkeys.

PubMed

Chabot, Donald J; Joyce, Joseph; Caulfield, Michael; Cook, James; Hepler, Robert; Wang, Su; Vietri, Nicholas J; Ruthel, Gordon; Shoop, Wesley; Pitt, Louise; Leffel, Elizabeth; Ribot, Wilson; Friedlander, Arthur M

2012-01-20

Bacillus anthracis, the causative agent of anthrax, is recognized as one of the most serious bioterrorism threats. The current human vaccines are based on the protective antigen component of the anthrax toxins. Concern about possible vaccine resistant strains and reliance on a single antigen has prompted the search for additional immunogens. Bacterial capsules, as surface-expressed virulence factors, are well-established components of several licensed vaccines. In a previous study we showed that an anthrax vaccine consisting of the B. anthracis poly-γ-D-glutamic acid capsule covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B protected mice against parenteral B. anthracis challenge. Here we tested this vaccine in rabbits and monkeys against an aerosol spore challenge. The vaccine induced anti-capsule antibody responses in both species, measured by ELISA and a macrophage opsono-adherence assay. While rabbits were not protected against a high aerosol challenge dose, significant protection was observed in monkeys receiving the capsule conjugate vaccine. The results confirm that the capsule is a protective immunogen against anthrax, being the first non-toxin antigen shown to be efficacious in monkeys and suggest that addition of capsule may broaden and enhance the protection afforded by protective antigen-based vaccines. Published by Elsevier Ltd.

Cost-Utility of Quadrivalent Versus Trivalent Influenza Vaccine in Germany, Using an Individual-Based Dynamic Transmission Model.

PubMed

Dolk, Christiaan; Eichner, Martin; Welte, Robert; Anastassopoulou, Anastassia; Van Bellinghen, Laure-Anne; Poulsen Nautrup, Barbara; Van Vlaenderen, Ilse; Schmidt-Ott, Ruprecht; Schwehm, Markus; Postma, Maarten

2016-12-01

Seasonal influenza infection is primarily caused by circulation of two influenza A strain subtypes and strains from two B lineages that vary each year. Trivalent influenza vaccine (TIV) contains only one of the two B-lineage strains, resulting in mismatches between vaccine strains and the predominant circulating B lineage. Quadrivalent influenza vaccine (QIV) includes both B-lineage strains. The objective was to estimate the cost-utility of introducing QIV to replace TIV in Germany. An individual-based dynamic transmission model (4Flu) using German data was used to provide realistic estimates of the impact of TIV and QIV on age-specific influenza infections. Cases were linked to health and economic outcomes to calculate the cost-utility of QIV versus TIV, from both a societal and payer perspective. Costs and effects were discounted at 3.0 and 1.5 % respectively, with 2014 as the base year. Univariate and probabilistic sensitivity analyses were conducted. Using QIV instead of TIV resulted in additional quality-adjusted life-years (QALYs) and cost savings from the societal perspective (i.e. it represents the dominant strategy) and an incremental cost-utility ratio (ICUR) of €14,461 per QALY from a healthcare payer perspective. In all univariate analyses, QIV remained cost-effective (ICUR <€50,000). In probabilistic sensitivity analyses, QIV was cost-effective in >98 and >99 % of the simulations from the societal and payer perspective, respectively. This analysis suggests that QIV in Germany would provide additional health gains while being cost-saving to society or costing €14,461 per QALY gained from the healthcare payer perspective, compared with TIV.

Immunogenicity and immunologic memory of meningococcal C conjugate vaccine in premature infants.

PubMed

Collins, Clare L; Ruggeberg, Jens U; Balfour, Gail; Tighe, Helen; Archer, Marion; Bowen-Morris, Jane; Diggle, Linda; Borrow, Ray; Balmer, Paul; Buttery, Jim P; Moxon, E Richard; Pollard, Andrew J; Heath, Paul T

2005-11-01

Protein-polysaccharide conjugate vaccines against Neisseria meningitidis serogroup C were introduced into the U.K. routine immunization schedule in 1999. This study is the first to describe both persistence of antibody and evidence for induction of immune memory using meningococcal C conjugate (MCC) vaccine in preterm infants. Immunogenicity and induction of immunologic memory by as MCC vaccine was assessed in premature infants; 62 preterm and 60 term controls received MCC at the accelerated schedule (2, 3 and 4 months of age). A meningococcal C polysaccharide challenge was administered at 12 months of age. Both groups achieved similar protective titers after primary immunization that then waned significantly by 1 year of age. Postchallenge serum bactericidal activity was significantly lower in preterm infants (P = 0.03); 73% of preterm versus 88% of term controls achieved a 4-fold rise in serum bactericidal activity (P = 0.07). MCC vaccine is immunogenic and primes for immunologic memory in preterm infants. The decreased memory responses in these preterm infants in conjunction with waning clinical efficacy data for all U.K. infants suggest a role for a routine booster dose of vaccine in all infants receiving MCC, especially those born preterm.

Burden of disease associated with cervical cancer in malaysia and potential costs and consequences of HPV vaccination.

PubMed

Aljunid, S; Zafar, A; Saperi, S; Amrizal, M

2010-01-01

An estimated 70% of cervical cancers worldwide are attributable to persistent infection with human papillomaviruses (HPV) 16 and 18. Vaccination against HPV 16/18 has been shown to dramatically reduce the incidence of associated precancerous and cancerous lesions. The aims of the present analyses were, firstly, to estimate the clinical and economic burden of disease attributable to HPV in Malaysia and secondly, to estimate long-term outcomes associated with HPV vaccination using a prevalence-based modeling approach. In the first part of the analysis costs attributable to cervical cancer and precancerous lesions were estimated; epidemiologic data were sourced from the WHO GLOBOCAN database and Malaysian national data sources. In the second part, a prevalence-based model was used to estimate the potential annual number of cases of cervical cancer and precancerous lesions that could be prevented and subsequent HPV-related treatment costs averted with the bivalent (HPV 16/18) and the quadrivalent (HPV 16/18/6/11) vaccines, at the population level, at steady state. A vaccine efficacy of 98% was assumed against HPV types included in both vaccines. Effectiveness against other oncogenic HPV types was based on the latest results from each vaccine's respective clinical trials. In Malaysia there are an estimated 4,696 prevalent cases of cervical cancer annually and 1,372 prevalent cases of precancerous lesions, which are associated with a total direct cost of RM 39.2 million with a further RM 12.4 million in indirect costs owing to lost productivity. At steady state, vaccination with the bivalent vaccine was estimated to prevent 4,199 cervical cancer cases per year versus 3,804 cases for the quadrivalent vaccine. Vaccination with the quadrivalent vaccine was projected to prevent 1,721 cases of genital warts annually, whereas the annual number of cases remained unchanged with the bivalent vaccine. Furthermore, vaccination with the bivalent vaccine was estimated to avert RM 45

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

Immunogenicity and safety of a new meningococcal A conjugate vaccine in Indian children aged 2-10 years: a phase II/III double-blind randomized controlled trial.

PubMed

Hirve, Siddhivinayak; Bavdekar, Ashish; Pandit, Anand; Juvekar, Sanjay; Patil, Malini; Preziosi, Marie-Pierre; Tang, Yuxiao; Marchetti, Elisa; Martellet, Lionel; Findlow, Helen; Elie, Cheryl; Parulekar, Varsha; Plikaytis, Brian; Borrow, Ray; Carlone, George; Kulkarni, Prasad S; Goel, Akshay; Suresh, Karupothula; Beri, Suresh; Kapre, Subhash; Jadhav, Suresh; Preaud, Jean-Marie; Viviani, Simonetta; LaForce, F Marc

2012-10-05

This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac™, Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY(®), GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 μg/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 μg/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac™ is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children. Copyright © 2012 Elsevier Ltd. All rights reserved.

A comparative analysis of the epidemiological impact and disease cost-savings of HPV vaccines in France

PubMed Central

Bresse, Xavier; Adam, Marjorie; Largeron, Nathalie; Roze, Stephane; Marty, Remi

2013-01-01

The aim was to compare the epidemiological and economic impact of 16/18 bivalent and 6/11/16/18 quadrivalent HPV vaccination in France, considering differences in licensed outcomes, protection against non-vaccine HPV types and prevention of HPV-6/11-related diseases. The differential impact of the two vaccines was evaluated using a published model adapted to the French setting. The target population was females aged 14–23 y and the time horizon was 100 y. A total of eight different scenarios compared vaccination impact in terms of reduction in HPV-16/18-associated carcinomas (cervical, vulvar, vaginal, anal, penile and head and neck), HPV-6/11-related genital warts and recurrent respiratory papillomatosis, and incremental reduction in cervical cancer due to potential cross-protection. Quadrivalent vaccine was associated with total discounted cost savings ranging from EUR 544–1,020 million vs. EUR 177–538 million with the bivalent vaccination (100-y time horizon). Genital wart prevention thanks to quadrivalent HPV vaccination accounted for EUR 306–380 million savings (37–56% of costs saved). In contrast, the maximal assumed cross-protection against cervical cancer resulted in EUR 13–33 million savings (4%). Prevention of vulvar, vaginal and anal cancers accounted for additional EUR 71–89 million savings (13%). In France, the quadrivalent HPV vaccination would result in significant incremental epidemiological and economic benefits vs. the bivalent vaccination, driven primarily by prevention of genital. The present analysis is the first in the French setting to consider the impact of HPV vaccination on all HPV diseases and non-vaccine types. PMID:23563511

Timing of two versus three doses of quadrivalent HPV vaccine and associated effectiveness against condyloma in Sweden: a nationwide cohort study

PubMed Central

F, Lamb; E, Herweijer; A, Ploner; I, Uhnoo; K, Sundström; P, Sparén; L, Arnheim-Dahlström

2017-01-01

Objective To assess incidence of condyloma after two doses of quadrivalent human papillomavirus (qHPV) vaccine, by time since first vaccine dose, in girls and women initiating vaccination before age 20 years. Design Register-based nationwide open cohort study. Setting Sweden. Participants Girls and women initiating qHPV vaccination before age 20 years between 2006 and 2012. The study cohort included 264 498 girls, of whom 72 042 had received two doses of qHPV vaccine and 185 456 had received all three doses. Main outcome measure Incidence rate ratios (IRRs) of condyloma estimated by time between first and second doses of qHPV in months (m) and age at vaccination, adjusted for attained age. Results For girls first vaccinated with two doses before the age of 17 years, the IRR of condyloma for 0–3 months between the first and second doses was 1.96 (95% CI 1.43 to 2.68) as compared with the standard three-dose schedule. The IRRs were 1.27 (95% CI 0.63 to 2.58) and 4.36 (95% CI 2.05 to 9.28) after receipt of two doses with 4–7 months and 8+ months between doses, respectively. For women first vaccinated after the age of 17 years, vaccination with two doses of qHPV vaccine and 0–3 months between doses was associated with an IRR of 2.12 (95% CI 1.62 to 2.77). For an interval of 4–7 months between doses, the IRR did not statistically significantly differ to the standard three-dose schedule (IRR=0.81, 95% CI 0.36 to 1.84). For women with 8+ months between dose 1 and dose 2 the IRR was 3.16 (95% CI 1.40 to 7.14). Conclusion A two-dose schedule for qHPV vaccine with 4–7 months between the first and second doses may be as effective against condyloma in girls and women initiating vaccination under 20 years as a three-dose schedule. Results from this nationwide study support immunogenicity data from clinical trials. PMID:28600369

Size determination of bacterial capsular oligosaccharides used to prepare conjugate vaccines.

PubMed

Ravenscroft, N; Averani, G; Bartoloni, A; Berti, S; Bigio, M; Carinci, V; Costantino, P; D'Ascenzi, S; Giannozzi, A; Norelli, F; Pennatini, C; Proietti, D; Ceccarini, C; Cescutti, P

1999-07-16

We recently described the use of ion exchange chromatography for analysis and the industrial scale preparation of pools of oligosaccharides of intermediate chain length from polysaccharides of Haemophilus influenzae type b (Hib) and Neisseria meningitidis groups A and C. These negatively charged "sized" oligosaccharides are activated and conjugated to the carrier protein (CRM197) to prepare the corresponding glycoconjugate vaccines. Characterization and accurate determination of the degree of polymerization (DP) of the pool of oligosaccharides is essential for the consistent production of these conjugate vaccines. This paper describes the colorimetric assays used for determination of the average DP of the Hib and meningococcal oligosaccharides, and the qualification of these assays achieved by size characterization of the respective oligosaccharides by use of physicochemical methods, including liquid chromatography, mass spectrometry (ionspray) and NMR spectroscopy.

Safety and immunogenicity of an intramuscular quadrivalent influenza vaccine in children 3 to 8 y of age: A phase III randomized controlled study.

PubMed

Pepin, Stephanie; Szymanski, Henryk; Rochín Kobashi, Ilya Angélica; Villagomez Martinez, Sandra; González Zamora, José Francisco; Brzostek, Jerzy; Huang, Li-Min; Chiu, Cheng-Hsun; Chen, Po-Yen; Ahonen, Anitta; Forstén, Aino; Seppä, Ilkka; Quiroz, René Farfán; Korhonen, Tiina; Rivas, Enrique; Monfredo, Celine; Hutagalung, Yanee; Menezes, Josemund; Vesikari, Timo

2016-12-01

A quadrivalent, inactivated, split-virion influenza vaccine containing a strain from both B lineages (IIV4) has been developed, but its safety and immunogenicity in young children has not been described. This was a phase III, randomized, double-blind, active-controlled, multi-center study to examine the immunogenicity and safety of IIV4 in children 3-8 y of age (EudraCT no. 2011-005374-33). Participants were randomized 5:1:1 to receive the 2013/2014 Northern Hemisphere formulation of IIV4, an investigational trivalent comparator (IIV3) containing the B/Victoria lineage strain, or the licensed Northern Hemisphere IIV3 containing the B/Yamagata lineage strain. Participants who had not previously received a full influenza vaccination schedule received 2 doses of vaccine 28 d apart; all others received a single dose. 1242 children were included. For all 4 strains, IIV4 induced geometric mean haemagglutination inhibition titres non-inferior to those induced by the IIV3 comparators. For both B strains, geometric mean antibody titres induced by IIV4 were superior to those induced by the IIV3 with the alternative lineage strain. Similar proportions of participants vaccinated with IIV4 and IIV3 reported solicited injection-site reactions, solicited systemic reactions, and vaccine-related adverse events. A single vaccine-related serious adverse event, thrombocytopenia, was reported 9 d after vaccination with IIV4 and resolved without sequelae. In conclusion, in children aged 3-8 y who received one dose or 2 doses 28 d apart, IIV4 had an acceptable safety profile, was as immunogenic as IIV3 for the shared strains, and had superior immunogenicity for the additional B strain.

Phase I clinical trial of O-Acetylated pectin conjugate, a plant polysaccharide based typhoid vaccine

PubMed Central

Szu, Shousun C.; Lin, Kimi F-Y; Hunt, Steven; Chu, Chiayung; Thinh, Nguyen Duc

2014-01-01

Background Typhoid fever remains an important cause of morbidity and mortality in the developing countries. Vi capsular polysaccharide conjugate vaccine demonstrated safety and efficacy in young children in high endemic regions. A novel typhoid conjugate vaccine based on plant polysaccharide pectin was studied in a phase I trial. Methods Fruit pectin, having the same carbohydrate backbone structure as Vi, was purified from citrus peel and used as the polysaccharide source to prepare a semi-synthetic typhoid conjugate vaccine. Pectin was chemically O-acetylated (OAcPec) to antigenically resemble Vi and conjugated to carrier protein rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. 25 healthy volunteers, 18–45 years old, were injected once with OAcPec-rEPA. Safety and IgG antibodies reactive with Vi and pectin were analyzed. Results No vaccine associated serious adverse reaction was reported. Six weeks after the injection of OAcPec-rEPA, 64% of the volunteers elicited >4 fold rise of anti-Vi IgG. At 26 weeks the level declined, but the difference between the levels at 6 and 26 weeks are not statistically significant. There is a direct correlation between the level of anti-Vi IgG before and after the injection (R2 = 0.96). The anti-Vi IgG can be absorbed by Vi, but not by pectin. There was no corresponding increase of anti-pectin after the injection, indicating the antibody response to OAcPec-rEPA was specific to Vi. There is no Vi-rEPA data in US adults for comparison of immune responses. The OAcPec-rEPA elicited significantly less IgG anti-Vi in US adults than those by Vi-rEPA in Vietnamese adults. Conclusion The O-acetylated pectin conjugate, a plant based typhoid vaccine, is safe and immunogenic in adult volunteers. PMID:24657719

Induction of immunologic memory following primary vaccination with the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine in infants.

PubMed

Knuf, Markus; Pankow-Culot, Heidemarie; Grunert, Detlef; Rapp, Michael; Panzer, Falko; Köllges, Ralph; Fanic, Aurélie; Habib, Ahsan; Borys, Dorota; Dieussaert, Ilse; Schuerman, Lode

2012-01-01

Induction of immunologic memory was assessed following primary vaccination with 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). Infants were randomized (1:1) to receive 3 doses of PHiD-CV or 7vCRM (7-valent CRM197-conjugated pneumococcal conjugate vaccine [PCV]) at 2, 3, and 4 months of age followed by 23-valent pneumococcal polysaccharide vaccine (23vPS) booster dose at 11 to 14 months of age. Pneumococcal geometric mean antibody concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers were measured. Postprimary immune responses were consistent with those in previous PHiD-CV and 7vCRM studies. Following 23vPS boosting, vaccine serotype-specific antibody GMCs increased 6.5- to 33.3-fold and 4.8- to 32.2-fold versus prebooster in the PHiD-CV and 7vCRM groups, respectively. Postbooster OPA titers increased 2.8- to 38.8-fold and 2.6- to 58.9-fold, respectively. Postbooster antibody GMCs exceeded postprimary levels but, for some serotypes, postbooster OPA geometric mean titers were lower than postprimary in both groups. An additional dose of the same PCV received for priming was administered to 52 children aged 46 to 50 months, resulting in higher responses versus postprimary vaccination for all serotypes, but not always higher than post-23vPS booster. Induction of immunologic memory following PHiD-CV priming was confirmed. Additional PCV boosting in 4-year-olds did not provide strong evidence of hyporesponsiveness induced by previous 23vPS boosting. However, our results did not rule out depletion of the memory B cell pool following 23vPS vaccination, resulting in subsequent attenuated immune responses, and therefore support the use of PCV rather than 23vPS for booster vaccination in the second year of life.

Safety of human papillomavirus vaccines: a review

PubMed Central

Stillo, Michela; Carrillo Santisteve, Paloma; Lopalco, Pier Luigi

2015-01-01

Introduction: Between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed for use: a quadrivalent (qHPVv) and a bivalent (bHPVv) vaccine. Since 2008, HPV vaccination programmes have been implemented in the majority of the industrialized countries. Since 2013, HPV vaccination has been part of the national programs of 66 countries including almost all countries in North America and Western Europe. Despite all the efforts made by individual countries, coverage rates are lower than expected. Vaccine safety represents one of the main concerns associated with the lack of acceptance of HPV vaccination both in the European Union/European Economic Area and elsewhere. Areas covered: Safety data published on bivalent and quadrivalent HPV vaccines, both in pre-licensure and post-licensure phase, are reviewed. Expert opinion: Based on the latest scientific evidence, both HPV vaccines seem to be safe. Nevertheless, public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs. Improved vaccine safety surveillance is the first step for effective communication based on scientific evidence. PMID:25689872

Safety of human papillomavirus vaccines: a review.

PubMed

Stillo, Michela; Carrillo Santisteve, Paloma; Lopalco, Pier Luigi

2015-05-01

Between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed for use: a quadrivalent (qHPVv) and a bivalent (bHPVv) vaccine. Since 2008, HPV vaccination programmes have been implemented in the majority of the industrialized countries. Since 2013, HPV vaccination has been part of the national programs of 66 countries including almost all countries in North America and Western Europe. Despite all the efforts made by individual countries, coverage rates are lower than expected. Vaccine safety represents one of the main concerns associated with the lack of acceptance of HPV vaccination both in the European Union/European Economic Area and elsewhere. Safety data published on bivalent and quadrivalent HPV vaccines, both in pre-licensure and post-licensure phase, are reviewed. Based on the latest scientific evidence, both HPV vaccines seem to be safe. Nevertheless, public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs. Improved vaccine safety surveillance is the first step for effective communication based on scientific evidence.

Immunogenicity of simultaneous versus sequential administration of a 23-valent pneumococcal polysaccharide vaccine and a quadrivalent influenza vaccine in older individuals: A randomized, open-label, non-inferiority trial.

PubMed

Nakashima, Kei; Aoshima, Masahiro; Ohfuji, Satoko; Yamawaki, Satoshi; Nemoto, Masahiro; Hasegawa, Shinya; Noma, Satoshi; Misawa, Masafumi; Hosokawa, Naoto; Yaegashi, Makito; Otsuka, Yoshihito

2018-03-21

It is unclear whether simultaneous administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a quadrivalent influenza vaccine (QIV) produces immunogenicity in older individuals. This study tested the hypothesis that the pneumococcal antibody response elicited by simultaneous administration of PPSV23 and QIV in older individuals is not inferior to that elicited by sequential administration of PPSV23 and QIV. We performed a single-center, randomized, open-label, non-inferiority trial comprising 162 adults aged ≥65 years randomly assigned to either the simultaneous (simultaneous injections of PPSV23 and QIV) or sequential (control; PPSV23 injected 2 weeks after QIV vaccination) groups. Pneumococcal immunoglobulin G (IgG) titers of serotypes 23F, 3, 4, 6B, 14, and 19A were assessed. The primary endpoint was the serotype 23F response rate (a ≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination). With the non-inferiority margin set at 20% fewer patients, the response rate of serotype 23F in the simultaneous group (77.8%) was not inferior to that of the sequential group (77.6%; difference, 0.1%; 90% confidence interval, -10.8% to 11.1%). None of the pneumococcal IgG serotype titers were significantly different between the groups 4-6 weeks after vaccination. Simultaneous administration did not show a significant decrease in seroprotection odds ratios for H1N1, H3N2, or B/Phuket influenza strains other than B/Texas. Additionally, simultaneous administration did not increase adverse reactions. Hence, simultaneous administration of PPSV23 and QIV shows an acceptable immunogenicity that is comparable to sequential administration without an increase in adverse reactions. (This study was registered with ClinicalTrials.gov [NCT02592486]).

Use of MenACWY-CRM vaccine in children aged 2 through 23 months at increased risk for meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, 2013.

