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Sample records for boost immunization regimen

  1. Adenovirus vector-induced immune responses in nonhuman primates: responses to prime boost regimens.

    PubMed

    Tatsis, Nia; Lasaro, Marcio O; Lin, Shih-Wen; Haut, Larissa H; Xiang, Zhi Q; Zhou, Dongming; Dimenna, Lauren; Li, Hua; Bian, Ang; Abdulla, Sarah; Li, Yan; Giles-Davis, Wynetta; Engram, Jessica; Ratcliffe, Sarah J; Silvestri, Guido; Ertl, Hildegund C; Betts, Michael R

    2009-05-15

    In the phase IIb STEP trial an HIV-1 vaccine based on adenovirus (Ad) vectors of the human serotype 5 (AdHu5) not only failed to induce protection but also increased susceptibility to HIV-1 infection in individuals with preexisting neutralizing Abs against AdHu5. The mechanisms underlying the increased HIV-1 acquisition rates have not yet been elucidated. Furthermore, it remains unclear if the lack of the vaccine's efficacy reflects a failure of the concept of T cell-mediated protection against HIV-1 or a product failure of the vaccine. Here, we compared two vaccine regimens based on sequential use of AdHu5 vectors or two different chimpanzee-derived Ad vectors in rhesus macaques that were AdHu5 seropositive or seronegative at the onset of vaccination. Our results show that heterologous booster immunizations with the chimpanzee-derived Ad vectors induced higher T and B cell responses than did repeated immunizations with the AdHu5 vector, especially in AdHu5-preexposed macaques.

  2. A two-dose heterologous prime-boost vaccine regimen eliciting sustained immune responses to Ebola Zaire could support a preventive strategy for future outbreaks

    PubMed Central

    Shukarev, Georgi; Callendret, Benoit; Luhn, Kerstin; Douoguih, Macaya

    2017-01-01

    ABSTRACT The consequences of the 2013–16 Ebola Zaire virus disease epidemic in West Africa were grave. The economies, healthcare systems and communities of Guinea, Sierra Leone and Liberia were devastated by over 18 months of active Ebola virus transmission, followed by sporadic resurgences potentially related to sexual transmission by survivors with viral persistence in body fluids following recovery. The need to develop and implement strategies to prevent and mitigate future outbreaks is now beyond dispute. The potential for unpredictable outbreaks of indeterminate duration, and control challenges posed by the possibility of sporadic re-emergence, mean that implementation of an effective vaccination program for outbreak containment necessitates a vaccine providing durable immunity. Heterologous prime-boost vaccine regimens deliver the same or similar antigens through different vaccine types, the first to prime and the second to boost the immune system. Ad26.ZEBOV/MVA-BN-Filo is an investigational Ebola Zaire vaccine regimen that uses this heterologous prime-boost approach. Preliminary Phase 1 data suggest that Ad26.ZEBOV/MVA-BN-Filo confers durable immunity for at least 240 d and is well-tolerated with a good safety profile. This regimen may therefore be suitable for prophylactic use in a regional or targeted population vaccination strategy, and could potentially aid prevention and control of future Ebola outbreaks. PMID:27925844

  3. Relationship Between Genital Drug Concentrations and Cervical Cellular Immune Activation and Reconstitution in HIV-1-Infected Women on a Raltegravir Versus a Boosted Atazanavir Regimen

    PubMed Central

    Palmer, Claire; Predhomme, Julie; Searls, Kristina; Kerr, Becky; Seifert, Sharon; Caraway, Patricia; Gardner, Edward M.; MaWhinney, Samantha; Anderson, Peter L.

    2015-01-01

    Abstract Determinants of HIV-infected women's genital tract mucosal immune health are not well understood. Because raltegravir (RAL) achieves relatively higher genital tract concentrations than ritonavir-boosted atazanavir (ATV), we examined whether an RAL-based regimen is associated with improved cervical immune reconstitution and less activation in HIV+ women compared to an ATV-based regimen. Peripheral blood, cervical brushings, cervical–vaginal lavage (CVL), and cervical biopsies were collected from HIV+ women on tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and either RAL (n=14) or ATV (n=19) with CD4+ T cells>300 cells/mm3 and HIV RNA<48 copies/ml. HLA-DR+CD38+ T cells were measured in blood and cervical cells using flow cytometry, CD4+ and CD8+ T cells were quantified in cervical biopsies by immunofluorescent analysis, and HIV RNA (VL), ATV, and RAL concentrations were measured in CVL. In a linear regression model of log(CVL concentration) versus both log(plasma concentration) and treatment group, the RAL CVL level was 519% (95% CI: 133, 1,525%) higher than for ATV (p<0.001). Genital tract VL was undetectable in 90% of subjects and did not differ by regimen. There were no significant differences between groups in terms of cervical %HLA-DR+CD38+CD4+ or CD8+ T cells, CD4+ or CD8+ T cells/mm2, or CD4:CD8 ratio. After adjusting for treatment time and group, the CVL:plasma drug ratio was not associated with the cervical CD4:CD8 ratio or immune activation (p>0.6). Despite significantly higher genital tract penetration of RAL compared to ATV, there were no significant differences in cervical immune activation or reconstitution between women on these regimens, suggesting both drug regimens achieve adequate genital tract levels to suppress virus replication. PMID:26059647

  4. A Novel Prime and Boost Regimen of HIV Virus-Like Particles with TLR4 Adjuvant MPLA Induces Th1 Oriented Immune Responses against HIV

    PubMed Central

    Poteet, Ethan; Lewis, Phoebe; Li, Feng; Zhang, Sheng; Gu, Jianhua; Chen, Changyi; Ho, Sam On; Do, Thai; Chiang, SuMing; Fujii, Gary; Yao, Qizhi

    2015-01-01

    HIV virus-like particles (VLPs) present the HIV envelope protein in its native conformation, providing an ideal vaccine antigen. To enhance the immunogenicity of the VLP vaccine, we sought to improve upon two components; the route of administration and the additional adjuvant. Using HIV VLPs, we evaluated sub-cheek as a novel route of vaccine administration when combined with other conventional routes of immunization. Of five combinations of distinct prime and boost sequences, which included sub-cheek, intranasal, and intradermal routes of administration, intranasal prime and sub-cheek boost (IN+SC) resulted in the highest HIV-specific IgG titers among the groups tested. Using the IN+SC regimen we tested the adjuvant VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV) + monophosphoryl lipid A (MPLA) at MPLA concentrations of 0, 7.5, 12.5, and 25 μg/dose in combination with our VLPs. Mice that received 12.5 or 25 μg/dose MPLA had the highest concentrations of Env-specific IgG2c (20.7 and 18.4 μg/ml respectively), which represents a Th1 type of immune response in C57BL/6 mice. This was in sharp contrast to mice which received 0 or 7.5 μg MPLA adjuvant (6.05 and 5.68 μg/ml of IgG2c respectively). In contrast to IgG2c, MPLA had minor effects on Env-specific IgG1; therefore, 12.5 and 25 μg/dose of MPLA induced the optimal IgG1/IgG2c ratio of 1.3. Additionally, the percentage of germinal center B cells increased significantly from 15.4% in the control group to 31.9% in the CALV + 25 μg MPLA group. These mice also had significantly more IL-2 and less IL-4 Env-specific CD8+ T cells than controls, correlating with an increased percentage of Env-specific central memory CD4+ and CD8+ T cells. Our study shows the strong potential of IN+SC as an efficacious route of administration and the effectiveness of VLPs combined with MPLA adjuvant to induce Env specific Th1-oriented HIV-specific immune responses. PMID:26312747

  5. A Plasmodium vivax plasmid DNA- and adenovirus-vectored malaria vaccine encoding blood stage antigens AMA1 and MSP142 in a prime/boost heterologous immunization regimen partially protects Aotus monkeys against blood stage challenge.

    PubMed

    Obaldia, Nicanor; Stockelman, Michael G; Otero, William; Cockrill, Jennifer A; Ganeshan, Harini; Abot, Esteban N; Zhang, Jianfeng; Limbach, Keith; Charoenvit, Yupin; Doolan, Denise L; Tang, De-Chu C; Richie, Thomas L

    2017-02-08

    Malaria is caused by parasites of the genus Plasmodium that are transmitted to humans by the bites of Anopheles mosquitoes. After the elimination of P. falciparum it is predicted that Plasmodium vivax will remain an important cause of morbidity and mortality outside of Africa, stressing the importance of developing a vaccine against malaria. In this study we assess the immunogenicity and protective efficacy of two P. vivax antigens, AMA1 and MSP142 in a recombinant DNA plasmid prime/adenoviral vector (Ad) boost regimen in Aotus monkeys. Groups of 4 to 5 monkeys were immunized with DNA alone, Ad alone, prime/boost regimens of each antigen, prime/boost with both antigens, and empty vector controls, and then subjected to blood stage challenge. The heterologous immunization regimen with the antigen pair was more protective than either antigen alone or both antigens delivered with a single vaccine platform, based on their ability to induced the longest pre-patent period and time to peak parasitemia; the lowest peak and mean parasitemia; the smallest area under the parasitemia curve and the highest self-cured rate. Overall, pre-challenge MSP1 antibody titers strongly correlated with decreased parasite burden. Nevertheless, a significant proportion of immunized animals developed anemia. In conclusion, P. vivax plasmid DNA/Ad5 vaccine encoding blood stage parasite antigens AMA1 and MSP142 in a heterologous prime/boost immunization regimen, provided significant protection against blood-stage challenge in Aotus monkeys, indicating the suitability of these antigens and regimen for further development.

  6. Exercise boosts immune response.

    PubMed

    Sander, Ruth

    2012-06-29

    Ageing is associated with a decline in normal functioning of the immune system described as 'immunosenescence'. This contributes to poorer vaccine response and increased incidence of infection and malignancy seen in older people. Regular exercise can enhance vaccination response, increase T-cells and boost the function of the natural killer cells in the immune system. Exercise also lowers levels of the inflammatory cytokines that cause the 'inflamm-ageing' that is thought to play a role in conditions including cardiovascular disease; type 2 diabetes; Alzheimer's disease; osteoporosis and some cancers.

  7. DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

    PubMed Central

    Hu, Xintao; Valentin, Antonio; Dayton, Frances; Kulkarni, Viraj; Alicea, Candido; Rosati, Margherita; Chowdhury, Bhabadeb; Gautam, Rajeev; Broderick, Kate E.; Sardesai, Niranjan Y.; Martin, Malcolm A.; Mullins, James I.

    2016-01-01

    HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24gag plasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27Gag. Analysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B+ CD107a+) targeting subdominant CE epitopes, compared with the responses elicited by the p57gag pDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth. PMID:27733554

  8. Heterologous Prime-Boost Immunisation Regimens Against Infectious Diseases

    DTIC Science & Technology

    2006-08-01

    Heterologous Prime-Boost Immunisation Regimens Against Infectious Diseases Susan Shahin and David Proll Human Protection and... diseases (such as malaria, tuberculosis and HIV) has been hindered by the lack of effective immunisation strategies that induce the cellular arm of...different animal and disease models. Since several intracellular pathogens are considered potential biowarfare threats, the objective of this review

  9. Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials

    PubMed Central

    Brown, Scott A.; Surman, Sherri L.; Sealy, Robert; Jones, Bart G.; Slobod, Karen S.; Branum, Kristen; Lockey, Timothy D.; Howlett, Nanna; Freiden, Pamela; Flynn, Patricia; Hurwitz, Julia L.

    2010-01-01

    Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans. PMID:20407589

  10. Immune reconstitution in severely immunosuppressed antiretroviral-naive HIV type 1-infected patients using a nonnucleoside reverse transcriptase inhibitor-based or a boosted protease inhibitor-based antiretroviral regimen: three-year results (The Advanz Trial): a randomized, controlled trial.

    PubMed

    Miró, José M; Manzardo, Christian; Pich, Judith; Domingo, Pere; Ferrer, Elena; Arribas, José R; Ribera, Esteban; Arrizabalaga, Julio; Loncá, Montserrat; Cruceta, Anna; de Lazzari, Elisa; Fuster, Montserrat; Podzamczer, Daniel; Plana, Montserrat; Gatell, José M

    2010-07-01

    Late diagnosis of HIV-1 infection is quite frequent in Western countries. Very few randomized clinical trials to determine the best antiretroviral treatment in patients with advanced HIV-1 infection have been performed. To compare immune reconstitution in two groups of very immunosuppressed (less than 100 CD4(+) cells/microl), antiretroviral-naive HIV-1-infected adults, 65 patients were randomly assigned in a 1:1 ratio to receive zidovudine + lamivudine + efavirenz (group A, 34 patients) or zidovudine + lamivudine + ritonavir-boosted indinavir (group B, 31 patients). The median (interquartile range) CD4(+) cell increase after 12 and 36 months was +199 (101, 258) and +299 (170, 464) cells/microl in the efavirenz arm and +136 (57, 235) and +228 (119, 465) cells/microl in the ritonavir-boosted indinavir arm (p > 0.05 for all time points). The proportion (95% confidence interval) of patients achieving HIV-1 RNA levels under 50 copies/ml was significantly greater in the efavirenz arm at 3 years by the intention-to-treat analysis [59% (41%, 75%) vs. 23% (10%, 41%)], whereas no differences were found in the on-treatment analysis. Immune activation (CD8(+)CD38(+) and CD8(+)CD38DR(+) T cells) was significantly lower for the efavirenz arm from month 6 to month 24. Adverse events were more frequent in the ritonavir-boosted indinavir arm. Almost all cases of disease progression and death were observed in the first year of treatment, with no significant differences between the two arms (p = 0.79 by the log-rank test). At 1 and 3 years, the immune reconstitution induced by an efavirenz-based regimen in very immunosuppressed patients was at least as potent as that induced by a ritonavir-boosted protease inhibitor-based antiretroviral regimen.

  11. Efavirenz versus boosted atazanavir-containing regimens and immunologic, virologic, and clinical outcomes

    PubMed Central

    Cain, Lauren E.; Caniglia, Ellen C.; Phillips, Andrew; Olson, Ashley; Muga, Roberto; Pérez-Hoyos, Santiago; Abgrall, Sophie; Costagliola, Dominique; Rubio, Rafael; Jarrín, Inma; Bucher, Heiner; Fehr, Jan; van Sighem, Ard; Reiss, Peter; Dabis, François; Vandenhende, Marie-Anne; Logan, Roger; Robins, James; Sterne, Jonathan A. C.; Justice, Amy; Tate, Janet; Touloumi, Giota; Paparizos, Vasilis; Esteve, Anna; Casabona, Jordi; Seng, Rémonie; Meyer, Laurence; Jose, Sophie; Sabin, Caroline; Hernán, Miguel A.

    2016-01-01

    Abstract Objective: To compare regimens consisting of either ritonavir-boosted atazanavir or efavirenz and a nucleoside reverse transcriptase inhibitor (NRTI) backbone with respect to clinical, immunologic, and virologic outcomes. Design: Prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States included in the HIV-CAUSAL Collaboration. Methods: HIV-positive, antiretroviral therapy-naive, and acquired immune deficiency syndrome (AIDS)-free individuals were followed from the time they started an atazanavir or efavirenz regimen. We estimated an analog of the “intention-to-treat” effect for efavirenz versus atazanavir regimens on clinical, immunologic, and virologic outcomes with adjustment via inverse probability weighting for time-varying covariates. Results: A total of 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths) and 18,786 individuals started an efavirenz regimen (389 deaths, 825 AIDS-defining illnesses or deaths). During a median follow-up of 31 months, the hazard ratios (95% confidence intervals) were 0.98 (0.77, 1.24) for death and 1.09 (0.91, 1.30) for AIDS-defining illness or death comparing efavirenz with atazanavir regimens. The 5-year survival difference was 0.1% (95% confidence interval: −0.7%, 0.8%) and the AIDS-free survival difference was −0.3% (−1.2%, 0.6%). After 12 months, the mean change in CD4 cell count was 20.8 (95% confidence interval: 13.9, 27.8) cells/mm3 lower and the risk of virologic failure was 20% (14%, 26%) lower in the efavirenz regimens. Conclusion: Our estimates are consistent with a smaller 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with atazanavir regimens. No overall differences could be detected with respect to 5-year survival or AIDS-free survival. PMID:27741139

  12. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.

    PubMed

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M; Lucas, Megan; Spencer, John S; Amara, Rama Rao; Plikaytis, Bonnie B; Posey, James E; Sable, Suraj B

    2016-05-13

    Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans.

  13. Boosting Tumor-Specific Immunity Using PDT

    PubMed Central

    Maeding, Nicole; Verwanger, Thomas; Krammer, Barbara

    2016-01-01

    Photodynamic therapy (PDT) is a cancer treatment with a long-standing history. It employs the application of nontoxic components, namely a light-sensitive photosensitizer and visible light, to generate reactive oxygen species (ROS). These ROS lead to tumor cell destruction, which is accompanied by the induction of an acute inflammatory response. This inflammatory process sends a danger signal to the innate immune system, which results in activation of specific cell types and release of additional inflammatory mediators. Activation of the innate immune response is necessary for subsequent induction of the adaptive arm of the immune system. This includes the priming of tumor-specific cytotoxic T lymphocytes (CTL) that have the capability to directly recognize and kill cells which display an altered self. The past decades have brought increasing appreciation for the importance of the generation of an adaptive immune response for long-term tumor control and induction of immune memory to combat recurrent disease. This has led to considerable effort to elucidate the immune effects PDT treatment elicits. In this review we deal with the progress which has been made during the past 20 years in uncovering the role of PDT in the induction of the tumor-specific immune response, with special emphasis on adaptive immunity. PMID:27782066

  14. Self-boosting vaccines and their implications for herd immunity.

    PubMed

    Arinaminpathy, Nimalan; Lavine, Jennie S; Grenfell, Bryan T

    2012-12-04

    Advances in vaccine technology over the past two centuries have facilitated far-reaching impact in the control of many infections, and today's emerging vaccines could likewise open new opportunities in the control of several diseases. Here we consider the potential, population-level effects of a particular class of emerging vaccines that use specific viral vectors to establish long-term, intermittent antigen presentation within a vaccinated host: in essence, "self-boosting" vaccines. In particular, we use mathematical models to explore the potential role of such vaccines in situations where current immunization raises only relatively short-lived protection. Vaccination programs in such cases are generally limited in their ability to raise lasting herd immunity. Moreover, in certain cases mass vaccination can have the counterproductive effect of allowing an increase in severe disease, through reducing opportunities for immunity to be boosted through natural exposure to infection. Such dynamics have been proposed, for example, in relation to pertussis and varicella-zoster virus. In this context we show how self-boosting vaccines could open qualitatively new opportunities, for example by broadening the effective duration of herd immunity that can be achieved with currently used immunogens. At intermediate rates of self-boosting, these vaccines also alleviate the potential counterproductive effects of mass vaccination, through compensating for losses in natural boosting. Importantly, however, we also show how sufficiently high boosting rates may introduce a new regime of unintended consequences, wherein the unvaccinated bear an increased disease burden. Finally, we discuss important caveats and data needs arising from this work.

  15. Heterologous Prime-Boost Regimens with a Recombinant Chimpanzee Adenoviral Vector and Adjuvanted F4 Protein Elicit Polyfunctional HIV-1-Specific T-Cell Responses in Macaques

    PubMed Central

    Lorin, Clarisse; Vanloubbeeck, Yannick; Baudart, Sébastien; Ska, Michaël; Bayat, Babak; Brauers, Geoffroy; Clarinval, Géraldine; Donner, Marie-Noëlle; Marchand, Martine; Koutsoukos, Marguerite; Mettens, Pascal; Cohen, Joe; Voss, Gerald

    2015-01-01

    HIV-1-specific CD4+ and CD8+ T lymphocytes are important for HIV-1 replication control. F4/AS01 consists of F4 recombinant fusion protein (containing clade B Gag/p24, Pol/RT, Nef and Gag/p17) formulated in AS01 Adjuvant System, and was shown to induce F4-specific polyfunctional CD4+ T-cell responses in humans. While replication-incompetent recombinant HIV-1/SIV antigen-expressing human adenoviral vectors can elicit high-frequency antigen-specific CD8+ T-cell responses, their use is hampered by widespread pre-existing immunity to human serotypes. Non-human adenovirus serotypes associated with lower prevalence may offer an alternative strategy. We evaluated the immunogenicity of AdC7-GRN (‘A’), a recombinant chimpanzee adenovirus type 7 vector expressing clade B Gag, RT and Nef, and F4/AS01 (‘P’), when delivered intramuscularly in homologous (PP or AA) and heterologous (AAPP or PPAA) prime-boost regimens, in macaques and mice. Vaccine-induced HIV-1-antigen-specific T cells in peripheral blood (macaques), liver, spleen, and intestinal and genital mucosa (mice) were characterized by intracellular cytokine staining. Vaccine-specific IgG antibodies (macaques) were detected using ELISA. In macaques, only the heterologous prime-boost regimens induced polyfunctional, persistent and balanced CD4+ and CD8+ T-cell responses specific to each HIV-1 vaccine antigen. AdC7-GRN priming increased the polyfunctionality of F4/AS01-induced CD4+ T cells. Approximately 50% of AdC7-GRN-induced memory CD8+ T cells exhibited an effector-memory phenotype. HIV-1-specific antibodies were detected with each regimen. In mice, antigen-specific CD4+ and CD8+ T-cell responses were detected in the mucosal and systemic anatomical compartments assessed. When administered in heterologous prime-boost regimens, AdC7-GRN and F4/AS01 candidate vaccines acted complementarily in inducing potent and persistent peripheral blood HIV-1-specific CD4+ and CD8+ T-cell responses and antibodies in macaques

  16. Fusion-Expressed CTB Improves Both Systemic and Mucosal T-Cell Responses Elicited by an Intranasal DNA Priming/Intramuscular Recombinant Vaccinia Boosting Regimen

    PubMed Central

    Qiu, Sugan; Ren, Xiaonan; Ben, Yinyin; Ren, Yanqin; Wang, Jing; Zhang, Xiaoyan; Wan, Yanmin; Xu, Jianqing

    2014-01-01

    Previous study showed that CTB (Cholera toxin subunit B) can be used as a genetic adjuvant to enhance the systemic immune responses. To further investigate whether it can also be used as a genetic adjuvant to improve mucosal immune responses, we constructed DNA and recombinant Tiantan vaccinia (rTTV) vaccines expressing OVA-CTB fusion antigen. Female C57BL/6 mice were immunized with an intranasal DNA priming/intramuscular rTTV boosting regimen. OVA specific T-cell responses were measured by IFN-γ ELISPOT and specific antibody responses were determined by ELISA. Compared to the nonadjuvant group (pSV-OVA intranasal priming/rTTV-OVA intramuscular boosting), pSV-OVA-CTB intranasal priming/rTTV-OVA-CTB intramuscular boosting group significantly improved the magnitudes of T-cell responses at spleen (1562 ± 567 SFCs/106 splenocytes versus 330 ± 182 SFCs/106 splenocytes, P < 0.01), mesenteric LN (96 ± 83 SFCs/106 lymphocytes versus 1 ± 2 SFCs/106 lymphocytes, P < 0.05), draining LNs of respiratory tract (109 ± 60 SFCs/106 lymphocytes versus 2 ± 2 SFCs/106 lymphocytes, P < 0.01) and female genital tract (89 ± 48 SFCs/106 lymphocytes versus 23 ± 21 SFCs/106 lymphocytes, P < 0.01). These results collectively demonstrated that fusion-expressed CTB could act as a potent adjuvant to improve both systemic and mucosal T-cell responses. PMID:24741585

  17. Construction and immunogenicity in a prime-boost regimen of a Semliki Forest virus-vectored experimental HIV clade A vaccine.

    PubMed

    Hanke, Tomás; Barnfield, Christina; Wee, Edmund G-T; Agren, Lena; Samuel, Rachel V; Larke, Natasha; Liljeström, Peter

    2003-02-01

    A novel, experimental subunit human immunodeficiency virus (HIV) vaccine, SFV.HIVA, was constructed. This consists of Semliki Forest virus (SFV), which is a suitable vaccine vector for use in humans, and a passenger gene encoding HIVA, which is an immunogen derived from HIV-1 clade A that is being currently tested in clinical trials of combined DNA- and modified vaccinia virus Ankara (MVA)-vectored vaccines in Oxford (UK) and Nairobi (Kenya). In the mouse, the SFV.HIVA vaccine was highly immunogenic for T cell-mediated immune responses and induced T cell memory that lasted for at least 6 months. SFV.HIVA was also compared to the vaccines currently used in the clinical trials and was shown to be as effective in T cell induction as pTHr.HIVA DNA but less immunogenic than MVA.HIVA. When tested in a prime-boost regimen, SFV.HIVA-induced responses could be boosted by MVA.HIVA. This work is a part of a long-term effort to build a panel of subunit vaccines expressing a common immunogen, which will allow both a direct comparison of various vaccine vectors and combined vaccination regimens in humans and provide more flexibility and/or a potential optimization of vaccinations for individuals based on their pre-existing anti-vector immunity.

  18. Sequential Immunization with gp140 Boosts Immune Responses Primed by Modified Vaccinia Ankara or DNA in HIV-Uninfected South African Participants

    PubMed Central

    Churchyard, Gavin; Mlisana, Koleka; Karuna, Shelly; Williamson, Anna-Lise; Williamson, Carolyn; Morris, Lynn; Tomaras, Georgia D.; De Rosa, Stephen C.; Gilbert, Peter B.; Gu, Niya; Yu, Chenchen; Mkhize, Nonhlanhla N.; Hermanus, Tandile; Allen, Mary; Pensiero, Michael; Barnett, Susan W.; Gray, Glenda; Bekker, Linda-Gail; Montefiori, David C.; Kublin, James; Corey, Lawrence

    2016-01-01

    Background The safety and immunogenicity of SAAVI DNA-C2 (4 mg IM), SAAVI MVA-C (2.9 x 109 pfu IM) and Novartis V2-deleted subtype C gp140 (100 mcg) with MF59 adjuvant in various vaccination regimens was evaluated in HIV-uninfected adults in South Africa. Methods Participants at three South African sites were randomized (1:1:1:1) to one of four vaccine regimens: MVA prime, sequential gp140 protein boost (M/M/P/P); concurrent MVA/gp140 (MP/MP); DNA prime, sequential MVA boost (D/D/M/M); DNA prime, concurrent MVA/gp140 boost (D/D/MP/MP) or placebo. Peak HIV specific humoral and cellular responses were measured. Results 184 participants were enrolled: 52% were female, all were Black/African, median age was 23 years (range, 18–42 years) and 79% completed all vaccinations. 159 participants reported at least one adverse event, 92.5% were mild or moderate. Five, unrelated, serious adverse events were reported. The M/M/P/P and D/D/MP/MP regimens induced the strongest peak neutralizing and binding antibody responses and the greatest CD4+ T-cell responses to Env. All peak neutralizing and binding antibody responses decayed with time. The MVA, but not DNA, prime contributed to the humoral and cellular immune responses. The D/D/M/M regimen was poorly immunogenic overall but did induce modest CD4+ T-cell responses to Gag and Pol. CD8+ T-cell responses to any antigen were low for all regimens. Conclusions The SAAVI DNA-C2, SAAVI MVA-C and Novartis gp140 with MF59 adjuvant in various combinations were safe and induced neutralizing and binding antibodies and cellular immune responses. Sequential immunization with gp140 boosted immune responses primed by MVA or DNA. The best overall immune responses were seen with the M/M/P/P regimen. Trial Registration ClinicalTrials.gov NCT01418235 PMID:27583368

  19. HIV-1 Subtype C Mosaic Gag Expressed by BCG and MVA Elicits Persistent Effector T Cell Responses in a Prime-Boost Regimen in Mice

    PubMed Central

    Jongwe, Tsungai Ivai; Chapman, Ros; Douglass, Nicola; Chetty, Shivan; Chege, Gerald; Williamson, Anna-Lise

    2016-01-01

    Over 90% of HIV/AIDS positive individuals in sub-Saharan Africa are infected with highly heterogeneous HIV-1 subtype C (HIV-1C) viruses. One of the best ways to reduce the burden of this disease is the development of an affordable and effective prophylactic vaccine. Mosaic immunogens are computationally designed to overcome the hurdle of HIV diversity by maximizing the expression of potential T cell epitopes. Mycobacterium bovis BCG ΔpanCD auxotroph and modified vaccinia Ankara (MVA) vaccines expressing HIV-1C mosaic Gag (GagM) were tested in a prime-boost regimen to demonstrate immunogenicity in a mouse study. The BCG-GagM vaccine was stable and persisted 11.5 weeks post vaccination in BALB/c mice. Priming with BCG-GagM and boosting with MVA-GagM elicited higher Gag-specific IFN-γ ELISPOT responses than the BCG-GagM only and MVA-GagM only homologous vaccination regimens. The heterologous vaccination also generated a more balanced and persistent CD4+ and CD8+ T cell Gag-specific IFN-γ ELISPOT response with a predominant effector memory phenotype. A Th1 bias was induced by the vaccines as determined by the predominant secretion of IFN-γ, TNF-α, and IL-2. This study shows that a low dose of MVA (104 pfu) can effectively boost a BCG prime expressing the same mosaic immunogen, generating strong, cellular immune responses against Gag in mice. Our data warrants further evaluation in non-human primates. A low dose vaccine would be an advantage in the resource limited countries of sub-Saharan Africa and India (where the predominating virus is HIV-1 subtype C). PMID:27427967

  20. First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus–Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

    PubMed Central

    Nyombayire, Julien; Anzala, Omu; Gazzard, Brian; Karita, Etienne; Bergin, Philip; Hayes, Peter; Kopycinski, Jakub; Omosa-Manyonyi, Gloria; Jackson, Akil; Bizimana, Jean; Farah, Bashir; Sayeed, Eddy; Parks, Christopher L.; Inoue, Makoto; Hironaka, Takashi; Hara, Hiroto; Shu, Tsugumine; Matano, Tetsuro; Dally, Len; Barin, Burc; Park, Harriet; Gilmour, Jill; Lombardo, Angela; Excler, Jean-Louis; Fast, Patricia; Laufer, Dagna S.; Cox, Josephine H.