PubMed

MacNeil, Jessica R; Rubin, Lorry; McNamara, Lucy; Briere, Elizabeth C; Clark, Thomas A; Cohn, Amanda C

2014-06-20

During its October 2013 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended use of a third meningococcal conjugate vaccine, MenACWY-CRM (Menveo, Novartis), as an additional option for vaccinating infants aged 2 through 23 months at increased risk for meningococcal disease. MenACWY-CRM is the first quadrivalent meningococcal conjugate vaccine licensed for use in children aged 2 through 8 months. MenACWY-D (Menactra, Sanofi Pasteur) is recommended for use in children aged 9 through 23 months who are at increased risk for meningococcal disease, and Hib-MenCY-TT (MenHibrix, GlaxoSmithKline) is recommended for use in children aged 6 weeks through 18 months at increased risk. This report summarizes information on MenACWY-CRM administration in infants and provides recommendations for vaccine use in infants aged 2 through 23 months who are at increased risk for meningococcal disease. Because the burden of meningococcal disease in infants is low in the United States and the majority of cases that do occur are caused by serogroup B, which is not included in any vaccine licensed in the United States, only those infants who are at increased risk for meningococcal disease are recommended to receive a meningococcal vaccine.

The Elimination of Haemophilus influenzae type b meningitis following conjugate vaccine introduction in Senegal.

PubMed

Cissé, Moussa Fafa; Breugelmans, J Gabrielle; Bâ, Mamadou; Diop, Mouhamed Boss; Faye, Papa Coumba; Mhlanga, Bekithemba; Mueller, Judith E; Koffi, David; Gessner, Bradford D

2010-06-01

Senegal introduced routine infant Haemophilus influenzae type b (Hib) conjugate vaccine during 2005. We evaluated acute bacterial meningitis surveillance data among children 0 to 59 months of age collected during January 2003 to September 2007 at the major pediatric referral hospital in the Dakar Region of Senegal. Hib vaccine effectiveness was assessed using a case-control design. A total of 1749 children with suspected bacterial meningitis were included in the current study of whom 142 (8%) had Hib identified. Among children less than age 1 year, the average annual Hib meningitis incidence decreased from 22 to 47 per 100,000 during 2003-2005 to 1.4 per 100,000 during 2007, while pneumococcal meningitis incidence remained stable. Before vaccine introduction, calculated incidences varied over 4-fold between districts within the Dakar Region for the years 2003 to 2005. Following use of Hib vaccine, pneumococcus has now become the most common etiology of pediatric acute bacterial meningitis in Dakar region. Senegal successfully implemented Hib conjugate vaccine into their routine infant immunization program with a resultant near elimination of Hib meningitis burden.

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.

Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial.

PubMed

Jain, Varsha K; Domachowske, Joseph B; Wang, Long; Ofori-Anyinam, Opokua; Rodríguez-Weber, Miguel A; Leonardi, Michael L; Klein, Nicola P; Schlichter, Gary; Jeanfreau, Robert; Haney, Byron L; Chu, Laurence; Harris, Jo-Ann S; Sarpong, Kwabena O; Micucio, Amanda C; Soni, Jyoti; Chandrasekaran, Vijayalakshmi; Li, Ping; Innis, Bruce L

2017-03-01

Children under 3 years of age may benefit from a double-dose of inactivated quadrivalent influenza vaccine (IIV4) instead of the standard-dose. We compared the only United States-licensed standard-dose IIV4 (0.25 mL, 7.5 µg hemagglutinin per influenza strain) versus double-dose IIV4 manufactured by a different process (0.5 mL, 15 µg per strain) in a phase III, randomized, observer-blind trial in children 6-35 months of age (NCT02242643). The primary objective was to demonstrate immunogenic noninferiority of the double-dose for all vaccine strains 28 days after last vaccination. Immunogenic superiority of the double-dose was evaluated post hoc. Immunogenicity was assessed in the per-protocol cohort (N = 2041), and safety was assessed in the intent-to-treat cohort (N = 2424). Immunogenic noninferiority of double-dose versus standard-dose IIV4 was demonstrated in terms of geometric mean titer (GMT) ratio and seroconversion rate difference. Superior immunogenicity against both vaccine B strains was observed with double-dose IIV4 in children 6-17 months of age (GMT ratio = 1.89, 95% confidence interval [CI] = 1.64-2.17, B/Yamagata; GMT ratio = 2.13, 95% CI = 1.82-2.50, B/Victoria) and in unprimed children of any age (GMT ratio = 1.85, 95% CI = 1.59-2.13, B/Yamagata; GMT ratio = 2.04, 95% CI = 1.79-2.33, B/Victoria). Safety and reactogenicity, including fever, were similar despite the higher antigen content and volume of the double-dose IIV4. There were no attributable serious adverse events. Double-dose IIV4 may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults. © The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society

Comparison of Strategies and Incidence Thresholds for Vi Conjugate Vaccines Against Typhoid Fever: A Cost-effectiveness Modeling Study.

PubMed

Lo, Nathan C; Gupta, Ribhav; Stanaway, Jeffrey D; Garrett, Denise O; Bogoch, Isaac I; Luby, Stephen P; Andrews, Jason R

2018-02-12

Typhoid fever remains a major public health problem globally. While new Vi conjugate vaccines hold promise for averting disease, the optimal programmatic delivery remains unclear. We aimed to identify the strategies and associated epidemiologic conditions under which Vi conjugate vaccines would be cost-effective. We developed a dynamic, age-structured transmission and cost-effectiveness model that simulated multiple vaccination strategies with a typhoid Vi conjugate vaccine from a societal perspective. We simulated 10-year vaccination programs with (1) routine immunization of infants (aged <1 year) through the Expanded Program on Immunization (EPI) and (2) routine immunization of infants through the EPI plus a 1-time catch-up campaign in school-aged children (aged 5-14 years). In the base case analysis, we assumed a 0.5% case-fatality rate for all cases of clinically symptomatic typhoid fever and defined strategies as highly cost-effective by using the definition of a low-income country (defined as a country with a gross domestic product of $1045 per capita). We defined incidence as the true number of clinically symptomatic people in the population per year. Vi conjugate typhoid vaccines were highly cost-effective when administered by routine immunization activities through the EPI in settings with an annual incidence of >50 cases/100000 (95% uncertainty interval, 40-75 cases) and when administered through the EPI plus a catch-up campaign in settings with an annual incidence of >130 cases/100000 (95% uncertainty interval, 50-395 cases). The incidence threshold was sensitive to the typhoid-related case-fatality rate, carrier contribution to transmission, vaccine characteristics, and country-specific economic threshold for cost-effectiveness. Typhoid Vi conjugate vaccines would be highly cost-effective in low-income countries in settings of moderate typhoid incidence (50 cases/100000 annually). These results were sensitive to case-fatality rates, underscoring the

Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study.

PubMed

Grönlund, O; Herweijer, E; Sundström, K; Arnheim-Dahlström, L

2016-12-01

To assess whether quadrivalent human papillomavirus (qHPV) vaccination is associated with increased incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease. This register-based open cohort study included all girls and women between 10 and 30 years of age in Sweden in 2006-2012 diagnosed with at least one of 49 prespecified autoimmune diseases (n = 70 265). Incidence rate ratios were estimated for new-onset autoimmune disease within 180 days of qHPV vaccination using Poisson regression adjusting for, country of birth, parental country of birth, parental income and parental education. A total of 70 265 girls and women had at least one of the 49 predefined autoimmune diseases; 16% of these individuals received at least one dose of qHPV vaccine. In unvaccinated girls and women, 5428 new-onset autoimmune diseases were observed during 245 807 person-years at a rate of 22.1 (95% CI 21.5-22.7) new events per 1000 person-years. In vaccinated girls and women, there were 124 new events during 7848 person-years at a rate of 15.8 (95% CI 13.2-18.8) per 1000 person-years. There was no increase in the incidence of new-onset autoimmune disease associated with qHPV vaccination during the risk period; on the contrary, we found a slightly reduced risk (incidence rate ratio 0.77, 95% CI 0.65-0.93). In this nationwide study, qHPV vaccination was not associated with increased incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease. © 2016 The Association for the Publication of the Journal of Internal Medicine.

Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man

PubMed Central

Downham, M R; Auton, T R; Rosul, A; Sharp, H L; Sjöström, L; Rushton, A; Richards, J P; Mant, T G K; Gardiner, S M; Bennett, T; Glover, J F

2003-01-01

Aims We aim to modulate the renin–angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man. Methods Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue (AI). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII). Results The AI–TT and AI–KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI–KLH conjugate vaccine resulted in a significant immune response to AI. A shift in diastolic blood pressure (DBP) dose–response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction. Conclusion KLH was shown to be a suitable alternative to TT as a carrier protein for AI, thus supporting continued evaluation of our AI–KLH conjugate vaccine for treatment of hypertension in man. PMID:14651724

Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial.

PubMed

Vesikari, Timo; Kirstein, Judith; Devota Go, Grace; Leav, Brett; Ruzycky, Mary Ellen; Isakov, Leah; de Bruijn, Marianne; Oberye, Janine; Heijnen, Esther

2018-05-01

Young children have immature immune systems and respond poorly to standard influenza vaccines. The oil-in-water emulsion adjuvant MF59 can increase antigen uptake, macrophage recruitment, lymph node migration, and avidity to influenza virus. Therefore, we aimed to assess the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted, quadrivalent, inactivated (subunit) influenza vaccine (aIIV4) compared with a US-licensed non-adjuvanted influenza vaccine in children. We did a multicentre, randomised controlled, observer-blinded, phase 3 trial of 146 sites including hospitals, clinics, and clinician offices in nine countries over two influenza seasons. We included children of either sex aged 6 months through 5 years. We stratified eligible participants and randomly assigned them (1:1), using a block size of four, to receive either aIIV4 or non-adjuvanted inactivated influenza vaccine (ie, trivalent inactivated influenza vaccine [IIV3] or quadrivalent inactivated influenza vaccine [IIV4]). We masked participants, parents or guardians, and outcome assessors to the administered vaccine. Designated personnel who were not masked administered aIIV4 in both seasons, or IIV3 in season one and IIV4 in season two. All vaccinations were administered intramuscularly. Children aged 6 through 35 months received one or two 0·25 mL doses, whereas those aged 3 through 5 years received one or two doses of 0·5 mL. The number of doses was dependent on previous vaccination status: vaccine-naive participants received a total of two doses of study vaccine, the first on day 1 and the second on day 29, whereas non-naive participants received only one dose on day 1. The primary outcome was relative vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population and in prespecified age and dose subgroups. Immunogenicity against homologous and heterologous strains of influenza and safety were also measured. This study is registered

Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: a strategy for enhancing immunogenicity of malaria vaccine candidates.

PubMed

Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L; Long, Carole A; Miller, Louis H; Saul, Allan; Mullen, Gregory E D

2007-05-16

Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) to a blood stage vaccine candidate and surface protein 25 (Pfs25) a mosquito stage vaccine candidate, were each independently chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66kD) relatively good immunogen in mice; Pfs25 is a poorly immunogenic protein when presented on alum to mice. Mice were immunized on days 0 and 28 with AMA1- or Pfs25-rEPA conjugates or unconjugated AMA1 or Pfs25, all formulated on Alhydrogel. Remarkably, sera from mice 14 days after the second immunization with Pfs25-rEPA conjugates displayed over a 1000-fold higher antibody titers as compared to unconjugated Pfs25. In contrast, AMA1 conjugated under the same conditions induced only a three-fold increase in antibody titers. When tested for functional activity, antibodies elicited by the AMA1-rEPA inhibited invasion of erythrocytes by blood-stage parasites and antibodies elicited by the Pfs25-rEPA conjugates blocked the development of the sexual stage parasites in the mosquito midgut. These results demonstrate that conjugation to rEPA induces a marked improvement in the antibody titer in mice for the poor immunogen (Pfs25) and for the larger protein (AMA1). These conjugates now need to be tested in humans to determine if mice are predictive of the response in humans.

Quadrivalent meningococcal (MenACWY-TT) conjugate vaccine or a fourth dose of H. influenzae-N. meningitidis C/Y conjugate vaccine (HibMenCY-TT) is immunogenic in toddlers who previously received three doses of HibMenCY-TT in infancy.

PubMed

Leonardi, Michael; Latiolais, Thomas; Sarpong, Kwabena; Simon, Michael; Twiggs, Jerry; Lei, Paul; Rinderknecht, Stephen; Blatter, Mark; Bianco, Veronique; Baine, Yaela; Friedland, Leonard R; Miller, Jacqueline M

2015-02-11

Immunogenicity and safety of a single dose of MenACWY-TT or a fourth dose of HibMenCY-TT were evaluated in the second year of life in HibMenCY-TT-primed toddlers. Healthy infants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus (DTaP-HBV-IPV) vaccine; or Hib-TT and DTaP-HBV-IPV (control). Recipients of HibMenCY-TT+DTaP-HBV-IPV were re-randomized (2:2:1) to receive MenACWY-TT at 12-15 months and DTaP at 15-18 months; MenACWY-TT co-administered with DTaP at 15-18 months; or HibMenCY-TT at 12-15 months and DTaP at 15-18 months. Controls received DTaP only at 15-18 months due to Hib conjugate vaccine shortage. Serum bactericidal activity using human complement (hSBA) and safety were assessed one month after meningococcal vaccination. After vaccination with MenACWY-TT at 12-15 months or MenACWY-TT+DTaP at 15-18 months, all subjects previously primed for serogroups C/Y had hSBA ≥1:8 for these serogroups. At least 96.1% also had hSBA ≥1:8 for serogroups A/W. All subjects in the HibMenCY-TT group had hSBA ≥1:8 for serogroups C/Y. All pre-defined statistical criteria for meningococcal immunogenicity were satisfied. All vaccination regimens had acceptable safety profiles. Children primed with three doses of HibMenCY-TT who then received a single dose of MenACWY-TT or a fourth dose of HibMenCY-TT had robust increases in hSBA titers for serogroups C/Y. These data provide support that MenACWY-TT, given with or without the fourth scheduled dose of DTaP could be administered as an alternative to a fourth dose of HibMenCY-TT in the second year of life. This study (110870/110871) is registered at www.clinicaltrials.gov NCT00614614. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Enhanced immune response to inactivated porcine circovirus type 2 (PCV2) vaccine by conjugation of chitosan oligosaccharides.

PubMed

Zhang, Guiqiang; Jia, Peiyuan; Cheng, Gong; Jiao, Siming; Ren, Lishi; Ji, Shaoyang; Hu, Tao; Liu, Hongtao; Du, Yuguang

2017-06-15

This study aimed to investigate the effect of chitosan oligosaccharide (COS) conjugation on the immunogenicity of porcine circovirus type-2 (PCV2) vaccine. Two conjugates (PCV2-COS-1 and PCV2-COS-2) were designed by covalent conjugation of an inactivated PCV2 vaccine with COS, and administered to C57BL/6 mice three times at two-week intervals. The results indicate that, as compared to PCV2 alone group, the PCV2-COS conjugates remarkably enhanced both humoral and cellular immunity against PCV2 by promoting T lymphocyte proliferation and initiating a mixed Th1/Th2 response, including the elevated production of PCV-2 specific antibodies and up-regulated secretion of inflammatory cytokines. Noticeably, the immunization with PCV2-COS-1 conjugate displayed similar or even better immune-stimulating effects than that by PCV2/ISA206 (a commercialized adjuvant) and showed no infection or pathological signs at injection sites of the mice. Presumably, the covalent linkage of PCV2 vaccine to COS might be a viable strategy to increase the efficacy against PCV2-associated diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dosing Schedules for Pneumococcal Conjugate Vaccine

PubMed Central

2014-01-01

Since second generation pneumococcal conjugate vaccines (PCVs) targeting 10 and 13 serotypes became available in 2010, the number of national policy makers considering these vaccines has steadily increased. An important consideration for a national immunization program is the timing and number of doses—the schedule—that will best prevent disease in the population. Data on disease epidemiology and the efficacy or effectiveness of PCV schedules are typically considered when choosing a schedule. Practical concerns, such as the existing vaccine schedule, and vaccine program performance are also important. In low-income countries, pneumococcal disease and deaths typically peak well before the end of the first year of life, making a schedule that provides PCV doses early in life (eg, a 6-, 10- and 14-week schedule) potentially the best option. In other settings, a schedule including a booster dose may address disease that peaks in the second year of life or may be seen to enhance a schedule already in place. A large and growing body of evidence from immunogenicity studies, as well as clinical trials and observational studies of carriage, pneumonia and invasive disease, has been systematically reviewed; these data indicate that schedules of 3 or 4 doses all work well, and that the differences between these regimens are subtle, especially in a mature program in which coverage is high and indirect (herd) effects help enhance protection provided directly by a vaccine schedule. The recent World Health Organization policy statement on PCVs endorsed a schedule of 3 primary doses without a booster or, as a new alternative, 2 primary doses with a booster dose. While 1 schedule may be preferred in a particular setting based on local epidemiology or practical considerations, achieving high coverage with 3 doses is likely more important than the specific timing of doses. PMID:24336059

An Assessment of the Expected Cost-Effectiveness of Quadrivalent Influenza Vaccines in Ontario, Canada Using a Static Model.

PubMed

Chit, Ayman; Roiz, Julie; Aballea, Samuel

2015-01-01

Ontario, Canada, immunizes against influenza using a trivalent inactivated influenza vaccine (IIV3) under a Universal Influenza Immunization Program (UIIP). The UIIP offers IIV3 free-of-charge to all Ontarians over 6 months of age. A newly approved quadrivalent inactivated influenza vaccine (IIV4) offers wider protection against influenza B disease. We explored the expected cost-utility and budget impact of replacing IIV3 with IIV4, within the context of Ontario's UIIP, using a probabilistic and static cost-utility model. Wherever possible, epidemiological and cost data were obtained from Ontario sources. Canadian or U.S. sources were used when Ontario data were not available. Vaccine efficacy for IIV3 was obtained from the literature. IIV4 efficacy was derived from meta-analysis of strain-specific vaccine efficacy. Conservatively, herd protection was not considered. In the base case, we used IIV3 and IIV4 prices of $5.5/dose and $7/dose, respectively. We conducted a sensitivity analysis on the price of IIV4, as well as standard univariate and multivariate statistical uncertainty analyses. Over a typical influenza season, relative to IIV3, IIV4 is expected to avert an additional 2,516 influenza cases, 1,683 influenza-associated medical visits, 27 influenza-associated hospitalizations, and 5 influenza-associated deaths. From a societal perspective, IIV4 would generate 76 more Quality Adjusted Life Years (QALYs) and a net societal budget impact of $4,784,112. The incremental cost effectiveness ratio for this comparison was $63,773/QALY. IIV4 remains cost-effective up to a 53% price premium over IIV3. A probabilistic sensitivity analysis showed that IIV4 was cost-effective with a probability of 65% for a threshold of $100,000/QALY gained. IIV4 is expected to achieve reductions in influenza-related morbidity and mortality compared to IIV3. Despite not accounting for herd protection, IIV4 is still expected to be a cost-effective alternative to IIV3 up to a price premium

Pneumonia Prevention during a Humanitarian Emergency: Cost-effectiveness of Haemophilus Influenzae Type B Conjugate Vaccine and Pneumococcal Conjugate Vaccine in Somalia.

PubMed

Gargano, Lisa M; Hajjeh, Rana; Cookson, Susan T

2015-08-01

Pneumonia is a leading cause of death among children less than five years old during humanitarian emergencies. Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae are the leading causes of bacterial pneumonia. Vaccines for both of these pathogens are available to prevent pneumonia. Problem This study describes an economic analysis from a publicly funded health care system perspective performed on a birth cohort in Somalia, a country that has experienced a protracted humanitarian emergency. An impact and cost-effectiveness analysis was performed comparing: no vaccine, Hib vaccine only, pneumococcal conjugate vaccine 10 (PCV10) only, and both together administered through supplemental immunization activities (SIAs). The main summary measure was the incremental cost per disability-adjusted life-years (DALYs) averted. One-way sensitivity analysis was conducted for uncertainty in parameter values. Each SIA would avert a substantial number of cases and deaths. Compared with no vaccine, the DALYs averted by two SIAs for two doses of Hib vaccine was US $202.93 (lower and upper limits: $121.80-$623.52), two doses of PCV10 was US $161.51 ($107.24-$227.21), and two doses of both vaccines was US $152.42 ($101.20-$214.42). Variables that influenced the cost-effectiveness for each strategy most substantially were vaccine effectiveness, case fatality rates (CFRs), and disease burden. The World Health Organization (WHO) defines a cost-effective intervention as costing one to three times the per capita gross domestic product (GDP; in 2011, for Somalia=US $112). Based on the presented model, Hib vaccine alone, PCV10 alone, or Hib vaccine and PCV10 given together in SIAs are cost-effective interventions in Somalia. The WHO/Strategic Advisory Group of Experts decision-making factors for vaccine deployment appear to have all been met: the disease burden is large, the vaccine-related risk is low, prevention in this setting is more feasible than treatment, the vaccine

Evaluation of the effectiveness of Haemophilus influenzae type b conjugate vaccine introduction against radiologically-confirmed hospitalized pneumonia in young children in Ukraine.

PubMed

Pilishvili, Tamara; Chernyshova, Liudmyla; Bondarenko, Anastasia; Lapiy, Fedir; Sychova, Irina; Cohen, Adam; Flannery, Brendan; Hajjeh, Rana

2013-07-01

Haemophilus influenzae type b (Hib) conjugate vaccine was included into the national vaccination schedule of Ukraine in 2006. The objective of this study was to demonstrate the effectiveness of Hib conjugate vaccine against radiologically-confirmed hospitalized pneumonia in children. Children <2 years old with radiologically confirmed pneumonia admitted to 11 participating hospitals in Kiev and Dnepropetrovsk between April 2007 and June 2009 were included in a case-control evaluation. Four controls were matched to each case by date of birth (within 14 days) and outpatient clinic. We estimated ORs for vaccination and vaccine effectiveness ((1 - OR)*100%) using conditional logistic regression, adjusting for comorbid conditions and contraindications for vaccination. We enrolled 188 case-children and 735 controls. Median age was 16 months (range 4-24 months). Fifty-one percent of cases and 67% of controls received ≥1 doses of Hib conjugate vaccine; 26% of cases and 37% of controls received ≥3 doses. The effectiveness of ≥1 dose Hib conjugate vaccine was estimated at 45% (95% CI 18%-63%). Our study showed that Hib infections are important causes of hospitalized radiologically confirmed pneumonia in young children in Ukraine. Copyright © 2013. Published by Mosby, Inc.

Health economic evaluation of Human Papillomavirus vaccines in women from Venezuela by a lifetime Markov cohort model.