    2017-01-01

    Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)–vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. Methods. Sixty-five HIV-1–uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35–vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH). Results. All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot–determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic. Conclusions. SeV-Gag primed functional, durable HIV-specific T

  1. Immunogenicity and protective efficacy against murine tuberculosis of a prime-boost regimen with BCG and a DNA vaccine expressing ESAT-6 and Ag85A fusion protein.

    PubMed

    Lu, Jia; Wang, Chun; Zhou, Zhiguang; Zhang, Ying; Cao, Tingting; Shi, Chunwei; Chen, Zhenhua; Chen, Lingxia; Cai, Changxue; Fan, Xionglin

    2011-01-01

    Heterologous prime-boost regimens utilizing BCG as a prime vaccine probably represent the best hope for the development of novel tuberculosis (TB) vaccines. In this study, we examined the immunogenicity and protective efficacy of DNA vaccine (pcD685A) expressing the fusion protein of Ag85A and ESAT-6 (r685A) and its booster effects in BCG-immunized mice. The recombinant r685A fusion protein stimulated higher level of antigen-specific IFN-γ release in tuberculin skin test- (TST-) positive healthy household contacts of active pulmonary TB patients than that in TST-negative population. Vaccination of C57BL/6 mice with pcD685A resulted in significant protection against challenge with virulent Mycobacterium tuberculosis H37Rv when compared with the control group. Most importantly, pcD685A could act as a BCG booster and amplify Th1-type cell-mediated immunity in the lung of BCG-vaccinated mice as shown the increased expression of IFN-γ. The most significant reduction in bacterial load of both spleen and lung was obtained in mice vaccinated with BCG prime and pcD685A DNA booster when compared with BCG or pcD685A alone. Thus, our study indicates that pcD685A may be an efficient booster vaccine against TB with a strong ability to enhance prior BCG immunity.

  2. Massage-like stroking boosts the immune system in mice

    PubMed Central

    Major, Benjamin; Rattazzi, Lorenza; Brod, Samuel; Pilipović, Ivan; Leposavić, Gordana; D’Acquisto, Fulvio

    2015-01-01

    Recent clinical evidence suggests that the therapeutic effect of massage involves the immune system and that this can be exploited as an adjunct therapy together with standard drug-based approaches. In this study, we investigated the mechanisms behind these effects exploring the immunomodulatory function of stroking as a surrogate of massage-like therapy in mice. C57/BL6 mice were stroked daily for 8 days either with a soft brush or directly with a gloved hand and then analysed for differences in their immune repertoire compared to control non-stroked mice. Our results show that hand- but not brush-stroked mice demonstrated a significant increase in thymic and splenic T cell number (p < 0.05; p < 0.01). These effects were not associated with significant changes in CD4/CD8 lineage commitment or activation profile. The boosting effects on T cell repertoire of massage-like therapy were associated with a decreased noradrenergic innervation of lymphoid organs and counteracted the immunosuppressive effect of hydrocortisone in vivo. Together our results in mice support the hypothesis that massage-like therapies might be of therapeutic value in the treatment of immunodeficiencies and related disorders and suggest a reduction of the inhibitory noradrenergic tone in lymphoid organs as one of the possible explanations for their immunomodulatory function. PMID:26046935

  3. Immuno-epidemiology of a population structured by immune status: a mathematical study of waning immunity and immune system boosting.

    PubMed

    Barbarossa, M V; Röst, G

    2015-12-01

    When the body gets infected by a pathogen the immune system develops pathogen-specific immunity. Induced immunity decays in time and years after recovery the host might become susceptible again. Exposure to the pathogen in the environment boosts the immune system thus prolonging the time in which a recovered individual is immune. Such an interplay of within host processes and population dynamics poses significant challenges in rigorous mathematical modeling of immuno-epidemiology. We propose a framework to model SIRS dynamics, monitoring the immune status of individuals and including both waning immunity and immune system boosting. Our model is formulated as a system of two ordinary differential equations (ODEs) coupled with a PDE. After showing existence and uniqueness of a classical solution, we investigate the local and the global asymptotic stability of the unique disease-free stationary solution. Under particular assumptions on the general model, we can recover known examples such as large systems of ODEs for SIRWS dynamics, as well as SIRS with constant delay.

  4. Improved immunogenicity and protective efficacy of a divalent DNA vaccine encoding Brucella L7/L12-truncated Omp31 fusion protein by a DNA priming and protein boosting regimen.

    PubMed

    Golshani, Maryam; Rafati, Sima; Siadat, Seyed Davar; Nejati-Moheimani, Mehdi; Shahcheraghi, Fereshteh; Arsang, Amin; Bouzari, Saeid

    2015-08-01

    Brucellosis is one of the most common zoonotic diseases caused by species of Brucella. At present, there is no commercially available vaccine for the human brucellosis. Brucella melitensis and Brucella abortus are the main causes of human brucellosis, worldwide. The outer membrane protein 31 (Omp31) and L7/L12 are immunodominant and protective antigens conserved among human Brucella pathogens. The purpose of the current study was to evaluate and compare the immunogenicity and protective efficacy of the L7/L12-TOmp31 construct administered as DNA/DNA and DNA/Pro vaccine regimens. Vaccination of BALB/c mice with the DNA/Pro regimen provided more protection levels against B. melitenisis and B. abortus challenge than did the DNA/DNA regimen. IgG1 and IgG2a titers were higher in the sera from DNA/Pro-immunized mice than in those from mice immunized with DNA alone. Moreover, splenocytes from DNA/Pro-immunized mice produced significantly higher levels of IFN-γ than did those from mice given DNA alone. The pcDNA-L7/L12-TOmp31 priming followed by rL7/L12-TOmp31 boosting led to improved protection against B. abortus or B. melitensis infection.

  5. Induction of HIV immunity in the genital tract after intranasal delivery of a MVA vector: enhanced immunogenicity after DNA prime-modified vaccinia virus Ankara boost immunization schedule.

    PubMed

    Gherardi, M Magdalena; Pérez-Jiménez, Eva; Nájera, José Luis; Esteban, Mariano

    2004-05-15

    Vaccines intended to prevent mucosal transmission of HIV should be able to induce multiple immune effectors in the host including Abs and cell-mediated immune responses at mucosal sites. The aim of this study was to characterize and to enhance the immunogenicity of a recombinant modified vaccinia virus Ankara (MVA) expressing HIV-1 Env IIIB Ag (MVAenv) inoculated in BALB/c mice by mucosal routes. Intravaginal inoculation of MVAenv was not immunogenic, whereas intranasally it induced a significant immune response to the HIV Ag. Intranasal codelivery of MVAenv plus cholera toxin (CT) significantly enhanced the cellular and humoral immune response against Env in the spleen and genitorectal draining lymph nodes, respectively. Heterologous DNAenv prime-MVAenv boost by intranasal immunization, together with CT, produced a cellular immune response in the spleen 10-fold superior to that in the absence of CT. A key finding of these studies was that both MVAenv/MVAenv and DNAenv/MVAenv schemes, plus CT, induced a specific mucosal CD8(+) T cell response in genital tissue and draining lymph nodes. In addition, both immunizations also generated systemic Abs, and more importantly, mucosal IgA and IgG Abs in vaginal washings. Specific secretion of beta-chemokines was also generated by both immunizations, with a stronger response in mice immunized by the DNA-CT/MVA-CT regimen. Our findings are of relevance in the area of vaccine development and support the optimization of protocols of immunization based on MVA as vaccine vectors to induce mucosal immune responses against HIV.

  6. Improved Protection of Rhesus Macaques against Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge by a Replication-Competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag Recombinant Priming/gp120 Boosting Regimen

    PubMed Central

    Zhao, Jun; Pinczewski, Joel; Gómez-Román, Victor R.; Venzon, David; Kalyanaraman, V. S.; Markham, Phillip D.; Aldrich, Kristine; Moake, Matthew; Montefiori, David C.; Lou, Yuanmei; Pavlakis, George N.; Robert-Guroff, Marjorie

    2003-01-01

    In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virusmac251. Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIVmac251 challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A∗01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8+ T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites. PMID:12857905

  7. Enhanced protective efficacy against Mycobacterium tuberculosis afforded by BCG prime-DNA boost regimen in an early challenge mouse model is associated with increased splenic interleukin-2-producing CD4 T-cell frequency post-vaccination.

    PubMed

    Kang, Han; Yuan, Qin; Ma, Hui; Hu, Zhi-Dong; Han, De-Ping; Wu, Kang; Lowrie, Douglas B; Fan, Xiao-Yong

    2014-12-01

    The development of improved vaccines and vaccination strategies against Mycobacterium tuberculosis has been hindered by a limited understanding of the immune correlates of anti-tuberculosis protective immunity. Simple measurement of interferon-γ frequency or production per se does not provide adequate prediction of immune protection. In this study, we examined the relationship between T-cell immune responses and protective efficacy conferred by the heterologous vaccination strategy, bacillus Calmette-Guérin (BCG) prime-Ag85A DNA boost (B/D), in an early challenge mouse model of pulmonary tuberculosis. The results demonstrated that mice vaccinated with the B/D regimen had a significantly reduced bacillary load compared with BCG-vaccinated mice, and the reduction in colony-forming units was associated with decreased pathology and lower levels of inflammatory cytokines in the infected lungs. Further analysis of immunogenicity showed that the superior protection afforded by the B/D regimen was associated with significantly increased frequency of splenic interleukin-2 (IL-2) -producing CD4 T cells and increased IL-2 production when measured as integrated mean fluorescence intensity post-vaccination as well. These data suggest that measurement of elevated frequency of IL-2-producing CD4 T cells or IL-2 production in the spleens of vaccinated mice can predict vaccine efficacy, at least in the B/D strategy, and add to the accumulating body of evidence suggesting that BCG prime-boost strategies may be a useful approach to the control of M. tuberculosis infection.

  8. Comparison of Acute and Late Toxicity of Two Regimens of 3- and 5-Week Concomitant Boost Prone IMRT to Standard 6-Week Breast Radiotherapy

    PubMed Central

    Raza, Shahzad; Lymberis, Stella C.; Ciervide, Raquel; Axelrod, Deborah; Fenton-Kerimian, Maria; Magnolfi, Chiara; Rosenstein, Barry; DeWyngaert, J. Keith; Formenti, Silvia C.

    2012-01-01

    Purpose: Limited information is available comparing toxicity of accelerated radiotherapy (RT) to that of standard fractionation RT for early stage breast cancer. We report early and late toxicities of two prone regimens of accelerated intensity-modulated radiation therapy (IMRT) with a concomitant boost (CB) to the tumor bed delivered over 3 or 5 weeks as compared to standard 6 week RT with a sequential electron boost. Methods: From 2/2003 to 12/2007, 169 consecutive patients with Stage I–II breast cancer were offered the choice to undergo prone RT with either: a 6-week standard RT regimen of 46 Gy/23 fractions (fx) to the whole breast (WB), followed by a14 Gy sequential boost (SB) to the tumor bed (6wSB), a 5-week regimen of 50 Gy to WB with an IMRT CB of 6.25 Gy in 25 fx (5wCB); or a 3-week protocol of 40.5 Gy to WB with an IMRT CB of 7.5 Gy in 15 fx (3wCB). These regimens were estimated as biologically equivalent, based on alpha/beta = 4 for tumor control. Toxicities were reported using RTOG and LENT/SOMA scoring. Results: 51/169 patients chose standard 6wSB, 28 selected 5wCB, and 90 enrolled in 3wCB protocol. Maximum acute toxicity was Grade 3 dermatitis in 4% of the patients in the 6wSB compared 1% in 3wCB. In general, acute complications (breast pain, fatigue, and dermatitis) were significantly less in the 3wCB than in the other schedules (P < 0.05). With a median follow-up of 61 months, the only Grade 3 late toxicity was telangiectasia in two patients: one in 3wCB and one in 5wCB group. Notably, fibrosis was comparable among the three groups (P = NS). Conclusion: These preliminary data suggest that accelerated regimens of breast RT over 3 or 5 weeks in the prone position, with an IMRT tumor bed CB, result in comparable late toxicity to standard fractionation with a sequential tumor boost delivered over 6 weeks. As predicted by radiobiological modeling the shorter regimen was associated with less acute effects. PMID:22649788

  9. Boosting Adaptive Immunity: A New Role for PAFR Antagonists

    PubMed Central

    Koga, Marianna M.; Bizzarro, Bruna; Sá-Nunes, Anderson; Rios, Francisco J.; Jancar, Sonia

    2016-01-01

    We have previously shown that the Platelet-Activating Factor Receptor (PAFR) engagement in murine macrophages and dendritic cells (DCs) promotes a tolerogenic phenotype reversed by PAFR-antagonists treatment in vitro. Here, we investigated whether a PAFR antagonist would modulate the immune response in vivo. Mice were subcutaneously injected with OVA or OVA with PAFR-antagonist WEB2170 on days 0 and 7. On day 14, OVA–specific IgG2a and IgG1 were measured in the serum. The presence of WEB2170 during immunization significantly increased IgG2a without affecting IgG1 levels. When WEB2170 was added to OVA in complete Freund’s adjuvant, enhanced IgG2a but not IgG1 production was also observed, and CD4+ FoxP3+ T cell frequency in the spleen was reduced compared to mice immunized without the antagonist. Similar results were observed in PAFR-deficient mice, along with increased Tbet mRNA expression in the spleen. Additionally, bone marrow-derived DCs loaded with OVA were transferred into naïve mice and their splenocytes were co-cultured with fresh OVA-loaded DCs. CD4+ T cell proliferation was higher in the group transferred with DCs treated with the PAFR-antagonist. We propose that the activation of PAFR by ligands present in the site of immunization is able to fine-tune the adaptive immune response. PMID:27966635

  10. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses

    PubMed Central

    Peng, K-W; Myers, R; Greenslade, A; Mader, E; Greiner, S; Federspiel, MJ; Dispenzieri, A; Russell, SJ

    2013-01-01

    Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m−2 was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m−2 should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing. PMID:22476202

  11. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses.

    PubMed

    Peng, K-W; Myers, R; Greenslade, A; Mader, E; Greiner, S; Federspiel, M J; Dispenzieri, A; Russell, S J

    2013-03-01

    Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m(-2) was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m(-2) should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing.

  12. Enhanced potency of plasmid DNA microparticle human immunodeficiency virus vaccines in rhesus macaques by using a priming-boosting regimen with recombinant proteins.

    PubMed

    Otten, Gillis R; Schaefer, Mary; Doe, Barbara; Liu, Hong; Srivastava, Indresh; Megede, Jan zur; Kazzaz, Jina; Lian, Ying; Singh, Manmohan; Ugozzoli, Mildred; Montefiori, David; Lewis, Mark; Driver, David A; Dubensky, Thomas; Polo, John M; Donnelly, John; O'Hagan, Derek T; Barnett, Susan; Ulmer, Jeffrey B

    2005-07-01

    DNA vaccines have been used widely in experimental primate models of human immunodeficiency virus (HIV), but their effectiveness has been limited. In this study, we evaluated three technologies for increasing the potency of DNA vaccines in rhesus macaques. These included DNA encoding Sindbis virus RNA replicons (pSINCP), cationic poly(lactide-co-glycolide) (PLG) microparticles for DNA delivery, and recombinant protein boosting. The DNA-based pSINCP replicon vaccines encoding HIV Gag and Env were approximately equal in potency to human cytomegalovirus (CMV) promoter-driven conventional DNA vaccines (pCMV). The PLG microparticle DNA delivery system was particularly effective at enhancing antibody responses induced by both pCMV and pSINCP vaccines and had less effect on T cells. Recombinant Gag and Env protein boosting elicited rapid and strong recall responses, in some cases to levels exceeding those seen after DNA or DNA/PLG priming. Of note, Env protein boosting induced serum-neutralizing antibodies and increased frequencies of gamma interferon-producing CD4 T cells severalfold. Thus, PLG microparticles are an effective means of delivering DNA vaccines in nonhuman primates, as demonstrated for two different types of DNA vaccines encoding two different antigens, and are compatible for use with DNA prime-protein boost regimens.

  13. Natural immune boosting in pertussis dynamics and the potential for long-term vaccine failure.

    PubMed

    Lavine, Jennie S; King, Aaron A; Bjørnstad, Ottar N

    2011-04-26

    Incidence of whooping cough, unlike many other childhood diseases for which there is an efficacious vaccine, has been increasing over the past twenty years despite high levels of vaccine coverage. Its reemergence has been particularly noticeable among teenagers and adults. Many hypotheses have been put forward to explain these two patterns, but parsimonious reconciliation of clinical data on the limited duration of immunity with both pre- and postvaccine era age-specific incidence remains a challenge. We consider the immunologically relevant, yet epidemiologically largely neglected, possibility that a primed immune system can respond to a lower dose of antigen than a naive one. We hypothesize that during the prevaccine era teenagers' and adults' primed immunity was frequently boosted by reexposure, so maintaining herd immunity in the face of potentially eroding individual immunity. In contrast, low pathogen circulation in the current era, except during epidemic outbreaks, allows immunity to be lost before reexposure occurs. We develop and analyze an age-structured model that encapsulates this hypothesis. We find that immune boosting must be more easily triggered than primary infection to account for age-incidence data. We make age-specific and dynamical predictions through bifurcation analysis and simulation. The boosting model proposed here parsimoniously captures four key features of pertussis data from highly vaccinated countries: (i) the shift in age-specific incidence, (ii) reemergence with high vaccine coverage, (iii) the possibility for cyclic dynamics in the pre- and postvaccine eras, and (iv) the apparent shift from susceptible-infectious-recovered (SIR)-like to susceptible-infectious-recovered-susceptible (SIRS)-like phenomenology of infection and immunity to Bordetella pertussis.

  14. Liver transplantation for hepatitis B: what is the best hepatitis B immune globulin/antiviral regimen?

    PubMed

    Angus, Peter W; Patterson, Scott J

    2008-10-01

    1. Prophylaxis using the combination of lamivudine and high-dose intravenous hepatitis B immunoglobulin (approximately 10,000 IU monthly) reduces the long-term risk of recurrence of hepatitis B in hepatitis B surface antigen-positive transplant recipients to 5% to 10%. However, this therapy is expensive and inconvenient for patients. 2. Recent studies have shown that similar results can be obtained, at far less cost, with much lower doses of intramuscular hepatitis B immune globulin (400-800 IU monthly) in combination with pretransplant and posttransplant lamivudine therapy. 3. The development of lamivudine resistance pre-transplant can lead to hepatic decompensation and increases the risk of posttransplant recurrence in patients receiving hepatitis B immune globulin/lamivudine prophylaxis. Newer nucleos(t)ide analogues with lower resistance rates such as entecavir, adefovir, and tenofovir should therefore replace lamivudine in hepatitis B prophylaxis. 4. Combination therapy with these newer agents and low-dose intramuscular hepatitis B immune globulin is likely to be the most cost effective hepatitis B immune globulin-containing regimen for the prevention of hepatitis B recurrence post-transplant. 5. Some form of hepatitis B virus prophylaxis needs be continued indefinitely post-transplant. However, the use of antivirals with very low rates of drug resistance will make it possible to stop hepatitis B immune globulin therapy in many patients currently receiving hepatitis B immune globulin/nucleos(t)ide combination therapy.

  15. Presentation of antigen in immune complexes is boosted by soluble bacterial immunoglobulin binding proteins.

    PubMed

    Léonetti, M; Galon, J; Thai, R; Sautès-Fridman, C; Moine, G; Ménez, A

    1999-04-19

    Using a snake toxin as a proteic antigen (Ag), two murine toxin-specific monoclonal antibodies (mAbs), splenocytes, and two murine Ag-specific T cell hybridomas, we showed that soluble protein A (SpA) from Staphylococcus aureus and protein G from Streptococcus subspecies, two Ig binding proteins (IBPs), not only abolish the capacity of the mAbs to decrease Ag presentation but also increase Ag presentation 20-100-fold. Five lines of evidence suggest that this phenomenon results from binding of an IBP-Ab-Ag complex to B cells possessing IBP receptors. First, we showed that SpA is likely to boost presentation of a free mAb, suggesting that the IBP-boosted presentation of an Ag in an immune complex results from the binding of IBP to the mAb. Second, FACS analyses showed that an Ag-Ab complex is preferentially targeted by SpA to a subpopulation of splenocytes mainly composed of B cells. Third, SpA-dependent boosted presentation of an Ag-Ab complex is further enhanced when splenocytes are enriched in cells containing SpA receptors. Fourth, the boosting effect largely diminishes when splenocytes are depleted of cells containing SpA receptors. Fifth, the boosting effect occurs only when IBP simultaneously contains a Fab and an Fc binding site. Altogether, our data suggest that soluble IBPs can bridge immune complexes to APCs containing IBP receptors, raising the possibility that during an infection process by bacteria secreting these IBPs, Ag-specific T cells may activate IBP receptor-containing B cells by a mechanism of intermolecular help, thus leading to a nonspecific immune response.

  16. Mathematical modeling and analysis of combinational immune boost for tumor elimination

    NASA Astrophysics Data System (ADS)

    Nakada, Naoki; Nagata, Mizuho; Takeuchi, Yasuhiro; Nakaoka, Shinji

    2016-04-01

    The immune system has an ability to recognize tumor as non-self antigen, and initiates inflammatory response to eliminate tumor. A dendritic cell (DCs) population is one of immune cell subsets that specifically uptakes foreign antigen and then presents to T cells. Dendritic cell boost ex vivo is operated to enhance immune response against tumor that in general comes to fail due to several complex reasons. Although dendritic cell therapy has been operated in clinical trials by boosting tumor immune responses, less is known about dynamic behaviors generated by interactions among immune cell subsets and tumor cells. In this paper, we construct and analyze a mathematical model describing tumor killing by T cells activated by dendritic cells. A handling time representing a waiting time required for T cells to be activated during antigen presentation is incorporated in our model. Mathematical analyses imply that successful tumor elimination depends on the amount of T cells activated ex vivo when introduced. Moreover, numerical simulations imply that an immune escape basin in which tumor can escape from T cell responses increases when the handling time increases, indicating that efficient tumor elimination might result in immediate T cell inactivation due to rapid decline of antigenic stimulation.

  17. Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens

    PubMed Central

    López-Cortés, Luis F.; Castaño, Manuel A.; López-Ruz, Miguel A.; Rios-Villegas, María J.; Hernández-Quero, José; Merino, Dolores; Jiménez-Aguilar, Patricia; Marquez-Solero, Manuel; Terrón-Pernía, Alberto; Tellez-Pérez, Francisco; Viciana, Pompeyo; Orihuela-Cañadas, Francisco; Palacios-Baena, Zaira; Vinuesa-Garcia, David; Fajardo-Pico, Jose M.; Romero-Palacios, Alberto; Ojeda-Burgos, Guillermo; Pasquau-Liaño, Juan

    2016-01-01

    Background and Objective Significant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens. Methods This retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). Results A total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8−81.8) and 91.5% (CI95, 89.6–93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations. Conclusion Switching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for

  18. Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers.

    PubMed

    Joachim, Agricola; Munseri, Patricia J; Nilsson, Charlotta; Bakari, Muhammad; Aboud, Said; Lyamuya, Eligius F; Tecleab, Teghesti; Liakina, Valentina; Scarlatti, Gabriella; Robb, Merlin L; Earl, Patricia L; Moss, Bernard; Wahren, Britta; Mhalu, Fred; Ferrari, Guido; Sandstrom, Eric; Biberfeld, Gunnel

    2017-01-27

    We explored the duration of immune responses and the effect of a late third HIV-modified vaccinia virus Ankara (MVA) boost in HIV-DNA primed and HIV-MVA boosted Tanzanian volunteers. Twenty volunteers who had previously received three HIV-DNA and two HIV-MVA immunizations were given a third HIV-MVA immunization 3 years after the second HIV-MVA boost. At the time of the third HIV-MVA, 90% of the vaccinees had antibodies to HIV-1 subtype C gp140 (median titer 200) and 85% to subtype B gp160 (median titer 100). The majority of vaccinees had detectable antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, 70% against CRF01_AE virus-infected cells (median titer 239) and 84% against CRF01_AE gp120-coated cells (median titer 499). A high proportion (74%) of vaccinees had IFN-γ ELISpot responses, 63% to Gag and 42% to Env, 3 years after the second HIV-MVA boost. After the third HIV-MVA, there was an increase in Env-binding antibodies and ADCC-mediating antibodies relative to the response seen at the time of the third HIV-MVA vaccination, p < .0001 and p < .05, respectively. The frequency of IFN-γ ELISpot responses increased to 95% against Gag or Env and 90% to both Gag and Env, p = .064 and p = .002, respectively. In conclusion, the HIV-DNA prime/HIV-MVA boost regimen elicited potent antibody and cellular immune responses with remarkable durability, and a third HIV-MVA immunization significantly boosted both antibody and cellular immune responses relative to the levels detected at the time of the third HIV-MVA, but not to higher levels than after the second HIV-MVA.

  19. Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

    PubMed Central

    Townsley, Samantha; Mohamed, Zeinab; Guo, Wenjin; McKenna, Jennifer; Cleveland, Brad; LaBranche, Celia; Beaumont, David; Shen, Xiaoying; Yates, Nicole L.; Pinter, Abraham; Tomaras, Georgia D.; Ferrari, Guido; Montefiori, David C.

    2016-01-01

    ABSTRACT Poxvirus prime-protein boost used in the RV144 trial remains the only immunization strategy shown to elicit a modest level of protection against HIV-1 acquisition in humans. Although neutralizing antibodies (NAb) were generated, they were against sensitive viruses, not the more resistant “tier 2” isolates that dominate circulating strains. Instead, risk reduction correlated with antibodies recognizing epitopes in the V1/V2 region of HIV-1 envelope glycoprotein (Env). Here, we examined whether tier 2 virus NAb and V1/V2-specific non-NAb could be elicited by a poxvirus prime-gp120 boost strategy in a rabbit model. We studied two clade B Envs that differ in multiple parameters, including tissue origin, neutralization sensitivity, and presence of the N197 (N7) glycan that was previously shown to modulate the exposure of conserved epitopes on Env. We demonstrate that immunized rabbits generated cross-reactive neutralizing activities against >50% of the tier 2 global HIV-1 isolates tested. Some of these activities were directed against the CD4 binding site (CD4bs). These rabbits also generated antibodies that recognized protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. However, there are subtle differences in the specificities and the response rates of V1/V2-specific antibodies between animals immunized with different Envs, with or without the N7 glycan. These findings demonstrate that antibody responses that have been correlated with protection against HIV-1 acquisition in humans can be elicited in a preclinical model by a poxvirus prime-gp120 boost strategy and that improvements may be achievable by optimizing the nature of the priming and boosting immunogens. IMPORTANCE The only vaccine approach shown to elicit any protective efficacy against HIV-1 acquisition is based on a poxvirus prime-protein boost regimen (RV144 Thai trial). Reduction of risk was associated with

  20. Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients

    SciTech Connect

    Penoncello, Gregory P.; Ding, George X.

    2016-04-01

    The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2 cm{sup 3} for head and neck plans and brain plans and a contiguous volume of 5 cm{sup 3} for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens.

  1. Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients.

    PubMed

    Penoncello, Gregory P; Ding, George X

    2016-01-01

    The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2cm(3) for head and neck plans and brain plans and a contiguous volume of 5cm(3) for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens.

  2. Immunogenicity analysis following human immunodeficiency virus recombinant DNA and recombinant vaccinia virus Tian Tan prime-boost immunization.

    PubMed

    Liu, Cunxia; Du, Shouwen; Li, Chang; Wang, Yuhang; Wang, Maopeng; Li, Yi; Yin, Ronglan; Li, Xiao; Ren, Dayong; Qin, Yanqing; Ren, Jingqiang; Jin, Ningyi

    2013-06-01

    This study assessed and compared the immunogenicity of various immunization strategies in mice using combinations of recombinant DNA (pCCMp24) and recombinant attenuated vaccinia virus Tian Tan (rddVTT-CCMp24). Intramuscular immunization was performed on days 0 (prime) and 21 (boost). The immunogenicity of the vaccine schedules was determined by measuring human immunodeficiency virus (HIV)-specific binding antibody levels and cytokine (interleukin-2 and interleukin-4) concentrations in peripheral blood, analyzing lymphocyte proliferation capacity against HIV epitopes and CD4(+)/CD8(+) cell ratio, and monitoring interferon-gamma levels at different times post-immunization. The results showed that pCCMp24, rddVTT-CCMp24 and their prime-boost immunization induced humoral and cellular immune responses. The pCCMp24/rddVTT-CCMp24 immunization strategy increased CD8(+) T cells and induced more IFN-γ-secreting cells compared with single-shot rDNA. The prime-boost immunization strategy also induced the generation of cellular immunological memory to HIV epitope peptides. These results demonstrated that prime-boost immunization with rDNA and rddVTT-CCMp24 had a tendency to induce greater cellular immune response than single-shot vaccinations, especially IFN-γ response, providing a basis for further studies.

  3. [A kinetic study of gamma interferon production in herpes simplex virus-1 DNA prime-protein boost regimen comparing to DNA or subunit vaccination].

    PubMed

    Arefian, Ehsan; Bamdad, Taravat; Soleimanjahi, Hoorieh; Akhood, Mohamad Reza; Parsania, Masaoud; Ghaemi, Amir

    2009-01-01

    The vast majority of the world's population is infected with Herpes simplex virus (HSV). Although antiviral therapy can reduce the incidence of reactivation and asymptomatic viral shedding, and limit morbidity and mortality from active disease, it cannot cure infection. Therefore, the development of an effective vaccine is an important global health priority. In this study, the induction of IFN-gamma production was compared by different herpes simplex virus 1 (HSV1) vaccines. Glycoprotein D (gD1) as a major immunogenic HSV1 glycoprotein was chosen to our study. Balb/c mice were administered with DNA vaccine encoding gD1, subunit glycoprotein vaccine including insect cells infected by a gD1 recombinant Baculovirus, prime DNA vaccine boosted by subunit glycoprotein vaccine, inactivated KOS strain as a positive control, PcDNA3 plasmid and Sf9 cells as a negative control. Evaluation tests showed kinetics of IFN-gamma mRNA at 8, 16 and 32 hours after restimulation sharply decreased whereas, IFN-gamma protein is significantly increased. Our results revealed that at 14 days after immunization IFN-gamma secretion of stimulated cells in all of the vaccinate groups dramatically raised rather than secreted IFN-gamma levels in mice that were analyzed at 7 days after vaccination. In comparison to other groups; Prime-Boost immunization dramatically caused vigorous and prompt IFN-gamma production at 7 days after immunization and 8 hours after restimulation.

  4. Perforin and gamma interferon expression are required for CD4+ and CD8+ T-cell-dependent protective immunity against a human parasite, Trypanosoma cruzi, elicited by heterologous plasmid DNA prime-recombinant adenovirus 5 boost vaccination.

    PubMed

    de Alencar, Bruna C G; Persechini, Pedro M; Haolla, Filipe A; de Oliveira, Gabriel; Silverio, Jaline C; Lannes-Vieira, Joseli; Machado, Alexandre V; Gazzinelli, Ricardo T; Bruna-Romero, Oscar; Rodrigues, Mauricio M

    2009-10-01

    A heterologous prime-boost strategy using plasmid DNA, followed by replication-defective recombinant adenovirus 5, is being proposed as a powerful way to elicit CD4(+) and CD8(+) T-cell-mediated protective immunity against intracellular pathogens. We confirmed this concept and furthered existing research by providing evidence that the heterologous prime-boost regimen using the gene encoding amastigote surface protein 2 elicited CD4(+) and CD8(+) T-cell-mediated protective immunity (reduction of acute parasitemia and prolonged survival) against experimental infection with Trypanosoma cruzi. Protective immunity correlated with the presence of in vivo antigen-specific cytotoxic activity prior to challenge. Based on this, our second goal was to determine the outcome of infection after heterologous prime-boost immunization of perforin-deficient mice. These mice were highly susceptible to infection. A detailed analysis of the cell-mediated immune responses in immunized perforin-deficient mice showed an impaired gamma interferon (IFN-gamma) secretion by immune spleen cells upon restimulation in vitro with soluble recombinant antigen. In spite of a normal numeric expansion, specific CD8(+) T cells presented several functional defects detected in vivo (cytotoxicity) and in vitro (simultaneous expression of CD107a/IFN-gamma or IFN-gamma/tumor necrosis factor alpha) paralleled by a decreased expression of CD44 and KLRG-1. Our final goal was to determine the importance of IFN-gamma in the presence of highly cytotoxic T cells. Vaccinated IFN-gamma-deficient mice developed highly cytotoxic cells but failed to develop any protective immunity. Our study thus demonstrated a role for perforin and IFN-gamma in a number of T-cell-mediated effector functions and in the antiparasitic immunity generated by a heterologous plasmid DNA prime-adenovirus boost vaccination strategy.

  5. Perforin and Gamma Interferon Expression Are Required for CD4+ and CD8+ T-Cell-Dependent Protective Immunity against a Human Parasite, Trypanosoma cruzi, Elicited by Heterologous Plasmid DNA Prime-Recombinant Adenovirus 5 Boost Vaccination▿

    PubMed Central

    de Alencar, Bruna C. G.; Persechini, Pedro M.; Haolla, Filipe A.; de Oliveira, Gabriel; Silverio, Jaline C.; Lannes-Vieira, Joseli; Machado, Alexandre V.; Gazzinelli, Ricardo T.; Bruna-Romero, Oscar; Rodrigues, Mauricio M.

    2009-01-01

    A heterologous prime-boost strategy using plasmid DNA, followed by replication-defective recombinant adenovirus 5, is being proposed as a powerful way to elicit CD4+ and CD8+ T-cell-mediated protective immunity against intracellular pathogens. We confirmed this concept and furthered existing research by providing evidence that the heterologous prime-boost regimen using the gene encoding amastigote surface protein 2 elicited CD4+ and CD8+ T-cell-mediated protective immunity (reduction of acute parasitemia and prolonged survival) against experimental infection with Trypanosoma cruzi. Protective immunity correlated with the presence of in vivo antigen-specific cytotoxic activity prior to challenge. Based on this, our second goal was to determine the outcome of infection after heterologous prime-boost immunization of perforin-deficient mice. These mice were highly susceptible to infection. A detailed analysis of the cell-mediated immune responses in immunized perforin-deficient mice showed an impaired gamma interferon (IFN-γ) secretion by immune spleen cells upon restimulation in vitro with soluble recombinant antigen. In spite of a normal numeric expansion, specific CD8+ T cells presented several functional defects detected in vivo (cytotoxicity) and in vitro (simultaneous expression of CD107a/IFN-γ or IFN-γ/tumor necrosis factor alpha) paralleled by a decreased expression of CD44 and KLRG-1. Our final goal was to determine the importance of IFN-γ in the presence of highly cytotoxic T cells. Vaccinated IFN-γ-deficient mice developed highly cytotoxic cells but failed to develop any protective immunity. Our study thus demonstrated a role for perforin and IFN-γ in a number of T-cell-mediated effector functions and in the antiparasitic immunity generated by a heterologous plasmid DNA prime-adenovirus boost vaccination strategy. PMID:19651871

  6. Ginseng, the 'Immunity Boost': The Effects of Panax ginseng on Immune System

    PubMed Central

    Kang, Soowon; Min, Hyeyoung

    2012-01-01

    Thousands of literatures have described the diverse role of ginseng in physiological processes such as cancer, neurodegenerative disorders, insulin resistance, and hypertension. In particular, ginseng has been extensively reported to maintain homeostasis of the immune system and to enhance resistance to illness or microbial attacks through the regulation of immune system. Immune system comprises of different types of cells fulfilling their own specialized functions, and each type of the immune cells is differentially influenced and may be simultaneously controlled by ginseng treatment. This review summarizes the current knowledge on the effects of ginseng on immune system. We discuss how ginseng regulates each type of immune cells including macrophages, natural killer cells, dendritic cells, T cells, and B cells. We also describe how ginseng exhibits beneficial effects on controlling inflammatory diseases and microbial infections. PMID:23717137

  7. Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8 T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice.

    PubMed

    Hu, Zhidong; Wong, Ka-Wing; Zhao, Hui-Min; Wen, Han-Li; Ji, Ping; Ma, Hui; Wu, Kang; Lu, Shui-Hua; Li, Feng; Li, Zhong-Ming; Shu, Tsugumine; Xu, Jian-Qing; Lowrie, Douglas B; Fan, Xiao-Yong

    2017-03-22

    Accumulating evidence has shown the protective role of CD8(+) T cells in vaccine-induced immunity against Mycobacterium tuberculosis (Mtb) despite controversy over their role in natural immunity. However, the current vaccine BCG is unable to induce sufficient CD8(+) T cell responses, especially in the lung. Sendai virus, a respiratory RNA virus, is here engineered firstly as a novel recombinant anti-TB vaccine (SeV85AB) that encodes Mtb immuno-dominant antigens, Ag85A and Ag85B. A single mucosal vaccination elicited potent antigen-specific T cell responses and a degree of protection against Mtb challenge similar to the effect of BCG in mice. Depletion of CD8(+) T cells abrogated the protective immunity afforded by SeV85AB vaccination. Interestingly, only SeV85AB vaccination induced high levels of lung-resident memory CD8(+) T (TRM) cells, and this led to a rapid and strong recall of antigen-specific CD8(+) T cell responses against Mtb challenge infection. Furthermore, when used in a BCG prime-SeV85AB boost strategy, SeV85AB vaccine significantly enhanced protection above that seen after BCG vaccination alone. Our findings suggest that CD8(+) TRM cells that arise in lungs responding to this mucosal vaccination might help to protect against TB, and SeV85AB holds notable promise to improve BCG's protective efficacy in a prime-boost immunization regimen.

  8. Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients

    PubMed Central

    2014-01-01

    Background Alpha fetoprotein (AFP) is an oncofetal antigen over-expressed by many hepatocellular cancers (HCC). We previously demonstrated that HLA-A2-restricted epitopes derived from AFP are immunogenic in vitro and in vivo despite high circulating levels of this oncofetal antigen. In order to test a more broadly applicable, HLA-unrestricted, inexpensive, cell-free vaccine platform capable of activating tumor antigen-specific CD8+ and CD4+ T cells, we tested full length AFP in a plasmid DNA construct in combination with an AFP-expressing replication-deficient adenovirus (AdV) in a prime-boost vaccine strategy. Methods HCC patients who had an AFP+ tumor and previous treatment for HCC were screened and two patients received vaccination with three plasmid DNA injections followed by a single AdV injection, all delivered intramuscularly (i.m.). Results The vaccine was well tolerated and safe. Both patients showed immunologic evidence of immunization. The first patient had a weak AFP-specific T cell response, a strong AdV-specific cellular response and recurred with an AFP-expressing HCC at nine months. The second patient developed a strong AFP-specific CD8+ and CD4+ cellular response and an AdV neutralizing antibody response, and recurred at 18 months without an increase in serum AFP. Conclusions The AFP DNA prime-AdV boost vaccine was safe and immunogenic. Circulating anti-AdV neutralizing antibodies at baseline did not prohibit the development of AFP-specific cellular immunity. The patient who developed CD8+ and CD4+ AFP-specific T cell immunity had more favorable progression-free survival. The observations with these two patients support development of this vaccine strategy in a larger clinical trial. Trial registration ClinicalTrials.gov: NCT00093548 PMID:24708667

  9. T cells induced by recombinant chimpanzee adenovirus alone and in prime-boost regimens decrease chimeric EcoHIV/NDK challenge virus load.

    PubMed

    Roshorm, Yaowaluck; Cottingham, Mathew G; Potash, Mary-Jane; Volsky, David J; Hanke, Tomáš

    2012-12-01

    The popularity of nonreplicating adenoviruses of chimpanzee origin (ChAdVs) as vectors for subunit vaccines is on the rise. This is mainly for their excellent safety and impressive immunogenicity observed in human studies to date. Here, we recloned the chimpanzee adenovirus sero type 68 (ChAdV-68), also designated SAdV-25 and AdC68, genome and demonstrated its straightforward genetic manipulation facilitated by the use of bacterial artificial chromosome recombineering. To generate the ChAdV68.GagB vaccine, the HIV-1 consensus clade B Gag-derived Tg was inserted into the E1 region. In part confirming previous observations, the ChAdV68.GagB vaccine alone and in heterologous prime-boost regimens with plasmid DNA- and modified vaccinia virus Ankara (MVA)-vectored vaccines induced robust polyfunctional HIV-1-specific CD8(+) and CD4(+) T-cell responses with a gut-homing phenotype. Importantly, we showed that when a single epitope is expressed as an immunodominant CD8(+) T-cell determinant, responses elicited by ChAdV68.GagB alone and in combination lowered surrogate challenge EcoHIV/NDK (where EcoHIV is chimeric ecotropic HIV) virus load in mice both at the peak T-cell frequencies 2 weeks after vaccination and 16 weeks later indicating development of protective effector memory. These results parallel the immunogenicity of similar vaccine regimens in macaques and an ongoing phase I/IIa trial in humans, and support further development of vaccines vectored by ChAdVs.

  10. Induction of multi-antigen multi-stage immune responses against Plasmodium falciparum in rhesus monkeys, in the absence of antigen interference, with heterologous DNA prime/poxvirus boost immunization

    PubMed Central

    Jiang, George; Charoenvit, Yupin; Moreno, Alberto; Baraceros, Maria F; Banania, Glenna; Richie, Nancy; Abot, Steve; Ganeshan, Harini; Fallarme, Victoria; Patterson, Noelle B; Geall, Andrew; Weiss, Walter R; Strobert, Elizabeth; Caro-Aquilar, Ivette; Lanar, David E; Saul, Allan; Martin, Laura B; Gowda, Kalpana; Morrissette, Craig R; Kaslow, David C; Carucci, Daniel J; Galinski, Mary R; Doolan, Denise L

    2007-01-01

    The present study has evaluated the immunogenicity of single or multiple Plasmodium falciparum (Pf) antigens administered in a DNA prime/poxvirus boost regimen with or without the poloxamer CRL1005 in rhesus monkeys. Animals were primed with PfCSP plasmid DNA or a mixture of PfCSP, PfSSP2/TRAP, PfLSA1, PfAMA1 and PfMSP1-42 (CSLAM) DNA vaccines in PBS or formulated with CRL1005, and subsequently boosted with ALVAC-Pf7, a canarypox virus expressing the CSLAM antigens. Cell-mediated immune responses were evaluated by IFN-γ ELIspot and intracellular cytokine staining, using recombinant proteins and overlapping synthetic peptides. Antigen-specific and parasite-specific antibody responses were evaluated by ELISA and IFAT, respectively. Immune responses to all components of the multi-antigen mixture were demonstrated following immunization with either DNA/PBS or DNA/CRL1005, and no antigen interference was observed in animals receiving CSLAM as compared to PfCSP alone. These data support the down-selection of the CSLAM antigen combination. CRL1005 formulation had no apparent effect on vaccine-induced T cell or antibody responses, either before or after viral boost. In high responder monkeys, CD4+IL-2+ responses were more predominant than CD8+ T cell responses. Furthermore, CD8+ IFN-γ responses were detected only in the presence of detectable CD4+ T cell responses. Overall, this study demonstrates the potential for multivalent Pf vaccines based on rational antigen selection and combination, and suggests that further formulation development to increase the immunogenicity of DNA encoded antigens is warranted. PMID:17925026

  11. Enhancement of survivin-specific anti-tumor immunity by adenovirus prime protein-boost immunity strategy with DDA/MPL adjuvant in a murine melanoma model.

    PubMed

    Wang, Yu-Qian; Zhang, Hai-Hong; Liu, Chen-Lu; Wu, Hui; Wang, Peng; Xia, Qiu; Zhang, Li-Xing; Li, Bo; Wu, Jia-Xin; Yu, Bin; Gu, Tie-Jun; Yu, Xiang-Hui; Kong, Wei

    2013-09-01

    As an ideal tumor antigen, survivin has been widely used for tumor immunotherapy. Nevertheless, no effective protein vaccine targeting survivin has been reported, which may be due to its poor ability to induce cellular immunity. Thus, a suitable immunoadjuvant and optimized immunization strategy can greatly enhance the cellular immune response to this protein vaccine. DDA/MPL (monophosphoryl lipid A formulated with cationic dimethyldioctadecylammonium) has been reported to enhance the antigen uptake and presentation to T cells as an adjuvant. Meanwhile, a heterologous prime-boost strategy can enhance the cellular immunity of a protein vaccine by applying different antigen-presenting systems. Here, DDA/MPL and an adenovirus prime-protein boost strategy were applied to enhance the specific anti-tumor immunity of a truncated survivin protein vaccine. Antigen-specific IFN-γ-secreting T cells were increased by 10-fold, and cytotoxic T lympohocytes (CTLs) were induced effectively when the protein vaccine was combined with the DDA/MPL adjuvant. Meanwhile, the Th1 type cellular immune response was strongly enhanced and tumor inhibition was significantly increased by 96% with the adenovirus/protein prime-boost strategy, compared to the protein homologous prime-boost strategy. Moreover, this adjuvanted heterologous prime-boost strategy combined with oxaliplatin could significantly enhance the efficiency of tumor growth inhibition through promoting the proliferation of splenocytes. Thus, our results provide a novel vaccine strategy for cancer therapy using an adenovirus prime-protein boost strategy in a murine melanoma model, and its combination with oxaliplatin may further enhance the anti-tumor efficacy while alleviating side effects of the drug.

  12. Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination.

    PubMed

    Smith, K A; Qiu, Z; Wong, R; Tam, V L; Tam, B L; Joea, D K; Quach, A; Liu, X; Pold, M; Malyankar, U M; Bot, A

    2011-01-01

    Active immunotherapy of cancer has yet to yield effective therapies in the clinic. To evaluate the translatability of DNA-based vaccines we analyzed the profile of T-cell immunity by plasmid vaccination in a murine model, using transcriptome microarray analysis and flow cytometry. DNA vaccination resulted in specific T cells expressing low levels of co-inhibitory molecules (most notably PD-1), strikingly different from the expression profile elicited by peptide immunization. In addition, the T-cell response primed through this dual-antigen-expressing plasmid (MART-1/Melan-A and tyrosinase) translated into a substantial proliferation capacity and functional conversion to antitumor effector cells after tyrosinase and MART-1/Melan-A peptide analog boost. Furthermore, peptide boost rescued the immune response against the subdominant tyrosinase epitope. This immunization approach could be adapted to elicit potent immunity against multiple tumor antigens, resulting in a broader immune response that was more effective in targeting human tumor cells. Finally, this study sheds light on a novel mechanism of immune homeostasis through synchronous regulation of co-inhibitory molecules on T cells, highly relevant to heterologous prime boost approaches involving DNA vaccines as priming agents.

  13. Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

    NASA Astrophysics Data System (ADS)

    Komarova, Natalia L.; Barnes, Eleanor; Klenerman, Paul; Wodarz, Dominik

    2003-02-01

    Drug therapies against persistent human infections such as hepatitis C virus, hepatitis B virus, and HIV fail to consistently eradicate the infection from the host. Hence, recent emphasis has shifted to the study of antiviral therapy aimed at boosting specific immune responses. It was argued that structured therapy interruptions were required to achieve this, because such regimes have shown promising results in early HIV infection. Using mathematical models, we show that, contrary to this notion, a single phase of drug therapy can result in the establishment of sustained immunity. We present a simple relationship between timing of therapy and efficacy of the drugs required for success. In the presence of strong viral suppression, we show that therapy should be stopped relatively early, and that a longer duration of treatment leads to failure. On the other hand, in the presence of weaker viral suppression, stopping treatment too early is detrimental, and therapy has to be continued beyond a time threshold. We discuss our modeling results primarily in the context of HCV therapy during chronic infection. Although the therapy regimes explored here also have implications for HIV, virus-mediated destruction of specific immune cells renders success unlikely during the chronic phase of the infection.

  14. Metabolic engineering of Salmonella vaccine bacteria to boost human Vγ2Vδ2 T cell immunity.

    PubMed

    Workalemahu, Grefachew; Wang, Hong; Puan, Kia-Joo; Nada, Mohanad H; Kuzuyama, Tomohisa; Jones, Bradley D; Jin, Chenggang; Morita, Craig T

    2014-07-15

    Human Vγ2Vδ2 T cells monitor isoprenoid metabolism by recognizing foreign (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), a metabolite in the 2-C-methyl-D-erythritol-4-phosphate pathway used by most eubacteria and apicomplexan parasites, and self isopentenyl pyrophosphate, a metabolite in the mevalonate pathway used by humans. Whereas microbial infections elicit prolonged expansion of memory Vγ2Vδ2 T cells, immunization with prenyl pyrophosphates or aminobisphosphonates elicit short-term Vγ2Vδ2 expansion with rapid anergy and deletion upon subsequent immunizations. We hypothesized that a live, attenuated bacterial vaccine that overproduces HMBPP would elicit long-lasting Vγ2Vδ2 T cell immunity by mimicking a natural infection. Therefore, we metabolically engineered the avirulent aroA(-) Salmonella enterica serovar Typhimurium SL7207 strain by deleting the gene for LytB (the downstream enzyme from HMBPP) and functionally complementing for this loss with genes encoding mevalonate pathway enzymes. LytB(-) Salmonella SL7207 had high HMBPP levels, infected human cells as efficiently as did the wild-type bacteria, and stimulated large ex vivo expansions of Vγ2Vδ2 T cells from human donors. Importantly, vaccination of a rhesus monkey with live lytB(-) Salmonella SL7207 stimulated a prolonged expansion of Vγ2Vδ2 T cells without significant side effects or anergy induction. These studies provide proof-of-principle that metabolic engineering can be used to derive live bacterial vaccines that boost Vγ2Vδ2 T cell immunity. Similar engineering of metabolic pathways to produce lipid Ags or B vitamin metabolite Ags could be used to derive live bacterial vaccine for other unconventional T cells that recognize nonpeptide Ags.

  15. Fewer doses of HPV vaccine result in immune response similar to three-dose regimen

    Cancer.gov

    NCI scientists report that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody levels against two of the most carcinogenic types of HPV (16 and 18), compared to a standard three dose regimen.

  16. Prime-boost vaccination with Bacillus Calmette Guerin and a recombinant adenovirus co-expressing CFP10, ESAT6, Ag85A and Ag85B of Mycobacterium tuberculosis induces robust antigen-specific immune responses in mice.

    PubMed

    Li, Wu; Li, Min; Deng, Guangcun; Zhao, Liping; Liu, Xiaoming; Wang, Yujiong

    2015-08-01

    Tuberculosis (TB) remains to be a prevalent health issue worldwide. At present, Mycobacterium bovis Bacillus Calmette Guerin (BCG) is the singular anti-TB vaccine available for the prevention of disease in humans; however, this vaccine only provides limited protection against Mycobacterium tuberculosis (Mtb) infection. Therefore, the development of alternative vaccines and strategies for increasing the efficacy of vaccination against TB are urgently required. The present study aimed to evaluate the ability of a recombinant adenoviral vector (Ad5-CEAB) co-expressing 10-kDa culture filtrate protein, 6-kDa early-secreted antigenic target, antigen 85 (Ag85)A and Ag85B of Mtb to boost immune responses following primary vaccination with BCG in mice. The mice were first subcutaneously primed with BCG and boosted with two doses of Ad5-CEAB via an intranasal route. The immunological effects of Ad5-CEAB boosted mice primed with BCG were then evaluated using a series of immunological indexes. The results demonstrated that the prime-boost strategy induced a potent antigen-specific immune response, which was primarily characterized by an enhanced T cell response and increased production of cytokines, including interferon-γ, tumor necrosis factor-α and interleukin-2, in mice. In addition, this vaccination strategy was demonstrated to have an elevated humoral response with increased concentrations of antigen-specific bronchoalveolar lavage secretory immunoglobulin (Ig)A and serum IgG in mice compared with those primed with BCG alone. These data suggested that the regimen of subcutaneous BCG prime and mucosal Ad5-CEAB boost was a novel strategy for inducing a broad range of antigen-specific immune responses to Mtb antigens in vivo, which may provide a promising strategy for further development of adenoviral-based vaccine against Mtb infection.

  17. Immune responses in mice induced by prime-boost schemes of the Plasmodium falciparum apical membrane antigen 1 (PfAMA1)-based DNA, protein and recombinant modified vaccinia Ankara vaccines.

    PubMed

    Miao, Jun; Li, Xun; Liu, Zhongxiang; Xue, Caifang; Bujard, Hermann; Cui, Liwang

    2006-09-11

    The apical membrane antigen 1 (AMA1) of malaria parasites is a leading vaccine candidate. Its expression in merozoites and sporozoites and its importance for erythrocyte and hepatocyte invasion underline the significance of both humoral and cellular immunities against this antigen in malaria protection. We have generated a DNA construct and a recombinant poxvirus (rMVA) for expressing the Plasmodium falciparum AMA1 ectodomain, produced recombinant AMA1 protein (rAMA1) and evaluated their antigenicity in mice using single and combinatory vaccine schemes. Our results showed that although vaccinations of mice by either DNA or rMVA alone did not yield high antibody responses, they had primed significant numbers of rAMA1-responsive splenocytes. Under heterologous prime-boost schemes, priming with DNA followed by boosting with rMVA or rAMA1 protein resulted in a significant increase in antibody titers. In addition, the antibody titers to AMA1 appeared to be correlated with the levels of inhibition of merozoite invasion of erythrocytes in vitro. Furthermore, different prime-boost schemes resulted in different AMA1-specific antibody isotype (IgG1/IgG2a) ratios, providing us with an indication about Th1 or Th2 responses the vaccination regimens have induced. This study has yielded useful information for further in vivo evaluation of the suitability and effectiveness of the heterologous prime-boost strategy in AMA1 vaccination.

  18. Breastmilk-Saliva Interactions Boost Innate Immunity by Regulating the Oral Microbiome in Early Infancy

    PubMed Central

    Al-Shehri, Saad S.; Knox, Christine L.; Liley, Helen G.; Cowley, David M.; Wright, John R.; Henman, Michael G.; Hewavitharana, Amitha K.; Charles, Bruce G.; Shaw, Paul N.; Sweeney, Emma L.; Duley, John A.

    2015-01-01

    Introduction Xanthine oxidase (XO) is distributed in mammals largely in the liver and small intestine, but also is highly active in milk where it generates hydrogen peroxide (H2O2). Adult human saliva is low in hypoxanthine and xanthine, the substrates of XO, and high in the lactoperoxidase substrate thiocyanate, but saliva of neonates has not been examined. Results Median concentrations of hypoxanthine and xanthine in neonatal saliva (27 and 19 μM respectively) were ten-fold higher than in adult saliva (2.1 and 1.7 μM). Fresh breastmilk contained 27.3±12.2 μM H2O2 but mixing baby saliva with breastmilk additionally generated >40 μM H2O2, sufficient to inhibit growth of the opportunistic pathogens Staphylococcus aureus and Salmonella spp. Oral peroxidase activity in neonatal saliva was variable but low (median 7 U/L, range 2–449) compared to adults (620 U/L, 48–1348), while peroxidase substrate thiocyanate in neonatal saliva was surprisingly high. Baby but not adult saliva also contained nucleosides and nucleobases that encouraged growth of the commensal bacteria Lactobacillus, but inhibited opportunistic pathogens; these nucleosides/bases may also promote growth of immature gut cells. Transition from neonatal to adult saliva pattern occurred during the weaning period. A survey of saliva from domesticated mammals revealed wide variation in nucleoside/base patterns. Discussion and Conclusion During breast-feeding, baby saliva reacts with breastmilk to produce reactive oxygen species, while simultaneously providing growth-promoting nucleotide precursors. Milk thus plays more than a simply nutritional role in mammals, interacting with infant saliva to produce a potent combination of stimulatory and inhibitory metabolites that regulate early oral–and hence gut–microbiota. Consequently, milk-saliva mixing appears to represent unique biochemical synergism which boosts early innate immunity. PMID:26325665

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

    PubMed

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

    2008-04-01

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

  20. Fewer Doses of HPV Vaccine Result in Immune Response Similar to Three-Dose Regimen

    MedlinePlus

    ... Releases NCI News Note Fewer doses of HPV vaccine result in immune response similar to three-dose ... that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody ...

  1. Prime-boost vaccination with plasmid DNA followed by recombinant vaccinia virus expressing BgGARP induced a partial protective immunity to inhibit Babesia gibsoni proliferation in dogs.