PubMed

Bardach, Ariel Esteban; Garay, Osvaldo Ulises; Calderón, María; Pichón-Riviére, Andrés; Augustovski, Federico; Martí, Sebastián García; Cortiñas, Paula; Gonzalez, Marino; Naranjo, Laura T; Gomez, Jorge Alberto; Caporale, Joaquín Enzo

2017-02-02

Cervical cancer (CC) and genital warts (GW) are a significant public health issue in Venezuela. Our objective was to assess the cost-effectiveness of the two available vaccines, bivalent and quadrivalent, against Human Papillomavirus (HPV) in Venezuelan girls in order to inform decision-makers. A previously published Markov cohort model, informed by the best available evidence, was adapted to the Venezuelan context to evaluate the effects of vaccination on health and healthcare costs from the perspective of the healthcare payer in an 11-year-old girls cohort of 264,489. Costs and quality-adjusted life years (QALYs) were discounted at 5%. Eight scenarios were analyzed to depict the cost-effectiveness under alternative vaccine prices, exchange rates and dosing schemes. Deterministic and probabilistic sensitivity analyses were performed. Compared to screening only, the bivalent and quadrivalent vaccines were cost-saving in all scenarios, avoiding 2,310 and 2,143 deaths, 4,781 and 4,431 CCs up to 18,459 GW for the quadrivalent vaccine and gaining 4,486 and 4,395 discounted QALYs respectively. For both vaccines, the main determinants of variations in the incremental costs-effectiveness ratio after running deterministic and probabilistic sensitivity analyses were transition probabilities, vaccine and cancer-treatment costs and HPV 16 and 18 distribution in CC cases. When comparing vaccines, none of them was consistently more cost-effective than the other. In sensitivity analyses, for these comparisons, the main determinants were GW incidence, the level of cross-protection and, for some scenarios, vaccines costs. Immunization with the bivalent or quadrivalent HPV vaccines showed to be cost-saving or cost-effective in Venezuela, falling below the threshold of one Gross Domestic Product (GDP) per capita (104,404 VEF) per QALY gained. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results.

First characterization of immunogenic conjugates of Vi negative Salmonella Typhi O-specific polysaccharides with rEPA protein for vaccine development.

PubMed

Salman, M; St Michael, F; Ali, A; Jabbar, A; Cairns, C; Hayes, A C; Rahman, M; Iqbal, M; Haque, A; Cox, A D

2017-11-01

Efficacious typhoid vaccines for young children will significantly reduce the disease burden in developing world. The Vi polysaccharide based conjugate vaccines (Vi-rEPA) against Salmonella Typhi Vi positive strains has shown high efficacy but may be ineffective against Vi negative S. Typhi. In this study, for the first time, we report the synthesis and evaluation of polysaccharide-protein conjugates of Vi negative S. Typhi as potential vaccine candidates. Four different conjugates were synthesized using recombinant exoprotein A of Pseudomonas aeruginosa (rEPA) and human serum albumin (HSA) as the carrier proteins, using either direct reductive amination or an intermediate linker molecule, adipic acid dihydrazide (ADH). Upon injection into mice, a significantly higher antibody titer was observed in mice administrated with conjugate-1 (OSP-HSA) (P=0.0001) and conjugate 2 (OSP-rEPA) (P≤0.0001) as compared to OSP alone. In contrast, the antibody titer elicited by conjugate 3 (OSP ADH -HSA) and conjugate 4 (OSP ADH -rEPA) were insignificant (P=0.1684 and P=0.3794, respectively). We conclude that reductive amination is the superior method to prepare the S. Typhi OSP glycoconjugate. Moreover, rEPA was a better carrier protein than HSA. Thus OSP-rEPA conjugate seems to be efficacious typhoid vaccines candidate, it may be evaluated further and recommended for the clinical trials. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

The effects of stopper drying on moisture levels of Haemophilus influenzae conjugate vaccine.

PubMed

Earle, J P; Bennett, P S; Larson, K A; Shaw, R

1992-01-01

The discovery and development of increasingly potent biological and pharmaceutical products have resulted in very small amounts of the active ingredient in final product formulations. Pediatric vaccines with sub-milliliter dose sizes pose unique problems for final formulation and lyophilization, especially when stabilizers used are present in small amounts or are hygroscopic. Lyophilized Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) (PedvaxHIB) has a plug weight of about 3 mg in its final formulation. Microgram amounts of water absorbed by the lyophilized plug can cause drastic changes in the moisture content of the product. In a small percentage of the final containers absorption of moisture by the vaccine may cause aesthetic defects (plug collapse) over time, or at elevated temperatures. This paper describes drying methods developed to control residual moisture levels in stoppers used as final container closures. Results on the moisture stability of the product capped with dried and non-dried stoppers are presented.

Bacterial meningitis and Haemophilus influenzae type b conjugate vaccine, Malawi.

PubMed

McCormick, David W; Molyneux, Elizabeth M

2011-04-01

A retrospective database review showed that Haemophilus influenzae type b conjugate vaccine decreased the annual number of cases of H. influenzae type b meningitis in children in Blantyre, Malawi. Among young bacterial meningitis patients, HIV prevalence was high (36.7% during 1997-2009), and pneumococcus was the most common etiologic agent (57% in 2009).

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2017-18 Influenza Season.

PubMed

Grohskopf, Lisa A; Sokolow, Leslie Z; Broder, Karen R; Walter, Emmanuel B; Bresee, Joseph S; Fry, Alicia M; Jernigan, Daniel B

2017-08-25

This report updates the 2016-17 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines (MMWR Recomm Rep 2016;65[No. RR-5]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. A licensed, recommended, and age-appropriate vaccine should be used.For the 2017-18 season, quadrivalent and trivalent influenza vaccines will be available. Inactivated influenza vaccines (IIVs) will be available in trivalent (IIV3) and quadrivalent (IIV4) formulations. Recombinant influenza vaccine (RIV) will be available in trivalent (RIV3) and quadrivalent (RIV4) formulations. Live attenuated influenza vaccine (LAIV4) is not recommended for use during the 2017-18 season due to concerns about its effectiveness against (H1N1)pdm09 viruses during the 2013-14 and 2015-16 seasons. Recommendations for different vaccine types and specific populations are discussed. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended product is available.Updates to the recommendations described in this report reflect discussions during public meetings of ACIP held on October 20, 2016; February 22, 2017; and June 21, 2017. New and updated information in this report includes the following:•Vaccine viruses included in the 2017-18 U.S. trivalent influenza vaccines will be an A/Michigan/45/2015 (H1N1)pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-like virus (Victoria lineage). Quadrivalent influenza vaccines will contain these three viruses and an additional influenza B vaccine virus, a B/Phuket/3073/2013-like virus (Yamagata lineage).• Information on recent licensures and labelling changes is discussed, including licensure of Afluria Quadrivalent (IIV4; Seqirus, Parkville, Victoria, Australia); Flublok Quadrivalent (RIV4; Protein Sciences, Meriden

Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo.

PubMed

Arutla, Viswanath; Leal, Joseph; Liu, Xiaowei; Sokalingam, Sriram; Raleigh, Michael; Adaralegbe, Adejimi; Liu, Li; Pentel, Paul R; Hecht, Sidney M; Chang, Yung

2017-05-08

Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC 50 ) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and

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

A preclinical study comparing approaches for augmenting the immunogenicity of a heptavalent KLH-conjugate vaccine against epithelial cancers.

PubMed

Ragupathi, Govind; Koide, Fusataka; Sathyan, Natarajan; Kagan, Ella; Spassova, Maria; Bornmann, William; Gregor, Polly; Reis, Celso A; Clausen, Henrik; Danishefsky, Samuel J; Livingston, Philip O

2003-10-01

Previously using a series of monovalent vaccines, we demonstrated that the optimal method for inducing an antibody response against cancer cell-surface antigens is covalent conjugation of the antigens to keyhole limpet hemocyanin (KLH) and the use of a saponin adjuvant. We have prepared a heptavalent-KLH conjugate vaccine containing the seven epithelial cancer antigens GM2, Globo H, Lewis(y), TF(c), Tn(c), STn(c), and glycosylated MUC1. In preparation for testing this vaccine in the clinic, we tested the impact on antibody induction of administering the individual conjugates plus adjuvant compared with a mixture of the seven conjugates plus adjuvant, and of several variables thought to augment immunogenicity. These include approaches for decreasing suppressor cell activity or increasing helper T-lymphocyte activity (low dose cyclophosphamide or anti-CTLA-4 MAb), different saponin adjuvants at various doses (QS-21 and GPI-0100), and different methods of formulation (lyophilization and use of polysorbate 80). We find that: (1). Immunization with the heptavalent-KLH conjugate plus GPI-0100 vaccine induces antibodies against the seven antigens of comparable titer to those induced by the individual-KLH conjugate vaccines, high titers of antibodies against Tn (median ELISA titer IgM/IgG 320/10240), STn (640/5120), TF (320/10240), MUC1 (80/20480), and globo H (640/40); while lower titers of antibodies against Lewis(y)()(160/0) and only occasional antibodies against GM2 are induced. (2). These antibodies reacted with the purified synthetic antigens by ELISA, and with naturally expressed antigens on the cancer cell surface by FACS. (3). None of the approaches for further altering the suppressor cell/helper T-cell balance nor changes to the standard formulation by lyophilization or use of polysorbate 80 had any impact on antibody titers. (4). An optimal dose of saponin adjuvant, QS-21 (50 microg) or GPI-0100 (1000 microg), is required for optimal antibody titers. This

Bacterial Meningitis and Haemophilus influenzae Type b Conjugate Vaccine, Malawi

PubMed Central

Molyneux, Elizabeth M.

2011-01-01

A retrospective database review showed that Haemophilus influenzae type b conjugate vaccine decreased the annual number of cases of H. influenzae type b meningitis in children in Blantyre, Malawi. Among young bacterial meningitis patients, HIV prevalence was high (36.7% during 1997–2009), and pneumococcus was the most common etiologic agent (57% in 2009). PMID:21470461

[Human papillomavirus vaccine. Efficacy and safety].

PubMed

Bruni, Laia; Serrano, Beatriz; Bosch, Xavier; Castellsagué, Xavier

2015-05-01

Human papillomavirus (HPV) related disease remains a major cause of morbidity and mortality worldwide. Prophylactic vaccines have been recognized as the most effective intervention to control for HPV-related diseases. This article reviews the major phaseii/iii trials of the bivalent (HPVs16/18), quadrivalent (HPVs6/11/16/18), and the recently approved 9-valent vaccine (HPVs6/11/16/18/31/33/45/52/58). Large trials have been conducted showing the safety, immunogenicity and high efficacy of the bivalent and quadrivalent vaccines in the prevention of pre-invasive lesions and infection, especially when administered at young ages before exposure to HPV. Trials of the 9-valent vaccine have also demonstrated the safety, immunogenicity and efficacy of the vaccine in the prevention of infection and disease associated with the vaccine types, and its potential to substantially increase the overall prevention of HPV-related diseases. Post-licensure country reports have shown the recent and early impact of these vaccines at population level after the implementation of established HPV vaccination programs, including decreases in the prevalence of vaccine HPV types, the incidence of genital warts, and the incidence of high-grade cervical abnormalities. If widely implemented, current HPV vaccines may drastically reduce the incidence of cervical cancer and other HPV-related cancers and diseases. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

The effect of Haemophilus influenzae type b and pneumococcal conjugate vaccines on childhood pneumonia incidence, severe morbidity and mortality.

PubMed

Theodoratou, Evropi; Johnson, Sue; Jhass, Arnoupe; Madhi, Shabir A; Clark, Andrew; Boschi-Pinto, Cynthia; Bhopal, Sunil; Rudan, Igor; Campbell, Harry

2010-04-01

With the aim of populating the Lives Saved Tool (LiST) with parameters of effectiveness of existing interventions, we conducted a systematic review of the literature assessing the effect of Haemophilus influenzae type b (Hib) and pneumococcal (PC) conjugate vaccines on incidence, severe morbidity and mortality from childhood pneumonia. We summarized cluster randomized controlled trials (cRCTs) and case-control studies of Hib conjugate vaccines and RCTs of 9- and 11-valent PC conjugate vaccines conducted in developing countries across outcome measures using standard meta-analysis methods. We used a set of standardized rules developed for the purpose of populating the LiST tool with required parameters to promote comparability across reviews of interventions against the major causes of childhood mortality. The estimates could be adjusted further to account for factors such as PC vaccine serotype content, PC serotype distribution and human immunodeficiency virus prevalence but this was not included as part of the LiST model approach. The available evidence from published data points to a summary effect of the Hib conjugate vaccine on clinical pneumonia of 4%, on clinical severe pneumonia of 6% and on radiologically confirmed pneumonia of 18%. Respective effectiveness estimates for PC vaccines (all valent) on clinical pneumonia is 7%, clinical severe pneumonia is 7% and radiologically confirmed pneumonia is 26%. The findings indicated that radiologically confirmed pneumonia, as a severe morbidity proxy for mortality, provided better estimates for the LiST model of effect of interventions on mortality reduction than did other outcomes evaluated. The LiST model will use this to estimate the pneumonia mortality reduction which might be observed when scaling up Hib and PC conjugate vaccination in the context of an overall package of child health interventions.

Estimating the cost-effectiveness profile of a universal vaccination programme with a nine-valent HPV vaccine in Austria.

PubMed

Boiron, L; Joura, E; Largeron, N; Prager, B; Uhart, M

2016-04-16

HPV is a major cancer-causing factor in both sexes in the cervix, vulva, vagina, anus, penis, oropharynx as well as the causal factor in other diseases such as genital warts and recurrent respiratory papillomatis. In the context of the arrival of a nonavalent HPV vaccine (6/11/16/18/31/33/45/52/58), this analysis aims to estimate the public health impact and the incremental cost-effectiveness of a universal (girls and boys) vaccination program with a nonavalent HPV vaccine as compared to the current universal vaccination program with a quadrivalent HPV vaccine (6/11/16/18), in Austria. A dynamic transmission model including a wide range of health and cost outcomes related to cervical, anal, vulvar, vaginal diseases and genital warts was calibrated to Austrian epidemiological data. The clinical impact due to the 5 new types was included for cervical and anal diseases outcomes only. In the base case, a two-dose schedule, lifelong vaccine type-specific protection and a vaccination coverage rate of 60% and 40% for girls and boys respectively for the 9-year old cohorts were assumed. A cost-effectiveness threshold of €30,000/QALY-gained was considered. Universal vaccination with the nonavalent vaccine was shown to reduce the incidence of HPV16/18/31/33/45/52/58 -related cervical cancer by 92%, the related CIN2/3 cases by 96% and anal cancer by 83% and 76% respectively in females and males after 100 years, relative to 75%, 76%, 80% and 74% with the quadrivalent vaccine, respectively. Furthermore, the nonavalent vaccine was projected to prevent an additional 14,893 cases of CIN2/3 and 2544 cases of cervical cancer, over 100 years. Depending on the vaccine price, the strategy was shown to be from cost-saving to cost-effective. The present evaluation showed that vaccinating 60% of girls and 40% of boys aged 9 in Austria with a 9-valent vaccine will substantially reduce the incidence of cervical cancer, CIN and anal cancer compared to the existing strategy. The vaccination

Increased Protection against Pneumococcal Disease by Mucosal Administration of Conjugate Vaccine plus Interleukin-12

PubMed Central

Lynch, Joyce M.; Briles, David E.; Metzger, Dennis W.

2003-01-01

Streptococcus pneumoniae is a common cause of respiratory tract infections, its main entry route being the nasal mucosa. The recent development of pneumococcal polysaccharide conjugate vaccines has led to a dramatic improvement in protection against invasive disease in infants and children, but these vaccines have been found to be only 50 to 60% protective against bacterial carriage. In this study, we investigated the efficacy of intranasal (i.n.) conjugate vaccine delivery using interleukin-12 (IL-12) as a mucosal adjuvant. Immunized mice treated with IL-12 demonstrated increased expression of lung and splenic gamma interferon and IL-10 mRNAs; high levels of antibody, particularly serum immunoglobulin G2a (IgG2a) and respiratory IgA; and significantly increased opsonic activity. After intraperitoneal challenge with type 3 pneumococci, there was 75% survival of i.n. vaccinated mice compared to 0% survival of unvaccinated mice. In addition, after i.n. challenge with type 14 pneumococci, vaccinated mice possessed fewer bacterial colonies in the upper respiratory tract than unvaccinated mice. However, no significant difference in type 14 carriage was observed between vaccinated and unvaccinated groups following intramuscular vaccination, the typical route of vaccination in humans. Using mice with a genetic disruption in IgA expression, it was found that pneumococcus-specific IgA played a significant role in the clearance of bacteria from the upper respiratory tract. We conclude that i.n vaccination in the presence of IL-12 is able to enhance systemic and mucosal immune responses to pneumococci and efficiently protect against both invasive infection and bacterial carriage. PMID:12874361

Impact of the introduction of the pneumococcal conjugate vaccine in the Brazilian routine childhood national immunization program.

PubMed

Moreira, Marta; Cintra, Otavio; Harriague, Julie; Hausdorff, William P; Hoet, Bernard

2016-05-27

Brazil introduced the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix™, GSK Vaccines) in the routine childhood immunization program in 2010 with a 3+1 schedule (with catch-up for children <2 years-old). This review represents the first analysis of the overall impact of a second-generation pneumococcal conjugate vaccine on nasopharyngeal carriage and all the major pneumococcal disease manifestations in a single, pneumococcal conjugate vaccine-naïve, developing country. A total of 15 published articles and 13 congress abstracts were included in the analysis. In children <5 years-old, studies showed a positive impact of PHiD-CV on the incidence of vaccine-type and any-type invasive pneumococcal disease (including decreases in pneumococcal meningitis morbidity and mortality), on pneumonia incidence and mortality, and on otitis media. Nasopharyngeal carriage of vaccine-type and any-type pneumococci decreased after the primary doses, with no early signs of replacement with other pathogens. Finally, herd protection against vaccine-type invasive pneumococcal disease and pneumonia in unvaccinated subjects was shown in some studies for some age groups. In conclusion, pneumococcal disease decreased after the introduction of PHiD-CV into the Brazilian national immunization program. Further follow-up is needed to evaluate the long-term overall impact of PHiD-CV in the Brazilian population. Copyright © 2016 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.

Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: An epidemiological surveillance mechanism for alternate vaccination schemes

PubMed Central

Hernández-Ávila, Mauricio; Torres-Ibarra, Leticia; Stanley, Margaret; Salmerón, Jorge; Cruz-Valdez, Aurelio; Muñoz, Nubia; Herrero, Rolando; Villaseñor-Ruíz, Ignacio F; Lazcano-Ponce, Eduardo

2016-01-01

The cost of HPV vaccines and the need for 3 doses remains a barrier for their inclusion in routine vaccination schedules for girls in low and middle income countries. In a non-inferiority study, we aimed to compare the immunogenicity of a standard 3 doses and a 2 doses schedule. We enrolled 450 participants in an open-label non-randomized clinical trial to evaluate the immunogenicity induced at different ages by the licensed HPV6/11/16/18 quadrivalent vaccine in a 2 doses schedule (0–6 months, n = 150 girls aged 9–10 y) and 3 doses schedule (0, 2, and 6 months; n = 150 girls aged 9–10 y and n=150 women aged 18 to 24 years). To assess the antibody response, blood samples were obtained at Month 7 and 21 after the first vaccination from participants in all study groups. cLIA testing was performed at Merck Research Laboratories. Antibody levels were expressed as milli-Merck units (mMU) per ml. Primary outcome was non-inferiority (95% CI, lower bound >0.5) of the geometric mean titers (GMT) ratios for HPV6, HPV11, HPV16 and HPV18 antibodies 7 and 21 months after the first dose among girls receiving 2 doses compared with young women and girls receiving 3 doses. All vaccinees were seropositive for both HPV16 and HPV18 antibodies at month 7. At month 21, 98.5 and 56.6% of women 18–24 y old were seropositive for HPV16 and 18, respectively. For girls in the three doses group, seropositivity rates were 99.3 and 86.3% for HPV16 and 18, respectively. For girls in the two doses group rates were 99.3 and 70.2% for HPV16 and 18, respectively. The two doses schedule was non-inferior compared to the 3 doses schedule in same-age girls and to the group of adult women after 21 months of the first vaccine dose. Our results are in agreement with similar trials evaluating the immune response of a 2 doses schedule of both HPV vaccines, supporting the recent WHO recommendation as well as the Mexican policy to incorporate the 2 doses schedule for girls aged 9–11 y. PMID:26211489

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2017–18 Influenza Season

PubMed Central

Sokolow, Leslie Z.; Broder, Karen R.; Walter, Emmanuel B.; Bresee, Joseph S.; Fry, Alicia M.; Jernigan, Daniel B.

2017-01-01

Summary This report updates the 2016–17 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines (MMWR Recomm Rep 2016;65[No. RR-5]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. A licensed, recommended, and age-appropriate vaccine should be used. For the 2017–18 season, quadrivalent and trivalent influenza vaccines will be available. Inactivated influenza vaccines (IIVs) will be available in trivalent (IIV3) and quadrivalent (IIV4) formulations. Recombinant influenza vaccine (RIV) will be available in trivalent (RIV3) and quadrivalent (RIV4) formulations. Live attenuated influenza vaccine (LAIV4) is not recommended for use during the 2017–18 season due to concerns about its effectiveness against (H1N1)pdm09 viruses during the 2013–14 and 2015–16 seasons. Recommendations for different vaccine types and specific populations are discussed. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended product is available. Updates to the recommendations described in this report reflect discussions during public meetings of ACIP held on October 20, 2016; February 22, 2017; and June 21, 2017. New and updated information in this report includes the following: •Vaccine viruses included in the 2017–18 U.S. trivalent influenza vaccines will be an A/Michigan/45/2015 (H1N1)pdm09–like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008–like virus (Victoria lineage). Quadrivalent influenza vaccines will contain these three viruses and an additional influenza B vaccine virus, a B/Phuket/3073/2013–like virus (Yamagata lineage). • Information on recent licensures and labelling changes is discussed, including licensure of Afluria Quadrivalent (IIV4; Seqirus, Parkville, Victoria, Australia); Flublok Quadrivalent (RIV4

Clinical and economic impact of school-based nonavalent human papillomavirus vaccine on women in Singapore: a transmission dynamic mathematical model analysis.