    PubMed

    Cao, Shinuo; Mousa, Ahmed Abdelmoniem; Aboge, Gabriel Oluga; Kamyingkird, Ketsarin; Zhou, Mo; Moumouni, Paul Franck Adjou; Terkawi, Mohamad Alaa; Masatani, Tatsunori; Nishikawa, Yoshifumi; Suzuki, Hiroshi; Fukumoto, Shinya; Xuan, Xuenan

    2013-12-01

    A heterologous prime-boost vaccination regime with DNA and recombinant vaccinia virus (rvv) vectors expressing relevant antigens has been shown to induce effective immune responses against several infectious pathogens. In this study, we describe the effectiveness of the prime-boost strategy by immunizing dogs with a recombinant plasmid followed by vaccinia virus, both of which expressed the glutamic acid-rich protein (BgGARP) of Babesia gibsoni. The dogs immunized with the prime-boost regime developed a significantly high level of specific antibodies against BgGARP when compared with the control groups. The antibody level was strongly increased after a booster immunization with a recombinant vaccinia virus. Two weeks after the booster immunization with a recombinant vaccinia virus expressing BgGARP, the dogs were challenged with B. gibsoni parasite. The dogs immunized with the prime-boost regime showed partial protection, manifested as a significantly low level of parasitemia. These results indicated that this type of DNA/rvv prime-boost immunization approach may have use against B. gibsoni infection in dogs.

  2. Vaccine strategies against Babesia bovis based on prime-boost immunizations in mice with modified vaccinia Ankara vector and recombinant proteins.

    PubMed

    Jaramillo Ortiz, José Manuel; Del Médico Zajac, María Paula; Zanetti, Flavia Adriana; Molinari, María Paula; Gravisaco, María José; Calamante, Gabriela; Wilkowsky, Silvina Elizabeth

    2014-08-06

    In this study, a recombinant modified vaccinia virus Ankara vector expressing a chimeric multi-antigen was obtained and evaluated as a candidate vaccine in homologous and heterologous prime-boost immunizations with a recombinant protein cocktail. The chimeric multi-antigen comprises immunodominant B and T cell regions of three Babesia bovis proteins. Humoral and cellular immune responses were evaluated in mice to compare the immunogenicity induced by different immunization schemes. The best vaccination scheme was achieved with a prime of protein cocktail and a boost with the recombinant virus. This scheme induced high level of specific IgG antibodies and secreted IFN and a high degree of activation of IFNγ(+) CD4(+) and CD8(+) specific T cells. This is the first report in which a novel vaccine candidate was constructed based on a rationally designed multi-antigen and evaluated in a prime-boost regime, optimizing the immune response necessary for protection against bovine babesiosis.

  3. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

    PubMed Central

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  4. AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates.

    PubMed

    Jeyanathan, Mangalakumari; Shao, Zhongqi; Yu, Xuefeng; Harkness, Robin; Jiang, Rong; Li, Junqiang; Xing, Zhou; Zhu, Tao

    2015-01-01

    Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen-specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application.

  5. DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity

    DTIC Science & Technology

    2013-02-14

    adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. Methodology/Principal Findings: The vaccine regimen...falciparum malaria vaccine, in healthy, malaria -nave adults’’, work unit number 62787A 870 F 1432. The funders had no role in study design, data...fused to hepatitis B surface protein. RTS,S provides 50% protection against controlled human malaria infection, mediated primarily by the induction of

  6. Blocking Junctional Adhesion Molecule C Enhances Dendritic Cell Migration and Boosts the Immune Responses against Leishmania major

    PubMed Central

    Ballet, Romain; Emre, Yalin; Jemelin, Stéphane; Charmoy, Mélanie; Tacchini-Cottier, Fabienne; Imhof, Beat A.

    2014-01-01

    The recruitment of dendritic cells to sites of infections and their migration to lymph nodes is fundamental for antigen processing and presentation to T cells. In the present study, we showed that antibody blockade of junctional adhesion molecule C (JAM-C) on endothelial cells removed JAM-C away from junctions and increased vascular permeability after L. major infection. This has multiple consequences on the output of the immune response. In resistant C57BL/6 and susceptible BALB/c mice, we found higher numbers of innate immune cells migrating from blood to the site of infection. The subsequent migration of dendritic cells (DCs) from the skin to the draining lymph node was also improved, thereby boosting the induction of the adaptive immune response. In C57BL/6 mice, JAM-C blockade after L. major injection led to an enhanced IFN-γ dominated T helper 1 (Th1) response with reduced skin lesions and parasite burden. Conversely, anti JAM-C treatment increased the IL-4-driven T helper 2 (Th2) response in BALB/c mice with disease exacerbation. Overall, our results show that JAM-C blockade can finely-tune the innate cell migration and accelerate the consequent immune response to L. major without changing the type of the T helper cell response. PMID:25474593

  7. Immune response to 1 and 2 dose regimens of measles vaccine in Pakistani children.

    PubMed

    Hussain, Hamidah; Akram, Dure Samin; Chandir, Subhash; Khan, Aamir J; Memon, Ashraf; Halsey, Neal A

    2013-12-01

    Measles is a significant problem in Pakistan despite vaccine coverage rates reported at 80%. The purpose of this study was to determine the serologic response in children after one dose of measles vaccine at 9 mo versus two doses at 9 and 15 mo of age. From March through December 2006, children were enrolled from immunization clinics and squatter settlements in Karachi. Blood samples were taken from children in Group A at 9-10 mo of age prior to measles vaccine and 8 to 11 weeks later; from children in Group B at 16-17 mo of age after receiving 2 doses of measles vaccine; and from children in Group C who had received at least one dose of measles vaccine by 5 y of age. After the first dose of measles vaccine, 107/147 (73%) of children in Group A were seropositive, 157/180 (87%) of children in Group B were seropositive after two doses and 126/200 (63%) of children in Group C were seropositive at 5 y of age. The post-vaccination geometric mean antibody concentrations were higher in females than males in groups A (irrespective of pre-vaccination antibody levels) and B. The serologic response to one and two doses of measles vaccine was lower in children in Karachi than has been reported in many other countries. Two doses of vaccine were significantly better than one dose. An in-depth investigation is needed to determine the reason for the lower-than-expected protection rates. Differences in immunogenicity between genders need to be further studied. Recent introduction of supplemental measles vaccine doses should help control measles in Pakistan.

  8. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.

    PubMed

    Arriola Apelo, Sebastian I; Neuman, Joshua C; Baar, Emma L; Syed, Faizan A; Cummings, Nicole E; Brar, Harpreet K; Pumper, Cassidy P; Kimple, Michelle E; Lamming, Dudley W

    2016-02-01

    Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

  9. Immunity, safety and protection of an Adenovirus 5 prime--Modified Vaccinia virus Ankara boost subunit vaccine against Mycobacterium avium subspecies paratuberculosis infection in calves.

    PubMed

    Bull, Tim J; Vrettou, Christina; Linedale, Richard; McGuinnes, Catherine; Strain, Sam; McNair, Jim; Gilbert, Sarah C; Hope, Jayne C

    2014-10-29

    Vaccination is the most cost effective control measure for Johne's disease caused by Mycobacterium avium subspecies paratuberculosis (MAP) but currently available whole cell killed formulations have limited efficacy and are incompatible with the diagnosis of bovine tuberculosis by tuberculin skin test. We have evaluated the utility of a viral delivery regimen of non-replicative human Adenovirus 5 and Modified Vaccinia virus Ankara recombinant for early entry MAP specific antigens (HAV) to show protection against challenge in a calf model and extensively screened for differential immunological markers associated with protection. We have shown that HAV vaccination was well tolerated, could be detected using a differentiation of infected and vaccinated animals (DIVA) test, showed no cross-reactivity with tuberculin and provided a degree of protection against challenge evidenced by a lack of faecal shedding in vaccinated animals that persisted throughout the 7 month infection period. Calves given HAV vaccination had significant priming and boosting of MAP derived antigen (PPD-J) specific CD4+, CD8+ IFN-γ producing T-cell populations and, upon challenge, developed early specific Th17 related immune responses, enhanced IFN-γ responses and retained a high MAP killing capacity in blood. During later phases post MAP challenge, PPD-J antigen specific IFN-γ and Th17 responses in HAV vaccinated animals corresponded with improvements in peripheral bacteraemia. By contrast a lack of IFN-γ, induction of FoxP3+ T cells and increased IL-1β and IL-10 secretion were indicative of progressive infection in Sham vaccinated animals. We conclude that HAV vaccination shows excellent promise as a new tool for improving control of MAP infection in cattle.

  10. Optimization of Prime-Boost Vaccination Strategies Against Mouse-Adapted Ebolavirus in a Short-Term Protection Study.

    PubMed

    Aviles, Jenna; Bello, Alexander; Wong, Gary; Fausther-Bovendo, Hugues; Qiu, Xiangguo; Kobinger, Gary

    2015-10-01

    In nonhuman primates, complete protection against an Ebola virus (EBOV) challenge has previously been achieved after a single injection with several vaccine platforms. However, long-term protection against EBOV after a single immunization has not been demonstrated to this date. Interestingly, prime-boost regimens have demonstrated longer protection against EBOV challenge, compared with single immunizations. Since prime-boost regimens have the potential to achieve long-term protection, determining optimal vector combinations is crucial. However, testing prime-boost efficiency in long-term protection studies is time consuming and resource demanding. Here, we investigated the optimal prime-boost combination, using DNA, porcine-derived adeno-associated virus serotype 6 (AAV-po6), and human adenovirus serotype 5 (Ad5) vector, in a short-term protection study in the mouse model of EBOV infection. In addition, we also investigated which immune parameters were indicative of a strong boost. Each vaccine platform was titrated in mice to identify which dose (single immunization) induced approximately 20% protection after challenge with a mouse-adapted EBOV. These doses were then used to determine the protection efficacy of various prime-boost combinations, using the same mouse model. In addition, humoral and cellular immune responses against EBOV glycoprotein were analyzed by an enzyme-linked immunosorbent assay, a neutralizing antibody assay, and an interferon γ-specific enzyme-linked immunospot assay. When DNA was used as a prime, Ad5 boost induced the best protection, which correlated with a higher cellular response. In contrast, when AAV-po6 or Ad5 were injected first, better protection was achieved after DNA boost, and this correlated with a higher total glycoprotein-specific immunoglobulin G titer. Prime-boost regimens using independent vaccine platforms may provide a useful strategy to induce long-term immune protection against filoviruses.

  11. The Mycobacterium bovis BCG prime-Rv0577 DNA boost vaccination induces a durable Th1 immune response in mice.

    PubMed

    Gu, Dongqing; Chen, Wei; Mi, Youjun; Gong, Xueli; Luo, Tao; Bao, Lang

    2016-04-01

    Tuberculosis remains a major global health problem and effective vaccines are urgently needed. In this study, we used the combined DNA- and protein-based vaccines of immunodominant antigen Rv0577 to boost BCG and evaluated their immunogenicity in BALB/c mice. Our data suggest that the booster vaccine may substantially enhance the immunogenicity of BCG and strengthen both CD4+ T cell-mediated Th1 and CD8+ T cell-mediated cytolytic responses. Compared with the protein-based vaccine, the DNA-based vaccine can induce more durable Th1 immune response, characterized by high levels of antibody response, proliferation response, percentages of CD4+/CD8+ and cytokine secretion in antigen-stimulated splenocyte cultures. In conclusion, we for the first time, developed a protein- and plasmid DNA-based booster vaccine based on Rv0577. Our findings suggest that antigen Rv0577-based DNA vaccine is immunogenic and can efficiently boost BCG, which could be helpful in the design of an efficient vaccination strategy against TB.

  12. Heterologous Prime-Boost Oral Immunization with GK-1 Peptide from Taenia crassiceps Cysticerci Induces Protective Immunity▿

    PubMed Central

    Fragoso, Gladis; Esquivel-Guadarrama, Fernando; Santana, M. Angélica; Bobes, Raul J.; Hernández, Beatriz; Cervantes, Jacquelynne; Segura, René; Goldbaum, Fernando A.; Sciutto, Edda; Rosas, Gabriela

    2011-01-01

    Oral immunization is a goal in vaccine development, particularly for pathogens that enter the host through the mucosal system. This study was designed to explore the immunogenic properties of the Taenia crassiceps protective peptide GK-1 administered orally. Mice were orally immunized with the synthetic GK-1 peptide in its linear form with or without the Brucella lumazine synthase (BLS) protein adjuvant or as a chimera recombinantly bound to BLS (BLS-GK-1). Mice were boosted twice with GK-1 only at 15-day intervals. A significant rate of protection of 64.7% was achieved in GK-1-immunized mice, and that rate significantly increased to 91.8 and 96% when mice were primed with GK-1 coadministered with BLS as an adjuvant and BLS as a carrier, respectively. Specific antibodies and T cell activation and proliferation accompanied the protection induced, revealing the potent immunogenicity of GK-1. Through immunohistochemical studies, GK-1 was detected in T and B cell zones of the Peyer's patches (PP) and mesenteric lymph nodes. In the latter, abundant proliferating cells were detected by 5′-bromo-2′-deoxyuridine incorporation. No proliferation was detected in PP. Altogether, these results portray the potent immunogenic properties of GK-1 administered orally and reinforce the usefulness of BLS as an adjuvant and adequate vaccine delivery system for oral vaccines. PMID:21593234

  13. Oral Immunization with Recombinant Vaccinia Virus Prime and Intramuscular Protein Boost Provides Protection against Intrarectal Simian-Human Immunodeficiency Virus Challenge in Macaques.

    PubMed

    Thippeshappa, Rajesh; Tian, Baoping; Cleveland, Brad; Guo, Wenjin; Polacino, Patricia; Hu, Shiu-Lok

    2015-12-30

    Human immunodeficiency virus type 1 (HIV-1) acquisition occurs predominantly through mucosal transmission. We hypothesized that greater mucosal immune responses and protective efficacy against mucosal HIV-1 infection may be achieved by prime-boost immunization at mucosal sites. We used a macaque model to determine the safety, immunogenicity, and protective efficacy of orally delivered, replication-competent but attenuated recombinant vaccinia viruses expressing full-length HIV-1 SF162 envelope (Env) or simian immunodeficiency virus (SIV) Gag-Pol proteins. We examined the dose and route that are suitable for oral immunization with recombinant vaccinia viruses. We showed that sublingual inoculation of two vaccinia virus-naive pigtailed macaques with 5 × 10(8) PFU of recombinant vaccinia viruses was safe. However, sublingual inoculation with a higher dose or tonsillar inoculation resulted in secondary oral lesions, indicating the need to optimize the dose and route for oral immunization with replication-competent vaccinia virus vectors. Oral priming alone elicited antibody responses to vaccinia virus and to the SF162 Env protein. Intramuscular immunization with the SF162 gp120 protein at either 20 or 21 weeks postpriming resulted in a significant boost in antibody responses in both systemic and mucosal compartments. Furthermore, we showed that immune responses induced by recombinant vaccinia virus priming and intramuscular protein boosting provided protection against intrarectal challenge with the simian-human immunodeficiency virus SHIV-SF162-P4.

  14. Induction of mucosal and systemic antibody and T-cell responses following prime–boost immunization with novel adjuvanted human immunodeficiency virus-1-vaccine formulations

    PubMed Central

    Cristillo, Anthony D.; Ferrari, Maria Grazia; Hudacik, Lauren; Lewis, Brad; Galmin, Lindsey; Bowen, Britany; Thompson, DeVon; Petrovsky, Nikolai; Markham, Phillip; Pal, Ranajit

    2011-01-01

    As sexual transmission of human immunodeficiency virus-1 (HIV-1) occurs via the mucosa, an ideal HIV-1 vaccine should induce both mucosal and systemic immunity. We therefore sought to evaluate the induction of mucosal responses using a DNA env prime–gp120 protein boost approach in which sequential nasal and parenteral protein administration was performed with two novel carbohydrate-based adjuvants. These adjuvants, Advax-M and Advax-P, were specifically designed for mucosal and systemic immune enhancement, respectively. Murine intranasal immunization with gp120/Advax-M adjuvant elicited gp120-specific IgA in serum and mucosal secretions that was markedly enhanced by DNA priming. Boosting of DNA-primed mice with gp120/Advax-M and gp120/Advax-P by sequential intranasal and intramuscular immunization, or vice versa, elicited persistent mucosal gp120-specific IgA, systemic IgG and memory T- and B-cell responses. Induction of homologous, but not heterologous, neutralizing activity was noted in the sera of all immunized groups. While confirmation of efficacy is required in challenge studies using non-human primates, these results suggest that the combination of DNA priming with sequential nasal and parenteral protein boosting, with appropriate mucosal and systemic adjuvants, could generate strong mucosal and systemic immunity and may block HIV-1 mucosal transmission and infection. PMID:21169215

  15. Skin-Specific Unsaturated Fatty Acids Boost the Staphylococcus aureus Innate Immune Response.

    PubMed

    Nguyen, Minh Thu; Hanzelmann, Dennis; Härtner, Thomas; Peschel, Andreas; Götz, Friedrich

    2015-10-26

    Antimicrobial fatty acids (AFAs) protect the human epidermis against invasion by pathogenic bacteria. In this study, we questioned whether human skin fatty acids (FAs) can be incorporated into the lipid moiety of lipoproteins and whether such incorporation would have an impact on innate immune stimulation in the model organism Staphylococcus aureus USA300 JE2. This organism synthesized only saturated FAs. However, when feeding USA300 with unsaturated FAs present on human skin (C16:1, C18:1, or C18:2), those were taken up, elongated stepwise by two carbon units, and finally found in the bacterial (phospho)lipid fraction. They were also observed in the lipid moiety of lipoproteins. When USA300 JE2 was fed with the unsaturated FAs, the cells and cell lysates showed an increased innate immune activation with various immune cells and peripheral blood mononuclear cells (PBMCs). Immune activation was highest with linoleic acid (C18:2). There are several pieces of evidence that the enhanced immune stimulating effect was due to the incorporation of unsaturated FAs in lipoproteins. First, the enhanced stimulation was dependent on Toll-like receptor 2 (TLR2). Second, an lgt mutant, unable to carry out lipidation of prolipoproteins, was unable to carry out immune stimulation when fed with unsaturated FAs. Third, the supplied FAs did not significantly affect growth, protein release, or expression of the model lipoprotein Lpl1. Although S. aureus is unable to synthesize unsaturated FAs, it incorporates long-chain unsaturated FAs into its lipoproteins, with the effect that the cells are better recognized by the innate immune system. This is an additional mechanism how our skin controls bacterial colonization and infection.

  16. Protective immune responses elicited by immunization with a chimeric blood-stage malaria vaccine persist but are not boosted by Plasmodium yoelii challenge infection

    PubMed Central

    Alaro, James R.; Lynch, Michele M.; Burns, James M.

    2010-01-01

    An efficacious malaria vaccine remains elusive despite concerted efforts. Using the Plasmodium yoelii murine model, we previously reported that immunization with the C-terminal 19 kDa domain of merozoite surface protein 1 (MSP119) fused to full-length MSP8 protected against lethal P. yoelii 17XL, well beyond that achieved by single or combined immunizations with the component antigens. Here, we continue the evaluation of the chimeric PyMSP1/8 vaccine. We show that immunization with rPyMSP1/8 vaccine elicited an MSP8-restricted T cell response that was sufficient to provide help for both PyMSP119 and PyMSP8 specific B cells to produce high and sustained levels of protective antibodies. The enhanced efficacy of immunization with rPyMSP1/8, in comparison to a combined formulation of rPyMSP142 and rPyMSP8, was not due to improved conformation of protective B cell epitopes in the chimeric molecule. Unexpectedly, rPyMSP1/8 vaccine-induced antibody responses were not boosted by exposure to P. yoelii 17XL infected RBCs. However, rPyMSP1/8 immunized and infected mice mounted robust responses to a diverse set of blood-stage antigens. The data support the further development of an MSP1/8 chimeric vaccine but also suggest that vaccines that prime for responses to a diverse set of parasite proteins will be required to maximize vaccine efficacy. PMID:20709001

  17. Gua Sha, a press-stroke treatment of the skin, boosts the immune response to intradermal vaccination

    PubMed Central

    Liu, Jinxuan; Zhang, Xiaoying; Huang, Zhen; Zang, Yuhui; Chen, Jiangning; Dong, Lei

    2016-01-01

    Objective The skin is an important immunological barrier of the body as well as an optimal route for vaccine administration. Gua Sha, which involves press-stroke treatment of the skin, is an effective folk therapy, widely accepted in East Asia, for various symptoms; however, the mechanisms underlying its therapeutic effects have not been clarified. We investigated the influence of Gua Sha on the immunological features of the skin. Methods Gua Sha was performed on BALB/c mice and the effects were evaluated using anatomical, histological, and cytometric methods as well as cytokine determination locally and systemically. The effect on intradermal vaccination was assessed with antigen-specific subtype antibody responses. Results Blood vessel expansion, erythrocyte extravasation, and increased ratios of immune active cells were observed in the skin tissue following the treatment. Pro-inflammatory cytokines were up-regulated, and immunosuppressive cytokines, down-regulated, in the treated and untreated skin and systemic circulation; no obvious variations were detected in case of anti-inflammatory cytokines. Interestingly, intradermal delivery of a model vaccine following Gua Sha induced about three-fold higher IgG titers with a more Th1-biased antibody subtype profile. Conclusion Gua Sha treatment can up-regulate the innate and adaptive immune functions of the skin and boost the response against intradermal antigens. Thus, Gua Sha may serve as a safe, inexpensive, and independent physical adjuvant for intradermal vaccination. PMID:27672506

  18. Immunization with Brugia malayi Myosin as Heterologous DNA Prime Protein Boost Induces Protective Immunity against B. malayi Infection in Mastomys coucha

    PubMed Central

    Gupta, Jyoti; Misra, Sweta; Misra-Bhattacharya, Shailja

    2016-01-01

    The current control strategies employing chemotherapy with diethylcarbamazine, ivermectin and albendazole have reduced transmission in some filaria-endemic areas, there is growing interest for complementary approaches, such as vaccines especially in light of threat of parasite developing resistance to mainstay drugs. We earlier demonstrated recombinant heavy chain myosin of B. malayi (Bm-Myo) as a potent vaccine candidate whose efficacy was enhanced by heterologous DNA prime/protein boost (Myo-pcD+Bm-Myo) vaccination in BALB/c mice. BALB/c mouse though does not support the full developmental cycle of B. malayi, however, the degree of protection may be studied in terms of transformation of challenged infective larvae (L3) to next stage (L4) with an ease of delineating the generated immunological response of host. In the current investigation, DNA vaccination with Bm-Myo was therefore undertaken in susceptible rodent host, Mastomys coucha (M. coucha) which sustains the challenged L3 and facilitates their further development to sexually mature adult parasites with patent microfilaraemia. Immunization schedule consisted of Myo-pcD and Myo-pcD+Bm-Myo followed by B. malayi L3 challenge and the degree of protection was evaluated by observing microfilaraemia as well as adult worm establishment. Myo-pcD+Bm-Myo immunized animals not only developed 78.5% reduced blood microfilarial density but also decreased adult worm establishment by 75.3%. In addition, 75.4% of the recovered live females revealed sterilization over those of respective control animals. Myo-pcD+Bm-Myo triggered higher production of specific IgG and its isotypes which induced marked cellular adhesion and cytotoxicity (ADCC) to microfilariae (mf) and L3 in vitro. Both Th1 and Th2 cytokines were significantly up-regulated displaying a mixed immune response conferring considerable protection against B. malayi establishment by engendering a long-lasting effective immune response and therefore emerges as a

  19. HIV's evasion of host's NK cell response and novel ways of its countering and boosting anti-HIV immunity.

    PubMed

    Ahmad, Ali; Ahmad, Rasheed

    2003-07-01

    NK cells were characterized by their ability to spontaneously kill certain tumor and virus-infected cells. They constitute first line of defense against invading pathogens and usually become activated in viral infections particularly in early phases. Activated NK cells play a crucial role in the induction and amplification of virus-specific immunity by providing IFN-gamma and "danger signal". The functional activities of NK cells are regulated by a balance between the engagement of their inhibitory and activating receptors. In recent years, the discovery of several MHC and non-MHC binding NK receptors has provided important insights regarding NK cell biology and its role in viral infections. These receptors are increasingly being viewed as important regulators of immune response. Like many other viruses, HIV also seems to activate NK cells. However, several studies have reported compromised NK cell functions in HIV-infected individuals. The virus employs several strategies to counter the host's NK cell response, e.g., a differential downregulation of MHC class I molecules on the surface of infected cells, a dysregulated production of NK cell function-enhancing cytokines, direct inhibitory effects of certain viral proteins on NK cell functions, and changes in the expression of NK cell receptors, etc. The individuals expressing activating NK cell receptors and their cognate MHC ligands have activated NK cells. The development of AIDS is significantly delayed in these individuals after HIV infection. The discovery of NK receptors and their ligands has opened new avenues of developing AIDS vaccine and boosting innate and adaptive antiviral immunity in HIV-infected individuals.

  20. Broad and potent cellular and humoral immune responses after a second late HIV-modified vaccinia virus ankara vaccination in HIV-DNA-primed and HIV-modified vaccinia virus Ankara-boosted Swedish vaccinees.

    PubMed

    Nilsson, Charlotta; Godoy-Ramirez, Karina; Hejdeman, Bo; Bråve, Andreas; Gudmundsdotter, Lindvi; Hallengärd, David; Currier, Jeffrey R; Wieczorek, Lindsay; Hasselrot, Klara; Earl, Patricia L; Polonis, Victoria R; Marovich, Mary A; Robb, Merlin L; Sandström, Eric; Wahren, Britta; Biberfeld, Gunnel

    2014-03-01

    We have previously shown that an HIV vaccine regimen including three HIV-DNA immunizations and a single HIV-modified vaccinia virus Ankara (MVA) boost was safe and highly immunogenic in Swedish volunteers. A median 38 months after the first HIV-MVA vaccination, 24 volunteers received 10(8) plaque-forming units of HIV-MVA. The vaccine was well tolerated. Two weeks after this HIV-MVA vaccination, 18 (82%) of 22 evaluable vaccinees were interferon (IFN)-γ enzyme-linked immunospot (ELISpot) reactive: 18 to Gag and 10 (45%) to Env. A median minimal epitope count of 4 to Gag or Env was found in a subset of 10 vaccinees. Intracellular cytokine staining revealed CD4(+) and/or CD8(+) T cell responses in 23 (95%) of 24 vaccinees, 19 to Gag and 19 to Env. The frequency of HIV-specific CD4(+) and CD8(+) T cell responses was equally high (75%). A high proportion of CD4(+) and CD8(+) T cell responses to Gag was polyfunctional with production of three or more cytokines (40% and 60%, respectively). Of the Env-specific CD4(+) T cells 40% were polyfunctional. Strong lymphoproliferative responses to Aldrithiol-2 (AT-2)-treated subtype A, B, C, and A_E virus were demonstrable in 21 (95%) of 22 vaccinees. All vaccinees developed binding antibodies to Env and Gag. Neutralizing antibodies were detected in a peripheral blood mononuclear cell (PBMC)-based assay against subtype B and CRF01_AE viruses. The neutralizing antibody response rates were influenced by the vaccine dose and/or mode of delivery used at the previous HIV-MVA vaccination. Thus, a second late HIV-MVA boost induced strong and broad cellular immune responses and improved antibody responses. The data support further exploration of this vaccine concept.

  1. Strategic use of dual regimens of boosted protease inhibitors plus maraviroc in poorly adherent subjects in view of long-acting drugs

    PubMed Central

    Capetti, Amedeo Ferdinando; Micale, Mariangela; Carenzi, Laura; Niero, Fosca; Landonio, Simona; Vimercati, Stefania; Dedivitiis, Gianfranco; Rizzardini, Giuliano

    2017-01-01

    Abstract In view of the forthcoming long-acting antiretrovirals, measures should be taken to prevent the selection of HIV drug resistance mutations. All subjects who had been switched to boosted protease inhibitors plus maraviroc (bPIs/MVC) with baseline HIV-1 RNA >50 copies/mL between June, 2014, and April, 2015, were retrospectively evaluated. HIV-1 RNA, CD4+ T-cells, serum glucose, creatinine, ALT, and adverse events were controlled every 3 to 4 months. We retrospectively analyzed 44 patients: 18 were taking darunavir/ritonavir (DRV/r) and 26 atazanavir/ritonavir (ATV/r) once daily, plus MVC 300 mg once daily. Seven subjects were in CDC stage C. All had a follow-up of at least 24 weeks, 28 exceeded 48 weeks, and 21 exceeded 72 weeks. All had experienced at least 1 viral failure and had selected at least 1 resistance-associated mutation (RAM). At baseline, 38 had plasma HIV-1 RNA 50-499 copies/mL and 6 had ≥500. At week 24, none had viremia >500 and 30 (68.2%) had suppressed HIV-1 RNA below 50 copies/mL. Of the subgroup with 48 weeks’ follow-up, 23 had HIV-1 RNA 50-499 copies/mL, 5 had ≥500, and 20/28 suppressed to <50 copies/mL. Of the longest observed subgroup (72 weeks), 17 had HIV-1 RNA 50-499 copies/mL, and 4 had ≥500 copies/mL and 15/21 (71.4%) suppressed to <50 copies/mL. This combination allowed fair suppression of viral replication, with minor genotypic evolution in 6 subjects, and seems to be a feasible strategy to prevent damaging future options. PMID:28207500

  2. Effector T cells boost regulatory T cell expansion by IL-2, TNF, OX40, and plasmacytoid dendritic cells depending on the immune context.

    PubMed

    Baeyens, Audrey; Saadoun, David; Billiard, Fabienne; Rouers, Angéline; Grégoire, Sylvie; Zaragoza, Bruno; Grinberg-Bleyer, Yenkel; Marodon, Gilles; Piaggio, Eliane; Salomon, Benoît L

    2015-02-01

    CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a major role in peripheral tolerance. Multiple environmental factors and cell types affect their biology. Among them, activated effector CD4(+) T cells can boost Treg cell expansion through TNF or IL-2. In this study, we further characterized this effector T (Teff) cell-dependent Treg cell boost in vivo in mice. This phenomenon was observed when both Treg and Teff cells were activated by their cognate Ag, with the latter being the same or different. Also, when Treg cells highly proliferated on their own, there was no additional Treg cell boost by Teff cells. In a condition of low inflammation, the Teff cell-mediated Treg cell boost involved TNF, OX40L, and plasmacytoid dendritic cells, whereas in a condition of high inflammation, it involved TNF and IL-2. Thus, this feedback mechanism in which Treg cells are highly activated by their Teff cell counterparts depends on the immune context for its effectiveness and mechanism. This Teff cell-dependent Treg cell boost may be crucial to limit inflammatory and autoimmune responses.

  3. Differential Effects of Viremia and Microbial Translocation on Immune Activation in HIV-Infected Patients Throughout Ritonavir-Boosted Darunavir Monotherapy

    PubMed Central

    BenMarzouk-Hidalgo, Omar J.; Torres-Cornejo, Almudena; Gutiérrez-Valencia, Alicia; Ruiz-Valderas, Rosa; Viciana, Pompeyo; López-Cortés, Luis F.

    2015-01-01

    Abstract The purpose of this article is to evaluate the evolution of microbial translocation (MT) and its role in CD4+ and CD8+ T cells immune activation (IA) in HIV-1-infected patients on ritonavir-boosted darunavir monotherapy (mtDRV/rtv). Prospective study of consecutive HIV-1-infected patients switched to mtDRV/rtv as a simplification regimen. Subjects were classified according to the virological behavior during a 24-month follow-up as continuous undetectable viral load, blips, intermittent viremia, and virological failure (VF). MT was evaluated by plasma LPS and 16S genomic rDNA (16S rDNA) levels, whereas IA was assessed by the coexpression of HLA-DR and CD38 in CD4+ and CD8+ T cells, and plasma sCD14 levels. Seventy-one patients were included in this substudy of the MonDar cohort (ClinicalTrials.gov: NCT01505722). At baseline, CD4+ (ρ = −0.352, P = 0.01) and CD8+ T-cell activation (ρ = −0.468, P < 0.001) were correlated with time with viral suppression, but not with MT markers. A significant decrease in plasma LPS levels was found only in patients without VF (baseline, 77.8 vs month 24, 60.4 pg/mL; P < 0.001]. Both plasma 16S rDNA and sCD14 levels were unchanged irrespective of the viral behavior. The only variable independently associated with a decrease in CD4+ and CD8+ T cells activation was an undetectable HIV-1 viremia (β = 4.78, P < 0.001 and β = 2.93, P = 0.005, respectively). MT does not have a pivotal role in T-cell activation, at least in patients with long-term viral suppression. The viremic episodes and VF are the main factors related to CD4+ and CD8+ T-cells IA, even during mtDRV/rtv. PMID:25929922

  4. Immunological Cross-Reactivity between Malaria Vaccine Target Antigen P48/45 in Plasmodium vivax and P. falciparum and Cross–Boosting of Immune Responses

    PubMed Central

    Cao, Yi; Bansal, Geetha P.; Merino, Kristen; Kumar, Nirbhay

    2016-01-01

    In general, malaria immunity has been suggested to be species specific with very little, if any, known cross-reactivity between Plasmodium vivax and P. falciparum, both of which are responsible for >90% of human malaria, and co-endemic in many countries. It is therefore believed that species-specific immunity may be needed to target different species of Plasmodium. Pfs48/45 and Pvs48/45 are well established targets in the sexual stages of the malaria parasites, and are being pursued for the development of transmission blocking vaccines. Comparison of their sequences reveals 61% and 55% identity at the DNA and protein level, respectively raising the possibility that these two target antigens might share cross-reacting epitopes. Having succeeded in expressing recombinant Pfs48/45 and Pvs48/45 proteins, we hypothesized that these proteins will not only exhibit immunological cross–reactivity but also cross-boost immune responses. Mice were immunized with purified recombinant proteins using CFA, Montanide ISA-51 and alum as adjuvants, and the sera were analyzed by ELISA, Western blotting and indirect fixed and live IFA to address the hypothesis. Our studies revealed that Pvs48/45-immune sera showed strong cross-reactivity to full length Pfs48/45 protein, and the majority of this cross reactivity was in the amino-terminal and carboxyl-terminal sub-fragments of Pfs48/45. In cross-boosting experiments Pfs48/45 and Pvs48/45 antigens were able to cross-boost each other in mouse immunization studies. Additionally we also noticed an effect of adjuvants in the overall magnitude of observed cross-reactivity. These studies may have significant implications for immunity targeting transmission of both the species of malaria parasites. PMID:27438603

  5. HIV Envelope Trimer Specific Immune Response Is Influenced by Different Adjuvant Formulations and Heterologous Prime-Boost

    PubMed Central

    Apostólico, Juliana de Souza; Boscardin, Silvia Beatriz; Yamamoto, Márcio Massao; de Oliveira-Filho, Jethe Nunes; Kalil, Jorge; Cunha-Neto, Edecio; Rosa, Daniela Santoro

    2016-01-01

    The development of a preventive vaccine against human immunodeficiency virus (HIV-1) infection is the most efficient method to control the epidemic. The ultimate goal is to develop a vaccine able to induce specific neutralizing, non-neutralizing antibodies and cellular mediated immunity (CMI). Humoral and CMI responses can be directed to glycoproteins that are normally presented as a trimeric spike on the virus surface (gp140). Despite safer, subunit vaccines are normally less immunogenic/effective and need to be delivered together with an adjuvant. The choice of a suitable adjuvant can induce effective humoral and CMI that utterly lead to full protection against disease. In this report, we established a hierarchy of adjuvant potency on humoral and CMI when admixed with the recombinant HIV gp140 trimer. We show that vaccination with gp140 in the presence of different adjuvants can induce high-affinity antibodies, follicular helper T cells and germinal center B cells. The data show that poly (I:C) is the most potent adjuvant to induce specific CMI responses evidenced by IFN-γ production and CD4+/CD8+ T cell proliferation. Furthermore, we demonstrate that combining some adjuvants like MPL plus Alum and MPL plus MDP exert additive effects that impact on the magnitude and quality of humoral responses while mixing MDP with poly (I:C) or with R848 had no impact on total IgG titers but highly impact IgG subclass. In addition, heterologous DNA prime- protein boost yielded higher IgG titers when compare to DNA alone and improved the quality of humoral response when compare to protein immunization as evidenced by IgG1/IgG2a ratio. The results presented in this paper highlight the importance of selecting the correct adjuvant-antigen combination to potentiate desired cells for optimal stimulation. PMID:26727218

  6. Sterile Immunity to Malaria after DNA Prime/Adenovirus Boost Immunization Is Associated with Effector Memory CD8+T Cells Targeting AMA1 Class I Epitopes

    PubMed Central

    Sedegah, Martha; Hollingdale, Michael R.; Farooq, Fouzia; Ganeshan, Harini; Belmonte, Maria; Kim, Yohan; Peters, Bjoern; Sette, Alessandro; Huang, Jun; McGrath, Shannon; Abot, Esteban; Limbach, Keith; Shi, Meng; Soisson, Lorraine; Diggs, Carter; Chuang, Ilin; Tamminga, Cindy; Epstein, Judith E.; Villasante, Eileen; Richie, Thomas L.

    2014-01-01

    Background Fifteen volunteers were immunized with three doses of plasmid DNA encoding P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) and boosted with human adenovirus-5 (Ad) expressing the same antigens (DNA/Ad). Four volunteers (27%) demonstrated sterile immunity to controlled human malaria infection and, overall, protection was statistically significantly associated with ELISpot and CD8+ T cell IFN-γ activities to AMA1 but not CSP. DNA priming was required for protection, as 18 additional subjects immunized with Ad alone (AdCA) did not develop sterile protection. Methodology/Principal Findings We sought to identify correlates of protection, recognizing that DNA-priming may induce different responses than AdCA alone. Among protected volunteers, two and three had higher ELISpot and CD8+ T cell IFN-γ responses to CSP and AMA1, respectively, than non-protected volunteers. Unexpectedly, non-protected volunteers in the AdCA trial showed ELISpot and CD8+ T cell IFN-γ responses to AMA1 equal to or higher than the protected volunteers. T cell functionality assessed by intracellular cytokine staining for IFN-γ, TNF-α and IL-2 likewise did not distinguish protected from non-protected volunteers across both trials. However, three of the four protected volunteers showed higher effector to central memory CD8+ T cell ratios to AMA1, and one of these to CSP, than non-protected volunteers for both antigens. These responses were focused on discrete regions of CSP and AMA1. Class I epitopes restricted by A*03 or B*58 supertypes within these regions of AMA1 strongly recalled responses in three of four protected volunteers. We hypothesize that vaccine-induced effector memory CD8+ T cells recognizing a single class I epitope can confer sterile immunity to P. falciparum in humans. Conclusions/Significance We suggest that better understanding of which epitopes within malaria antigens can confer sterile immunity and design of vaccine approaches

  7. Dietary N-Carbamylglutamate Supplementation Boosts Intestinal Mucosal Immunity in Escherichia coli Challenged Piglets

    PubMed Central

    Zhang, Fengrui; Zeng, Xiangfang; Yang, Fengjuan; Huang, Zhimin; Liu, Hong; Ma, Xi; Qiao, Shiyan

    2013-01-01

    N-carbamylglutamate (NCG) has been shown to enhance performance in neonatal piglets. However, few studies have demonstrated the effect of NCG on the intestinal mucosal barrier. This study was conducted to determine the effects of dietary NCG supplementation on intestinal mucosal immunity in neonatal piglets after an Escherichia coli (E. coli) challenge. New-born piglets (4 d old) were assigned randomly to one of four treatments (n = 7), including (I) sham challenge, (II) sham challenge +50 mg/kg NCG, (III) E. coli challenge, and (IV) E. coli challenge +50 mg/kg NCG. On d 8, pigs in the E. coli challenge groups (III and IV) were orally challenged with 5 mL of E. coli K88 (108 CFU/mL), whereas pigs in the sham challenge groups (I and II) were orally dosed with an equal volume of water. On d 13, all piglets were sacrificed, and samples were collected and examined. The results show that average daily gain in the E. coli challenged piglets (III and IV) was decreased (PE.coli<0.05). However, it tended to be higher in the NCG treated piglets (II and IV). Ileum secretory IgA, as well as IFN-γ, IL-2, IL-4 and IL-10 in ileal homogenates, were increased in E. coli challenged piglets (III and IV). Similarly, ileum SIgA and IL-10 levels, and CD4+ percentage in NCG treated piglets (II and IV) were higher than no-NCG treated piglets (PNCG<0.05). However, the IL-2 level was only decreased in the piglets of E. coli challenge + NCG group (IV) compared with E. coli challenge group (III) (P<0.05). No change in the IL-2 level of the sham challenged piglets (III) was observed. In conclusion, dietary NCG supplementation has some beneficial effects on intestinal mucosal immunity in E. coli challenged piglets, which might be associated with stimulated lymphocyte proliferation and cytokine synthesis. Our findings have an important implication that NCG may be used to reduce diarrhea in neonatal piglets. PMID:23840434

  8. DNA prime Listeria boost induces a cellular immune response to SIV antigens in the rhesus macaque model that is capable of limited suppression of SIV239 viral replication.

    PubMed

    Boyer, Jean D; Robinson, Tara M; Maciag, Paulo C; Peng, Xiaohui; Johnson, Ross S; Pavlakis, George; Lewis, Mark G; Shen, Anding; Siliciano, Robert; Brown, Charles R; Weiner, David B; Paterson, Yvonne

    2005-03-01

    DNA vaccines and recombinant Listeria monocytogenes that express and secrete SIV Gag and Env antigens were combined in a nonhuman primate prime-boost immunogenicity study followed by a challenge with SIV239. We report that recombinant DNA vaccine delivered intramuscularly, and recombinant L. monocytogenes delivered orally each individually have the ability to induce CD8+ and CD4+ T cell immune responses in a nonhuman primate. Four rhesus monkeys were immunized at weeks 0, 4, 8, and 12 with the pCSIVgag and pCSIVenv DNA plasmids and boosted with SIV expressing L. monocytogenes vaccines at weeks 16, 20, and 28. Four rhesus monkeys received only the L. monocytogenes vaccines at weeks 16, 20, and 28. A final group of monkeys served as a control group. Blood samples were taken before vaccination and 2 weeks post each injection and analyzed by ELISPOT for CD4+ and CD8+ T cell responses. Moderate vaccine induced SIV-specific cellular immune responses were observed following immunization with either DNA or L. monocytogenes vectors. However, the SIV antigen-specific immune responses were significantly increased when Rhesus macaques were primed with SIV DNA vaccines and boosted with the SIV expressing L. monocytogenes vectors. In addition, the combined vaccine was able to impact SIV239 viral replication following an intrarectal challenge. This study demonstrates for the first time that oral L. monocytogenes can induce a cellular immune response in a nonhuman primate and is able to enhance the efficacy of a DNA vaccine as well as provide modest protection against SIV239 challenge.

  9. Immune responses of mice to prime-boost vaccination with the recombinant DNA and Fowlpox virus both expressing HIV-2 Gag-gp105.

    PubMed

    Song, Y; Zhang, L S; Wang, H; Jin, H; Li, Ch; Jin, N

    2010-01-01

    Human immunodeficiency viruses 1 and 2 (HIV-1, 2) present a public health problem for which there is neither an effective antiviral therapy nor a preventive vaccine. In this study, the immune responses of mice to prime-boost vaccination with the recombinant DNA (rDNA) and recombinant Fowlpox virus (rFPV) both expressing HIV-2 Gag-gp105 chimeric protein, were compared to those elicited by each vector alone. Mice primed with the rDNA and boosted with the rFPV showed HIV-2-specific antibody levels, splenic CD4+ and CD8+ T-lymphocyte numbers, and Gag-gp105-specific cytotoxic T-lymphocytes (CTL) activity increased by 20-30% as compared with those elicited by these vaccines alone. These findings suggested that the prime-boost strategy combining rDNA and rFPV elicited significant Gag-gp105 - specific cellular and humoral immune responses, thus supporting this novel approach to the immunization against HIV infections.

  10. Homologous Boosting with Adenoviral Serotype 5 HIV Vaccine (rAd5) Vector Can Boost Antibody Responses despite Preexisting Vector-Specific Immunity in a Randomized Phase I Clinical Trial

    PubMed Central

    Sarwar, Uzma N.; Novik, Laura; Enama, Mary E.; Plummer, Sarah A.; Koup, Richard A.; Nason, Martha C.; Bailer, Robert T.; McDermott, Adrian B.; Roederer, Mario; Mascola, John R.; Ledgerwood, Julie E.; Graham, Barney S.

    2014-01-01

    Background Needle-free delivery improves the immunogenicity of DNA vaccines but is also associated with more local reactogenicity. Here we report the first comparison of Biojector and needle administration of a candidate rAd5 HIV vaccine. Methods Thirty-one adults, 18–55 years, 20 naive and 11 prior rAd5 vaccine recipients were randomized to receive single rAd5 vaccine via needle or Biojector IM injection at 1010 PU in a Phase I open label clinical trial. Solicited reactogenicity was collected for 5 days; clinical safety and immunogenicity follow-up was continued for 24 weeks. Results Overall, injections by either method were well tolerated. There were no serious adverse events. Frequency of any local reactogenicity was 16/16 (100%) for Biojector compared to 11/15 (73%) for needle injections. There was no difference in HIV Env-specific antibody response between Biojector and needle delivery. Env-specific antibody responses were more than 10-fold higher in subjects receiving a booster dose of rAd5 vaccine than after a single dose delivered by either method regardless of interval between prime and boost. Conclusions Biojector delivery did not improve antibody responses to the rAd5 vaccine compared to needle administration. Homologous boosting with rAd5 gene-based vectors can boost insert-specific antibody responses despite pre-existing vector-specific immunity. Trial Registration Clinicaltrials.gov NCT00709605 NCT00709605 PMID:25264782

  11. Homologous prime-boost strategy with TgPI-1 improves the immune response and protects highly susceptible mice against chronic Toxoplasma gondii infection.

    PubMed

    Sánchez, Vanesa R; Fenoy, Ignacio M; Picchio, Mariano S; Soto, Ariadna S; Arcon, Nadia; Goldman, Alejandra; Martin, Valentina

    2015-10-01

    Subunit-based vaccines are safer than live or attenuated pathogen vaccines, although they are generally weak immunogens. Thus, proper combination of immunization strategies and adjuvants are needed to increase their efficacy. We have previously protected C3H/HeN mice from Toxoplasma gondii infection by immunization with the serine protease inhibitor-1 (TgPI-1) in combination with alum. In this work, we explore an original vaccination protocol that combines administration of recombinant TgPI-1 by intradermal and intranasal routes in order to enhance protection in the highly susceptible C57BL/6 strain. Mice primed intradermally with rTgPI-1 plus alum and boosted intranasally with rTgPI-1 plus CpG-ODN elicited a strong specific Th1/Th2 humoral response, along with a mucosal immune response characterized by specific-IgA in intestinal lavages. A positive cellular response of mesentheric lymph node cells and Th1/Th2 cytokine secretion in the ileon were also detected. When immunized mice were challenged with the cystogenic Me49 T. gondii strain, they displayed up to 62% reduction in brain parasite burden. Moreover, adoptive transfer of mesenteric lymph node cells from vaccinated to naïve mice induced significant protection against infection. These results demonstrate that this strategy that combines the administration of TgPI-1 by two different routes, intradermal priming and intranasal boost, improves protective immunity against T. gondii chronic infection in highly susceptible mice.

  12. rBCG30-induced immunity and cross-protection against Mycobacterium leprae challenge are enhanced by boosting with the Mycobacterium tuberculosis 30-kilodalton antigen 85B.

    PubMed

    Gillis, Thomas P; Tullius, Michael V; Horwitz, Marcus A

    2014-09-01

    Leprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy.

  13. Robust vaccine-elicited cellular immune responses in breast milk following systemic simian immunodeficiency virus DNA prime and live virus vector boost vaccination of lactating rhesus monkeys.

    PubMed

    Wilks, Andrew B; Christian, Elizabeth C; Seaman, Michael S; Sircar, Piya; Carville, Angela; Gomez, Carmen E; Esteban, Mariano; Pantaleo, Giuseppe; Barouch, Dan H; Letvin, Norman L; Permar, Sallie R

    2010-12-01

    Breast milk transmission of HIV remains an important mode of infant HIV acquisition. Enhancement of mucosal HIV-specific immune responses in milk of HIV-infected mothers through vaccination may reduce milk virus load or protect against virus transmission in the infant gastrointestinal tract. However, the ability of HIV/SIV strategies to induce virus-specific immune responses in milk has not been studied. In this study, five uninfected, hormone-induced lactating, Mamu A*01(+) female rhesus monkey were systemically primed and boosted with rDNA and the attenuated poxvirus vector, NYVAC, containing the SIVmac239 gag-pol and envelope genes. The monkeys were boosted a second time with a recombinant Adenovirus serotype 5 vector containing matching immunogens. The vaccine-elicited immunodominant epitope-specific CD8(+) T lymphocyte response in milk was of similar or greater magnitude than that in blood and the vaginal tract but higher than that in the colon. Furthermore, the vaccine-elicited SIV Gag-specific CD4(+) and CD8(+) T lymphocyte polyfunctional cytokine responses were more robust in milk than in blood after each virus vector boost. Finally, SIV envelope-specific IgG responses were detected in milk of all monkeys after vaccination, whereas an SIV envelope-specific IgA response was only detected in one vaccinated monkey. Importantly, only limited and transient increases in the proportion of activated or CCR5-expressing CD4(+) T lymphocytes in milk occurred after vaccination. Therefore, systemic DNA prime and virus vector boost of lactating rhesus monkeys elicits potent virus-specific cellular and humoral immune responses in milk and may warrant further investigation as a strategy to impede breast milk transmission of HIV.

  14. Selective Changes in the Immune Profile of Tumor-Draining Lymph Nodes After Different Neoadjuvant Chemoradiation Regimens for Locally Advanced Cervical Cancer

    SciTech Connect

    Battaglia, Alessandra; Buzzonetti, Alexia; Martinelli, Enrica; Fanelli, Mara; Petrillo, Marco; Ferrandina, Gabriella; Scambia, Giovanni; Fattorossi, Andrea

    2010-04-15

    Purpose: To assess how neoadjuvant chemoradiation regimens modulate the immune system state in tumor-draining lymph nodes (TDLN), in the setting of advanced cervical cancer. Methods and Materials: Tumor-draining lymph nodes of patients undergoing chemotherapy only (nonirradiated, NI-TDLN) and chemoradiation with lower-dose (39.6 Gy, LD-TDLN) and higher-dose radiation (50 Gy, HD-TDLN) were analyzed by multicolor flow cytometry. Results: Enlarging our previous data, LD-TDLN showed features overall indicative of an enhanced antitumor response as compared with NI-TDLN, namely a significant Th1 and Tc1 polarization and a lower amount of the potent CD4{sup +}Foxp3{sup +}CD25{sup high} regulatory T cell (Treg) subset identified by neuropilin-1 expression. Conversely, compared with NI-TDLN, HD-TDLN showed features overall indicative of an impaired antitumor response, namely a significantly inverted CD4/CD8 cell ratio, a higher Nrp1{sup +}Treg frequency, and a higher frequency of CCR4{sup +}Treg, a Treg subset facilitated in migrating out from TDLN to suppress the immune response against distant cancer cells. Moreover, the Th1 and Tc1 polarization induced by LD radiation was lost, and there was an unfavorable tolerogenic/immunogenic dendritic cell ratio compared with LD-TDLN. Conclusions: Even minor differences in radiation dose in neoadjuvant regimens for locally advanced cervical cancer are crucial for determining the balance between a tolerogenic and an efficacious antitumor immune response in TDLN. Because most of the anticancer immune response takes place in TDLN, the present findings also emphasize the importance of chemoradiation protocols in the context of immunotherapeutic trials.

  15. Relevance of long-lived CD8+ T effector memory cells for protective immunity elicited by heterologous prime-boost vaccination

    PubMed Central

    Vasconcelos, José R.; Dominguez, Mariana R.; Araújo, Adriano F.; Ersching, Jonatan; Tararam, Cibele A.; Bruna-Romero, Oscar; Rodrigues, Mauricio M.

    2012-01-01

    Owing to the importance of major histocompatibility complex class Ia-restricted CD8+ T cells for host survival following viral, bacterial, fungal, or parasitic infection, it has become largely accepted that these cells should be considered in the design of a new generation of vaccines. For the past 20 years, solid evidence has been provided that the heterologous prime-boost regimen achieves the best results in terms of induction of long-lived protective CD8+ T cells against a variety of experimental infections. Although this regimen has often been used experimentally, as is the case for many vaccines, the mechanism behind the efficacy of this vaccination regimen is still largely unknown. The main purpose of this review is to examine the characteristics of the protective CD8+ T cells generated by this vaccination regimen. Part of its efficacy certainly relies on the generation and maintenance of large numbers of specific lymphocytes. Other specific characteristics may also be important, and studies on this direction have only recently been initiated. So far, the characterization of these protective, long-lived T cell populations suggests that there is a high frequency of polyfunctional T cells; these cells cover a large breadth and display a T effector memory (TEM) phenotype. These TEM cells are capable of proliferating after an infectious challenge and are highly refractory to apoptosis due to a control of the expression of pro-apoptotic receptors such as CD95. Also, they do not undergo significant long-term immunological erosion. Understanding the mechanisms that control the generation and maintenance of the protective activity of these long-lived TEM cells will certainly provide important insights into the physiology of CD8+ T cells and pave the way for the design of new or improved vaccines. PMID:23264773

  16. A prime-boost immunization with Tc52 N-terminal domain DNA and the recombinant protein expressed in Pichia pastoris protects against Trypanosoma cruzi infection.

    PubMed

    Matos, Marina N; Sánchez Alberti, Andrés; Morales, Celina; Cazorla, Silvia I; Malchiodi, Emilio L

    2016-06-14

    We have previously reported that the N-terminal domain of the antigen Tc52 (NTc52) is the section of the protein that confers the strongest protection against Trypanosoma cruzi infection. To improve vaccine efficacy, we conducted here a prime-boost strategy (NTc52PB) by inoculating two doses of pcDNA3.1 encoding the NTc52 DNA carried by attenuated Salmonella (SNTc52), followed by two doses of recombinant NTc52 expressed in Picchia pastoris plus ODN-CpG as adjuvant. This strategy was comparatively analyzed with the following protocols: (1) two doses of NTc52+ODN-CpG by intranasal route followed by two doses of NTc52+ODN-CpG by intradermal route (NTc52CpG); (2) four doses of SNTc52; and (3) a control group with four doses of Salmonella carrying the empty plasmid. All immunized groups developed a predominant Th1 cellular immune response but with important differences in antibody development and protection against infection. Thus, immunization with just SNTc52 induces a strong specific cellular response, a specific systemic antibody response that is weak yet functional (considering lysis of trypomastigotes and inhibition of cell invasion), and IgA mucosal immunity, protecting in both the acute and chronic stages of infection. The group that received only recombinant protein (NTc52CpG) developed a strong antibody immune response but weaker cellular immunity than the other groups, and the protection against infection was clear in the acute phase of infection but not in chronicity. The prime-boost strategy, which combines DNA and protein vaccine and both mucosal and systemic immunizations routes, was the best assayed protocol, inducing strong cellular and humoral responses as well as specific mucosal IgA, thus conferring better protection in the acute and chronic stages of infection.

  17. Phase 1 studies of the safety and immunogenicity of electroporated HER2/CEA DNA vaccine followed by adenoviral boost immunization in patients with solid tumors

    PubMed Central

    2013-01-01

    Background DNA electroporation has been demonstrated in preclinical models to be a promising strategy to improve cancer immunity, especially when combined with other genetic vaccines in heterologous prime-boost protocols. We report the results of 2 multicenter phase 1 trials involving adult cancer patients (n=33) with stage II-IV disease. Methods Patients were vaccinated with V930 alone, a DNA vaccine containing equal amounts of plasmids expressing the extracellular and trans-membrane domains of human HER2, and a plasmid expressing CEA fused to the B subunit of Escherichia coli heat labile toxin (Study 1), or a heterologous prime-boost vaccination approach with V930 followed by V932, a dicistronic adenovirus subtype-6 viral vector vaccine coding for the same antigens (Study 2). Results The use of the V930 vaccination with electroporation alone or in combination with V932 was well-tolerated without any serious adverse events. In both studies, the most common vaccine-related side effects were injection site reactions and arthralgias. No measurable cell-mediated immune response (CMI) to CEA or HER2 was detected in patients by ELISPOT; however, a significant increase of both cell-mediated immunity and antibody titer against the bacterial heat labile toxin were observed upon vaccination. Conclusion V930 vaccination alone or in combination with V932 was well tolerated without any vaccine-related serious adverse effects, and was able to induce measurable immune responses against bacterial antigen. However, the prime-boost strategy did not appear to augment any detectable CMI responses against either CEA or HER2. Trial registration Study 1 – ClinicalTrials.gov, NCT00250419; Study 2 – ClinicalTrials.gov, NCT00647114. PMID:23497415

  18. αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors

    PubMed Central

    Casiraghi, Costanza; Gianni, Tatiana

    2016-01-01

    We report that αvβ3 integrin strongly affects the innate immune response in epithelial cells. αvβ3 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by αvβ3 integrin. The boosting was exerted specifically by αvβ3 integrin but not by αvβ6 or αvβ8 integrin. Current and previous work indicates that integrin-TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response. PMID:26842473

  19. Fewer doses of HPV vaccine result in immune response similar to three-dose regimen | Division of Cancer Prevention

    Cancer.gov

    NCI scientists report that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody levels against two of the most carcinogenic types of HPV (16 and 18), compared to a standard three dose regimen. Among women who received only one dose, antibody levels were also high and remained stable four years after vaccination. The results suggest that fewer doses of an HPV vaccine may confer necessary long-term protection against new infection and appeared Nov. 4, 2013, in Cancer Prevention Research... |

  20. Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania☆,☆☆

    PubMed Central

    Bakari, Muhammad; Aboud, Said; Nilsson, Charlotta; Francis, Joel; Buma, Deus; Moshiro, Candida; Aris, Eric A.; Lyamuya, Eligius F.; Janabi, Mohamed; Godoy-Ramirez, Karina; Joachim, Agricola; Polonis, Victoria R.; Bråve, Andreas; Earl, Patricia; Robb, Merlin; Marovich, Mary; Wahren, Britta; Pallangyo, Kisali; Biberfeld, Gunnel; Mhalu, Fred; Sandström, Eric

    2016-01-01

    and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses. PMID:21864626

  1. DNA vaccine prime and recombinant FPV vaccine boost: an important candidate immunization strategy to control bluetongue virus type 1.