PubMed

Tay, S K; Hsu, T-Y; Pavelyev, A; Walia, A; Kulkarni, A S

2018-03-01

To examine the epidemiological and economic impact of a nine-valent (nonavalent) human papillomavirus (HPV) 6/11/16/18/31/33/45/52/58 vaccine programme for young teenagers in Singapore. Mathematical modelling. Pharmaco-economic simulation projection. Singapore demography. Clinical, epidemiological and financial data from Singapore were used in a validated HPV transmission dynamic mathematical model to analyse the impact of nonavalent HPV vaccination over quadrivalent and bivalent vaccines in a school-based 2-dose vaccination for 11- to 12-year-old girls in the country. The model assumed routine cytology screening in the current rate (50%) and vaccine coverage rate of 80%. Changes over a 100-year time period in the incidence and mortality rates of cervical cancer, case load of genital warts, and incremental cost-effectiveness ratio (ICER). Compared with bivalent and quadrivalent HPV vaccination programmes, nonavalent HPV universal vaccination resulted in an additional reduction of HPV31/33/45/52/58 related CIN1 of 40.5%, CIN 2/3 of 35.4%, cervical cancer of 23.5%, and cervical cancer mortality of 20.2%. Compared with bivalent HPV vaccination, there was an additional reduction in HPV-6/11 related CIN1 of 75.7%, and genital warts of 78.9% in women and 73.4% in men. Over the 100 years, after applying a discount of 3%, disease management cost will be reduced by 32.5% (versus bivalent) and 7.5% (versus quadrivalent). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year gained was SGD 929 compared with bivalent vaccination and SGD 9864 compared with quadrivalent vaccination. Universal two-dose nonavalent HPV vaccination for 11- to 12-year-old adolescent women is very cost-effective in Singapore. Nonavalent HPV vaccination of 11- to 12-year-old girls is cost-effective in Singapore. © 2017 Royal College of Obstetricians and Gynaecologists.

[Evaluation of the cost-effectiveness of two alternative human papillomavirus vaccines as prophylaxis against uterine cervical cancer].

PubMed

Bolaños-Díaz, Rafael; Tejada, Romina A; Beltrán, Jessica; Escobedo-Palza, Seimer

2016-01-01

To determine the cost-effectiveness of human papillomavirus (HPV) vaccination and cervical lesion screening versus screening alone for the prevention of uterine cervical cancer (UCC). This cost-effectiveness evaluation from the perspective of the Ministry of Health employed a Markov model with a 70-year time horizon and three alternatives for UCC prevention (screening alone, screening + bivalent vaccine, and screening + quadrivalent vaccine) in a hypothetical cohort of 10-year-old girls. Our model, which was particularly sensitive to variations in coverage and in the prevalence of persistent infection by oncologic genotypes not included in the vaccine, revealed that HPV vaccination and screening is more cost-effective than screening alone, assuming a payment availability from S/ 2 000 (US dollars (USD) 1 290.32) per subject. In the deterministic analysis, the bivalent vaccine was marginally more cost-effective than the quadrivalent vaccine (S/ 48 [USD 30.97] vs. S/ 166 [USD 107.10] per quality-adjusted life-year, respectively). However, in the probabilistic analysis, both interventions generated clouds of overlapping points and were thus cost-effective and interchangeable, although the quadrivalent vaccine tended to be more cost-effective. Assuming a payment availability from S/ 2000 [USD 1,290.32], screening and vaccination were more cost-effective than screening alone. The difference in cost-effectiveness between the two vaccines lacked probabilistic robustness, and therefore the vaccines can be considered interchangeable from a cost-effectiveness perspective.

Beyond new vaccine introduction: the uptake of pneumococcal conjugate vaccine in the African Region.

PubMed

Olayinka, Folake; Ewald, Leah; Steinglass, Robert

2017-01-01

The number of vaccines available to low-income countries has increased dramatically over the last decade. Overall infant immunization coverage in the WHO African region has stagnated in the past few years while countries' ability to maintain high immunization coverage rates following introduction of new vaccines has been uneven. This case study examines post-introduction coverage among African countries that introduced PCV between 2008 and 2013 and the factors affecting Pneumococcal Conjugate Vaccine (PCV) introduction. Nearly one-third of countries did not achieve 80% infant PCV3 coverage by two years post-introduction and 58% of countries experienced a decline in coverage between post introduction years two and four. Major factors affecting coverage rates included introduction without adequate preparation, insufficient supply chain capacity and management, poor communication between organizations and with the public, and data collection systems that were insufficient to meet information needs. Deliberately addressing these issues as well as longstanding weaknesses during new vaccine introduction can strengthen the immunization and broader health system. Further study is required to identify and address factors that affect maintenance of high coverage following introduction of new vaccines in the African region. Immunization with PCV is one of the most important interventions protecting against pneumonia, the second leading cause of death for children under five globally.

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

PubMed Central

Pravetoni, M.; Harris, A.C.; Birnbaum, A.K.; Pentel, P.R.

2013-01-01

Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines. PMID:23220743

Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial.

PubMed

Cadorna-Carlos, Josefina B; Nolan, Terry; Borja-Tabora, Charissa Fay; Santos, Jaime; Montalban, M Cecilia; de Looze, Ferdinandus J; Eizenberg, Peter; Hall, Stephen; Dupuy, Martin; Hutagalung, Yanee; Pépin, Stéphanie; Saville, Melanie

2015-05-15

Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains and one strain from each B lineage (Yamagata and Victoria) may offer broader protection against seasonal influenza than inactivated trivalent influenza vaccine (IIV3), containing a single B strain. This study examined the safety, immunogenicity, and lot consistency of an IIV4 candidate. This phase III, randomized, controlled, multicenter trial in children/adolescents (9 through 17 years) and adults (18 through 60 years) was conducted in Australia and in the Philippines in 2012. The study was double-blind for IIV4 lots and open-label for IIV4 vs IIV3. Children/adolescents were randomized 2:2:2:1 and adults 10:10:10:1 to receive one of three lots of IIV4 or licensed IIV3. Safety data were collected for up to 6 months post-vaccination. Hemagglutination inhibition and seroneutralization antibody titers were assessed pre-vaccination and 21 days post-vaccination. 1648 adults and 329 children/adolescents received IIV4, and 56 adults and 55 children/adolescents received IIV3. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for IIV3 and IIV4 recipients in both age groups. Injection-site pain, headache, malaise, and myalgia were the most frequently reported solicited reactions, most of which were mild and resolved within 3 days. No vaccine-related serious adverse events or deaths were reported. Post-vaccination antibody responses, seroconversion rates, and seroprotection rates for the 3 strains common to both vaccines were comparable for IIV3 and IIV4 in both age groups. Antibody responses to IIV4 were equivalent among vaccine lots and comparable between age groups for each of the 4 strains. IIV4 met all European Medicines Agency immunogenicity criteria for adults for all 4 strains. In both age groups, IIV4 was well tolerated and caused no safety concerns, induced robust antibody responses to all 4 influenza strains, and met all EMA immunogenicity

Characteristics of a new meningococcal serogroup B vaccine, bivalent rLP2086 (MenB-FHbp; Trumenba®).

PubMed

Gandhi, Ashesh; Balmer, Paul; York, Laura J

2016-08-01

Neisseria meningitidis is a common cause of bacterial meningitis, often leading to permanent sequelae or death. N. meningitidis is classified into serogroups based on the composition of the bacterial capsular polysaccharide; the 6 major disease-causing serogroups are designated A, B, C, W, X, and Y. Four of the 6 disease-causing serogroups (A, C, Y, and W) can be effectively prevented with available quadrivalent capsular polysaccharide protein conjugate vaccines; however, capsular polysaccharide conjugate vaccines are not effective against meningococcal serogroup B (MnB). There is no vaccine available for serogroup X. The public health need for an effective serogroup B vaccine is evident, as MnB is the most common cause of meningococcal disease in the United States and is responsible for almost half of all cases in persons aged 17 to 22 years. In fact, serogroup B meningococci were responsible for the recent meningococcal disease outbreaks on college campuses. However, development of a suitable serogroup B vaccine has been challenging, as serogroup B polysaccharide-based vaccines were found to be poorly immunogenic. Vaccine development for MnB focused on identifying potential outer membrane protein targets that elicit broadly protective immune responses across strains from the vast number of proteins that exist on the bacterial surface. Human factor H binding protein (fHBP; also known as LP2086), a conserved surface-exposed bacterial lipoprotein, was identified as a promising vaccine candidate. Two recombinant protein-based serogroup B vaccines that contain fHBP have been successfully developed and licensed in the United States under an accelerated approval process: bivalent rLP2086 (MenB-FHbp; Trumenba®) and 4CMenB (MenB-4 C; Bexsero®). This review will focus on bivalent rLP2086 only, including vaccine components, mechanism of action, and potential coverage across serogroup B strains in the United States.

Otitis media in children vaccinated during consecutive 7-valent or 10-valent pneumococcal conjugate vaccination schedules.

PubMed

Leach, Amanda Jane; Wigger, Christine; Andrews, Ross; Chatfield, Mark; Smith-Vaughan, Heidi; Morris, Peter Stanley

2014-08-11

In 2001 when 7-valent pneumococcal conjugate vaccine (PCV7) was introduced, almost all (90%) young Australian Indigenous children living in remote communities had some form of otitis media (OM), including 24% with tympanic membrane perforation (TMP). In late 2009, the Northern Territory childhood vaccination schedule replaced PCV7 with 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10). We conducted regular surveillance of all forms of OM in children in remote Indigenous communities between September 2008 and December 2012. This analysis compares children less than 36 months of age who received a primary course of at least two doses of PCV7 or PHiD-CV10, and not more than one dose of another pneumococcal vaccine. Mean ages of 444 PCV7- and 451 PHiD-CV10-vaccinated children were 20 and 18 months, respectively. Bilaterally normal middle ears were detected in 7% and 9% respectively. OM with effusion was diagnosed in 41% and 51% (Risk Difference 10% [95% Confidence Interval 3 to 17] p = 0.002), any suppurative OM (acute OM or any TMP) in 51% versus 39% (RD -12% [95% CI -19 to -5] p = 0.0004], and TMP in 17% versus 14% (RD -3% [95% CI -8 to 2] p = 0.2), respectively. Multivariate analyses described a similar independent negative association between suppurative OM and PHiD-CV10 compared to PCV7 (Odds Ratio = 0.6 [95% CI 0.4 to 0.8] p = 0.001). Additional children in the household were a risk factor for OM (OR = 2.4 [95% CI 2 to 4] p = 0.001 for the third additional child), and older age and male gender were associated with less disease. Other measured risk factors were non-significant. Similar clinical results were found for children who had received non-mixed PCV schedules. Otitis media remains a significant health and social issue for Australian Indigenous children despite PCV vaccination. Around 90% of young children have some form of OM. Children vaccinated in with PHiD-CV10 had less suppurative OM than

Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older.

PubMed

Jackson, Lisa A; Gurtman, Alejandra; van Cleeff, Martin; Frenck, Robert W; Treanor, John; Jansen, Kathrin U; Scott, Daniel A; Emini, Emilio A; Gruber, William C; Schmoele-Thoma, Beate

2013-08-02

Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations. This was an extension of a previous study in pneumococcal vaccine-naïve adults aged 50-64 years in which adults 60-64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50-59 were given PCV13. In this follow up study conducted about 4 years later, the 60-64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50-59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination. A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non-inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes. In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses. Copyright © 2013 The Authors. Published by Elsevier

An open-label, randomized, multicenter study of the safety, tolerability, and immunogenicity of quadrivalent human papillomavirus (types 6/11/16/18) vaccine given concomitantly with diphtheria, tetanus, pertussis, and poliomyelitis vaccine in healthy adolescents 11 to 17 years of age.

PubMed

Vesikari, Timo; Van Damme, Pierre; Lindblad, Niklas; Pfletschinger, Ulrich; Radley, David; Ryan, Desmond; Vuocolo, Scott; Haupt, Richard M; Guris, Dalya

2010-04-01

GARDASIL/SILGARD is a quadrivalent human papillomavirus (HPV) vaccine with activity against HPV 6/11/16/18. In many countries, GARDASIL is recommended for routine use among adolescents at the same age as other vaccines. In this study, we evaluated the immunogenicity and safety of GARDASIL administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis, and poliomyelitis vaccine). This was an open-label, randomized, multicenter study. We enrolled males (n = 260) and females (n = 583) aged 11 to 17 years. All subjects received a 0.5 mL dose of GARDASIL at day 1, month 2, and month 6, and a 0.5 mL dose of REPEVAX either on day 1 (opposite limb from GARDASIL) or at month 1. Antibody levels for all vaccine components were measured. We monitored systemic and injection-site adverse experiences (AEs) and serious adverse experiences. Immune response for all GARDASIL antigens following concomitant administration of the vaccines was demonstrated noninferior to nonconcomitant administration. Seroconversion for HPV 6, 11, 16, and 18 was >99.7% in both concomitant and nonconcomitant vaccination groups. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, and all polio and pertussis antigens. Concomitant administration of the 2 vaccines was generally well-tolerated, although there was a small increase in headache and injection-site swelling in the concomitant group. Overall, concomitant administration of GARDASIL and REPEVAX was generally well-tolerated and did not interfere with the immune response to either vaccine. Concomitant administration of vaccines would minimize the number of visits required to deliver each vaccine individually.

Immunogenicity and safety of a single dose of a CRM-conjugated meningococcal ACWY vaccine in children and adolescents aged 2-18 years in Taiwan: results of an open label study.

PubMed

Huang, Li-Min; Chiu, Nan-Chang; Yeh, Shu-Jen; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2014-09-08

MenACWY-CRM (Menveo®, Novartis Vaccines, Siena, Italy) is a quadrivalent meningococcal conjugate vaccine developed to help prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W, and Y. It is approved within the European Union in persons >2 years of age and in persons from 2 months to 55 years of age in the United States, among other countries. Little is known about the immunogenicity and safety of this vaccine in Taiwanese children >2 years and adolescents. This study assessed the immunogenicity and safety of a single injection of MenACWY-CRM vaccine in Taiwanese subjects aged 2-18 years old. In this phase III, multicentre, open-label study 341 subjects received one dose of MenACWY-CRM. Immunogenicity measures were rates of seroresponse (defined as the proportion of subjects with a postvaccination hSBA ≥1:8 if the prevaccination (baseline) titre was <1:4, or at least a fourfold higher hSBA titre than baseline if the prevaccination titre was ≥1:4), percentages of subjects with serum bactericidal activity (hSBA) ≥1:8 for serogroups A, C, W and Y and hSBA geometric mean titres (GMTs). Local and systemic reactions and all adverse events (AEs) were recorded for 7 days, and medically attended AEs for 1 month post-vaccination. Seroresponse rates after MenACWY-CRM vaccination at Day 29 for the serogroups A, C, W, and Y were 83%, 93%, 50%, and 65%, respectively. At Day 29 the percentages of subjects with hSBA ≥1:8 against all four serogroups A, C, W and Y were: 83%, 96%, 96% and 82%, respectively. GMTs against all serogroups rose by ≥7-fold from baseline to Day 29. The vaccine was well tolerated. A single dose of MenACWY-CRM demonstrated a robust immune response, and an acceptable safety profile in Taiwanese children and adolescents. Copyright © 2014 Elsevier Ltd. All rights reserved.

Aetiology of paediatric pneumonia after the introduction of pneumococcal conjugate vaccine

PubMed Central

Elemraid, Mohamed A.; Sails, Andrew D.; Eltringham, Gary J.A.; Perry, John D.; Rushton, Stephen P.; Spencer, David A.; Thomas, Matthew F.; Eastham, Katherine M.; Hampton, Fiona; Gennery, Andrew R.; Clark, Julia E.

2013-01-01

We describe the aetiology of community-acquired pneumonia in children before and after the introduction of the pneumococcal conjugate vaccination (PCV) programme in 2006. Prospective studies were conducted in 2001–2002 (pre-vaccine) and 2009–2011 (post-vaccine) of children aged 0–16 years with radiologically confirmed pneumonia seen in hospital. Investigations included culture, serology, immunofluorescence antibody and urine antigen testing, with an increased use of PCR assays and expanded panels of pathogens in the post-vaccine study. 241 and 160 children were enrolled in the pre- and post-vaccine studies, respectively (73% aged <5 years). Identification of a causative pathogen was higher post-vaccination (61%) than pre-vaccination (48.5%) (p=0.019). Rates of bacterial infections were not different between post- and pre-vaccine studies (17.5% versus 24%, p=0.258). Viral (31%) and mixed (12.5%) infections were found more often post-vaccination (19.5%, p=0.021) than pre-vaccination (5%, p=0.015). Rates of identified pneumococcal infections were comparable between pre- and post-vaccine studies (14.7% versus 17.4%, p=0.557). Diagnosis of pneumococcal infection post-vaccination improved when PCR was used compared to culture (21.6% versus 6%, p=0.0004). Serotypes included in PCV13 but not PCV7 were identified in 75% (18 out of 24) post-vaccination. Infection with nonvaccine pneumococcal serotypes continues to be a significant cause of pneumonia in children in the UK. PMID:23598951

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.

Immunization with the 7-valent conjugate pneumococcal vaccine: impact evaluation, continuing surveillance and future perspectives.

PubMed

Bechini, Angela; Boccalini, Sara; Bonanni, Paolo

2009-05-26

The 7-valent Pneumococcal Conjugate Vaccine (PCV) showed high efficacy against invasive pneumococcal diseases caused by vaccine serotypes in children less than 2 years-old. Its effectiveness was confirmed under routine use in the US, Canada and several European countries. Disease surveillance and several studies showed that population indirect protection outweighs direct protection of immunized subjects. A substantial impact was also confirmed on pneumonia and acute otitis media. A limited increase in IPD caused by non-vaccine serotypes was registered to date, but far below the magnitude of the beneficial reduction in IPD due to vaccine serotypes. This fact underpins the need for ongoing improved surveillance. New tests based on PCR for the identification and typing of pneumococci represent a very interesting alternative to traditional cultural tests that should be evaluated in the near future. The World Health Organization has recognized the priority to introduce PCV into the routine infant immunization schedule in all countries, due to the extremely high yearly mortality toll for pneumococcal diseases in the world (1.6 million deaths estimated). Conjugate vaccines with additional serotypes are in advanced stage of development or under evaluation. These new products need to be compared with the existing vaccine, following WHO recommendations regarding correlates of protection, in order to show their possibility to substitute the current vaccine obtaining the same impressive level of efficacy and effectiveness.

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.

Cost-effectiveness analysis of quadrivalent influenza vaccination in at-risk adults and the elderly: an updated analysis in the U.K.

PubMed

Meier, G; Gregg, M; Poulsen Nautrup, B

2015-01-01

To update an earlier evaluation estimating the cost-effectiveness of quadrivalent influenza vaccination (QIV) compared with trivalent influenza vaccination (TIV) in the adult population currently recommended for influenza vaccination in the UK (all people aged ≥65 years and people aged 18-64 years with clinical risk conditions). This analysis takes into account updated vaccine prices, reference costs, influenza strain circulation, and burden of illness data. A lifetime, multi-cohort, static Markov model was constructed with seven age groups. The model was run in 1-year cycles for a lifetime, i.e., until the youngest patients at entry reached the age of 100 years. The base-case analysis was from the perspective of the UK National Health Service, with a secondary analysis from the societal perspective. Costs and benefits were discounted at 3.5%. Herd effects were not included. Inputs were derived from systematic reviews, peer-reviewed articles, and government publications and databases. One-way and probabilistic sensitivity analyses were performed. In the base-case, QIV would be expected to avoid 1,413,392 influenza cases, 41,780 hospitalizations, and 19,906 deaths over the lifetime horizon, compared with TIV. The estimated incremental cost-effectiveness ratio (ICER) was £14,645 per quality-adjusted life-year (QALY) gained. From the societal perspective, the estimated ICER was £13,497/QALY. A strategy of vaccinating only people aged ≥65 years had an estimated ICER of £11,998/QALY. Sensitivity analysis indicated that only two parameters, seasonal variation in influenza B matching and influenza A circulation, had a substantial effect on the ICER. QIV would be likely to be cost-effective compared with TIV in 68% of simulations with a willingness-to-pay threshold of <£20,000/QALY and 87% with a willingness-to-pay threshold of <£30,000/QALY. In this updated analysis, QIV was estimated to be cost-effective compared with TIV in the U.K.

Costs of vaccine delivery in the Gambia before and after, pentavalent and pneumococcal conjugate vaccine introductions.

PubMed

Usuf, E; Mackenzie, G; Lowe-Jallow, Y; Boye, B; Atherly, D; Suraratdecha, C; Griffiths, U K

2014-04-07

The Gambia introduced seven-valent pneumococcal conjugate vaccine (PCV) in August 2009 and switched to 13-valent PCV in April 2011. In April 2009 monovalent hepatitis B and combined Diphtheria-Tetanus-Pertussis and Haemophilus influenzae type b vaccines were transitioned to a combined pentavalent vaccine. The current schedule offers three doses of PCV and pentavalent, and continues to give children monovalent hepatitis B vaccine at birth. We estimated the overall costs of the Gambian immunisation programme and the incremental costs of introducing pentavalent and the seven-valent PCV. Twenty health facilities out of a total of 56 were surveyed. Data collected included number of vaccine doses delivered, staff time spent on vaccine delivery, distance travelled to collect vaccines, and cold chain expansion due to new vaccine introduction. National level data were collected from key informant interviews. Annualised costs were calculated in 2009 US$. With a PCV price of US$7 per dose, the incremental costs of introducing PCV was US$1.6 million, equivalent to US$25 per fully immunised child, with systems costs accounting for US$1.90. The switch to pentavalent vaccine resulted in cost savings of US$0.45 per fully immunised child. Total annual costs increased by 45% after the introduction of the new vaccines, amounting to US$ 3.0 million, or US$45 per fully immunised child. Vaccine prices were the most important determinant of total incremental costs and cold chain expansion the biggest cost component of systems costs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Vaccine recommendations for children and youth for the 2014/2015 influenza season.

PubMed

Moore, Dorothy L

2014-10-01

The Canadian Paediatric Society continues to encourage annual influenza vaccination for ALL children and youth ≥6 months of age. Recommendations from the National Advisory Committee on Immunization for the 2014/2015 influenza season include some important changes: Influenza vaccination is recommended for ALL individuals ≥6 months of age, with particular focus on those at high risk of influenza-related complications and their close contacts. Definitions of high-risk conditions and close contacts have not changed from those of 2013/2014.The preference for intranasal, live attenuated influenza vaccine (LAIV) over trivalent inactivated influenza vaccines for healthy children is restricted to individuals two to six years of age. There is insufficient evidence to recommend LAIV over trivalent inactivated influenza vaccines in older children or in children with chronic health conditions; either vaccine may be used unless there are specific contraindications.Quadrivalent influenza vaccines are expected to be available for the 2014/2015 season and may be used interchangeably with trivalent vaccines. They may offer improved protection.Trivalent or quadrivalent inactivated vaccines may be used in individuals with egg allergy; LAIV has not yet been evaluated in this population and is not recommended at this time.

Potential impact of a nonavalent HPV vaccine on HPV related low-and high-grade cervical intraepithelial lesions: A referral hospital-based study in Sicily

PubMed Central

Capra, Giuseppina; Giovannelli, Lucia; Matranga, Domenica; Bellavia, Carmelina; Guarneri, Maria Francesca; Fasciana, Teresa; Scaduto, Giovanna; Firenze, Alberto; Vassiliadis, Alessandra; Perino, Antonio

2017-01-01

ABSTRACT While bivalent and quadrivalent HPV vaccines have been used for about 10 years, a nonavalent vaccine against HPV types 6/11/16/18/31/33/45/52 and 58 has been recently approved by FDA and EMA and is now commercially available. The objective of our study was to evaluate the potential impact of the nonavalent vaccine on HPV infection and related low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), compared to the impact of the quadrivalent vaccine, in a female population living in Sicily (Italy). Low estimates of HPV vaccine impact were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes, alone or in association, but excluding presence of other HPV types; high estimates were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes alone or in association, in the presence of other HPV types. The nonavalent HPV vaccine showed increased impact, compared to the quadrivalent vaccine. Estimates of potential impact varied from 30.9% (low estimate) to 53.3% (high estimate) for LSIL, and from 56.9% to 81,0% for HSIL. The proportion of additional cases potentially prevented by the nonavalent vaccine was 14.4%–23.8% for LSIL, and 19.0%–32.8% for HSIL. The benefit of the nonavalent vaccine compared to the quadrivalent vaccine was more than 80% for both low and high impact estimates for LSIL and more than 50% for both low and high impact estimates for HSIL. The present study confirms that the switch from a first generation HPV vaccines to a nonavalent vaccine would increase the prevention of cervical HSIL in up to 90% of cases. PMID:28594305

Potential impact of a nonavalent HPV vaccine on HPV related low-and high-grade cervical intraepithelial lesions: A referral hospital-based study in Sicily.

PubMed

Capra, Giuseppina; Giovannelli, Lucia; Matranga, Domenica; Bellavia, Carmelina; Guarneri, Maria Francesca; Fasciana, Teresa; Scaduto, Giovanna; Firenze, Alberto; Vassiliadis, Alessandra; Perino, Antonio

2017-08-03

While bivalent and quadrivalent HPV vaccines have been used for about 10 years, a nonavalent vaccine against HPV types 6/11/16/18/31/33/45/52 and 58 has been recently approved by FDA and EMA and is now commercially available. The objective of our study was to evaluate the potential impact of the nonavalent vaccine on HPV infection and related low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), compared to the impact of the quadrivalent vaccine, in a female population living in Sicily (Italy). Low estimates of HPV vaccine impact were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes, alone or in association, but excluding presence of other HPV types; high estimates were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes alone or in association, in the presence of other HPV types. The nonavalent HPV vaccine showed increased impact, compared to the quadrivalent vaccine. Estimates of potential impact varied from 30.9% (low estimate) to 53.3% (high estimate) for LSIL, and from 56.9% to 81,0% for HSIL. The proportion of additional cases potentially prevented by the nonavalent vaccine was 14.4%-23.8% for LSIL, and 19.0%-32.8% for HSIL. The benefit of the nonavalent vaccine compared to the quadrivalent vaccine was more than 80% for both low and high impact estimates for LSIL and more than 50% for both low and high impact estimates for HSIL. The present study confirms that the switch from a first generation HPV vaccines to a nonavalent vaccine would increase the prevention of cervical HSIL in up to 90% of cases.

Process development of a New Haemophilus influenzae type b conjugate vaccine and the use of mathematical modeling to identify process optimization possibilities.

PubMed

Hamidi, Ahd; Kreeftenberg, Hans; V D Pol, Leo; Ghimire, Saroj; V D Wielen, Luuk A M; Ottens, Marcel

2016-05-01

Vaccination is one of the most successful public health interventions being a cost-effective tool in preventing deaths among young children. The earliest vaccines were developed following empirical methods, creating vaccines by trial and error. New process development tools, for example mathematical modeling, as well as new regulatory initiatives requiring better understanding of both the product and the process are being applied to well-characterized biopharmaceuticals (for example recombinant proteins). The vaccine industry is still running behind in comparison to these industries. A production process for a new Haemophilus influenzae type b (Hib) conjugate vaccine, including related quality control (QC) tests, was developed and transferred to a number of emerging vaccine manufacturers. This contributed to a sustainable global supply of affordable Hib conjugate vaccines, as illustrated by the market launch of the first Hib vaccine based on this technology in 2007 and concomitant price reduction of Hib vaccines. This paper describes the development approach followed for this Hib conjugate vaccine as well as the mathematical modeling tool applied recently in order to indicate options for further improvements of the initial Hib process. The strategy followed during the process development of this Hib conjugate vaccine was a targeted and integrated approach based on prior knowledge and experience with similar products using multi-disciplinary expertise. Mathematical modeling was used to develop a predictive model for the initial Hib process (the 'baseline' model) as well as an 'optimized' model, by proposing a number of process changes which could lead to further reduction in price. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:568-580, 2016. © 2016 American Institute of Chemical Engineers.

Making new vaccines affordable: a comparison of financing processes used to develop and deploy new meningococcal and pneumococcal conjugate vaccines.

PubMed

Hargreaves, James R; Greenwood, Brian; Clift, Charles; Goel, Akshay; Roemer-Mahler, Anne; Smith, Richard; Heymann, David L

2011-11-26

Mechanisms to increase access to health products are varied and controversial. Two innovative mechanisms have been used to accelerate the development of low-price supply lines for conjugate vaccines. The Meningitis Vaccine Project is a so-called push mechanism that facilitated technology transfer to an Indian company to establish capacity to manufacture a vaccine. The Advanced Market Commitment for pneumococcal vaccines is a so-called pull mechanism that guarantees companies a supplement paid in addition to the purchase price for vaccines for a specific period. We compare these approaches, identifying key dimensions of each and considering their potential for replication. We also discuss issues that the Global Alliance for Vaccines and Immunisation (GAVI) face now that these new vaccines are available. Progress towards GAVI's strategic aims is needed and funding is crucial. Approaches that decrease the financial pressure on GAVI and greatly increase political and financial engagement by low-income countries should also be considered. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effectiveness of Haemophilus influenzae type b conjugate vaccine introduction into routine childhood immunization in Kenya

PubMed Central

Cowgill, Karen D.; Ndiritu, Moses; Nyiro, Joyce; Slack, Mary P. E.; Chiphatsi, Salome; Ismail, Amina; Kamau, Tatu; Mwangi, Isaiah; English, Mike; Newton, Charles R. J. C.; Feikin, Daniel R.; Scott, J. Anthony G.

2006-01-01

Context Haemophilus influenzae type b (Hib) conjugate vaccine is not perceived as a public health priority in Africa because data on Hib disease burden and vaccine effectiveness are scarce. Hib immunization was introduced in Kenyan infants in 2001. Objective to define invasive Hib disease incidence and Hib vaccine program effectiveness. Design, Setting, Patients culture-based surveillance for invasive Hib disease at Kilifi District Hospital from 2000 to 2005 was linked to demographic surveillance of 38,000 children aged <5 years in Kilifi District, Kenya. HIV infection and Hib vaccination status were determined for children with Hib disease admitted 2002–2005. Interventions Conjugate Hib vaccine within the routine childhood immunization program at ages 6, 10 and 14 weeks from November 2001 Main outcome measures Incidence of culture-proven Hib invasive disease before and after vaccine introduction and vaccine program effectiveness (1-incidence rate ratio) Results Prior to vaccine introduction the median age of Hib cases was 8 months; case fatality was 23%. Among children aged <5 years the annual incidence of invasive Hib disease 1 year before and 1 and 3 years after vaccine introduction was 66, 47 and 7.6 per 100,000, respectively. For children <2 years, incidence was 119, 82 and 16, respectively. In 2004–2005 vaccine effectiveness was 88% (95% CI 73–96%) among children <5 years and 87% (95% CI 66–96%) among children <2 years. Of 53 Hib cases admitted during 2002–2005, 29 (55%) were age-ineligible to have received vaccine, 12 (23%) had not been vaccinated despite being eligible, and 12 (23%) had received ≥2 doses of vaccine (2 were HIV-positive). Conclusions In Kenya, introduction of Hib vaccine into the routine childhood immunization program reduced Hib disease incidence among children aged <5 years to 12% of its baseline level. This impact was not observed until the third year after vaccine introduction. PMID:16896110

The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review

PubMed Central

2013-01-01

Background Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST). Methods We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST. Results We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects

The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review.

PubMed

Davis, Stephanie; Feikin, Daniel; Johnson, Hope L

2013-01-01

Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST). We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥ 2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST. We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects with meningitis etiology

The Antibody Response Following a Booster With Either a 10- or 13-valent Pneumococcal Conjugate Vaccine in Toddlers Primed With a 13-valent Pneumococcal Conjugate Vaccine in Early Infancy.

PubMed

Trück, Johannes; Jawad, Sena; Goldblatt, David; Roalfe, Lucy; Snape, Matthew D; Voysey, Merryn; Pollard, Andrew J

2016-07-01

Both the 13- and 10-valent pneumococcal conjugate vaccines (PCV-13; PCV-10) are immunogenic and effective against vaccine-type pneumococcal disease when given to young children. However, limited data are available regarding the interchangeability of these 2 vaccines. UK children (n = 178) who had previously been vaccinated with PCV-13 at 2 and 4 months were randomized to receive either a PCV-13 or a PCV-10 booster at 12 months of age. PCV-13 vaccine-type antipolysaccharide serum immunoglobulin G (IgG) concentrations and opsonophagocytic assay titers were measured before and at 1 and 12 months following vaccination. The primary objective was to assess noninferiority of PCV-10 compared with PCV-13. For 8 of the PCV-10 serotypes at least 97% of participants in both groups had IgG concentrations ≥0.35 µg/mL at 1 month after vaccination; inferior responses were seen for serotypes 5 and 9V following the PCV-10 compared with the PCV-13 booster. Post booster geometric mean IgG concentrations and opsonophagocytic assay titers were significantly superior for most serotypes in PCV-13 compared with PCV-10 recipients, whereas similar or inferior responses were seen for serotypes 4, 18C, and 19F. Although some increase in antibody was seen in PCV-10 recipients against the serotypes 6A and 19A (serotypes that cross-react with 6B and 19F in PCV-10, respectively) at 1-month post booster, these responses were significantly lower than in the PCV-13 group. In PCV-13 primed infants, a PCV-10 booster is generally less immunogenic than a PCV-13 booster. For the 3 serotypes in PCV-10 with higher antigen content and/or conjugation to diphtheria or tetanus toxoid carrier proteins, higher or similar booster responses were seen in PCV-10 recipients. Although these findings suggest that responses are generally better with a PCV-13 booster among PCV-13 primed children, the clinical significance of these differences in immunogenicity is unclear.

Treatment with belimumab in systemic lupus erythematosus does not impair antibody response to 13-valent pneumococcal conjugate vaccine.

PubMed

Nagel, J; Saxne, T; Geborek, P; Bengtsson, A A; Jacobsen, S; Svaerke Joergensen, C; Nilsson, J-Å; Skattum, L; Jönsen, A; Kapetanovic, M C

2017-09-01

Background/purpose The objective of this study was to explore the impact of systemic lupus erythematosus and belimumab given in addition to standard of care therapy on 13-valent conjugated pneumococcal vaccine (PCV13) response. Methods Forty-seven systemic lupus erythematosus patients and 21 healthy controls were immunized with a single dose of 13-valent conjugated pneumococcal vaccine. Forty systemic lupus erythematosus patients were treated with traditional disease-modifying anti rheumatic drugs, 11 of those received belimumab in addition, and 32 patients were treated with concomitant prednisolone. Quantification of serotype specific IgG levels to 12 pneumococcal capsular polysaccharides was performed in serum taken before and four to six weeks after vaccination using multiplex fluorescent microsphere immunoassay. IgG levels against serotypes 23F and 6B were also analyzed using standard enzyme-linked immunosorbent assays. Opsonophagocytic assay was performed on serotype 23F to evaluate the functionality of the antibodies. Pre- and post-vaccination log transformed antibody levels were compared to determine the impact of systemic lupus erythematosus diagnosis and different treatments on antibody response. Results Systemic lupus erythematosus patients as a group showed lower post-vaccination antibody levels and lower fold increase of antibody levels after vaccination compared to controls ( p = 0.02 and p = 0.009, respectively). Systemic lupus erythematosus patients treated with belimumab in addition to standard of care therapy or with only hydroxychloroquine did not differ compared to controls, whereas the other treatment groups had significantly lower fold increase of post-vaccination antibody levels. Higher age was associated with lower post-vaccination antibody levels among systemic lupus erythematosus patients. Conclusion Belimumab given in addition to traditional disease-modifying anti rheumatic drugs or prednisolone did not further impair antibody

Impact of quadrivalent human papillomavirus vaccine in women at increased risk of genital warts burden: Population-based cross-sectional survey of Czech women aged 16 to 40 years.

PubMed

Petráš, Marek; Adámková, Věra

2015-11-17

To assess the impact of a quadrivalent human papillomavirus vaccine (4HPV) in women at increased risk of genital warts (GWs) acquisition. The study was conducted using a population-based cross-sectional survey of 19,199 women aged 16 to 40 years randomly chosen from the general population in the Czech Republic between January 2013 and March 2014. A total of 1086 women reported having received the 4HPV vaccine. The vaccine's effectiveness was estimated not only in the general population of women but also in those at increased risk due to having a sexual partner with GWs or prior GWs history. The acquisition of GWs was dramatically reduced by 90.6% (80.1-95.6%) in immunised women at least one year after the completion of the 4HPV vaccination in comparison with unimmunised women. Recurrent GWs prevalences of 1.1% (95% CI, 0.0-5.9) and 10.9% (95% CI, 9.1-12.9) in immunised and unimmunised women with prior GWs history, respectively, resulted in a vaccine effectiveness of 89.0% (38.6-98.0%). The notably strong protective effect of 4HPV immunisation in women who had a sexual partner with GWs was demonstrated by a very low age-adjusted odds ratio of 0.02 (95% CI 0.01-0.10) in contrast to unimmunised women. To lower the chance of genital warts acquisition in the general population and in populations at increased risk, only current 4HPV or incoming 9HPV vaccination should be recommended to provide effective protection. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Putative suppressing effect of IgG Fc-conjugated haemagglutinin (HA) stalk of influenza virus H7N9 on the neutralizing immunogenicity of Fc-conjugated HA head: implication for rational design of HA-based influenza vaccines.

PubMed

He, B; Xia, S; Yu, F; Fu, Y; Li, W; Wang, Q; Lu, L; Jiang, S

2016-02-01

The emergence of influenza A H7N9 in infection has posed a great threat to public health globally. Poor immunogenicity of H7N9 haemagglutinin (HA) is a major obstacle to the development of an effective H7N9 vaccine. Here, we found that the vaccine containing the H7HA head conjugated with IgG Fc (Hd-Fc) induced strong neutralizing antibody responses and protection against H7N9 infection, whilst the Fc-conjugated H7HA stalk (St-Fc)-based vaccine could not induce neutralizing antibodies, although the St-Fc-immunized mice were partially protected. The vaccines containing the full-length extracellular domain of HA conjugated with Fc and the mixture of Hd-Fc plus St-Fc induced significantly lower neutralizing antibody and haemagglutination inhibition titres than the Hd-Fc-based vaccine. These results suggest that the St-Fc may have inhibitory effects on the neutralizing immunogenicity of Hd-Fc. Therefore, the neutralizing domain(s), such as the receptor-binding domain, in the HA head should be kept and the non-neutralizing domain(s) in the HA stalk with the ability to potentially suppress the neutralizing immunogenicity of HA head should be removed from Fc-conjugated HA-based influenza vaccines to increase the neutralizing antibody response.

The effect of a booster dose of quadrivalent or bivalent HPV vaccine when administered to girls previously vaccinated with two doses of quadrivalent HPV vaccine.

PubMed

Gilca, Vladimir; Sauvageau, Chantal; Boulianne, Nicole; De Serres, Gatson; Crajden, Mel; Ouakki, Manale; Trevisan, Andrea; Dionne, Marc

2015-01-01

This randomized, blinded study evaluated the immunogenicity and safety of a booster dose of Gardasil (qHPV) or Cervarix (bHPV) when administered to 12-13 year-old girls who were vaccinated at the age of 9-10 with 2 doses of qHPV (0-6 months). 366 out of 416 eligible girls participated in this follow-up study. Antibody titers were measured just before and one month post-booster. A Luminex Total IgG assay was used for antibody assessment and results are presented in Liminex Units (LU). Three years post-primary vaccination, 99-100% of subjects had detectable antibodies to 4HPV genotypes included in the qHPV with GMTs varying from 50 to 322 LU depending on genotype. After a booster dose of qHPV, a ≥4 fold increase of antibody titers to genotypes included in the vaccine was observed in 88-98% of subjects. Post-booster GMTs varied from 1666 to 4536 LU depending on genotype. These GMTs were 1.1 to 1.8-fold higher when compared to those observed one month post-second dose. After a booster of bHPV, a ≥4 fold increase of antibody titers to HPV16 and HPV18 was observed in 93-99% of subjects. The anti-HPV16 and HPV18 GMTs were 5458 and 2665 LU, respectively. These GMTs were 1.2 and 1.8 higher than those observed in the qHPV group (both P < 0.01). In bHPV group a 1.4-1.6-fold increase of antibody GMTs to HPV6 and HPV11was also observed (P < 0.001). The safety profile was acceptable for both vaccines. Both qHPV and bHPV increase antibody titers when given as a booster to girls previously vaccinated with 2 doses of qHPV. The magnitude of the immune response after booster is vaccine-dependent and has the same pattern as that reported after primary vaccination with qHPV or bHPV. When given as a booster, both vaccines have an acceptable safety profile. Longer follow-up studies are warranted to assess the need of booster doses.

Cost-Effectiveness of Haemophilus inuenzae Type b Conjugate Vaccine in Low- and Middle-Income Countries: Regional Analysis and Assessment of Major Determinants

PubMed Central

Griffiths, Ulla Kou; Clark, Andrew; Hajjeh, Rana

2017-01-01

Objectives To estimate the cost-effectiveness of Haemophilus influenzae type b (Hib) conjugate vaccine in low-and middle-income countries and identify the model variables, which are most important for the result. Study design A static decision tree model was developed to predict incremental costs and health impacts. Estimates were generated for 4 country groups: countries eligible for funding by the GAVI Alliance in Africa and Asia, lower middle-income countries, and upper middle-income countries. Values, including disease incidence, case fatality rates, and treatment costs, were based on international country estimates and the scientific literature. Results From the societal perspective, it is estimated that the probability of Hib conjugate vaccine cost saving is 34%–53% in Global Alliance for Vaccines and Immunization eligible African and Asian countries, respectively. In middle-income countries, costs per discounted disability adjusted life year averted are between US$37 and US$733. Variation in vaccine prices and risks of meningitis sequelae and mortality explain most of the difference in results. For all country groups, disease incidence cause the largest part of the uncertainty in the result. Conclusions Hib conjugate vaccine is cost saving or highly cost-effective in low- and middle-income settings. This conclusion is especially influenced by the recent decline in Hib conjugate vaccine prices and new data revealing the high costs of lost productivity associated with meningitis sequelae. PMID:23773595

Cost-effectiveness of Haemophilus influenzae type b conjugate vaccine in low- and middle-income countries: regional analysis and assessment of major determinants.

PubMed

Griffiths, Ulla Kou; Clark, Andrew; Hajjeh, Rana

2013-07-01

To estimate the cost-effectiveness of Haemophilus influenzae type b (Hib) conjugate vaccine in low- and middle-income countries and identify the model variables, which are most important for the result. A static decision tree model was developed to predict incremental costs and health impacts. Estimates were generated for 4 country groups: countries eligible for funding by the GAVI Alliance in Africa and Asia, lower middle-income countries, and upper middle-income countries. Values, including disease incidence, case fatality rates, and treatment costs, were based on international country estimates and the scientific literature. From the societal perspective, it is estimated that the probability of Hib conjugate vaccine cost saving is 34%-53% in Global Alliance for Vaccines and Immunization eligible African and Asian countries, respectively. In middle-income countries, costs per discounted disability adjusted life year averted are between US$37 and US$733. Variation in vaccine prices and risks of meningitis sequelae and mortality explain most of the difference in results. For all country groups, disease incidence cause the largest part of the uncertainty in the result. Hib conjugate vaccine is cost saving or highly cost-effective in low- and middle-income settings. This conclusion is especially influenced by the recent decline in Hib conjugate vaccine prices and new data revealing the high costs of lost productivity associated with meningitis sequelae. Copyright © 2013. Published by Mosby, Inc.

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.

Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP).

PubMed

Cohn, Amanda C; MacNeil, Jessica R; Clark, Thomas A; Ortega-Sanchez, Ismael R; Briere, Elizabeth Z; Meissner, H Cody; Baker, Carol J; Messonnier, Nancy E

2013-03-22

Meningococcal disease describes the spectrum of infections caused by Neisseria meningiditis, including meningitdis, bacteremia, and bacteremic pneumonia. Two quadrivalent meningococcal polysaccharide-protein conjugate vaccines that provide protection against meningococcal serogroups A, C, W, and Y (MenACWY-D [Menactra, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania] and MenACWY-CRM [Menveo, manufactured by Novartis Vaccines, Cambridge, Massachusetts]) are licensed in the United States for use among persons aged 2 through 55 years. MenACWY-D also is licensed for use among infants and toddlers aged 9 through 23 months. Quadrivalent meningococcal polysaccharide vaccine (MPSV4 [Menommune, manufactured by sanofi pasteur, Inc., Swiftwater, Pennsylvania]) is the only vaccine licensed for use among persons aged ≥56 years. A bivalent meningococcal polysaccharide protein conjugate vaccine that provides protection against meningococcal serogroups C and Y along with Haemophilus influenzae type b (Hib) (Hib-MenCY-TT [MenHibrix, manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium]) is licensed for use in children aged 6 weeks through 18 months. This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of meningococcal disease in the United States, specifically the changes in the recommendations published since 2005 (CDC. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2005;54 [No. RR-7]). As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations; it is intended for use by clinicians as a resource. ACIP recommends routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for adolescents aged 11 or 12 years, with a booster dose at age 16 years. ACIP also recommends routine vaccination for

Haemophilus influenzae type b conjugate vaccine impact against purulent meningitis in Rwanda.

PubMed

Muganga, Narcisse; Uwimana, Jeannine; Fidele, Ngabo; Gahimbare, Laetitia; Gessner, Bradford D; Mueller, Judith E; Mhlanga, Bekithemba R; Katsande, Reggis; Herbinger, Karl-Heinz; Rugambwa, Celse

2007-09-28

Rwanda introduced Haemophilus influenzae type b (Hib) conjugate vaccine in January 2002 and simultaneously implemented pediatric bacterial meningitis surveillance at a major referral hospital in the capital Kigali. We reviewed clinical and laboratory information collected during January 2002 to June 2006. Due to a variety of laboratory limitations, only eight confirmed Hib cases were identified, all before 2004. However, the proportion of cerebrospinal fluid with purulence decreased from 26.0% during 2002, to 15.9% during 2003, 9.7% during 2004 and 8.4% in 2005 (p<0.001). Vaccine effectiveness of two or three doses of Hib vaccine against purulent meningitis was 52% (95% confidence interval, 5-75%). In an African setting with few resources and in which few confirmed Hib meningitis cases were identified, Hib vaccine impact nevertheless could be demonstrated against the outcome of purulent meningitis and was found to be high.