    PubMed

    Li, Junping; Yang, Tao; Xu, Qingyuan; Sun, Encheng; Feng, Yufei; Lv, Shuang; Zhang, Qin; Wang, Haixiu; Wu, Donglai

    2015-10-01

    Bluetongue virus (BTV) is the causative agent of bluetongue (BT), an important sheep disease that caused great economic loss to the sheep industry. There are 26 BTV serotypes based on the outer protein VP2. However, the serotypes BTV-1 and BTV-16 are the two most prevalent serotypes in China. Vaccination is the most effective method of preventing viral infections. Therefore, the need for an effective vaccine against BTV is urgent. In this study, DNA vaccines and recombinant fowlpox virus (rFPV) vaccines expressing VP2 alone or VP2 in combination with VP5 or co-expressing the VP2 and VP5 proteins of BTV-1 were evaluated in both mice and sheep. Several strategies were tested in mice, including DNA vaccine prime and boost, rFPV vaccine prime and boost, and DNA vaccine prime and rFPV vaccine boost. We then determined the best vaccine strategy in sheep. Our results indicated that a strategy combining a DNA vaccine prime (co-expressing VP2 and VP5) followed by an rFPV vaccine boost (co-expressing VP2 and VP5) induced a high titer of neutralizing antibodies in sheep. Therefore, our data suggest that a DNA vaccine consisting of a pCAG-(VP2+VP5) prime and an rFPV-(VP2+VP5) boost is an important candidate for the design of a novel vaccine against BTV-1.

  2. A neurotoxic regimen of methamphetamine exacerbates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus

    PubMed Central

    2010-01-01

    Methamphetamine (MA) use is associated with activation of microglia and, at high doses, can induce neurotoxicity. Given the changes in the neuroinflammatory environment associated with MA, we investigated whether MA administration would interfere with the thermoregulatory and neuroinflammatory response to a subsequent peripheral immune stimulus. C57BL6/J mice were given four i.p. injections of either 5 mg/kg MA or saline at two hour intervals. Twenty-four hours following the first MA injection, mice were given 100 μg/kg LPS or saline i.p. and blood and brains were collected. Here we report that mice exposed to MA developed higher fevers in response to LPS than did those given LPS alone. MA also exacerbated the LPS-induced increase in central cytokine mRNA. MA alone increased microglial Iba1 expression and expression was further increased when mice were exposed to both MA and LPS, suggesting that MA not only activated microglia but also influenced their response to a peripheral immune stimulus. Taken together, these data show that MA administration exacerbates the normal central immune response, most likely by altering microglia. PMID:21092194

  3. One-prime multi-boost strategy immunization with recombinant DNA, adenovirus, and MVA vector vaccines expressing HPV16 L1 induces potent, sustained, and specific immune response in mice.

    PubMed

    Li, Li-Li; Wang, He-Rong; Zhou, Zhi-Yi; Luo, Jing; Xiao, Xiang-Qian; Wang, Xiao-Li; Li, Jin-Tao; Zhou, Yu-Bai; Zeng, Yi

    2016-04-01

    Human papillomavirus (HPV) is associated with various human diseases, including cancer, and developing vaccines is a cost-efficient strategy to prevent HPV-related disease. The major capsid protein L1, which an increasing number of studies have confirmed is typically expressed early in infection, is a promising antigen for such a vaccine, although the E6 and E7 proteins have been characterized more extensively. Thus, the L1 gene from HPV16 was inserted into a recombinant vector, AdHu5, and MVA viral vectors, and administered by prime-boost immunization. Virus-like particles were used as control antigens. Our results indicate that prime-boost immunization with heterologous vaccines induced robust and sustained cellular and humoral response specific to HPV16 L1. In particular, sera obtained from mice immunized with DNA + DNA + Ad + MVA had excellent antitumor activity in vivo. However, the data also confirm that virus-like particles can only elicit low levels cellular immunity and not be long-lasting, and are therefore unsuitable for treatment of existing HPV infections.

  4. A comparative analysis of HIV-specific mucosal/systemic T cell immunity and avidity following rDNA/rFPV and poxvirus-poxvirus prime boost immunisations.

    PubMed

    Ranasinghe, Charani; Eyers, Fiona; Stambas, John; Boyle, David B; Ramshaw, Ian A; Ramsay, Alistair J

    2011-04-05

    In this study we have firstly compared a range of recombinant DNA poxvirus prime-boost immunisation strategies and shown that combined intramuscular (i.m.) 2× DNA-HIV/intranasal (i.n.) 2× FPV-HIV prime-boost immunisation can generate high-level of HIV-specific systemic (spleen) and mucosal (genito-rectal nodes, vaginal tissues and lung tissues) T cell responses and HIV-1 p24 Gag-specific serum IgG1, IgG2a and mucosal IgG, SIgA responses in vaginal secretions in BALB/c mice. Data indicate that following rDNA priming, two rFPV booster immunisations were necessary to generate good antibody and mucosal T cell immunity. This data also revealed that mucosal uptake of recombinant fowl pox (rFPV) was far superior to plasmid DNA. To further evaluate CD8+ T cell immunity, i.m. 2× DNA-HIV/i.n. 1× FPV-HIV immunisation strategy was directly compared with single shot poxvirus/poxvirus, i.n. FPV-HIV/i.m. VV-HIV immunisation. Results indicate that the latter strategy was able to generate strong sustained HIV-specific CD8+ T cells with higher avidity, broader cytokine/chemokine profiles and better protection following influenza-K(d)Gag(197-205) challenge compared to rDNA poxvirus prime-boost strategy. Our findings further substantiate the importance of vector selection/combination, order and route of delivery when designing effective vaccines for HIV-1.

  5. Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap

    PubMed Central

    Mayer, Kenneth H.; Elizaga, Marnie L.; Bekker, Linda-Gail; Allen, Mary; Morris, Lynn; Montefiori, David; De Rosa, Stephen C.; Sato, Alicia; Gu, Niya; Tomaras, Georgia D.; Tucker, Timothy; Barnett, Susan W.; Mkhize, Nonhlanhla N.; Shen, Xiaoying; Downing, Katrina; Williamson, Carolyn; Pensiero, Michael; Corey, Lawrence; Williamson, Anna-Lise

    2016-01-01

    A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 109 PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4+ T-cell and CD8+ T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4+ T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4+ T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.) PMID:27098021

  6. Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap.

    PubMed

    Gray, Glenda E; Mayer, Kenneth H; Elizaga, Marnie L; Bekker, Linda-Gail; Allen, Mary; Morris, Lynn; Montefiori, David; De Rosa, Stephen C; Sato, Alicia; Gu, Niya; Tomaras, Georgia D; Tucker, Timothy; Barnett, Susan W; Mkhize, Nonhlanhla N; Shen, Xiaoying; Downing, Katrina; Williamson, Carolyn; Pensiero, Michael; Corey, Lawrence; Williamson, Anna-Lise

    2016-06-01

    A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 10(9) PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4(+) T-cell and CD8(+) T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4(+) T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4(+) T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.).

  7. Dendritic Cell Targeting Effectively Boosts T Cell Responses Elicited by an HIV Multiepitope DNA Vaccine.

    PubMed

    Apostólico, Juliana de Souza; Lunardelli, Victória Alves Santos; Yamamoto, Marcio Massao; Souza, Higo Fernando Santos; Cunha-Neto, Edecio; Boscardin, Silvia Beatriz; Rosa, Daniela Santoro

    2017-01-01

    Despite several efforts in the last decades, an efficacious HIV-1 vaccine is still not available. Different approaches have been evaluated, such as recombinant proteins, viral vectors, DNA vaccines, and, most recently, dendritic cell (DC) targeting. This strategy is based on DC features that place them as central for induction of immunity. Targeting is accomplished by the use of chimeric monoclonal antibodies directed to DC surface receptors fused to the antigen of interest. In this work, we targeted eight promiscuous HIV-derived CD4(+) T cell epitopes (HIVBr8) to the DEC205(+) DCs by fusing the multiepitope immunogen to the heavy chain of αDEC205 (αDECHIVBr8), in the presence of the TLR3 agonist poly (I:C). In addition, we tested a DNA vaccine encoding the same epitopes using homologous or heterologous prime-boost regimens. Our results showed that mice immunized with αDECHIVBr8 presented higher CD4(+) and CD8(+) T cell responses when compared to mice that received the DNA vaccine (pVAXHIVBr8). In addition, pVAXHIVBr8 priming followed by αDECHIVBr8 boosting induced higher polyfunctional proliferative and cytokine-producing T cell responses to HIV-1 peptides than homologous DNA immunization or heterologous αDEC prime/DNA boost. Based on these results, we conclude that homologous prime-boost and heterologous boosting immunization strategies targeting CD4(+) epitopes to DCs are effective to improve HIV-specific cellular immune responses when compared to standalone DNA immunization. Moreover, our results indicate that antigen targeting to DC is an efficient strategy to boost immunity against a multiepitope immunogen, especially in the context of DNA vaccination.

  8. Dendritic Cell Targeting Effectively Boosts T Cell Responses Elicited by an HIV Multiepitope DNA Vaccine

    PubMed Central

    Apostólico, Juliana de Souza; Lunardelli, Victória Alves Santos; Yamamoto, Marcio Massao; Souza, Higo Fernando Santos; Cunha-Neto, Edecio; Boscardin, Silvia Beatriz; Rosa, Daniela Santoro

    2017-01-01

    Despite several efforts in the last decades, an efficacious HIV-1 vaccine is still not available. Different approaches have been evaluated, such as recombinant proteins, viral vectors, DNA vaccines, and, most recently, dendritic cell (DC) targeting. This strategy is based on DC features that place them as central for induction of immunity. Targeting is accomplished by the use of chimeric monoclonal antibodies directed to DC surface receptors fused to the antigen of interest. In this work, we targeted eight promiscuous HIV-derived CD4+ T cell epitopes (HIVBr8) to the DEC205+ DCs by fusing the multiepitope immunogen to the heavy chain of αDEC205 (αDECHIVBr8), in the presence of the TLR3 agonist poly (I:C). In addition, we tested a DNA vaccine encoding the same epitopes using homologous or heterologous prime-boost regimens. Our results showed that mice immunized with αDECHIVBr8 presented higher CD4+ and CD8+ T cell responses when compared to mice that received the DNA vaccine (pVAXHIVBr8). In addition, pVAXHIVBr8 priming followed by αDECHIVBr8 boosting induced higher polyfunctional proliferative and cytokine-producing T cell responses to HIV-1 peptides than homologous DNA immunization or heterologous αDEC prime/DNA boost. Based on these results, we conclude that homologous prime-boost and heterologous boosting immunization strategies targeting CD4+ epitopes to DCs are effective to improve HIV-specific cellular immune responses when compared to standalone DNA immunization. Moreover, our results indicate that antigen targeting to DC is an efficient strategy to boost immunity against a multiepitope immunogen, especially in the context of DNA vaccination. PMID:28223987

  9. Vaccination of Mice Using the West Nile Virus E-Protein in a DNA Prime-Protein Boost Strategy Stimulates Cell-Mediated Immunity and Protects Mice against a Lethal Challenge

    PubMed Central

    De Filette, Marina; Soehle, Silke; Ulbert, Sebastian; Richner, Justin; Diamond, Michael S.; Sinigaglia, Alessandro; Barzon, Luisa; Roels, Stefan; Lisziewicz, Julianna; Lorincz, Orsolya; Sanders, Niek N.

    2014-01-01

    West Nile virus (WNV) is a mosquito-borne flavivirus that is endemic in Africa, the Middle East, Europe and the United States. There is currently no antiviral treatment or human vaccine available to treat or prevent WNV infection. DNA plasmid-based vaccines represent a new approach for controlling infectious diseases. In rodents, DNA vaccines have been shown to induce B cell and cytotoxic T cell responses and protect against a wide range of infections. In this study, we formulated a plasmid DNA vector expressing the ectodomain of the E-protein of WNV into nanoparticles by using linear polyethyleneimine (lPEI) covalently bound to mannose and examined the potential of this vaccine to protect against lethal WNV infection in mice. Mice were immunized twice (prime – boost regime) with the WNV DNA vaccine formulated with lPEI-mannose using different administration routes (intramuscular, intradermal and topical). In parallel a heterologous boost with purified recombinant WNV envelope (E) protein was evaluated. While no significant E-protein specific humoral response was generated after DNA immunization, protein boosting of DNA-primed mice resulted in a marked increase in total neutralizing antibody titer. In addition, E-specific IL-4 T-cell immune responses were detected by ELISPOT after protein boost and CD8+ specific IFN-γ expression was observed by flow cytometry. Challenge experiments using the heterologous immunization regime revealed protective immunity to homologous and virulent WNV infection. PMID:24503579

  10. Immune-mediated mechanisms influencing the efficacy of anticancer therapies.

    PubMed

    Coffelt, Seth B; de Visser, Karin E

    2015-04-01

    Conventional anticancer therapies, such as chemotherapy, radiotherapy, and targeted therapy, are designed to kill cancer cells. However, the efficacy of anticancer therapies is not only determined by their direct effects on cancer cells but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit several changes in immune-related parameters including the composition, phenotype, and function of immune cells. Here we discuss the impact of innate and adaptive immune cells on the success of anticancer therapy. In this context we examine the opportunities to exploit host immune responses to boost tumor clearing, and highlight the challenges facing the treatment of advanced metastatic disease.

  11. Comparison of homologous and heterologous prime-boost immunizations combining MVA-vectored and plant-derived VP2 as a strategy against IBDV.

    PubMed

    Richetta, Matías; Gómez, Evangelina; Lucero, María Soledad; Chimeno Zoth, Silvina; Gravisaco, María José; Calamante, Gabriela; Berinstein, Analía

    2017-01-03

    Different immunogens such as subunit, DNA or live viral-vectored vaccines against Infectious Bursal Disease virus (IBDV) have been evaluated in the last years. However, the heterologous prime-boost approach using recombinant modified vaccinia Ankara virus (rMVA), which has shown promising results in both mammals and chickens, has not been tried against this pathogen yet. IBD is a highly contagious and immunosuppressive disease of poultry that affects mainly young chicks. It is caused by IBDV, a double-stranded RNA virus carrying its main antigenic epitopes on the capsid protein VP2. Our objective was to evaluate the immune response elicited by two heterologous prime-boost schemes combining an rMVA carrying the VP2 mature gene (rVP2) and a recombinant VP2 protein produced in Nicotiana benthamiana (pVP2), and to compare them with the performance of the homologous pVP2-pVP2 scheme usually used in our laboratory. The SPF chickens immunized with the three evaluated schemes elicited significantly higher anti-VP2 antibody titers (p<0.001) and seroneutralizing titers (p<0.05) and had less T-cell infiltration (p<0.001), histological damage (p<0.001) and IBDV particles (p<0.001) in their bursae of Fabricius when compared with control groups. No significant differences were found between both heterologous schemes and the homologous one. However, the rVP2-pVP2 scheme showed significantly higher anti-VP2 antibody titers than pVP2-rVP2 and a similar tendency was found in the seroneutralization assay. Conversely, pVP2-rVP2 had the best performance when evaluated through bursal parameters despite having a less potent humoral immune response. These findings suggest that the order in which rVP2 and pVP2 are combined can influence the immune response obtained. Besides, the lack of a strong humoral immune response did not lessen the ability to protect from IBDV challenge. Therefore, further research is needed to evaluate the mechanisms by which these immunogens are working in order to

  12. Microspheres-prime/rMVA-boost vaccination enhances humoral and cellular immune response in IFNAR(-/-) mice conferring protection against serotypes 1 and 4 of bluetongue virus.

    PubMed

    Marín-López, Alejandro; Calvo-Pinilla, Eva; Barriales, Diego; Lorenzo, Gema; Benavente, Javier; Brun, Alejandro; Martínez-Costas, Jose Manuel; Ortego, Javier

    2017-03-16

    Bluetongue virus (BTV) is the causative agent of bluetongue disease (BT), which affects domestic and wild ruminants. At the present, 27 different serotypes have been documented. Vaccination has been demonstrated as one of the most effective methods to avoid viral dissemination. To overcome the drawbacks associated with the use of inactivated and attenuated vaccines we engineered a new recombinant BTV vaccine candidate based on proteins VP2, VP7, and NS1 of BTV-4 that were incorporated into avian reovirus muNS-Mi microspheres (MS-VP2/VP7/NS1) and recombinant modified vaccinia virus Ankara (rMVA). The combination of these two antigen delivery systems in a heterologous prime-boost vaccination strategy generated significant levels of neutralizing antibodies in IFNAR(-/-) mice. Furthermore, this immunization strategy increased the ratio of IgG2a/IgG1 in sera, indicating an induction of a Th1 response, and elicited a CD8 T cell response. Immunized mice were protected against lethal challenges with the homologous serotype 4 and the heterologous serotype 1 of BTV. All these results support the strategy based on microspheres in combination with rMVAs as a promising multiserotype vaccine candidate against BTV.

  13. Mucosal priming of newborn mice with S. Typhi Ty21a expressing anthrax protective antigen (PA) followed by parenteral PA-boost induces B and T cell-mediated immunity that protects against infection bypassing maternal antibodies.

    PubMed

    Ramirez, Karina; Ditamo, Yanina; Galen, James E; Baillie, Les W J; Pasetti, Marcela F

    2010-08-23

    The currently licensed anthrax vaccine has several limitations and its efficacy has been proven only in adults. Effective immunization of newborns and infants requires adequate stimulation of their immune system, which is competent but not fully activated. We explored the use of the licensed live attenuated S. Typhi vaccine strain Ty21a expressing Bacillus anthracis protective antigen [Ty21a(PA)] followed PA-alum as a strategy for immunizing the pediatric population. Newborn mice primed with a single dose of Ty21a(PA) exhibited high frequencies of mucosal IgA-secreting B cells and IFN-gamma-secreting T cells during the neonatal period, none of which was detected in newborns immunized with a single dose of PA-alum. Priming with Ty21a(PA) followed by PA-boost resulted in high levels of PA-specific IgG, toxin neutralizing and opsonophagocytic antibodies and increased frequency of bone marrow IgG plasma cells and memory B cells compared with repeated immunization with PA-alum alone. Robust B and T cell responses developed even in the presence of maternal antibodies. The prime-boost protected against systemic and respiratory infection. Mucosal priming with a safe and effective S. Typhi-based anthrax vaccine followed by PA-boost could serve as a practical and effective prophylactic approach to prevent anthrax early in life.

  14. Mucosal priming of newborn mice with S. Typhi Ty21a expressing anthrax protective antigen (PA) followed by parenteral PA-boost induces B and T cell-mediated immunity that protects against infection bypassing maternal antibodies

    PubMed Central

    Ramirez, Karina; Ditamo, Yanina; Galen, James E.; Baillie, Les W. J.; Pasetti, Marcela F.

    2010-01-01

    The currently licensed anthrax vaccine has several limitations and its efficacy has been proven only in adults. Effective immunization of newborns and infants requires adequate stimulation of their immune system, which is competent but not fully activated. We explored the use of the licensed live attenuated S. Typhi vaccine strain Ty21a expressing Bacillus anthracis protective antigen [Ty21a(PA)] followed PA-alum as a strategy for immunizing the pediatric population. Newborn mice primed with a single dose of Ty21a(PA) exhibited high frequencies of mucosal IgA-secreting B cells and IFN-γ-secreting T cells during the neonatal period, none of which was detected in newborns immunized with a single dose of PA-alum. Priming with Ty21a(PA) followed by PA-boost resulted in high levels of PA-specific IgG, toxin-neutralizing and opsonophagocytic antibodies and increased frequency of bone marrow IgG plasma cells and memory B cells compared with repeated immunization with PA-alum alone. Robust B and T cell responses developed even in the presence of maternal antibodies. The prime-boost protected against systemic and respiratory infection. Mucosal priming with a safe and effective S. Typhi-based anthrax vaccine followed by PA-boost could serve as a practical and effective prophylactic approach to prevent anthrax early in life. PMID:20619377

  15. Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial

    PubMed Central

    Joseph, Sarah; Geldmacher, Christof; Munseri, Patricia J.; Aboud, Said; Missanga, Marco; Mann, Philipp; Wahren, Britta; Ferrari, Guido; Polonis, Victoria R.; Robb, Merlin L.; Weber, Jonathan; Tatoud, Roger; Maboko, Leonard; Hoelscher, Michael; Lyamuya, Eligius F.; Biberfeld, Gunnel; Sandström, Eric; Kroidl, Arne; Bakari, Muhammad; Nilsson, Charlotta; McCormack, Sheena

    2016-01-01

    Background A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA). Methods Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30–71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart. Results The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding antibodies to subtype C Env (included in HIV-DNA and protein boost), subtype B Env (included only in HIV-DNA) and CRF01_AE Env (included only in HIV-MVA) were significantly boosted by the CN54rgp140/GLA-AF immunizations. Functional antibodies detected using an infectious molecular clone virus/peripheral blood mononuclear cell neutralization assay, a pseudovirus/TZM-bl neutralization assay or by assays for antibody-dependent cellular cytotoxicity (ADCC) were not significantly boosted. In contrast, T-cell proliferative responses to subtype B MN antigen and IFN-γ ELISpot responses to Env peptides were significantly enhanced. Four volunteers not primed with HIV-DNA and HIV-MVA before the CN54rgp140/GLA-AF immunizations mounted an antibody response, while cell-mediated responses were rare. After the two Env subtype C protein immunizations, a trend towards higher median subtype C Env binding antibody titers was found in vaccinees who had received HIV-DNA and HIV

  16. Immune responses against hepatitis C virus genotype 3a virus-like particles in mice: A novel VLP prime-adenovirus boost strategy.

    PubMed

    Kumar, Anuj; Das, Soma; Mullick, Ranajoy; Lahiri, Priyanka; Tatineni, Ranjitha; Goswami, Debashree; Bhat, Prasanna; Torresi, Joseph; Gowans, Eric James; Karande, Anjali Anoop; Das, Saumitra

    2016-02-17

    Chronic hepatitis C virus (HCV) infection represents a major health threat to global population. In India, approximately 15-20% of cases of chronic liver diseases are caused by HCV infection. Although, new drug treatments hold great promise for HCV eradication in infected individuals, the treatments are highly expensive. A vaccine for preventing or treating HCV infection would be of great value, particularly in developing countries. Several preclinical trials of virus-like particle (VLP) based vaccine strategies are in progress throughout the world. Previously, using baculovirus based system, we have reported the production of hepatitis C virus-like particles (HCV-LPs) encoding structural proteins for genotype 3a, which is prevalent in India. In the present study, we have generated HCV-LPs using adenovirus based system and tried different immunization strategies by using combinations of both kinds of HCV-LPs with other genotype 3a-based immunogens. HCV-LPs and peptides based ELISAs were used to evaluate antibody responses generated by these combinations. Cell-mediated immune responses were measured by using T-cell proliferation assay and intracellular cytokine staining. We observed that administration of recombinant adenoviruses expressing HCV structural proteins as final booster enhances both antibody as well as T-cell responses. Additionally, reduction of binding of VLP and JFH1 virus to human hepatocellular carcinoma cells demonstrated the presence of neutralizing antibodies in immunized sera. Taken together, our results suggest that the combined regimen of VLP followed by recombinant adenovirus could more effectively inhibit HCV infection, endorsing the novel vaccine strategy.

  17. Effect of concentrate supplementation during the dry period on colostrum quality and effect of colostrum feeding regimen on passive transfer of immunity, calf health, and performance.

    PubMed

    Dunn, A; Ashfield, A; Earley, B; Welsh, M; Gordon, A; McGee, M; Morrison, S J

    2017-01-01

    The objectives were to evaluate the effect of (1) supplementing concentrates to multiparous Holstein cows during the dry period on colostral and milk immunoglobulin G (IgG) concentration; and (2) feeding calves colostrum at either 5 or 10% of their body weight (BW) on passive transfer of immunity, health, and performance. Holstein multiparous cows (n=37) were assigned to 1 of 2 nutritional treatments during an 8-wk dry period: (1) offered ad libitum grass silage only (GS) or (2) offered ad libitum access to the same grass silage plus concentrate [total mixed ration in a 75:25 dry matter (DM) ratio], providing a mean concentrate DM intake of 3.0kg/cow per day (GSC). Both treatment groups were offered identical levels of mineral and vitamin supplementation. Calves from these cows were weighed immediately after birth and fed either 5% (5BW) or 10% (10BW) of their BW in colostrum from their own dams within 2.5h of birth. Calves in the 10BW group received their second feed of colostrum from first-milking colostrum. Concentrate supplementation during the dry period had no effect on colostral IgG concentration, first-milking IgG yield, or fat, protein, and lactose contents. However, cows in GSC produced a greater mean milk yield over the first 8 milkings compared with cows in the GS group. Concentrate supplementation had no effect on calf BW or BW gain, serum IgG, or apparent efficiency of absorption (AEA) at 24h after birth. However, offspring from the GSC group had fewer cases of enteritis during the first 56d of life compared with offspring from the GS group. Calves in the 10BW group had greater mean serum IgG concentration for the first 3d following birth; however, at 24h after birth, we observed no treatment effect on AEA. The rate of enteritis was greater for calves in the 5BW treatment compared with 10BW. The colostrum-feeding regimen had no effect on BW gain or on the incidence of pneumonia among calf treatment groups. In conclusion, concentrate supplementation

  18. Response to First-Line Ritonavir-Boosted Protease Inhibitors (PI/r)-Based Regimens in HIV Positive Patients Presenting to Care with Low CD4 Counts: Data from the Icona Foundation Cohort

    PubMed Central

    d’Arminio Monforte, Antonella; Cozzi-Lepri, Alessandro; Maggiolo, Franco; Rizzardini, Giuliano; Manconi, Paolo Emilio; Gianotti, Nicola; Quirino, Tiziana; Pinnetti, Carmela; Rusconi, Stefano; De Luca, Andrea; Antinori, Andrea

    2016-01-01

    Background There are no data comparing the response to PI/r-based regimens in people presenting for care with low CD4 counts or AIDS (LC). Aim To compare the response to LPV/r-, DRV/r- or ATV/r-based cART regimens in LC initiating cART from ART-naive. Methods We included people enrolled in Icona with either CD4 counts ≤350 cells/mm3 (low CD4-LC) or CD4 counts ≤200 cells/mm3 (very low CD4-VLC) and/or AIDS, starting their first PI/r-based regimen after 2008. Initial regimens were compared by intention-to-treat: i) time to viral failure (VF) (first of 2 consecutive VL>200 copies/mL after≥6 months); II) time to PI/r discontinuation/switching for any cause (TD) and for toxicity (TDT); III) treatment failure (TF) (VF or TD). Kaplan-Meier and Cox analyses were used. Results 1,362 LC patients were included (DRV/r 607; ATV/r 552; LPV/r 203); 813 VLC. In a median of 18 months (IQR:7–35), the 1-year probability of VF and TF were 2.8% (1.9–3.8) and 21.1% (18.7–23.4). In the adjusted analysis, patients initiating ATV/r had a 53% lower chance, and those initiating DRV/r a 61% lower chance of TD, as compared to LPV/r; the risk of TF was more likely in people starting LPV/r. Results were similar among VLC; in this subgroup LPV/r including regimens demonstrated a lower chance of VF. Conclusions We confirmed in LC a low chance of virological failure by 1 year, with small differences according to PI/r. However, larger differences were observed when comparing longer-term endpoints such as treatment failure. These results are important for people presenting late for care. PMID:27348592

  19. Phagocytosed Clofazimine Biocrystals can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

    PubMed Central

    Yoon, Gi S.; Sud, Sudha; Keswani, Rahul K.; Baik, Jason; Standiford, Theodore J.; Stringer, Kathleen A.; Rosania, Gus R.

    2015-01-01

    Clofazimine (CFZ) is an FDA-approved leprostatic and anti-inflammatory drug that massively accumulates in macrophages, forming insoluble, intracellular crystal-like drug inclusions (CLDIs) during long-term oral dosing. Interestingly, when added to cells in vitro, soluble CFZ is cytotoxic because it depolarizes mitochondria and induces apoptosis. Accordingly, we hypothesized that in vivo, macrophages detoxify CFZ by sequestering it in CLDIs. To test this hypothesis, CLDIs of CFZ-treated mice were biochemically isolated, and then incubated with macrophages in vitro. The cell biological effects of phagocytosed CLDIs were compared to those of soluble CFZ. Unlike soluble CFZ, phagocytosis of CLDIs did not lead to mitochondrial destabilization or apoptosis. Rather, CLDIs altered immune signaling response pathways downstream of Toll-like receptor (TLR) ligation, leading to enhanced interleukin-1 receptor antagonist (IL-1RA) production, dampened NF-κB activation and tissue necrosis factor alpha (TNFα) production, and ultimately decreased TLR expression levels. In aggregate, our results constitute evidence that macrophages detoxify soluble CFZ by sequestering it in a biocompatible, insoluble form. The altered cellular response to TLR ligation suggests that CLDI formation may also underlie CFZ’s anti-inflammatory activity. PMID:25909959

  20. Effect of traditional Chinese medicine for treating human immunodeficiency virus infections and acquired immune deficiency syndrome: Boosting immune and alleviating symptoms.