Pneumococcal Conjugate Vaccines and Otitis Media: An Appraisal of the Clinical Trials

PubMed Central

Fletcher, Mark A.; Fritzell, Bernard

2012-01-01

Streptococcus pneumoniae is the predominant otitis media pathogen and its prevention through effective vaccination could diminish childhood illness and antibiotic use. This paper reviews 5 pneumococcal conjugate vaccine (PCV) trials that used otitis media as an endpoint: Northern California Kaiser Permanente (NCKP; vaccine, 7-valent PCV [PCV7]-CRM); Finnish Otitis Media (FinOM; vaccines, PCV7-CRM or PCV7-OMPC); Native American Trial (vaccine, PCV7-CRM); Pneumococcal Otitis Efficacy Trial (POET; vaccine, 11-valent PCV [PCV11]-PD). For the microbiological endpoint, vaccine efficacy against vaccine-serotype pneumococcal otitis media was about 60% across trials. Against the clinical endpoint of all episodes, vaccine efficacy was 7% (PCV7-CRM/NCKP), 6% (PCV7-CRM/FinOM), −1% (PCV7-OMPC/FinOM), and −0.4% (PCV7-CRM/Native American Trial); 34% against first episodes of ear, nose, and throat specialist-referral cases (PCV11-PD/POET). Both follow-up through 2 years of age, for the 5 trials, and long-term follow-up, for PCV7-CRM/NCKP and PCV7-CRM/FinOM, demonstrated greater vaccine efficacy against recurrent AOM and tympanostomy-tube placement, suggesting that vaccination against early episodes of AOM may prevent subsequent episodes of complicated otitis media. Although study designs varied by primary endpoint measured, age at follow-up, source of middle-ear fluid for culture, case ascertainment, and type of randomization, each clinical trial demonstrated vaccine efficacy against microbiological and/or clinical otitis media. PMID:22701486

Safety of the 11-valent pneumococcal vaccine conjugated to non-typeable Haemophilus influenzae-derived protein D in the first 2 years of life and immunogenicity of the co-administered hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio virus, Haemophilus influenzae type b and control hepatitis A vaccines.

PubMed

Prymula, Roman; Chlibek, Roman; Splino, Miroslav; Kaliskova, Eva; Kohl, Igor; Lommel, Patricia; Schuerman, Lode

2008-08-18

This randomized (1:1), double-blind, multicenter study, included 4,968 healthy infants to receive either the 11-valent pneumococcal protein D (PD)-conjugate study vaccine or the hepatitis A vaccine (HAV) (control) at 3, 4, 5, and 12-15 months of age. The three-dose primary course of both vaccines was co-administered with combined hexavalent DTPa-HBV-IPV/Hib vaccine. The pneumococcal PD-conjugate study vaccine did not impact the immune response of co-administered hexavalent vaccine and the control HAV vaccine induced seropositivity (antibodies >or=15 mIU/mL) in all infants. The incidence of solicited symptoms was higher with the 11-valent pneumococcal PD-conjugate study vaccine, yet similar to that induced by concomitant DTPa-HBV-IPV/Hib vaccine. Overall, the reactogenicity and safety profile of the 11-valent pneumococcal PD-conjugate vaccine when co-administered with the hexavalent DTPa-HBV-IPV/Hib vaccine, as well as the immunogenicity of the co-administered hexavalent vaccine, were consistent with previous reports for the licensed DTPa-HBV-IPV/Hib and pneumococcal conjugate vaccines.

Clinical effectiveness and cost-effectiveness of quadrivalent human papillomavirus vaccination in HIV-negative men who have sex with men to prevent recurrent high-grade anal intraepithelial neoplasia.

PubMed

Deshmukh, Ashish A; Chiao, Elizabeth Y; Das, Prajnan; Cantor, Scott B

2014-12-05

We examined the long-term clinical and economic benefits of quadrivalent human papillomavirus (qHPV) vaccine as a secondary/adjunct prevention strategy in the prevention of recurrent high-grade intraepithelial neoplasia (HGAIN) in HIV-negative men who have sex with men (MSM) and are 27 years or older. We constructed a Markov model to evaluate the clinical effectiveness and cost-effectiveness of two strategies: (1) no qHPV vaccine after treatment for HGAIN versus (2) qHPV vaccine after treatment for HGAIN. Model parameters, including natural history of anal cancer, vaccine efficacy measured in terms of hazard ratio (HR) (decrease in the risk of recurrent HGAIN), HGAIN treatment efficacy, utilities, and costs, were obtained from the literature. The outcomes were measured in terms of lifetime risk of anal cancer, lifetime cost, quality-adjusted life years, and incremental cost-effectiveness ratios (ICERs). Sensitivity analysis was conducted on all model parameters. We found that vaccinating HIV-negative MSM reduced the lifetime risk of anal cancer by 60.77% at an ICER of US$87,240 per quality-adjusted life-year. The results were highly sensitive to vaccine efficacy, transition of HGAIN to anal cancer, cost of treatment for HGAIN, vaccine degree of protection over time, and the vaccine duration of protection and less sensitive to HPV clearance, cost of qHPV vaccine, and the transitions from normal to low-grade anal intraepithelial neoplasia (LGAIN) and normal to HGAIN. With an HR of 0.3, the ICER was well below a $50,000 willingness-to-pay threshold; with an HR of 0.5, the ICER was still below a threshold of $100,000. The most critical disease-related factor influencing the cost-effectiveness was the progression of HGAIN to anal cancer. At an annual transition probability below 0.001, the ICER was below $50,000. Vaccinating HIV-negative MSM treated for HGAIN decreases the lifetime risk of anal cancer and is likely to be a cost-effective intervention. Published by

Long-term persistence of immunity and B-cell memory following Haemophilus influenzae type B conjugate vaccination in early childhood and response to booster.

PubMed

Perrett, K P; John, T M; Jin, C; Kibwana, E; Yu, L-M; Curtis, N; Pollard, A J

2014-04-01

Protection against Haemophilus influenzae type b (Hib), a rapidly invading encapsulated bacteria, is dependent on maintenance of an adequate level of serum antibody through early childhood. In many countries, Hib vaccine booster doses have been implemented after infant immunization to sustain immunity. We investigated the long-term persistence of antibody and immunological memory in primary-school children following infant (with or without booster) Hib vaccination. Anti-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) concentration and the frequency of circulating Hib-specific memory B cells were measured before a booster of a Hib-serogroup C meningococcal (MenC) conjugate vaccine and again 1 week, 1 month, and 1 year after the booster in 250 healthy children aged 6-12 years in an open-label phase 4 clinical study. Six to 12 years following infant priming with 3 doses of Hib conjugate vaccine, anti-PRP IgG geometric mean concentrations were 3.11 µg/mL and 0.71 µg/mL and proportions with anti-PRP IgG ≥1.0 µg/mL were 79% and 43% in children who had or had not, respectively, received a fourth Hib conjugate vaccine dose (mean age, 3.9 years). Higher baseline and post-Hib-MenC booster responses (anti-PRP IgG and memory B cells) were found in younger children and in those who had received a fourth Hib dose. Sustained Hib conjugate vaccine-induced immunity in children is dependent on time since infant priming and receipt of a booster. Understanding the relationship between humoral and cellular immunity following immunization with conjugate vaccines may direct vaccine design and boosting strategies to sustain individual and population immunity against encapsulated bacteria in early childhood. Clinical Trials Registration ISRCTN728588998.

The effectiveness of conjugate Haemophilus influenzae type B vaccine in The Gambia 14 years after introduction.

PubMed

Howie, Stephen R C; Oluwalana, Claire; Secka, Ousman; Scott, Susana; Ideh, Readon C; Ebruke, Bernard E; Balloch, Anne; Sambou, Sana; Erskine, James; Lowe, Yamundow; Corrah, Tumani; Adegbola, Richard A

2013-12-01

The Gambia was the first country in Africa to introduce conjugate Haemophilus influenzae type b (Hib) vaccine, which, as in other developing countries but unlike industrialized countries, is delivered as a 3-dose primary series with no booster. This study assessed its effectiveness 14 years after introduction. Using methods standardized during >20 years in the study site, clinical and microbiological surveillance for invasive Hib disease (primarily meningitis) in the Western Region of The Gambia from 2007 to 2010 was complemented with studies of Hib carriage in children aged 1 to <2 years, Hib antibody levels in children aged <5 years, and Hib vaccine coverage and timing in children aged 1 to <2 years. The incidence of Hib meningitis remained low (averaging 1.3 per 100 000 children aged <5 years annually), as did the Hib oropharyngeal carriage rate (0.9%). Hib antibody levels were protective in >99% of those surveyed, albeit with lower titers in older children; and coverage of conjugate Hib vaccination was high (91% having 3 doses at 1-2 years of age) using a schedule that was delivered at median ages of 2.6 months, 4.3 months, and 6 months for the first, second, and third doses, respectively. Conjugate Hib vaccine was delivered on time in a 3-dose primary series without booster to a high proportion of eligible children and this was associated with effective disease control up to 14 years after introduction. It is important that surveillance continues in this first African country to introduce the vaccine to determine if effective control persists or if a booster dose becomes necessary as has been the case in industrialized countries.

Pneumococcal conjugate vaccine provides early protective antibody responses in children after related and unrelated allogeneic hematopoietic stem cell transplantation.

PubMed

Meisel, Roland; Kuypers, Lisa; Dirksen, Uta; Schubert, Ralf; Gruhn, Bernd; Strauss, Gabriele; Beutel, Karin; Groll, Andreas H; Duffner, Ulrich; Blütters-Sawatzki, Renate; Holter, Wolfgang; Feuchtinger, Tobias; Grüttner, Hans-Peter; Schroten, Horst; Zielen, Stefan; Ohmann, Christian; Laws, Hans-Jürgen; Dilloo, Dagmar

2007-03-15

Following allogeneic hematopoietic stem cell transplantation (alloHSCT), children are at risk of life-threatening pneumococcal infections. Whereas vaccination with polysaccharide vaccines fails to elicit protective immunity in most alloHSC transplant recipients, pneumococcal conjugate vaccines may effectively prevent invasive disease by eliciting T-cell-dependent antibody responses. Here, we report safety and immunogenicity in 53 children immunized with a regimen of 3 consecutive doses of a heptavalent pneumococcal conjugate vaccine (7vPCV) in monthly intervals starting 6 to 9 months after alloHSCT. Immunization was well tolerated with no vaccine-related serious adverse events. Serologic response rates evaluable in 43 patients ranged from 41.9% to 86.0% and 58.1% to 93.0% after 2 and 3 vaccinations, respectively, with 55.8% and 74.4% of patients achieving protective antibody levels to all 7 vaccine serotypes. Our study provides the first evidence that vaccination with 7vPCV is safe and elicits protective antipneumococcal antibody responses in pediatric recipients of related or unrelated donor alloHSC transplants within the first year following transplantation. This trial was registered at www.clinicaltrials.gov as NCT00169728.

Synthesis and Evaluation of GM2-Monophosphoryl Lipid A Conjugate as a Fully Synthetic Self-Adjuvant Cancer Vaccine.

PubMed

Zhou, Zhifang; Mandal, Satadru S; Liao, Guochao; Guo, Jiatong; Guo, Zhongwu

2017-09-12

An efficient method was developed for the synthesis of a GM2 derivative suitable for the conjugation with various biomolecules. This GM2 derivative was covalently linked to keyhole limpet hemocyanin (KLH) and monophosphoryl lipid A (MPLA) to form novel therapeutic cancer vaccines. Immunological evaluations of the resultant conjugates in mice revealed that they elicited robust GM2-specific overall and IgG antibody responses. Moreover, the GM2-MPLA conjugate was disclosed to elicit strong immune responses without the use of an adjuvant, proving its self-adjuvant property. The antisera of both conjugates showed strong binding and mediated similarly effective complement-dependent cytotoxicity to GM2-expressing cancer cell line MCF-7. Based on these results, it was concluded that both GM2-MPLA and GM2-KLH are promising candidates as therapeutic cancer vaccines, whereas fully synthetic GM2-MPLA, which has homogeneous and well-defined structure and self-adjuvant property, deserves more attention and studies.

The Effect of History of Abnormal Pap Smear or Preceding HPV infection on the Humoral Immune Response to Quadrivalent Human Papilloma virus (qHPV) Vaccine in Women with Systemic Lupus Erythematosus.

PubMed

Dhar, J Patricia; Essenmacher, Lynnette; Dhar, Renee; Magee, Ardella; Ager, Joel; Sokol, Robert J

2018-04-30

To determine if natural human papillomavirus (HPV) infection would induce an anamnestic response to quadrivalent (qHPV) vaccine in women with Systemic Lupus Erythematosus (SLE). Thirty four women (19-50 years) with mild to moderate and minimally active or inactive SLE received standard qHPV vaccine. Neutralizing antibody titers to HPV 6, 11, 16 and18 were evaluated pre- and post- vaccine using HPV competitive Luminex Immunoassay. For each HPV type, logistic regressions were performed to explore the relationship between a positive titer at baseline with their final geometric mean titer and with the rise in titer. Fisher's Exact Test was used to assess the association of at least one positive HPV antibody test at baseline and history of abnormal pap. History of abnormal pap smear/cervical neoplasia occurred in 52.9%. Baseline anti HPV antibody titers: 21% = negative for all 4 HPV types, 79% = positive for ≥1 of the HPV types. Statistical analysis showed: those with a history of abnormal pap smear/cervical neoplasia were likely to have a positive anti-HPV antibody result pre-vaccine to ≥ 1 of the 4 types, p = 0.035 Fisher's Exact Test. In general, HPV exposed women showed higher post vaccine GMTs than HPV unexposed women with higher point estimates. However, when examining the rise in titers using logistic regression, there was no evidence of an anamnestic response. Prior HPV infection and cervical neoplasia in SLE are linked with no anamnestic response to HPV vaccine. This supports not checking HPV-antibodies pre-vaccine. Women with SLE should be vaccinated for HPV.

Risk of Guillain-Barré syndrome after meningococcal conjugate vaccination.

PubMed

Velentgas, Priscilla; Amato, Anthony A; Bohn, Rhonda L; Chan, K Arnold; Cochrane, Thomas; Funch, Donnie P; Dashevsky, Inna; Duddy, April L; Gladowski, Patricia; Greenberg, Steven A; Kramer, Judith M; McMahill-Walraven, Cheryl; Nakasato, Cynthia; Spettell, Claire M; Syat, Beth L; Wahl, Peter M; Walker, Alexander M; Zhang, Fang; Brown, Jeffrey S; Platt, Richard

2012-12-01

A new meningococcal conjugate vaccine (MCV4) was introduced in 2005. Shortly after, case reports of Guillain-Barré syndrome (GBS), a serious demyelinating disease, began to be reported to the Vaccine Adverse Event Reporting System. In 2006, the Centers for Disease Control and Prevention and the Food and Drug Administration requested the evaluation of GBS risk after MCV4 vaccination. We conducted a study to assess the risk of GBS after MCV4 vaccination using health plan administrative and claims data together with the review of primary medical records of potential cases. Retrospective cohort study among 12.6 million 11- to 21-year-old members of five US health plans with a total membership of 50 million. Automated enrollment and medical claims data from March 2005 through August 2008 were used to identify the population, the vaccinations administered, and the medical services associated with possible GBS. Medical records were reviewed and adjudicated by a neurologist panel to confirm cases of GBS. The study used distributed data analysis methods that minimized sharing of protected health information. We confirmed 99 GBS cases during 18,322,800 person-years (5.4/1,000,000 person-years). More than 1.4 million MCV4 vaccinations were observed. No confirmed cases of GBS occurred within 6 weeks after vaccination. The upper 95% CI for the attributable risk of GBS associated with MCV4 is estimated as 1.5 cases per 1,000,000 doses. Among members of five US health plans, MCV4 vaccination was not associated with increased GBS risk. Copyright © 2012 John Wiley & Sons, Ltd.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine compared with two trivalent inactivated influenza vaccines containing alternate B strains in adults: A phase 3, randomized noninferiority study.

PubMed

Treanor, John T; Albano, Frank R; Sawlwin, Daphne C; Graves Jones, Alison; Airey, Jolanta; Formica, Neil; Matassa, Vince; Leong, Jane

2017-04-04

Vaccination is the most effective means of influenza prevention. Efficacy of trivalent vaccines may be enhanced by including both B strain lineages. This phase 3, double-blind study assessed the immunogenicity and safety/tolerability of a quadrivalent inactivated influenza vaccine (IIV4) versus the United States (US)-licensed 2014-2015 trivalent inactivated influenza vaccine (IIV3-Yamagata [IIV3-YAM]; Afluria) and IIV3 containing the alternate Victoria B strain (IIV3-VIC) in adults ≥18years. Participants (n=3484) were randomized 2:1:1 and stratified by age to receive IIV4 (n=1741), IIV3-YAM (n=871), or IIV3-VIC (n=872). The primary objective was to demonstrate noninferiority of the immunological response to IIV4 versus IIV3-YAM and IIV3-VIC. Noninferiority was assessed by hemagglutination inhibition geometric mean titer (GMT) ratio (IIV3/IIV4; upper bound of two-sided 95% confidence interval [CI]≤1.5) and seroconversion rate (SCR) difference (IIV3 - IIV4; upper bound of two-sided 95% CI≤10%) for vaccine strains. Solicited local and systemic adverse events (AEs) were assessed for 7days postvaccination, AEs recorded for 28days postvaccination, and serious AEs for 6months postvaccination. IIV4 elicited a noninferior immune response for matched strains, and superior response for unmatched B strains not contained in IIV3 comparators. Adjusted GMT ratios (95% CI) for A/H1N1, A/H3N2, B/YAM, and B/VIC strains were 0.93 (0.88, 0.99), 0.93 (0.88, 0.98), 0.87 (IIV3-YAM; 0.82, 0.93), and 0.95 (IIV3-VIC; 0.88, 1.03), respectively. Corresponding values for SCR differences (95% CI) were -1.1 (-4.5, 2.3), -1.7 (-5.0, 1.7), -3.2 (IIV3-YAM; -7.4, 0.9), and -1.6 (IIV3-VIC; -5.8, 2.5). AEs were generally mild and experienced by 52.9% of participants. Serious AEs were reported with a slightly higher frequency with IIV4 (2.3%) versus IIV3-YAM (1.6%) and IIV3-VIC (1.5%). IIV4 demonstrated immunological noninferiority to the US-licensed IIV3, and superiority for unmatched B strains

Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial.

PubMed

Tapia, Milagritos D; Sow, Samba O; Tamboura, Boubou; Tégueté, Ibrahima; Pasetti, Marcela F; Kodio, Mamoudou; Onwuchekwa, Uma; Tennant, Sharon M; Blackwelder, William C; Coulibaly, Flanon; Traoré, Awa; Keita, Adama Mamby; Haidara, Fadima Cheick; Diallo, Fatoumata; Doumbia, Moussa; Sanogo, Doh; DeMatt, Ellen; Schluterman, Nicholas H; Buchwald, Andrea; Kotloff, Karen L; Chen, Wilbur H; Orenstein, Evan W; Orenstein, Lauren A V; Villanueva, Julie; Bresee, Joseph; Treanor, John; Levine, Myron M

2016-09-01

Despite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza. We did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689. We did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months

Cost-effectiveness analysis of the 10- and 13-valent pneumococcal conjugate vaccines in Argentina.

PubMed

Urueña, Analía; Pippo, Tomás; Betelu, María Sol; Virgilio, Federico; Giglio, Norberto; Gentile, Angela; Jimenez, Salvador García; Jáuregui, Bárbara; Clark, Andrew D; Diosque, Máximo; Vizzotti, Carla

2011-07-12

Since the 10-valent pneumococcal conjugate vaccine (PCV-10) and 13-valent pneumococcal conjugate vaccine (PCV-13) were recently licensed for use in Argentina, both vaccines were evaluated to estimate the costs, health benefits and cost-effectiveness of adding a PCV to the routine child immunization schedule. The integrated TRIVAC vaccine cost-effectiveness model from Pan American Health Organization's ProVac Initiative (Version 1.0.65) was used to assess the health outcomes of 20 successive cohorts from birth to 5 years of age. PCV-10 and PCV-13 were each compared to a scenario assuming no PCV vaccination. A 3+1 (three doses+booster) schedule and a vaccination price of US$ 20.75 per dose was assumed in the base case for both vaccines. Introduction of PCV-13 rather than PCV-10 would increase the number of life years gained (LYG) by at least 10%. The number of LYG (and LYG after adjustment for DALY morbidity weights) was 56,882 (64,252) for PCV-10 compared to 65,038 (71,628) for PCV-13. From the health system perspective, the cost per DALY averted was US$ 8973 and US$ 10,948 for PCV-10 and PCV-13 respectively, and US$ 8546 and US$ 10,510 respectively, after incorporating costs saved by households. When PCV13 was compared to PCV10 directly, the additional benefits of PCV-13 was conferred at a cost of US$ 28,147 per DALY averted. Cost-effectiveness was influenced mainly by vaccine price, serotype replacement, pneumonia mortality and discount rate. Routine vaccination against S. pneumoniae in Argentina would be cost-effective with either PCV-10 or PCV-13. PCV-13, with higher coverage of local serotypes, would prevent more cases of pneumonia, invasive pneumococcal disease, sequelae and deaths with a higher number of LYG and DALYs averted, but PCV-10, due its higher impact in the prevention of AOM, would save more costs to the healthcare system. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cost-effectiveness of pneumococcal conjugate vaccination in Croatia.

PubMed

Vučina, V Višekruna; Filipović, S Kurečić; Kožnjak, N; Stamenić, V; Clark, A D; Mounaud, B; Blau, J; Hoestlandt, C; Kaić, B

2015-05-07

Pneumococcus is a known cause of meningitis, pneumonia, sepsis, and acute otitis media in children and adults globally. Two new vaccines for children have the potential to prevent illness, disability, and death, but these vaccines are expensive. The Croatian Ministry of Health has considered introducing the vaccine in the past, but requires economic evidence to ensure that the limited funds available for health care will be used in the most effective way. Croatia appointed a multidisciplinary team of experts to evaluate the cost-effectiveness of introducing pneumococcal conjugate vaccination (PCV) into the national routine child immunization program. Both 10-valent and 13-valent PCV (PCV10 and PCV13) were compared to a scenario assuming no vaccination. The TRIVAC decision-support model was used to estimate cost-effectiveness over the period 2014-2033. We used national evidence on demographics, pneumococcal disease incidence and mortality, the age distribution of disease in children, health service utilization, vaccine coverage, vaccine timeliness, and serotype coverage. Vaccine effectiveness was based on evidence from the scientific literature. Detailed health care costs were not available from the Croatian Institute for Health Insurance at the time of the analysis so assumptions and World Health Organization (WHO) estimates for Croatia were used. We assumed a three-dose primary vaccination schedule, and an initial price of US$ 30 per dose for PCV10 and US$ 35 per dose for PCV13. We ran univariate sensitivity analyses and multivariate scenario analyses. Either vaccine is estimated to prevent approximately 100 hospital admissions and one death each year in children younger than five in Croatia. Compared to no vaccine, the discounted cost-effectiveness of either vaccine is estimated to be around US$ 69,000-77,000 per disability-adjusted life-years (DALYs) averted over the period 2014-2033 (from the government or societal perspective). Only two alternative scenarios

The Effectiveness of Conjugate Haemophilus influenzae Type B Vaccine in The Gambia 14 Years After Introduction

PubMed Central

Howie, Stephen R. C.; Oluwalana, Claire; Secka, Ousman; Scott, Susana; Ideh, Readon C.; Ebruke, Bernard E.; Balloch, Anne; Sambou, Sana; Erskine, James; Lowe, Yamundow; Corrah, Tumani; Adegbola, Richard A.

2013-01-01

Background. The Gambia was the first country in Africa to introduce conjugate Haemophilus influenzae type b (Hib) vaccine, which, as in other developing countries but unlike industrialized countries, is delivered as a 3-dose primary series with no booster. This study assessed its effectiveness 14 years after introduction. Methods. Using methods standardized during >20 years in the study site, clinical and microbiological surveillance for invasive Hib disease (primarily meningitis) in the Western Region of The Gambia from 2007 to 2010 was complemented with studies of Hib carriage in children aged 1 to <2 years, Hib antibody levels in children aged <5 years, and Hib vaccine coverage and timing in children aged 1 to <2 years. Results. The incidence of Hib meningitis remained low (averaging 1.3 per 100 000 children aged <5 years annually), as did the Hib oropharyngeal carriage rate (0.9%). Hib antibody levels were protective in >99% of those surveyed, albeit with lower titers in older children; and coverage of conjugate Hib vaccination was high (91% having 3 doses at 1–2 years of age) using a schedule that was delivered at median ages of 2.6 months, 4.3 months, and 6 months for the first, second, and third doses, respectively. Conclusions. Conjugate Hib vaccine was delivered on time in a 3-dose primary series without booster to a high proportion of eligible children and this was associated with effective disease control up to 14 years after introduction. It is important that surveillance continues in this first African country to introduce the vaccine to determine if effective control persists or if a booster dose becomes necessary as has been the case in industrialized countries. PMID:24046305

Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats

PubMed Central

Pravetoni, Marco; Vervacke, Jeffrey S.; Distefano, Mark D.; Tucker, Ashli M.; Laudenbach, Megan; Pentel, Paul R.

2014-01-01

Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund’s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID:24797666

Safety, immunogenicity, and lot-to-lot consistency of a split-virion quadrivalent influenza vaccine in younger and older adults: A phase III randomized, double-blind clinical trial

PubMed Central

Sesay, Sanie; Brzostek, Jerzy; Meyer, Ingo; Donazzolo, Yves; Leroux-Roels, Geert; Rouzier, Régine; Astruc, Béatrice; Szymanski, Henryk; Toursarkissian, Nicole; Vandermeulen, Corinne; Kowalska, Edyta; Van Damme, Pierre; Salamand, Camille; Pepin, Stephanie

2018-01-01

ABSTRACT Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014–2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18–60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains. PMID:28968138

Patterns of binding of aluminum-containing adjuvants to Haemophilus influenzae type b and meningococcal group C conjugate vaccines and components

PubMed Central

Otto, Robert B.D.; Burkin, Karena; Amir, Saba Erum; Crane, Dennis T.; Bolgiano, Barbara

2015-01-01

The basis of Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroup C (MenC) glycoconjugates binding to aluminum-containing adjuvants was studied. By measuring the amount of polysaccharide and protein in the non-adsorbed supernatant, the adjuvant, aluminum phosphate, AlPO4, was found to be less efficient than aluminum hydroxide, Al(OH)3 at binding to the conjugates, at concentrations relevant to licensed vaccine formulations and when equimolar. At neutral pH, binding of TT conjugates to AlPO4 was facilitated through the carrier protein, with only weak binding of AlPO4 to CRM197 being observed. There was slightly higher binding of either adjuvant to tetanus toxoid conjugates, than to CRM197 conjugates. This was verified in AlPO4 formulations containing DTwP–Hib, where the adsorption of TT-conjugated Hib was higher than CRM197-conjugated Hib. At neutral pH, the anionic Hib and MenC polysaccharides did not appreciably bind to AlPO4, but did bind to Al(OH)3, due to electrostatic interactions. Phosphate ions reduced the binding of the conjugates to the adjuvants. These patterns of adjuvant adsorption can form the basis for future formulation studies with individual and combination vaccines containing saccharide-protein conjugates. PMID:26194164

Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices--United States, 2013-2014.

PubMed

2013-09-20

This report updates the 2012 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccines for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2012;61:613-8). Routine annual influenza vaccination is recommended for all persons aged ≥ 6 months. For the 2013-14 influenza season, it is expected that trivalent live attenuated influenza vaccine (LAIV3) will be replaced by a quadrivalent LAIV formulation (LAIV4). Inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Vaccine virus strains included in the 2013-14 U.S. trivalent influenza vaccines will be an A/California/7/2009 (H1N1)-like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012-like virus. Quadrivalent vaccines will include an additional influenza B virus strain, a B/Brisbane/60/2008-like virus, intended to ensure that both influenza B virus antigenic lineages (Victoria and Yamagata) are included in the vaccine. This report describes recently approved vaccines, including LAIV4, IIV4, trivalent cell culture-based inactivated influenza vaccine (ccIIV3), and trivalent recombinant influenza vaccine (RIV3). No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one product is otherwise appropriate. This information is intended for vaccination providers, immunization program personnel, and public health personnel. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates also will be found at this website. Vaccination and health-care providers should check the CDC influenza website periodically for additional information.

Herd effects of child vaccination with pneumococcal conjugate vaccine against pneumococcal non-invasive community-acquired pneumonia: What is the evidence?

PubMed

van Werkhoven, Cornelis H

2017-05-04

Quantification of pneumococcal conjugate vaccines (PCVs) herd effects are mainly performed on invasive pneumococcal disease (IPD) but there is conflicting evidence regarding herd effects of PCVs on non-IPD pneumococcal community-acquired pneumonia. This review summarizes the available literature on herd effects of PCVs on non-IPD pneumococcal community-acquired pneumonia.

A novel enzyme-linked immuno-sorbent assay (ELISA) for the quantification of total and free polysaccharide in Haemophilus influenzae b-Tetanus toxoid conjugate vaccines in monovalent and combined vaccine formulations.

PubMed

Saydam, Manolya; Rigsby, Peter; Mawas, Fatme

2014-01-01

Current Haemophilus influenzae b conjugate vaccines (Hib), which are made of purified capsular polysaccharide (poly-ribosyl-ribitol-phosphate; PRP) conjugated to a carrier protein, are almost completely evaluated by physico-chemical methods to ensure the integrity and stability of the vaccine and consistency of manufacture of batches. The absence of a potency assay makes the quantification of total PRP content (in SI units) and of % free polysaccharide in final fills or bulk components of Hib vaccines critical release tests for both manufacturers and national control authorities. Here we describe a simple and sensitive Enzyme-Linked Immuno-sorbent Assay (ELISA) which has been developed to quantify total and free PRP content in Hib-TT vaccine alone or when in combination with other vaccines. The assay is robust, specific and highly sensitive. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Influence of Pneumococcal Conjugate Vaccine on Acute Otitis Media with Severe Middle Ear Inflammation: A Retrospective Multicenter Study.

PubMed

Sugino, Hirotoshi; Tsumura, Shigeru; Kunimoto, Masaru; Noda, Masuhiro; Chikuie, Daisuke; Noda, Chieko; Yamashita, Mariko; Watanabe, Hiroshi; Ishii, Hidemasa; Tashiro, Toru; Iwata, Kazuhiro; Kono, Takashi; Tsumura, Kaoru; Sumiya, Takahiro; Takeno, Sachio; Hirakawa, Katsuhiro

2015-01-01

The Japanese guidelines for acute otitis media in children recommend classifying acute otitis media by age, manifestations and local findings, and also recommend myringotomy for moderate-grade cases with severe local findings, severe-grade cases, and treatment-resistant cases. The heptavalent pneumococcal conjugate vaccine was released in Japan in February 2010. In Hiroshima City, public funding allowing free inoculation with this vaccine was initiated from January 2011, and the number of vaccinated individuals has since increased dramatically. This study investigated changes in the number of myringotomies performed to treat acute otitis media during the 5-year period from January 2008 to December 2012 at two hospitals and five clinics in the Asa Area of Hiroshima City, Japan. A total of 3,165 myringotomies for acute otitis media were performed. The rate of procedures per child-year performed in <5-year-old children decreased by 29.1% in 2011 and by 25.2% in 2012 compared to the mean rate performed in the 3 years prior to the introduction of public funding. A total of 895 myringotomies were performed for 1-year-old infants. The rate of myringotomies per child-year performed for acute otitis media in 1-year-old infants decreased significantly in the 2 years after the introduction of public funding for heptavalent pneumococcal conjugate vaccine compared to all years before introduction (p<0.000001). Our results suggest a benefit of heptavalent pneumococcal conjugate vaccine for acute otitis media in reducing the financial burden of myringotomy. In addition, this vaccine may help prevent acute otitis media with severe middle ear inflammation in 1-year-old infants.

Impact of quadrivalent human papillomavirus vaccine on genital warts in an opportunistic vaccination structure.

PubMed

Lurie, Samuel; Mizrachi, Yossi; Chodick, Gabi; Katz, Rachel; Schejter, Eduardo

2017-08-01

Genital warts are the most common sexually transmitted disease and have a detrimental impact on quality of life. Genital warts could be prevented by prophylactic HPV vaccination. The objective was to study real-life benefit of opportunistic HPV vaccination on age and gender specific incidence of genital warts. We performed a register-based population cohort study from publicly funded health-care provider in Israel. The incidence of genital warts was assessed during three time frame intervals: 2006-2008 (pre-vaccination effect period) 2009-2012 (early post-vaccination effect period) and 2013-2015 (late post-vaccination effect period), with an average annual number of members of 1,765,481, 1,906,774 and 2,042,678 in the years 2006-2008, 2009-2012 and 2013-2015, respectively. Among females, annual incidence of genital warts per 100,000 women decreased from 210.43 to 161.71 (OR 0.76, 95%CI 0.71-0.82, p<0.001) and to 146.8 (OR 0.69, 95%CI 0.66-0.72, p<0.001) between pre-vaccination period and early and late post-vaccination periods, respectively. Among males, annual incidence of genital warts per 100,000 men decreased from 262.85 to 232.40 (OR 0.88, 95%CI 0.83-0.93, p<0.001) and to 234.01 (OR 0.88, 95%CI 0.86-0.91, p<0.001) between pre-vaccination period and early and late post-vaccination periods, respectively. There is a potential benefit in reducing incidence of genital warts even in opportunistic HPV vaccination structure. This information may be relevant for health-care providers in countries where national immunization programs do not include HPV vaccines. Copyright © 2017 Elsevier Inc. All rights reserved.

Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States.

PubMed

Shepard, Colin W; Ortega-Sanchez, Ismael R; Scott, R Douglas; Rosenstein, Nancy E

2005-05-01

The US Food and Drug Administration approved a meningococcal conjugate A/C/Y/W-135 vaccine (MCV-4) for use in persons aged 11 to 55 years in January, 2005; licensure for use in younger age groups is expected in 2 to 4 years. To evaluate and compare the projected health and economic impact of MCV-4 vaccination of US adolescents, toddlers, and infants. Cost-effectiveness analysis from a societal perspective based on data from Active Bacterial Core Surveillance (ABCs) and other published and unpublished sources. Sensitivity analyses in which key input measures were varied over plausible ranges were performed. A hypothetical 2003 US population cohort of children 11 years of age and a 2003 US birth cohort. Hypothetical routine vaccination of adolescents (1 dose at 11 years of age), toddlers (1 dose at 1 year of age), and infants (3 doses at 2, 4, and 6 months of age). Each vaccination scenario was compared with a "no-vaccination" scenario. Meningococcal cases and deaths prevented, cost per case prevented, cost per life-year saved, and cost per quality-adjusted life-year saved. Routine MCV-4 vaccination of US adolescents (11 years of age) would prevent 270 meningococcal cases and 36 deaths in the vaccinated cohort over 22 years, a decrease of 46% in the expected burden of disease. Before program costs are counted, adolescent vaccination would reduce direct disease costs by $18 million and decrease productivity losses by $50 million. At a cost per vaccination (average public-private price per dose plus administration fees) of $82.50, adolescent vaccination would cost society $633000 per meningococcal case prevented and $121000 per life-year saved. Key variables influencing results were disease incidence, case-fatality ratio, and cost per vaccination. The cost-effectiveness of toddler vaccination is essentially equivalent to adolescent vaccination, whereas infant vaccination would be much less cost-effective. Routine MCV-4 vaccination of US children would reduce the burden

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.

Distance to health services affects local-level vaccine efficacy for pneumococcal conjugate vaccine (PCV) among rural Filipino children.

PubMed

Root, Elisabeth Dowling; Lucero, Marilla; Nohynek, Hanna; Anthamatten, Peter; Thomas, Deborah S K; Tallo, Veronica; Tanskanen, Antti; Quiambao, Beatriz P; Puumalainen, Taneli; Lupisan, Socorro P; Ruutu, Petri; Ladesma, Erma; Williams, Gail M; Riley, Ian; Simões, Eric A F

2014-03-04

Pneumococcal conjugate vaccines (PCVs) have demonstrated efficacy against childhood pneumococcal disease in several regions globally. We demonstrate how spatial epidemiological analysis of a PCV trial can assist in developing vaccination strategies that target specific geographic subpopulations at greater risk for pneumococcal pneumonia. We conducted a secondary analysis of a randomized, placebo-controlled, double-blind vaccine trial that examined the efficacy of an 11-valent PCV among children less than 2 y of age in Bohol, Philippines. Trial data were linked to the residential location of each participant using a geographic information system. We use spatial interpolation methods to create smoothed surface maps of vaccination rates and local-level vaccine efficacy across the study area. We then measure the relationship between distance to the main study hospital and local-level vaccine efficacy, controlling for ecological factors, using spatial autoregressive models with spatial autoregressive disturbances. We find a significant amount of spatial variation in vaccination rates across the study area. For the primary study endpoint vaccine efficacy increased with distance from the main study hospital from -14% for children living less than 1.5 km from Bohol Regional Hospital (BRH) to 55% for children living greater than 8.5 km from BRH. Spatial regression models indicated that after adjustment for ecological factors, distance to the main study hospital was positively related to vaccine efficacy, increasing at a rate of 4.5% per kilometer distance. Because areas with poor access to care have significantly higher VE, targeted vaccination of children in these areas might allow for a more effective implementation of global programs.

Distance to health services affects local-level vaccine efficacy for pneumococcal conjugate vaccine (PCV) among rural Filipino children

PubMed Central

Root, Elisabeth Dowling; Lucero, Marilla; Nohynek, Hanna; Anthamatten, Peter; Thomas, Deborah S. K.; Tallo, Veronica; Tanskanen, Antti; Quiambao, Beatriz P.; Puumalainen, Taneli; Lupisan, Socorro P.; Ruutu, Petri; Ladesma, Erma; Williams, Gail M.; Riley, Ian; Simões, Eric A. F.

2014-01-01

Pneumococcal conjugate vaccines (PCVs) have demonstrated efficacy against childhood pneumococcal disease in several regions globally. We demonstrate how spatial epidemiological analysis of a PCV trial can assist in developing vaccination strategies that target specific geographic subpopulations at greater risk for pneumococcal pneumonia. We conducted a secondary analysis of a randomized, placebo-controlled, double-blind vaccine trial that examined the efficacy of an 11-valent PCV among children less than 2 y of age in Bohol, Philippines. Trial data were linked to the residential location of each participant using a geographic information system. We use spatial interpolation methods to create smoothed surface maps of vaccination rates and local-level vaccine efficacy across the study area. We then measure the relationship between distance to the main study hospital and local-level vaccine efficacy, controlling for ecological factors, using spatial autoregressive models with spatial autoregressive disturbances. We find a significant amount of spatial variation in vaccination rates across the study area. For the primary study endpoint vaccine efficacy increased with distance from the main study hospital from −14% for children living less than 1.5 km from Bohol Regional Hospital (BRH) to 55% for children living greater than 8.5 km from BRH. Spatial regression models indicated that after adjustment for ecological factors, distance to the main study hospital was positively related to vaccine efficacy, increasing at a rate of 4.5% per kilometer distance. Because areas with poor access to care have significantly higher VE, targeted vaccination of children in these areas might allow for a more effective implementation of global programs. PMID:24550454

Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage.

PubMed

Võrno, Triin; Lutsar, Katrin; Uusküla, Anneli; Padrik, Lee; Raud, Terje; Reile, Rainer; Nahkur, Oliver; Kiivet, Raul-Allan

2017-11-01

Estonia has high cervical cancer incidence and low screening coverage. We modelled the impact of population-based bivalent, quadrivalent or nonavalent HPV vaccination alongside cervical cancer screening. A Markov cohort model of the natural history of HPV infection was used to assess the cost-effectiveness of vaccinating a cohort of 12-year-old girls with bivalent, quadrivalent or nonavalent vaccine in two doses in a national, school-based vaccination programme. The model followed the natural progression of HPV infection into subsequent genital warts (GW); premalignant lesions (CIN1-3); cervical, oropharyngeal, vulvar, vaginal and anal cancer. Vaccine coverage was assumed to be 70%. A time horizon of 88years (up to 100years of age) was used to capture all lifetime vaccination costs and benefits. Costs and utilities were discounted using an annual discount rate of 5%. Vaccination of 12-year-old girls alongside screening compared to screening alone had an incremental cost-effectiveness ratio (ICER) of €14,007 (bivalent), €14,067 (quadrivalent) and €11,633 (nonavalent) per quality-adjusted life-year (QALY) in the base-case scenario and ranged between €5367-21,711, €5142-21,800 and €4563-18,142, respectively, in sensitivity analysis. The results were most sensitive to changes in discount rate, vaccination regimen, vaccine prices and cervical cancer screening coverage. Vaccination of 12-year-old girls alongside current cervical cancer screening can be considered a cost-effective intervention in Estonia. Adding HPV vaccination to the national immunisation schedule is expected to prevent a considerable number of HPV infections, genital warts, premalignant lesions, HPV related cancers and deaths. Although in our model ICERs varied slightly depending on the vaccine used, they generally fell within the same range. Cost-effectiveness of HPV vaccination was found to be most dependent on vaccine cost and duration of vaccine immunity, but not on the type of vaccine

Economic evaluation of pneumococcal conjugate vaccination in The Gambia.

PubMed

Kim, Sun-Young; Lee, Gene; Goldie, Sue J

2010-09-03

Gambia is the second GAVI support-eligible country to introduce the 7-valent pneumococcal conjugate vaccine (PCV7), but a country-specific cost-effectiveness analysis of the vaccine is not available. Our objective was to assess the potential impact of PCVs of different valences in The Gambia. We synthesized the best available epidemiological and cost data using a state-transition model to simulate the natural histories of various pneumococcal diseases. For the base-case, we estimated incremental cost (in 2005 US dollars) per disability-adjusted life year (DALY) averted under routine vaccination using PCV9 compared to no vaccination. We extended the base-case results for PCV9 to estimate the cost-effectiveness of PCV7, PCV10, and PCV13, each compared to no vaccination. To explore parameter uncertainty, we performed both deterministic and probabilistic sensitivity analyses. We also explored the impact of vaccine efficacy waning, herd immunity, and serotype replacement, as a part of the uncertainty analyses, by assuming alternative scenarios and extrapolating empirical results from different settings. Assuming 90% coverage, a program using a 9-valent PCV (PCV9) would prevent approximately 630 hospitalizations, 40 deaths, and 1000 DALYs, over the first 5 years of life of a birth cohort. Under base-case assumptions ($3.5 per vaccine), compared to no intervention, a PCV9 vaccination program would cost $670 per DALY averted in The Gambia. The corresponding values for PCV7, PCV10, and PCV13 were $910, $670, and $570 per DALY averted, respectively. Sensitivity analyses that explored the implications of the uncertain key parameters showed that model outcomes were most sensitive to vaccine price per dose, discount rate, case-fatality rate of primary endpoint pneumonia, and vaccine efficacy against primary endpoint pneumonia. Based on the information available now, infant PCV vaccination would be expected to reduce pneumococcal diseases caused by S. pneumoniae in The Gambia

[Determination of vaccination quotas for pneumococcal conjugate vaccine in children on the basis of routine data of the statutory health insurance].

PubMed

Theidel, U; Braem, A; Rückinger, S

2013-05-01

The pneumococcal conjugate vaccine is recommended since July 2006 for all children up to 24 months by the Standing Committee on Vaccination (STIKO) in Germany. Immunisation includes 4 doses; a single dose should be administered at completed 2, 3, 4 months and 11-14 months of age. To analyse the immunization coverage, timeliness and completeness of vaccinations, a claims data analysis was conducted. The evaluation was based on routine claims data of a statutory health insurance covering the period from May 2008-September 2009. Overall, 81.2% (5 484/6 755) of all live births of mothers and fathers of the insurance received at least one vaccination dose. In 91.3% and 72.0% of these cases, the second and third dose was administered, respectively. A vaccination cycle of 4 doses was often not completed and the recommended time points for vaccination were not met in two-thirds of all children. Due to the limited and relatively short observation period, a conclusion about the rate of fully completed vaccination cycles was not possible. © Georg Thieme Verlag KG Stuttgart · New York.

Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

PubMed

Claeys, Carine; Drame, Mamadou; García-Sicilia, José; Zaman, Khalequ; Carmona, Alfonso; Tran, Phu My; Miranda, Mariano; Martinón-Torres, Federico; Thollot, Franck; Horn, Michael; Schwarz, Tino F; Behre, Ulrich; Merino, José M; Sadowska-Krawczenko, Iwona; Szymański, Henryk; Schu, Peter; Neumeier, Elisabeth; Li, Ping; Jain, Varsha K; Innis, Bruce L

2018-04-18

GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 μg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). The study

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

PubMed

Hansen, J; Zhang, L; Eaton, A; Baxter, R; Robertson, C A; Decker, M D; Greenberg, D P; Bassily, E; Klein, N P

2018-04-12

Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed

A novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus-toxoid conjugate vaccine is immunogenic and induces immune memory when co-administered with DTPa-HBV-IPV and conjugate pneumococcal vaccines in infants.