    PubMed

    Zou, Wen; Wang, Jian; Liu, Ying

    2016-01-01

    To respond to the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in China, the integration of antiretroviral therapy (ART) and traditional Chinese medicine (TCM) has important implications in health outcomes, especially in China where the use of TCM is widespread. The National Free TCM Pilot Program for HIV Infected People began in 5 provinces (Henan, Hebei, Anhui, Hubei, and Guangdong) in 2004, and quickly scaled up to 19 provinces, autonomous regions, and municipalities in China including some places with high prevalence, 26,276 adults have been treated thus far. Usually, people with HIV infection seek TCM for four main reasons: to enhance immune function, to treat symptoms, to improve quality of life, and to reduce side effects related to medications. Evidences from randomized controlled clinical trials suggested some beneficial effects of use of traditional Chinese herbal medicine for HIV infections and AIDS. More proofs from large, well-designed, rigorous trials is needed to give firm support. Challenges include interaction between herbs and antiretroviral drugs, stigma and discrimination. The Free TCM Program has made considerable progress in providing the necessary alternative care and treatment for HIV-infected people in China, and has strong government support for continued improvement and expansion, establishing and improving a work mechanism integrating Chinese and Western medicines.

  1. Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88.

    PubMed

    Zhang, Xiuli; Dervillez, Xavier; Chentoufi, Aziz Alami; Badakhshan, Tina; Bettahi, Ilham; Benmohamed, Lbachir

    2012-11-01

    Targeting of the mucosal immune system of the genital tract with subunit vaccines has failed to induce potent and durable local CD8(+) T cell immunity, which is crucial for protection against many sexually transmitted viral pathogens, including HSV type 2 (HSV-2), which causes genital herpes. In this study, we aimed to investigate the potential of a novel lipopeptide/adenovirus type 5 (Lipo/rAdv5) prime/boost mucosal vaccine for induction of CD8(+) T cell immunity to protect the female genital tract from herpes. The lipopeptide vaccine and the rAdv5 vaccine express the immunodominant HSV-2 CD8(+) T cell epitope (gB(498-505)), and both were delivered intravaginally in the progesterone-induced B6 mouse model of genital herpes. Compared with mice immunized with the homologous lipopeptide/lipopeptide (Lipo/Lipo) vaccine, the Lipo/rAdv5 prime/boost immunized mice 1) developed potent and sustained HSV-specific CD8(+) T cells, detected in both the genital tract draining nodes and in the vaginal mucosa; 2) had significantly lower virus titers; 3) had decreased overt signs of genital herpes disease; and 4) did not succumb to lethal infection (p < 0.005) after intravaginal HSV-2 challenge. Polyfunctional CD8(+) T cells, producing IFN-γ, TNF-α, and IL-2 and exhibiting cytotoxic activity, were associated with protection (p < 0.005). The protective CD8(+) T cell response was significantly compromised in the absence of the adapter MyD88 (p = 0.0001). Taken together, these findings indicate that targeting of the vaginal mucosa with a Lipo/rAdv5 prime/boost vaccine elicits a potent, MyD88-dependent, and long-lasting mucosal CD8(+) T cell protective immunity against sexually transmitted herpes infection and disease.

  2. Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses

    PubMed Central

    Silva, Mariana; Silva, Zélia; Marques, Graça; Ferro, Tiago; Gonçalves, Márcia; Monteiro, Mauro; van Vliet, Sandra J.; Mohr, Elodie; Lino, Andreia C.; Fernandes, Alexandra R.; Lima, Flávia A.; van Kooyk, Yvette; Matos, Teresa; Tadokoro, Carlos E.; Videira, Paula A.

    2016-01-01

    Dendritic cells (DCs) hold promise for anti-cancer immunotherapy. However, clinically, their efficiency is limited and novel strategies to improve DC-mediated anti-tumor responses are needed. Human DCs display high content of sialic acids, which inhibits their maturation and co-stimulation capacity. Here, we aimed to understand whether exogenous desialylation of DCs improves their anti-tumor immunity. Compared to fully sialylated DCs, desialylated human DCs loaded with tumor-antigens showed enhanced ability to induce autologous T cells to proliferate, to secrete Th1 cytokines, and to specifically induce tumor cell apoptosis. Desialylated DCs showed an increased expression of MHC-I and -II, co-stimulatory molecules and an augmented secretion of IL-12. Desialylated HLA-A*02:01 DCs pulsed with gp100 peptides displayed enhanced peptide presentation through MHC-I, resulting in higher activation ofgp100280–288 specific CD8+ cytotoxic T cells. Desialylated murine DCs also exhibited increased MHC and co-stimulatory molecules and higher antigen cross-presentation via MHC-I. These DCs showed higher ability to activate antigen-specific CD4+ and CD8+ T cells, and to specifically induce tumor cell apoptosis. Collectively, our data demonstrates that desialylation improves DCs' ability to elicit T cell-mediated anti-tumor activity, due to increased MHC-I expression and higher antigen presentation via MHC-I. Sialidase treatment of DCs may represent a technology to improve the efficacy of antigen loaded-DC-based vaccines for anti-cancer immunotherapy. PMID:27203391

  3. Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses.

    PubMed

    Silva, Mariana; Silva, Zélia; Marques, Graça; Ferro, Tiago; Gonçalves, Márcia; Monteiro, Mauro; van Vliet, Sandra J; Mohr, Elodie; Lino, Andreia C; Fernandes, Alexandra R; Lima, Flávia A; van Kooyk, Yvette; Matos, Teresa; Tadokoro, Carlos E; Videira, Paula A

    2016-07-05

    Dendritic cells (DCs) hold promise for anti-cancer immunotherapy. However, clinically, their efficiency is limited and novel strategies to improve DC-mediated anti-tumor responses are needed. Human DCs display high content of sialic acids, which inhibits their maturation and co-stimulation capacity. Here, we aimed to understand whether exogenous desialylation of DCs improves their anti-tumor immunity. Compared to fully sialylated DCs, desialylated human DCs loaded with tumor-antigens showed enhanced ability to induce autologous T cells to proliferate, to secrete Th1 cytokines, and to specifically induce tumor cell apoptosis. Desialylated DCs showed an increased expression of MHC-I and -II, co-stimulatory molecules and an augmented secretion of IL-12. Desialylated HLA-A*02:01 DCs pulsed with gp100 peptides displayed enhanced peptide presentation through MHC-I, resulting in higher activation ofgp100280-288 specific CD8+ cytotoxic T cells. Desialylated murine DCs also exhibited increased MHC and co-stimulatory molecules and higher antigen cross-presentation via MHC-I. These DCs showed higher ability to activate antigen-specific CD4+ and CD8+ T cells, and to specifically induce tumor cell apoptosis. Collectively, our data demonstrates that desialylation improves DCs' ability to elicit T cell-mediated anti-tumor activity, due to increased MHC-I expression and higher antigen presentation via MHC-I. Sialidase treatment of DCs may represent a technology to improve the efficacy of antigen loaded-DC-based vaccines for anti-cancer immunotherapy.

  4. Intradermal naked plasmid DNA immunization: mechanisms of action.

    PubMed

    Elnekave, Mazal; Furmanov, Karina; Hovav, Avi-Hai

    2011-08-01

    Plasmid DNA is a promising vaccine modality that is regularly examined in prime-boost immunization regimens. Recent advances in skin immunity increased our understanding of the sophisticated cutaneous immune network, which revived scientific interest in delivering vaccines to the skin. Intradermal administration of plasmid DNA via needle injection is a simple and inexpensive procedure that exposes the plasmid and its encoded antigen to the dermal immune surveillance system. This triggers unique mechanisms for eliciting local and systemic immunity that can confer protection against pathogens and tumors. Understanding the mechanisms of intradermal plasmid DNA immunization is essential for enhancing and modulating its immunogenicity. With regard to vaccination, this is of greater importance as this routine injection technique is highly desirable for worldwide immunization. This article will focus on the current understanding of the mechanisms involved in antigen expression and presentation during primary and secondary syringe and needle intradermal plasmid DNA immunization.

  5. Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT).

    PubMed

    Le Bourgeois, Amandine; Lestang, Elsa; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Blin, Nicolas; Clavert, Aline; Tessoulin, Benoit; Dubruille, Viviane; Mahe, Beatrice; Roland, Virginie; Gastinne, Thomas; Le Gouill, Steven; Moreau, Philippe; Mohty, Mohamad; Planche, Lucie; Chevallier, Patrice

    2013-03-01

    This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22-70)] who received a FB2 (fludarabine 120-150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced-intensity conditioning (RIC) allo-stem cells transplantations (SCT). With a median follow-up of 19 months (range: 2-53), the 2-yr overall survival, disease-free survival (DFS), relapse incidence, and non-relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2-yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm(3) ; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm(3) ) (2-yr OS: 81% vs. 44%, P = 0.007; 2-yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm(3) ) (2-yr OS: 76% vs. 50%, P = 0.03; 2-yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm(3) ; 2-yr OS: 80% vs. 45%, P = 0.004; 2-yr DFS: 76% vs. 42%, P = 0.01) at day +30 post-transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm(3) ) and a higher monocytes count (>590/mm(3) ) at day +30 post-transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT.

  6. Inclusion of a CRF01_AE HIV envelope protein boost with a DNA/MVA prime-boost vaccine: Impact on humoral and cellular immunogenicity and viral load reduction after SHIV-E challenge.

    PubMed

    Cox, Josephine H; Ferrari, Maria G; Earl, Patricia; Lane, James R; Jagodzinski, Linda L; Polonis, Victoria R; Kuta, Ellen G; Boyer, Jean D; Ratto-Kim, Silvia; Eller, Leigh-Anne; Pham, Doan-Trang; Hart, Lydia; Montefiori, David; Ferrari, Guido; Parrish, Stephanie; Weiner, David B; Moss, Bernard; Kim, Jerome H; Birx, Deborah; VanCott, Thomas C

    2012-02-27

    The current study assessed the immunogenicity and protective efficacy of various prime-boost vaccine regimens in rhesus macaques using combinations of recombinant DNA (rDNA), recombinant MVA (rMVA), and subunit gp140 protein. The rDNA and rMVA vectors were constructed to express Env from HIV-1 subtype CRF01_AE and Gag-Pol from CRF01_AE or SIVmac 239. One of the rMVAs, MVA/CMDR, has been recently tested in humans. Immunizations were administered at months 0 and 1 (prime) and months 3 and 6 (boost). After priming, HIV env-specific serum IgG was detected in monkeys receiving gp140 alone or rMVA but not in those receiving rDNA. Titers were enhanced in these groups after boosting either with gp140 alone or with rMVA plus gp140. The groups that received the rDNA prime developed env-specific IgG after boosting with rMVA with or without gp140. HIV Env-specific serum IgG binding antibodies were elicited more frequently and of higher titer, and breadth of neutralizing antibodies was increased with the inclusion of the subunit Env boost. T cell responses were measured by tetramer binding to Gag p11c in Mamu-A*01 macaques, and by IFN-γ ELISPOT assay to SIV-Gag. T cell responses were induced after vaccination with the highest responses seen in macaques immunized with rDNA and rMVA. Macaques were challenged intravenously with a novel SHIV-E virus (SIVmac239 Gag-Pol with an HIV-1 subtype E-Env CAR402). Post challenge with SHIV-E, antibody titers were boosted in all groups and peaked at 4 weeks. Robust T cell responses were seen in all groups post challenge and in macaques immunized with rDNA and rMVA a clear boosting of responses was seen. A greater than two-log drop in RNA copies/ml at peak viremia and earlier set point was achieved in macaques primed with rDNA, and boosted with rMVA/SHIV-AE plus gp140. Post challenge viremia in macaques immunized with other regimens was not significantly different to that of controls. These results demonstrate that a gp140 subunit and

  7. Application of SCR priming VLP boosting as a novel vaccination strategy against HIV-1.

    PubMed

    Sadat, Seyed Mehdi; Zabihollahi, Rezvan; Aghasadeghi, Mohammad Reza; Vahabpour, Rouhollah; Siadat, Seyed Davar; Memarnejadian, Arash; Azadmanesh, Kayhan; Parivar, Kazem

    2011-04-01

    Human immunodeficiency virus infection is a worldwide health problem and a protective vaccine is desperately needed to control the AIDS pandemics. To address this concern, we previously constructed single-cycle replicable (SCR) HIV-1 virions, which completely maintained the antigenic structures of HIV-1. Herein, to optimize a vaccination strategy, we studied the immunogenicity of produced SCR virions and adjuvant-formulated HIV-1 virus-like particles (VLPs) in homologous and heterologous prime-boosting regimens. Accordingly, BALB/c mice received three doses of immunogens in 3-week intervals and their immune responses were evaluated using ELISA, cytokine and IFN-γ ELISpot assays. These analyses not only indicated the superiority of SCR prime-VLP boosting for strong induction of specific IFN-γ producing cells, but also showed the capability of this strategy over the others for better stimulation of humoral response, which was evidenced with the detection of highest titer of total IgG against HIV ENV glycoprotein. Furthermore, determination of IgG subclasses and IFN-γ/IL4 secretion ratio in cultured splenocytes demonstrated the efficient augmentation of mixed responses with the dominancy of Th1 immunity following SCR/VLP immunization strategy. Our results additionally pointed towards the applicability of Montanide ISA 720 + CpG as a potent Th1-directing adjuvant mixture. Overall, this study suggests SCR prime-VLP boosting as a promising approach in HIV vaccine development.

  8. Enhanced Immunity to Plasmodium falciparum Circumsporozoite Protein (PfCSP) by Using Salmonella enterica Serovar Typhi Expressing PfCSP and a PfCSP-Encoding DNA Vaccine in a Heterologous Prime-Boost Strategy▿ †

    PubMed Central

    Chinchilla, Magaly; Pasetti, Marcela F.; Medina-Moreno, Sandra; Wang, Jin Yuan; Gomez-Duarte, Oscar G.; Stout, Rick; Levine, Myron M.; Galen, James E.

    2007-01-01

    Two Salmonella enterica serovar Typhi strains that express and export a truncated version of Plasmodium falciparum circumsporozoite surface protein (tCSP) fused to Salmonella serovar Typhi cytolysin A (ClyA) were constructed as a first step in the development of a preerythrocytic malaria vaccine. Synthetic codon-optimized genes (t-csp1 and t-csp2), containing immunodominant B- and T-cell epitopes present in native P. falciparum circumsporozoite surface protein (PfCSP), were fused in frame to the carboxyl terminus of the ClyA gene (clyA::t-csp) in genetically stabilized expression plasmids. Expression and export of ClyA-tCSP1 and ClyA-tCSP2 by Salmonella serovar Typhi vaccine strain CVD 908-htrA were demonstrated by immunoblotting of whole-cell lysates and culture supernatants. The immunogenicity of these constructs was evaluated using a “heterologous prime-boost” approach consisting of mucosal priming with Salmonella serovar Typhi expressing ClyA-tCSP1 and ClyA-tCSP2, followed by parenteral boosting with PfCSP DNA vaccines pVR2510 and pVR2571. Mice primed intranasally on days 0 and 28 with CVD 908-htrA(pSEC10tcsp2) and boosted intradermally on day 56 with PfCSP DNA vaccine pVR2571 induced high titers of serum NANP immunoglobulin G (IgG) (predominantly IgG2a); no serological responses to DNA vaccination were observed in the absence of Salmonella serovar Typhi-PfCSP priming. Mice primed with Salmonella serovar Typhi expressing tCSP2 and boosted with PfCSP DNA also developed high frequencies of gamma interferon-secreting cells, which surpassed those produced by PfCSP DNA in the absence of priming. A prime-boost regimen consisting of mucosal delivery of PfCSP exported from a Salmonella-based live-vector vaccine followed by a parenteral PfCSP DNA boosting is a promising strategy for the development of a live-vector-based malaria vaccine. PMID:17502396

  9. Potent, Persistent Induction and Modulation of Cellular Immune Responses in Rhesus Macaques Primed with Ad5hr-Simian Immunodeficiency Virus (SIV) env/rev, gag, and/or nef Vaccines and Boosted with SIV gp120

    PubMed Central

    Patterson, L. Jean; Malkevitch, Nina; Pinczewski, Joel; Venzon, David; Lou, Yuanmei; Peng, Bo; Munch, Cindy; Leonard, Melissa; Richardson, Ersell; Aldrich, Kristine; Kalyanaraman, V. S.; Pavlakis, George N.; Robert-Guroff, Marjorie

    2003-01-01

    Immunity elicited by multicomponent vaccines delivered by replication-competent Ad5hr-simian immunodeficiency virus (SIV) recombinants was systematically investigated. Rhesus macaques were immunized mucosally at weeks 0 and 12 with Ad5hr-SIVsmH4 env/rev, with or without Ad5hr-SIVmac239 gag or Ad5hr-SIVmac239 nef, or with all three recombinants. The total Ad5hr dosage was comparably adjusted among all animals with empty Ad5hr-ΔE3 vector. The macaques were boosted with SIV gp120 in monophosphoryl A-stable emulsion adjuvant at 24 and 36 weeks. Controls received Ad5hr-ΔE3 vector or adjuvant only. By ELISPOT analysis, all four SIV gene products elicited potent cellular immune responses that persisted 42 weeks post-initial immunization. Unexpectedly, modulation of this cellular immune response was observed among macaques receiving one, two, or three Ad5hr-SIV recombinants. Env responses were significantly enhanced throughout the immunization period in macaques immunized with Ad5hr-SIV env/rev plus Ad5hr-SIV gag and tended to be higher in macaques that also received Ad5hr-SIV nef. Macaques primed with all three recombinants displayed significant down-modulation in numbers of gamma interferon (IFN-γ)-secreting cells specific for SIV Nef, and the Env- and Gag-specific responses were also diminished. Modulation of antibody responses was not observed. Down-modulation was seen only during the period of Ad5hr-recombinant priming, not during subunit boosting, although SIV-specific IFN-γ-secreting cells persisted. The effect was not attributable to Ad5hr replication differences among immunization groups. Vaccine delivery via replication-competent live vectors, which can persistently infect new cells and continuously present low-level antigen, may be advantageous in overcoming competition among complex immunogens for immune recognition. Effects of current multicomponent vaccines on individual immune responses should be evaluated with regard to future vaccine design. PMID

  10. Comparative Analysis of SIV-specific Cellular Immune Responses Induced by Different Vaccine Platforms in Rhesus Macaques

    PubMed Central

    Valentin, Antonio; McKinnon, Katherine; Li, Jinyao; Rosati, Margherita; Kulkarni, Viraj; Pilkington, Guy R.; Bear, Jenifer; Alicea, Candido; Vargas-Inchaustegui, Diego A.; Patterson, L. Jean; Pegu, Poonam; Liyanage, Namal P. M.; Gordon, Shari N.; Vaccari, Monica; Wang, Yichuan; Hogg, Alison E.; Frey, Blake; Sui, Yongjun; Reed, Steven G.; Sardesai, Niranjan Y.; Berzofsky, Jay A.; Franchini, Genoveffa; Robert-Guroff, Marjorie; Felber, Barbara K.; Pavlakis, George N.

    2014-01-01

    To identify the most promising vaccine candidates for combinatorial strategies, we compared five SIV vaccine platforms including recombinant canary pox virus ALVAC, replication-competent adenovirus type 5 host range mutant RepAd, DNA, modified vaccinia Ankara (MVA), peptides and protein in distinct combinations. Three regimens used viral vectors (prime or boost) and two regimens used plasmid DNA. Analysis at necropsy showed that the DNA-based vaccine regimens elicited significantly higher cellular responses against Gag and Env than any of the other vaccine platforms. The T cell responses induced by most vaccine regimens disseminated systemically into secondary lymphoid tissues (lymph nodes, spleen) and effector anatomical sites (including liver, vaginal tissue), indicative of their role in viral containment at the portal of entry. The cellular and reported humoral immune response data suggest that combination of DNA and viral vectors elicits a balanced immunity with strong and durable responses able to disseminate into relevant mucosal sites. PMID:25229164

  11. Comparative analysis of SIV-specific cellular immune responses induced by different vaccine platforms in rhesus macaques.

    PubMed

    Valentin, Antonio; McKinnon, Katherine; Li, Jinyao; Rosati, Margherita; Kulkarni, Viraj; Pilkington, Guy R; Bear, Jenifer; Alicea, Candido; Vargas-Inchaustegui, Diego A; Jean Patterson, L; Pegu, Poonam; Liyanage, Namal P M; Gordon, Shari N; Vaccari, Monica; Wang, Yichuan; Hogg, Alison E; Frey, Blake; Sui, Yongjun; Reed, Steven G; Sardesai, Niranjan Y; Berzofsky, Jay A; Franchini, Genoveffa; Robert-Guroff, Marjorie; Felber, Barbara K; Pavlakis, George N

    2014-11-01

    To identify the most promising vaccine candidates for combinatorial strategies, we compared five SIV vaccine platforms including recombinant canary pox virus ALVAC, replication-competent adenovirus type 5 host range mutant RepAd, DNA, modified vaccinia Ankara (MVA), peptides and protein in distinct combinations. Three regimens used viral vectors (prime or boost) and two regimens used plasmid DNA. Analysis at necropsy showed that the DNA-based vaccine regimens elicited significantly higher cellular responses against Gag and Env than any of the other vaccine platforms. The T cell responses induced by most vaccine regimens disseminated systemically into secondary lymphoid tissues (lymph nodes, spleen) and effector anatomical sites (including liver, vaginal tissue), indicative of their role in viral containment at the portal of entry. The cellular and reported humoral immune response data suggest that combination of DNA and viral vectors elicits a balanced immunity with strong and durable responses able to disseminate into relevant mucosal sites.

  12. Relevance of a pre-existing measles immunity prior immunization with a recombinant measles virus vector.

    PubMed

    Knuchel, Marlyse C; Marty, René R; Morin, Teldja Neige Azzouz; Ilter, Orhan; Zuniga, Armando; Naim, Hussein Y

    2013-03-01

    Measles virus (MV) vectors are promising candidates for designing new recombinant vaccines since the parental live vaccines have a well-known safety and efficacy record. Like all viral vectors, the MV vector efficacy in inducing a protecting immune answer could be affected by the pre-existing immunity among the human population. In order to determine the optimal immunization route and regimen, we mimicked a MV pre-immunity by passively administrating MV neutralizing antibodies (MV-nAb) prior intramuscular (i.m.) and/or intranasal (i.n.) immunization with recombinant MV expressing the SIV-gag antigen (rMV-SIVgag). Our results revealed that 500 mIU of MV-nAb allowed the induction of a humoral and cellular immune response against the vector and the transgene, while higher titers of the MV-nAb were significantly inhibitory. In a prime-boost regimen, in the presence of MV-nAb, the intranasal-intramuscular (i.n.-i.m.) or intramuscular-intramuscular (i.m.-i.m.) routes induced higher humoral immune responses against the vector and the transgene (SIV-gag). In naive animals, cellular immune response was significantly higher by i.m. immunization; however, MV pre-immunity did not seem to affect the cellular immune response after an i.n. immunization.   In summary, we show that a pre-existing immunity of up to 500 mIU anti-MV neutralizing antibodies had little effect on the replication of rMV and did not inhibit the induction of significant humoral and cellular immune responses in immune-competent mice.

  13. [A novel immunization strategy to induce strong humoral responses against HIV-1 using combined DNA, recombinant vaccinia virus and protein vaccines].

    PubMed

    Liu, Chang; Wang, Shu-hui; Ren, Li; Hao, Yan-ling; Zhang, Qi-cheng; Liu, Ying

    2014-11-01

    To optimize the immunization strategy against HIV-1, a DNA vaccine was combined with a recombinant vaccinia virus (rTV) vaccine and a protein vaccine. Immune responses against HIV-1 were detected in 30 female guinea pigs divided into six groups. Three groups of guinea pigs were primed with HIV-1 DNA vaccine three times, boosted with rTV at week 14, and then boosted with gp140 protein at intervals of 4, 8 or 12 weeks. Simultaneously, the other three groups of animals were primed with rTV vaccine once, and then boosted with gp140 after 4, 8 or 12 weeks. The HIV-1 specific binding antibody and neutralizing antibody, in addition to the relative affinity of these antibodies, were detected at different time points after the final administration of vaccine in each group. The DNA-rTV-gp140 immune regimen induced higher titers and affinity levels of HIV-1 gp120/gp140 antibodies and stronger V1V2-gp70 antibodies than the rTV-gp140 regimen. In the guinea pigs that underwent the DNA-rTV-gp140 regimen, the highest V1V2-gp70 antibody was induced in the 12-week-interval group. However, the avidity of antibodies was improved in the 4-week-interval group. Using the rTV-gp140 immunization strategy, guinea pigs boosted at 8 or 12 weeks after rTV priming elicited stronger humoral responses than those boosted at 4 weeks after priming. In conclusion, this study shows that the immunization strategy of HIV-1 DNA vaccine priming, followed by rTV and protein vaccine boosting, could strengthen the humoral response against HIV-1. Longer intervals were better to induce V1V2-gp70-specific antibodies, while shorter intervals were more beneficial to enhance the avidity of antibodies.

  14. Immunity: plants as effective mediators.

    PubMed

    Sultan, M Tauseef; Butt, Masood Sadiq; Qayyum, Mir M Nasir; Suleria, Hafiz Ansar Rasul

    2014-01-01

    In the domain of nutrition, exploring the diet-health linkages is major area of research. The outcomes of such interventions led to widespread acceptance of functional and nutraceutical foods; however, augmenting immunity is a major concern of dietary regimens. Indeed, the immune system is incredible arrangement of specific organs and cells that enabled humans to carry out defense against undesired responses. Its proper functionality is essential to maintain the body homeostasis. Array of plants and their components hold immunomodulating properties. Their possible inclusion in diets could explore new therapeutic avenues to enhanced immunity against diseases. The review intended to highlight the importance of garlic (Allium sativum), green tea (Camellia sinensis), ginger (Zingiber officinale), purple coneflower (Echinacea), black cumin (Nigella sativa), licorice (Glycyrrhiza glabra), Astragalus and St. John's wort (Hypericum perforatum) as natural immune boosters. These plants are bestowed with functional ingredients that may provide protection against various menaces. Modes of their actions include boosting and functioning of immune system, activation and suppression of immune specialized cells, interfering in several pathways that eventually led to improvement in immune responses and defense system. In addition, some of these plants carry free radical scavenging and anti-inflammatory activities that are helpful against cancer insurgence. Nevertheless, interaction between drugs and herbs/botanicals should be well investigated before recommended for their safe use, and such information must be disseminated to the allied stakeholders.

  15. Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial

    PubMed Central

    Ma, Zhong-Min; Utay, Netanya S.; Wook-Chun, Tae; Mann, Surinder; Kashuba, Angela D.; Siewe, Basile; Albanese, Anthony; Troia-Cancio, Paolo; Sinclair, Elizabeth; Somasunderam, Anoma; Yotter, Tammy; Deeks, Steven G.; Landay, Alan; Pollard, Richard B.; Miller, Christopher J.; Moreno, Santiago; Asmuth, David M.

    2016-01-01

    Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory

  16. Priming T-cell responses with recombinant measles vaccine vector in a heterologous prime-boost setting in non-human primates.

    PubMed

    Bolton, Diane L; Santra, Sampa; Swett-Tapia, Cindy; Custers, Jerome; Song, Kaimei; Balachandran, Harikrishnan; Mach, Linh; Naim, Hussein; Kozlowski, Pamela A; Lifton, Michelle; Goudsmit, Jaap; Letvin, Norman; Roederer, Mario; Radošević, Katarina

    2012-09-07

    Licensed live attenuated virus vaccines capable of expressing transgenes from other pathogens have the potential to reduce the number of childhood immunizations by eliciting robust immunity to multiple pathogens simultaneously. Recombinant attenuated measles virus (rMV) derived from the Edmonston Zagreb vaccine strain was engineered to express simian immunodeficiency virus (SIV) Gag protein for the purpose of evaluating the immunogenicity of rMV as a vaccine vector in rhesus macaques. rMV-Gag immunization alone elicited robust measles-specific humoral and cellular responses, but failed to elicit transgene (Gag)-specific immune responses, following aerosol or intratracheal/intramuscular delivery. However, when administered as a priming vaccine to a heterologous boost with recombinant adenovirus serotype 5 expressing the same transgene, rMV-Gag significantly enhanced Gag-specific T lymphocyte responses following rAd5 immunization. Gag-specific humoral responses were not enhanced, however, which may be due to either the transgene or the vector. Cellular response priming by rMV against the transgene was highly effective even when using a suboptimal dose of rAd5 for the boost. These data demonstrate feasibility of using rMV as a priming component of heterologous prime-boost vaccine regimens for pathogens requiring strong cellular responses.