PubMed

Nolan, Terry; Lambert, Stephen; Roberton, Don; Marshall, Helen; Richmond, Peter; Streeton, Catherine; Poolman, Jan; Boutriau, Dominique

2007-12-12

Immunogenicity and safety of a novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus-toxoid conjugate vaccine (Hib-MenCY-TT) candidate was evaluated when co-administered with DTPa-HBV-IPV(Pediarix)+PCV7(Prevnar) at 2-4-6 months of age. Anti-PRP concentrations >or= 1.0 microg/mL were observed in 92.9-98.7%, rSBA-MenC/Y titres >or= 1:8 in >98%, rSBA-MenC/Y titres >or= 1:128 in >95.8 and >89.9% subjects. PRP and MenC responses were similar to respective controls (ActHIB and Menjugate) including for antibody persistence. Response to co-administered vaccines was not impaired. Polysaccharide challenge (PRP, PSC, PSY at 11-14 months of age) evidenced immune memory was induced for Hib, MenC/Y conjugate components. The safety profile of Hib-MenCY-TT was similar to controls. Hib-MenCY-TT administered according to the current US Hib vaccine schedule has the potential to induce protective antibodies against Hib and meningococcal-CY disease in infants and toddlers.

Estimated public health impact of nationwide vaccination of infants with 7-valent pneumococcal conjugate vaccine (PCV7) in China.

PubMed

Hu, ShanLian; Shi, Qiang; Chen, Chieh-I; Caldwell, Ronald; Wang, Bruce; Du, LiXia; He, JiangJiang; Roberts, Craig S

2014-09-01

The goal of this study was to provide a comprehensive analysis of the potential health impact of universal vaccination of infants with the 7-valent pneumococcal conjugate vaccine (PCV7) in China. A decision-analytic model designed for pneumococcal disease and outcomes of pneumococcal infection was populated with local age-specific incidence and mortality data to estimate the expected health benefits of vaccinating birth cohorts of approximately 16 million infants per year over a 10-year time horizon in China. The model incorporates both the direct impact on vaccinated children and the indirect effect of herd protection on unvaccinated children and adults. The model predicts that more than 16.2 million cases of pneumococcal disease and 709 411 deaths could be prevented in China over the initial 10-year period following the introduction of the PCV7 vaccine. The majority of these health benefits are due to the indirect effectiveness of the vaccine on the unvaccinated population, resulting in approximately 10.8 million cases prevented and 636 371 lives saved over 10 years. The results suggest that a policy of universal PCV7 vaccination among infants in China would have a substantial positive public health impact on the population of China. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

Immunogenicity of a combined schedule of 7-valent pneumococcal conjugate vaccine followed by a 23-valent polysaccharide vaccine in adult recipients of heart or lung transplants.

PubMed

Gattringer, R; Winkler, H; Roedler, S; Jaksch, P; Herkner, H; Burgmann, H

2011-10-01

A combined schedule of 7-valent pneumococcal conjugate vaccine (PCV7) followed by 23-valent pneumococcal polysaccharide vaccine (PPV23) was evaluated retrospectively in 26 adult recipients of heart or lung transplants. PCV7 was immunogenic in these patients but there appeared to be no benefit from the additional PPV23 dose. © 2011 John Wiley & Sons A/S.

Cost-effectiveness of HPV vaccination in Belize.

PubMed

Walwyn, Leslie; Janusz, Cara Bess; Clark, Andrew David; Prieto, Elise; Waight, Eufemia; Largaespada, Natalia

2015-05-07

Among women in Belize, cervical cancer is both the leading cancer and the leading cause of cancer deaths. Both the quadrivalent and bivalent human papillomavirus (HPV) vaccines are licensed in Belize. The Ministry of Health of Belize convened a multidisciplinary team to estimate the costs, health benefits, and cost-effectiveness of adding an HPV vaccine to the national immunization schedule. The CERVIVAC cost-effectiveness model (Version 1.123) was used to assess the lifetime health and economic outcomes of vaccinating one cohort of girls aged 10 years against HPV. The comparator was no HPV vaccination. The PAHO Revolving Fund negotiated price of US$ 13.79 per dose was used (for the quadrivalent vaccine) and national data sources were used to define demography, cervical cancer incidence and mortality, cervical cancer treatment costs, and vaccine delivery costs. Estimates from international agencies were used in scenario analysis. In a cohort of ∼4000 Belizean girls tracked over a lifetime, HPV vaccination is estimated to prevent 69 new cases of cervical cancer (undiscounted), and 51 cervical cancer deaths (undiscounted). Considering the potential cervical cancer treatment costs and lost wages avoided by households (societal perspective), the cost per disability-adjusted life year (DALY) averted was estimated to be US$ 429. This increased to US$ 1320 when cervical cancer treatment costs and lost wages were excluded from the analysis. Both estimates are far below the gross domestic product (GDP) per capita of Belize (US$ 4795). The lifetime health care costs saved by the women and their families represent more than 60% of the investment cost needed by the Government for the vaccine. Routine HPV vaccination would be highly cost-effective in Belize. If affordable, efforts should be made to expedite the introduction of this vaccine into the Belizean national immunization program. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cost-effectiveness of 13-valent pneumococcal conjugate vaccination in Mongolia.

PubMed

Sundaram, Neisha; Chen, Cynthia; Yoong, Joanne; Luvsan, Munkh-Erdene; Fox, Kimberley; Sarankhuu, Amarzaya; La Vincente, Sophie; Jit, Mark

2017-02-15

The Ministry of Health (MOH), Mongolia, is considering introducing 13-valent pneumococcal conjugate vaccine (PCV13) in its national immunization programme to prevent the burden of disease caused by Streptococcus pneumoniae. This study evaluates the cost-effectiveness and budget impact of introducing PCV13 compared to no PCV vaccination in Mongolia. The incremental cost-effectiveness ratio (ICER) of introducing PCV13 compared to no PCV vaccination was assessed using an age-stratified static multiple cohort model. The risk of various clinical presentations of pneumococcal disease (meningitis, pneumonia, non-meningitis non-pneumonia invasive pneumococcal disease and acute otitis media) at all ages for thirty birth cohorts was assessed. The analysis considered both health system and societal perspectives. A 3+0 vaccine schedule and price of US$3.30 per dose was assumed for the baseline scenario based on Gavi, the Vaccine Alliance's advance market commitment tail price. The ICER of PCV13 introduction is estimated at US$52 per disability-adjusted life year (DALY) averted (health system perspective), and cost-saving (societal perspective). Although indirect effects of PCV have been well-documented, a conservative scenario that does not consider indirect effects estimated PCV13 introduction to cost US$79 per DALY averted (health system perspective), and US$19 per DALY averted (societal perspective). Vaccination with PCV13 is expected to cost around US$920,000 in 2016, and thereafter US$820,000 every year. The programme is likely to reduce direct disease-related costs to MOH by US$440,000 in the first year, increasing to US$510,000 by 2025. Introducing PCV13 as part of Mongolia's national programme appears to be highly cost-effective when compared to no vaccination and cost-saving from a societal perspective at vaccine purchase prices offered through Gavi. Notwithstanding uncertainties around some parameters, cost-effectiveness of PCV introduction for Mongolia remains

SAFETY OF A CRM197-CONJUGATED HAEMOPHILUS INFLUENZAE TYPE B VACCINE IN KOREAN CHILDREN.

PubMed

Song, Hyoyoung; Bock, Hans; Guadagno, Alana; Costantini, Marco; Baehner, Frank; Kim, Yeon Ho; Ahn, Seung In; Son, Ki Hyuk; Yim, Dong-Seok

2015-07-01

Haemophilus influenzae type b (Hib) is a major cause of meningitis and pneumonia with high morbidity and mortality rates in young children. The introduction of effective and well-tolerated conjugate Hib vaccines, has nearly eradicated this disease in many countries. We investigated the safety of the Hib PRP-CRM197 vaccine in a multi-center post-marketing surveillance (PMS) study. Korean children (N = 764) aged 1-33 months were enrolled when receiving a routine primary immunization or a booster vaccine with Hib PRP-CRM197 and solicited and unsolicited adverse events (AEs) were recorded using a diary card for 7 and 28 days after each vaccination, respectively. In this study, AEs were reported by 66% of subjects but were generally mild, with 42% of subjects reporting solicited AEs and 46% reporting unsolicited AEs. Among the unsolicited AEs, 98% were determined to be unrelated to the study vaccine. The studied Hib PRP-CRM197 vaccine was well tolerated by the study group and found to have a similar safety profile to that reported in other clinical studies. This vaccine is suitable for routine immunization against Hib disease among Korean children. AEs due to this vaccine will continue to be monitored.

The Positive Correlation of the Enhanced Immune Response to PCV2 Subunit Vaccine by Conjugation of Chitosan Oligosaccharide with the Deacetylation Degree

PubMed Central

Zhang, Guiqiang; Cheng, Gong; Jia, Peiyuan; Jiao, Siming; Feng, Cui; Hu, Tao; Liu, Hongtao; Du, Yuguang

2017-01-01

Chitosan oligosaccharides (COS), the degraded products of chitosan, have been demonstrated to have versatile biological functions. In primary studies, it has displayed significant adjuvant effects when mixed with other vaccines. In this study, chitosan oligosaccharides with different deacetylation degrees were prepared and conjugated to porcine circovirus type 2 (PCV2) subunit vaccine to enhance its immunogenicity. The vaccine conjugates were designed by the covalent linkage of COSs to PCV2 molecules and administered to BALB/c mice three times at two-week intervals. The results indicate that, as compared to the PCV2 group, COS–PCV2 conjugates remarkably enhanced both humoral and cellular immunity against PCV2 by promoting lymphocyte proliferation and initiating a mixed T-helper 1 (Th1)/T-helper 2 (Th2) response, including raised levels of PCV2-specific antibodies and an increased production of inflammatory cytokines. Noticeably, with the increasing deacetylation degree, the stronger immune responses to PCV2 were observed in the groups with COS-PCV2 vaccination. In comparison with NACOS (chitin oligosaccharides)–PCV2 and LCOS (chitosan oligosaccharides with low deacetylation degree)–PCV2, HCOS (chitosan oligosaccharides with high deacetylation degree)–PCV2 showed the highest adjuvant effect, even comparable to that of PCV2/ISA206 (a commercialized adjuvant) group. In summary, COS conjugation might be a viable strategy to enhance the immune response to PCV2 subunit vaccine, and the adjuvant effect was positively correlated with the deacetylation degree of COS. PMID:28933754

The Positive Correlation of the Enhanced Immune Response to PCV2 Subunit Vaccine by Conjugation of Chitosan Oligosaccharide with the Deacetylation Degree.

PubMed

Zhang, Guiqiang; Cheng, Gong; Jia, Peiyuan; Jiao, Siming; Feng, Cui; Hu, Tao; Liu, Hongtao; Du, Yuguang

2017-07-26

Chitosan oligosaccharides (COS), the degraded products of chitosan, have been demonstrated to have versatile biological functions. In primary studies, it has displayed significant adjuvant effects when mixed with other vaccines. In this study, chitosan oligosaccharides with different deacetylation degrees were prepared and conjugated to porcine circovirus type 2 (PCV2) subunit vaccine to enhance its immunogenicity. The vaccine conjugates were designed by the covalent linkage of COSs to PCV2 molecules and administered to BALB/c mice three times at two-week intervals. The results indicate that, as compared to the PCV2 group, COS-PCV2 conjugates remarkably enhanced both humoral and cellular immunity against PCV2 by promoting lymphocyte proliferation and initiating a mixed T-helper 1 (Th1)/T-helper 2 (Th2) response, including raised levels of PCV2-specific antibodies and an increased production of inflammatory cytokines. Noticeably, with the increasing deacetylation degree, the stronger immune responses to PCV2 were observed in the groups with COS-PCV2 vaccination. In comparison with NACOS (chitin oligosaccharides)-PCV2 and LCOS (chitosan oligosaccharides with low deacetylation degree)-PCV2, HCOS (chitosan oligosaccharides with high deacetylation degree)-PCV2 showed the highest adjuvant effect, even comparable to that of PCV2/ISA206 (a commercialized adjuvant) group. In summary, COS conjugation might be a viable strategy to enhance the immune response to PCV2 subunit vaccine, and the adjuvant effect was positively correlated with the deacetylation degree of COS.

Optimization of a methamphetamine conjugate vaccine for antibody production in mice.

PubMed

Stevens, Misty W; Gunnell, Melinda G; Tawney, Rachel; Owens, S Michael

2016-06-01

There are still no approved medications for treating patients who abuse methamphetamine. Active vaccines for treating abuse of nicotine and cocaine are in clinical studies, but have not proven effective seemingly due to inadequate anti-drug antibody production. The current studies aimed to optimize the composition, adjuvant and route of administration of a methamphetamine conjugate vaccine, ICKLH-SMO9, in mice with the goal of generating significantly higher antibody levels. A range of hapten epitope densities were compared, as were the adjuvants Alhydrogel and a new Toll-like receptor 4 (TLR4) agonist called GLA-SE. While methamphetamine hapten density did not strongly affect the antibody response, the adjuvant did. Glucopyranosyl lipid A in a stable oil-in-water emulsion (GLA-SE) produced much higher levels of antibody in response to immunization compared with Alhydrogel; immunization with GLA-SE also produced antibodies with higher affinities for methamphetamine. GLA-SE has been used in human studies of vaccines for influenza among others and like some other clinical TLR4 agonists, it is safe and elicits a strong immune response. GLA-SE adjuvanted vaccines are typically administered by intramuscular injection and this also proved effective in these mouse studies. Clinical studies of the ICKLH-SMO9 methamphetamine vaccine adjuvanted with GLA-SE have the potential for demonstrating efficacy by generating much higher levels of antibody than substance abuse vaccines that have unsuccessfully used aluminum-based adjuvants. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: Up to 3.5 years of follow-up.

PubMed

Huang, Teng; Liu, Youping; Li, Yanping; Liao, Yuqin; Shou, Qiong; Zheng, Minghuan; Liao, Xueyan; Li, Rongcheng

2018-03-07

This was an extension study of a randomized, double-blind, placebo-controlled immunogenicity and safety study of the quadrivalent human papillomavirus (qHPV) (HPV 6, 11, 16, and 18) vaccine conducted in Chinese female subjects aged 9-45 years and male subjects aged 9-15 years. To investigate the persistence of anti-HPV 6, -11, -16, and -18 responses among Chinese subjects, subjects enrolled in the base study were followed up at around month 42 (approximately 3.5 years after vaccination). Among 600 subjects enrolled in the base study, a total of 468 subjects consented for participation in the extension study. Anti-HPV 6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA) and total IgG Luminex immunoassay (IgG LIA). Among the female subjects who received the qHPV vaccine, the proportions of subjects remained seropositive were high with both the cLIA and IgG LIA for HPV type 6, 11, and 16 through approximately 42 months following the first dose vaccination. For HPV 18, the seropositivity rate remained high as 82.0% with the IgG LIA, while it decreased to 53.6% with the cLIA, which was similar to the findings observed in other studies. The seropositivity rates remained high at month 42 for all qHPV types with both the cLIA and IgG LIA among the male subjects. Administration of a 3-dose regimen of qHPV vaccine induces durable anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses among Chinese subjects for at least 3.5 years after vaccination. ClinicalTrials.gov registry:NCT01427777. Copyright © 2018. Published by Elsevier Ltd.

Patterns of binding of aluminum-containing adjuvants to Haemophilus influenzae type b and meningococcal group C conjugate vaccines and components.

PubMed

Otto, Robert B D; Burkin, Karena; Amir, Saba Erum; Crane, Dennis T; Bolgiano, Barbara

2015-09-01

The basis of Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroup C (MenC) glycoconjugates binding to aluminum-containing adjuvants was studied. By measuring the amount of polysaccharide and protein in the non-adsorbed supernatant, the adjuvant, aluminum phosphate, AlPO4, was found to be less efficient than aluminum hydroxide, Al(OH)3 at binding to the conjugates, at concentrations relevant to licensed vaccine formulations and when equimolar. At neutral pH, binding of TT conjugates to AlPO4 was facilitated through the carrier protein, with only weak binding of AlPO4 to CRM197 being observed. There was slightly higher binding of either adjuvant to tetanus toxoid conjugates, than to CRM197 conjugates. This was verified in AlPO4 formulations containing DTwP-Hib, where the adsorption of TT-conjugated Hib was higher than CRM197-conjugated Hib. At neutral pH, the anionic Hib and MenC polysaccharides did not appreciably bind to AlPO4, but did bind to Al(OH)3, due to electrostatic interactions. Phosphate ions reduced the binding of the conjugates to the adjuvants. These patterns of adjuvant adsorption can form the basis for future formulation studies with individual and combination vaccines containing saccharide-protein conjugates. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine.

PubMed

Licciardi, Paul V; Toh, Zheng Quan; Clutterbuck, Elizabeth A; Balloch, Anne; Marimla, Rachel A; Tikkanen, Leena; Lamb, Karen E; Bright, Kathryn J; Rabuatoka, Uraia; Tikoduadua, Lisi; Boelsen, Laura K; Dunne, Eileen M; Satzke, Catherine; Cheung, Yin Bun; Pollard, Andrew J; Russell, Fiona M; Mulholland, Edward K

2016-06-01

A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The Meningitis Vaccine Project.

PubMed

LaForce, F Marc; Konde, Kader; Viviani, Simonetta; Préziosi, Marie-Pierre

2007-09-03

Epidemic meningococcal meningitis is an important public health problem in sub-Saharan Africa. Current control measures rely on reactive immunizations with polysaccharide (PS) vaccines that do not induce herd immunity and are of limited effectiveness in those under 2 years of age. Conversely, polysaccharide conjugate vaccines are effective in infants and have consistently shown an important effect on decreasing carriage, two characteristics that facilitate disease control. In 2001 the Meningitis Vaccine Project (MVP) was created as a partnership between PATH and the World Health Organization (WHO) with the goal of eliminating meningococcal epidemics in Africa through the development, licensure, introduction, and widespread use of conjugate meningococcal vaccines. Since group A Neisseria meningitidis (N. meningitidis) is the dominant pathogen causing epidemic meningitis in Africa MVP is developing an affordable (US$ 0.40 per dose) meningococcal A (Men A) conjugate vaccine through an innovative international partnership that saw transfer of a conjugation and fermentation technology to a developing country vaccine manufacturer. A Phase 1 study of the vaccine in India has shown that the product is safe and immunogenic. Phase 2 studies have begun in Africa, and a large demonstration study of the conjugate vaccine is envisioned for 2008-2009. After extensive consultations with African public health officials a vaccine introduction plan has been developed that includes introduction of the Men A conjugate vaccine into standard Expanded Programme on Immunization (EPI) schedules but also emphasizes mass vaccination of 1-29 years old to induce herd immunity, a strategy that has been shown to be highly effective when the meningococcal C (Men C) conjugate vaccine was introduced in several European countries. The MVP model is a clear example of the usefulness of a "push mechanism" to finance the development of a needed vaccine for the developing world.

Concomitant administration of a fully liquid, ready-to-use DTaP-IPV-HB-PRP-T hexavalent vaccine with a meningococcal serogroup C conjugate vaccine in infants.

PubMed

Vesikari, Timo; Borrow, Ray; Da Costa, Xavier; Richard, Patrick; Eymin, Cécile; Boisnard, Florence; Lockhart, Stephen

2017-01-11

DTaP-IPV-HB-PRP-T or hexavalent vaccines are indicated for primary and booster vaccination of infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b (Hib). The present study evaluates the safety and immunogenicity of a ready-to-use hexavalent vaccine when co-administered with a meningococcal serogroup C conjugate (MenC) vaccine in infants. This was a phase III, open-label, randomised, multicentre study conducted in Finland. Healthy infants, aged 46-74days (n=350), were randomised in a ratio of 1:1 to receive DTaP-IPV-HB-PRP-T vaccine at two, three and four months, either with a MenC vaccine co-administered at two and four months (Group 1; n=175) or without MenC vaccine (Group 2; n=175). All infants also received routine rotavirus and 13-valent pneumococcal conjugate vaccines. The proportion of participants with an anti-HBs concentration ⩾10mIU/mL assessed one month after the third dose of DTaP-IPV-HB-PRP-T vaccine was 97.5% [95%CI: 93.1-99.3] in the coadministration group and 96.1% [95%CI: 91.8-98.6] in the group without MenC vaccine. The proportion of participants with an anti-MenC SBA titre ⩾8 assessed one month after the second dose of MenC vaccine was 100% in the coadministration group. Both primary objectives were achieved. Secondary immunogenicity and safety analyses showed that co-administration of DTaP-IPV-HB-PRP-T and MenC vaccines did not impact the immune response to the antigens of each of the two vaccines. All vaccines were well tolerated and the safety profile of DTaP-IPV-HB-PRP-T vaccine was similar in both groups. ClinicalTrials.gov identifier: NCT01839175; EudraCT number: 2012-005547-24. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Pneumococcal Conjugate Vaccine and Pneumonia Prevention in Children with Congenital Heart Disease.

PubMed

Solórzano-Santos, Fortino; Espinoza-García, Lilia; Aguilar-Martínez, Glorinella; Beirana-Palencia, Luisa; Echániz-Avilés, Gabriela; Miranda-Novales, Guadalupe

2017-01-01

A successful strategy to prevent Streptococcus pneumoniae infections is the administration of pneumococcal conjugate vaccines (PCVs). To analyze the effectiveness of the 7- and 13-valent PCV for the prevention of all-cause pneumonia. A retrospective cohort of children younger than 5 years of age, with congenital heart disease (CHD) and different vaccination schedules, was analyzed. History of vaccination was confirmed with verifiable records. The outcome measure was all-cause pneumonia or bronchopneumonia. Protocol was approved by the Institutional Review Board. For comparisons, we used inferential statistics with Chi-square and Fisher's exact test; a p ≤ 0.5 was considered statistically significant. Relative and absolute risks reduction and number needed to treat were also calculated. A total of 348 patients were included: 196 with two or more doses of PCV (considered the vaccinated group), and 152 in the unvaccinated group. There was a statistically significant difference for pneumonia events (p < 0.001) between the vaccinated (26/196) and unvaccinated (51/152) groups. The relative risk reduction was 60.5%, and the absolute risk reduction, 20.3%. There were no differences between patients who received two, three or four doses. The number needed to vaccinate to prevent one event of pneumonia was 5 children. At least two doses of PCV in children with CHD reduced the risk of all-cause pneumonia.

Cost-effectiveness of pneumococcal conjugate vaccination in Georgia.

PubMed

Komakhidze, T; Hoestlandt, C; Dolakidze, T; Shakhnazarova, M; Chlikadze, R; Kopaleishvili, N; Goginashvili, K; Kherkheulidze, M; Clark, A D; Blau, J