  17. Alphavirus Replicon DNA Expressing HIV Antigens Is an Excellent Prime for Boosting with Recombinant Modified Vaccinia Ankara (MVA) or with HIV gp140 Protein Antigen

    PubMed Central

    Knudsen, Maria L.; Ljungberg, Karl; Tatoud, Roger; Weber, Jonathan; Esteban, Mariano; Liljeström, Peter

    2015-01-01

    Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells and antibodies. Studies in humans have shown that DNA vaccines are safe, but their immunogenicity needs further improvement. As a step towards this goal, we have previously demonstrated that immunogenicity is increased with the use of an alphavirus DNA-launched replicon (DREP) vector compared to conventional DNA vaccines. In this study, we investigated the effect of varying the dose and number of administrations of DREP when given as a prime prior to a heterologous boost with poxvirus vector (MVA) and/or HIV gp140 protein formulated in glucopyranosyl lipid A (GLA-AF) adjuvant. The DREP and MVA vaccine constructs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three administrations of 0.2 μg DREP induced lower HIV-specific T cell and IgG responses than the equivalent number of immunizations with 10 μg DREP. However, the two doses were equally efficient as a priming component in a heterologous prime-boost regimen. The magnitude of immune responses depended on the number of priming immunizations rather than the dose. A single low dose of DREP prior to a heterologous boost resulted in greatly increased immune responses compared to MVA or protein antigen alone, demonstrating that a mere 0.2 μg DREP was sufficient for priming immune responses. Following a DREP prime, T cell responses were expanded greatly by an MVA boost, and IgG responses were also expanded when boosted with protein antigen. When MVA and protein were administered simultaneously following multiple DREP primes, responses were slightly compromised compared to administering them sequentially. In conclusion, we have demonstrated efficient priming of HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the priming effect depends on number of primes administered rather than dose. PMID:25643354

  18. Alphavirus replicon DNA expressing HIV antigens is an excellent prime for boosting with recombinant modified vaccinia Ankara (MVA) or with HIV gp140 protein antigen.

    PubMed

    Knudsen, Maria L; Ljungberg, Karl; Tatoud, Roger; Weber, Jonathan; Esteban, Mariano; Liljeström, Peter

    2015-01-01

    Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells and antibodies. Studies in humans have shown that DNA vaccines are safe, but their immunogenicity needs further improvement. As a step towards this goal, we have previously demonstrated that immunogenicity is increased with the use of an alphavirus DNA-launched replicon (DREP) vector compared to conventional DNA vaccines. In this study, we investigated the effect of varying the dose and number of administrations of DREP when given as a prime prior to a heterologous boost with poxvirus vector (MVA) and/or HIV gp140 protein formulated in glucopyranosyl lipid A (GLA-AF) adjuvant. The DREP and MVA vaccine constructs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three administrations of 0.2 μg DREP induced lower HIV-specific T cell and IgG responses than the equivalent number of immunizations with 10 μg DREP. However, the two doses were equally efficient as a priming component in a heterologous prime-boost regimen. The magnitude of immune responses depended on the number of priming immunizations rather than the dose. A single low dose of DREP prior to a heterologous boost resulted in greatly increased immune responses compared to MVA or protein antigen alone, demonstrating that a mere 0.2 μg DREP was sufficient for priming immune responses. Following a DREP prime, T cell responses were expanded greatly by an MVA boost, and IgG responses were also expanded when boosted with protein antigen. When MVA and protein were administered simultaneously following multiple DREP primes, responses were slightly compromised compared to administering them sequentially. In conclusion, we have demonstrated efficient priming of HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the priming effect depends on number of primes administered rather than dose.

  19. Immunizations

    MedlinePlus

    ... Get Weight Loss Surgery? A Week of Healthy Breakfasts Shyness Immunizations KidsHealth > For Teens > Immunizations Print A A A What's in this article? Why Are Vaccinations Important? Why Do I Need Shots? Which Vaccinations Do ...

  20. Transient global T cell activation after vaccination of rhesus macaques with a DNA-poxvirus vaccine regimen for HIV.

    PubMed

    Soares, Andreia; Müller, Tracey L; Chege, Gerald K; Williamson, Anna-Lise; Burgers, Wendy A

    2015-07-09

    Persistent T cell activation following immunization with HIV vaccines may increase HIV acquisition risk. We investigated the magnitude and kinetics of T cell activation following vaccination of rhesus macaques with a candidate HIV vaccine consisting of a recombinant DNA and MVA vaccination regimen. We show that global CD4+ and CD8+ T cell activation, as measured by the expression of Ki67 and Bcl-2, peaked one week after boosting with MVA, but then waned rapidly to pre-vaccination levels. Furthermore, increased frequencies of CD4+ CCR5+ T cells, which represent potential HIV target cells, were short-lived and decreased to baseline levels within two months. Activated CD4+ T cells were predominantly of a central memory phenotype, and activated CD8+ T cells were distributed between central and effector memory phenotypes. Thus, only transient changes in T cell activation occurred following poxvirus vaccination, indicating a lack of persistent immune activation.

  1. Boosting of ALVAC-SIV Vaccine-Primed Macaques with the CD4-SIVgp120 Fusion Protein Elicits Antibodies to V2 Associated with a Decreased Risk of SIVmac251 Acquisition

    PubMed Central

    Gordon, Shari N.; Liyanage, Namal P. M.; Doster, Melvin N.; Vaccari, Monica; Vargas-Inchaustegui, Diego A.; Pegu, Poonam; Schifanella, Luca; Shen, Xiaoying; Tomaras, Georgia D.; Rao, Mangala; Billings, Erik A.; Schwartz, Jennifer; Prado, Ilia; Bobb, Kathryn; Zhang, Wenlei; Montefiori, David C.; Foulds, Kathryn E.; Ferrari, Guido; Robert-Guroff, Marjorie; Roederer, Mario; Phan, Tran B.; Forthal, Donald N.; Stablein, Donald M.; Phogat, Sanjay; Venzon, David J.; Fouts, Timothy

    2016-01-01

    The recombinant ALVAC vaccine coupled with the monomeric gp120/alum protein have decreased the risk of HIV and SIV acquisition. Ab responses to the V1/V2 regions have correlated with a decreased risk of virus acquisition in both humans and macaques. We hypothesized that the breadth and functional profile of Abs induced by an ALVAC/envelope protein regimen could be improved by substituting the monomeric gp120 boost, with the full-length single-chain (FLSC) protein. FLSC is a CD4-gp120 fusion immunogen that exposes cryptic gp120 epitopes to the immune system. We compared the immunogenicity and relative efficiency of an ALVAC-SIV vaccine boosted either with bivalent FLSC proteins or with monomeric gp120 in alum. FLSC was superior to monomeric gp120 in directing Abs to the C3 α2 helix, the V5 loop, and the V3 region that contains the putative CCR5 binding site. In addition, FLSC boosting elicited significantly higher binding Abs to V2 and increased both the Ab-dependent cellular cytotoxicity activity and the breadth of neutralizing Abs. However, the FLSC vaccine regimen demonstrated only a trend in vaccine efficacy, whereas the monomeric gp120 regimen significantly decreased the risk of SIVmac251 acquisition. In both vaccine regimens, anti-V2 Abs correlated with a decreased risk of virus acquisition but differed with regard to systemic or mucosal origin. In the FLSC regimen, serum Abs to V2 correlated, whereas in the monomeric gp120 regimen, V2 Abs in rectal secretions, the site of viral challenge, were associated with efficacy. PMID:27591322

  2. DNA vaccination by electroporation and boosting with recombinant proteins enhances the efficacy of DNA vaccines for Schistosomiasis japonica.

    PubMed

    Dai, Yang; Zhu, Yinchang; Harn, Donald A; Wang, Xiaoting; Tang, Jianxia; Zhao, Song; Lu, Fei; Guan, Xiaohong

    2009-12-01

    Schistosomiasis japonica is an endemic, zoonotic disease of major public health importance in China. Control programs combining chemotherapy and snail killing have not been able to block transmission of infection in lakes and marsh regions. Vaccination is needed as a complementary approach to the ongoing control programs. In the present study, we wanted to determine if the efficacies of DNA vaccines encoding the 23-kDa tetraspanin membrane protein (SjC23), triose phosphate isomerase (SjCTPI), and sixfold-repeated genes of the complementarity determining region 3 (CDR3) in the H chain of NP30 could be enhanced by boosting via electroporation in vivo and/or with cocktail protein vaccines. Mice vaccinated with cocktail DNA vaccines showed a significant worm reduction of 32.88% (P < 0.01) and egg reduction of 36.20% (P < 0.01). Vaccine efficacy was enhanced when animals were boosted with cocktail protein vaccines; adult worm and liver egg burdens were reduced 45.35% and 48.54%, respectively. Nearly identical results were obtained in mice boosted by electroporation in vivo, with adult worm and egg burdens reduced by 45.00% and 50.88%, respectively. The addition of a protein vaccine boost to this regimen further elevated efficacy to approximately 60% for adult worm burden and greater than 60% for liver egg reduction. The levels of interleukin-2, gamma interferon, and the ratios of immunoglobulin G2a (IgG2a)/IgG1 clearly showed that cocktail DNA vaccines induced CD4(+) Th1-type responses. Boosting via either electroporation or with recombinant proteins significantly increased associated immune responses over those seen in mice vaccinated solely with DNA vaccines. Thus, schistosome DNA vaccine efficacy was significantly enhanced via boosting by electroporation in vivo and/or cocktail protein vaccines.

  3. Recombinant poxvirus boosting of DNA-primed rhesus monkeys augments peak but not memory T lymphocyte responses.

    PubMed

    Santra, Sampa; Barouch, Dan H; Korioth-Schmitz, Birgit; Lord, Carol I; Krivulka, Georgia R; Yu, Faye; Beddall, Margaret H; Gorgone, Darci A; Lifton, Michelle A; Miura, Ayako; Philippon, Valerie; Manson, Kelledy; Markham, Phillip D; Parrish, John; Kuroda, Marcelo J; Schmitz, Jörn E; Gelman, Rebecca S; Shiver, John W; Montefiori, David C; Panicali, Dennis; Letvin, Norman L

    2004-07-27

    Although a consensus has emerged that an HIV vaccine should elicit a cytotoxic T lymphocyte (CTL) response, the characteristics of an effective vaccine-induced T lymphocyte response remain unclear. We explored this issue in the simian human immunodeficiency virus/rhesus monkey model in the course of assessing the relative immunogenicity of vaccine regimens that included a cytokine-augmented plasmid DNA prime and a boost with DNA or recombinant pox vectors. Recombinant vaccinia virus, recombinant modified vaccinia Ankara (MVA), and recombinant fowlpox were comparable in their immunogenicity. Moreover, whereas the magnitude of the peak vaccine-elicited T lymphocyte responses in the recombinant pox virus-boosted monkeys was substantially greater than that seen in the monkeys immunized with plasmid DNA alone, the magnitudes of recombinant pox boosted CTL responses decayed rapidly and were comparable to those of the DNA-alone-vaccinated monkeys by the time of viral challenge. Consistent with these comparable memory T cell responses, the clinical protection seen in all groups of experimentally vaccinated monkeys was similar. This study, therefore, indicates that the steady-state memory, rather than the peak effector vaccine-elicited T lymphocyte responses, may be the critical immune correlate of protection for a CTL-based HIV vaccine.

  4. Microneedle mediated intradermal delivery of adjuvanted recombinant HIV-1 CN54gp140 effectively primes mucosal boost inoculations.

    PubMed

    Pattani, Aditya; McKay, Paul F; Garland, Martin J; Curran, Rhonda M; Migalska, Katarzyna; Cassidy, Corona M; Malcolm, R Karl; Shattock, Robin J; McCarthy, Helen O; Donnelly, Ryan F

    2012-09-28

    Dissolving polymeric microneedle arrays formulated to contain recombinant CN54 HIVgp140 and the TLR4 agonist adjuvant MPLA were assessed for their ability to elicit antigen-specific immunity. Using this novel microneedle system we successfully primed antigen-specific responses that were further boosted by an intranasal mucosal inoculation to elicit significant antigen-specific immunity. This prime-boost modality generated similar serum and mucosal gp140-specific IgG levels to the adjuvanted and systemic subcutaneous inoculations. While the microneedle primed groups demonstrated a balanced Th1/Th2 profile, strong Th2 polarization was observed in the subcutaneous inoculation group, likely due to the high level of IL-5 secretion from cells in this group. Significantly, the animals that received a microneedle prime and intranasal boost regimen elicited a high level IgA response in both the serum and mucosa, which was greatly enhanced over the subcutaneous group. The splenocytes from this inoculation group secreted moderate levels of IL-5 and IL-10 as well as high amounts of IL-2, cytokines known to act in synergy to induce IgA. This work opens up the possibility for microneedle-based HIV vaccination strategies that, once fully developed, will greatly reduce risk for vaccinators and patients, with those in the developing world set to benefit most.

  5. Augmenting antitumor T-cell responses to mimotope vaccination by boosting with native tumor antigens.

    PubMed

    Buhrman, Jonathan D; Jordan, Kimberly R; U'ren, Lance; Sprague, Jonathan; Kemmler, Charles B; Slansky, Jill E

    2013-01-01

    Vaccination with antigens expressed by tumors is one strategy for stimulating enhanced T-cell responses against tumors. However, these peptide vaccines rarely result in efficient expansion of tumor-specific T cells or responses that protect against tumor growth. Mimotopes, or peptide mimics of tumor antigens, elicit increased numbers of T cells that crossreact with the native tumor antigen, resulting in potent antitumor responses. Unfortunately, mimotopes may also elicit cells that do not crossreact or have low affinity for tumor antigen. We previously showed that one such mimotope of the dominant MHC class I tumor antigen of a mouse colon carcinoma cell line stimulates a tumor-specific T-cell clone and elicits antigen-specific cells in vivo, yet protects poorly against tumor growth. We hypothesized that boosting the mimotope vaccine with the native tumor antigen would focus the T-cell response elicited by the mimotope toward high affinity, tumor-specific T cells. We show that priming T cells with the mimotope, followed by a native tumor-antigen boost, improves tumor immunity compared with T cells elicited by the same prime with a mimotope boost. Our data suggest that the improved tumor immunity results from the expansion of mimotope-elicited tumor-specific T cells that have increased avidity for the tumor antigen. The enhanced T cells are phenotypically distinct and enriched for T-cell receptors previously correlated with improved antitumor immunity. These results suggest that incorporation of native antigen into clinical mimotope vaccine regimens may improve the efficacy of antitumor T-cell responses.

  6. Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus

    SciTech Connect

    Kaur, Amitinder . E-mail: amitinder_kaur@hms.harvard.edu; Sanford, Hannah B.; Garry, Deirdre; Lang, Sabine; Klumpp, Sherry A.; Watanabe, Daisuke; Bronson, Roderick T.; Lifson, Jeffrey D.; Rosati, Margherita; Pavlakis, George N.; Felber, Barbara K.; Knipe, David M.; Desrosiers, Ronald C.

    2007-01-20

    The immunogenicity and protective capacity of replication-defective herpes simplex virus (HSV) vector-based vaccines were examined in rhesus macaques. Three macaques were inoculated with recombinant HSV vectors expressing Gag, Env, and a Tat-Rev-Nef fusion protein of simian immunodeficiency virus (SIV). Three other macaques were primed with recombinant DNA vectors expressing Gag, Env, and a Pol-Tat-Nef-Vif fusion protein prior to boosting with the HSV vectors. Robust anti-Gag and anti-Env cellular responses were detected in all six macaques. Following intravenous challenge with wild-type, cloned SIV239, peak and 12-week plasma viremia levels were significantly lower in vaccinated compared to control macaques. Plasma SIV RNA in vaccinated macaques was inversely correlated with anti-Rev ELISPOT responses on the day of challenge (P value < 0.05), anti-Tat ELISPOT responses at 2 weeks post challenge (P value < 0.05) and peak neutralizing antibody titers pre-challenge (P value 0.06). These findings support continued study of recombinant herpesviruses as a vaccine approach for AIDS.

  7. [Alternative hemodialysis regimens].

    PubMed

    Matos, Jorge Paulo Strogoff de; Lugon, Jocemir Ronaldo

    2010-03-01

    The mortality rate among patients on hemodialysis (HD) is extremely high. Remaining life expectancy for a patient initiating HD is only approximately one quarter of that of the general population at the same age bracket. The conventional HD regimen based on four-hour sessions three times a week was empirically established nearly four decades ago and needs to be revisited. Since the failure of the HEMO Study to demonstrate the clinical benefits of higher urea Kt/V for patients on conventional HD, an increasing interest for alternative HD regimens has emerged aiming at providing a treatment for improving survival rates. Short daily HD and long nocturnal HD stand out as the most promising alternative regimens. Economical obstacles which could hinder the clinical application of emerging knowledge in the field should be overcome.

  8. Immunization

    MedlinePlus

    ... remembers" the germ and can fight it again. Vaccines contain germs that have been killed or weakened. When given to a healthy person, the vaccine triggers the immune system to respond and thus ...

  9. Subcutaneous injection of water-soluble multi-walled carbon nanotubes in tumor-bearing mice boosts the host immune activity

    NASA Astrophysics Data System (ADS)

    Meng, Jie; Yang, Man; Jia, Fumin; Kong, Hua; Zhang, Weiqi; Wang, Chaoying; Xing, Jianmin; Xie, Sishen; Xu, Haiyan

    2010-04-01

    The immunological responses induced by oxidized water-soluble multi-walled carbon nanotubes on a hepatocarcinoma tumor-bearing mice model via a local administration of subcutaneous injection were investigated. Experimental results show that the subcutaneously injected carbon nanotubes induced significant activation of the complement system, promoted inflammatory cytokines' production and stimulated macrophages' phagocytosis and activation. All of these responses increased the general activity of the host immune system and inhibited the progression of tumor growth.

  10. Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression.

    PubMed

    Noguchi, Masanori; Arai, Gaku; Matsumoto, Kazumasa; Naito, Seiji; Moriya, Fukuko; Suekane, Shigetaka; Komatsu, Nobukazu; Matsueda, Satoko; Sasada, Tetsuro; Yamada, Akira; Kakuma, Tatsuyuki; Itoh, Kyogo

    2015-04-01

    The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.

  11. DNA prime and virus-like particle boost from a single H5N1 strain elicits broadly neutralizing antibody responses against head region of H5 hemagglutinin.

    PubMed

    Wang, Guiqin; Zhou, Fan; Buchy, Philippe; Zuo, Teng; Hu, Hongxing; Liu, Jingjing; Song, Yufeng; Ding, Heng; Tsai, Cheguo; Chen, Ze; Zhang, Linqi; Deubel, Vincent; Zhou, Paul

    2014-03-01

    Since 1996, highly pathogenic avian influenza (HPAI) H5N1 virus has presented a persistent threat to public health. Its high degree of genetic diversity also poses enormous challenges in developing effective vaccines. To search for vaccine regimens that could elicit broadly neutralizing antibody responses against diverse HPAI H5N1 strains, in the present study we tested H5 hemagglutinin (HA) from an A/Thailand/1(KAN)-1/2004 strain in a heterologous prime-boost vaccination. We demonstrated that priming mice with DNA and boosting with virus-like particle induced antibody responses that cross-neutralize all reported clades and subclades of HPAI H5N1 viruses and protect mice from high lethal dose HPAI H5N1 challenge in both active and passive immunizations. Unexpectedly, cross-divergent H5 neutralizing antibodies are directed to the HA head and block both attachment and postattachment of virus entry. Thus, we conclude that as a promising pan-H5 vaccine candidate this prime-boost regimen could be further developed in ferrets and in humans.

  12. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  13. Improvement influenza HA2 DNA vaccine cellular and humoral immune responses with Mx bio adjuvant.

    PubMed

    Soleimani, Sina; Shahsavandi, Shahla; Maddadgar, Omid

    2017-03-01

    Immunization with DNA vaccines as a novel alternative to conventional vaccination strategy requires adjuvant for improving vaccine efficacy. The conserved immunogenic HA2 subunit, which harbors neutralizing epitopes is a promising vaccine candidate against influenza viruses. In this study, for the first time we explore the idea of using host interferon inducible Mx protein to increase the immunogenicity of HA2 H9N2 influenza DNA vaccine. The potency and safety of the Mx adjuvanted-HA2 vaccine was evaluated in BALB/c mice by different prime-boost strategies. To assess the effect of the vaccination on the virus clearance rate, mice were challenged with homologous influenza virus. Administration of the adjuvanted vaccine and boosting with the same regimen could effectively enhance both humoral and cellular immune responses in treated mice. These data demonstrated that Mx as host defense peptide can be potentiated for improving influenza vaccine efficacy.

  14. LDA boost classification: boosting by topics

    NASA Astrophysics Data System (ADS)

    Lei, La; Qiao, Guo; Qimin, Cao; Qitao, Li

    2012-12-01

    AdaBoost is an efficacious classification algorithm especially in text categorization (TC) tasks. The methodology of setting up a classifier committee and voting on the documents for classification can achieve high categorization precision. However, traditional Vector Space Model can easily lead to the curse of dimensionality and feature sparsity problems; so it affects classification performance seriously. This article proposed a novel classification algorithm called LDABoost based on boosting ideology which uses Latent Dirichlet Allocation (LDA) to modeling the feature space. Instead of using words or phrase, LDABoost use latent topics as the features. In this way, the feature dimension is significantly reduced. Improved Naïve Bayes (NB) is designed as the weaker classifier which keeps the efficiency advantage of classic NB algorithm and has higher precision. Moreover, a two-stage iterative weighted method called Cute Integration in this article is proposed for improving the accuracy by integrating weak classifiers into strong classifier in a more rational way. Mutual Information is used as metrics of weights allocation. The voting information and the categorization decision made by basis classifiers are fully utilized for generating the strong classifier. Experimental results reveals LDABoost making categorization in a low-dimensional space, it has higher accuracy than traditional AdaBoost algorithms and many other classic classification algorithms. Moreover, its runtime consumption is lower than different versions of AdaBoost, TC algorithms based on support vector machine and Neural Networks.

  15. Revaccination of cattle with bacille Calmette-Guérin two years after first vaccination when immunity has waned, boosted protection against challenge with Mycobacterium bovis.

    PubMed

    Parlane, Natalie A; Shu, Dairu; Subharat, Supatsak; Wedlock, D Neil; Rehm, Bernd H A; de Lisle, Geoffrey W; Buddle, Bryce M

    2014-01-01

    In both humans and animals, controversy exists concerning the duration of protection induced by BCG vaccine against tuberculosis (TB) and whether revaccination enhances protection. A long-term study was undertaken to determine whether BCG-vaccinated calves would be protected against challenge with Mycobacterium bovis 2½ years after vaccination and to determine the effect of revaccination after 2 years. Seventy-nine calves were divided into five groups (n = 15-17 calves/group) with four of the groups vaccinated subcutaneously with 105 CFU of BCG Danish at 2-4 weeks of age and the fifth group serving as non-vaccinated controls. Three of the four BCG-vaccinated groups were revaccinated 2 years after the initial vaccination. One BCG-vaccinated group was revaccinated with BCG. A second group was vaccinated subcutaneously with a TB protein vaccine consisting of biopolyester particles (Biobeads) displaying two mycobacterial proteins, ESAT-6 and Antigen 85A, mixed with an adjuvant. A third group was vaccinated with TB proteins from M. bovis culture filtrate, mixed with an adjuvant. Twenty-three weeks after the BCG revaccination, all animals were challenged endotracheally with virulent M. bovis and a further 13 weeks later, animals were killed and necropsied to determine protection against TB. The BCG-vaccinated animals produced positive tuberculin caudal fold intradermal (15 of 62 animals) and IFN-γ TB test responses (six of 62 animals) at 6 months after vaccination, but not at subsequent time-points compared to the non-vaccinated animals. Calves receiving a single vaccination with BCG vaccine 2½ years prior to challenge were not protected against TB, while those revaccinated with BCG 2 years after the initial vaccination displayed significant reductions in lung and pulmonary lymph node lesion scores compared to the non-vaccinated animals. In contrast, no reduction in lesion scores was observed in the animals revaccinated with the TB protein vaccines with their immune

  16. Intranasal Mucosal Boosting with an Adenovirus-Vectored Vaccine Markedly Enhances the Protection of BCG-Primed Guinea Pigs against Pulmonary Tuberculosis

    PubMed Central

    Xing, Zhou; McFarland, Christine T.; Sallenave, Jean-Michel; Izzo, Angelo; Wang, Jun; McMurray, David N.

    2009-01-01

    Background Recombinant adenovirus-vectored (Ad) tuberculosis (TB) vaccine platform has demonstrated great potential to be used either as a stand-alone or a boost vaccine in murine models. However, Ad TB vaccine remains to be evaluated in a more relevant and sensitive guinea pig model of pulmonary TB. Many vaccine candidates shown to be effective in murine models have subsequently failed to pass the test in guinea pig models. Methods and Findings Specific pathogen-free guinea pigs were immunized with BCG, AdAg85A intranasally (i.n), AdAg85A intramuscularly (i.m), BCG boosted with AdAg85A i.n, BCG boosted with AdAg85A i.m, or treated only with saline. The animals were then infected by a low-dose aerosol of M. tuberculosis (M.tb). At the specified times, the animals were sacrificed and the levels of infection in the lung and spleen were assessed. In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study. Immunization with Ad vaccine alone had minimal beneficial effects. Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent. However, while BCG alone prolonged the survival of infected guinea pigs, the majority of BCG-immunized animals succumbed by 53 weeks post-M.tb challenge. In contrast, intranasal or intramuscular Ad vaccine boosting of BCG-primed animals markedly improved the survival rate with 60% of BCG/Ad i.n- and 40% of BCG/Ad i.m-immunized guinea pigs still surviving by 74 weeks post-aerosol challenge. Conclusions Boosting, particularly via the intranasal mucosal route, with AdAg85A vaccine is able to significantly enhance the long-term survival of BCG-primed guinea pigs following pulmonary M.tb challenge. Our results thus support further evaluation of this viral-vectored TB vaccine in clinical trials. PMID:19516906

  17. In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

    DOE PAGES

    Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.; ...

    2015-11-14

    Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data frommore » non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.« less

  18. IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization

    PubMed Central

    Luo, Yanping; Ma, Xingming; Liu, Xun; Lu, Xiaoling; Niu, Hongxia; Yu, Hongjuan; Bai, Chunxiang; Peng, Jinxiu; Xian, Qiaoyang; Wang, Yong

    2016-01-01

    Regulatory T cells (Tregs), which could be down-regulated by IL-28B, were reported to suppress T-cell-mediated immunity. The aim of this study was to investigate the role of IL-28B on the immune responses and protective efficacy of a tuberculosis (TB) subunit vaccine. First, a recombinant adenoviral vector expressing mouse IL-28B (rAd-mIL-28B) was constructed; then C57BL/6 mice were immunized with subunit vaccine ESAT6-Ag85B-Mpt64(190–198)-Mtb8.4-HspX (EAMMH) and rAd-mIL-28B together thrice or primed with Mycobacterium bovis bacillus Calmette–Gue′rin (BCG) and boosted by EAMMH and rAd-mIL-28B twice. At last the immune responses were evaluated, and the mice primed with BCG and boosted by subunit vaccines were challenged with virulent Mycobacterium tuberculosis H37Rv to evaluate the protective efficacy. The results showed that rAd-mIL-28B treatment significantly down-regulated the frequency of Tregs at 4 weeks after the last immunization but did not increase the Th1-type immune responses. Moreover, in the regimen of BCG priming and EAMMH boosting, rAd-mIL-28B treatment did not increase the antigen-specific cellular and humoral immune responses, and consequently did not reduce the bacteria load following H37Rv challenge. Instead, it induced more serious pathology reaction. In conclusion, IL-28B down-regulates Tregs following EAMMH vaccination but does not improve the protective immune responses. PMID:26521300

  19. IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization.

    PubMed

    Luo, Yanping; Ma, Xingming; Liu, Xun; Lu, Xiaoling; Niu, Hongxia; Yu, Hongjuan; Bai, Chunxiang; Peng, Jinxiu; Xian, Qiaoyang; Wang, Yong; Zhu, Bingdong

    2016-02-01

    Regulatory T cells (Tregs), which could be down-regulated by IL-28B, were reported to suppress T-cell-mediated immunity. The aim of this study was to investigate the role of IL-28B on the immune responses and protective efficacy of a tuberculosis (TB) subunit vaccine. First, a recombinant adenoviral vector expressing mouse IL-28B (rAd-mIL-28B) was constructed; then C57BL/6 mice were immunized with subunit vaccine ESAT6-Ag85B-Mpt64(190-198)-Mtb8.4-HspX (EAMMH) and rAd-mIL-28B together thrice or primed with Mycobacterium bovis bacillus Calmette-Gue'rin (BCG) and boosted by EAMMH and rAd-mIL-28B twice. At last the immune responses were evaluated, and the mice primed with BCG and boosted by subunit vaccines were challenged with virulent Mycobacterium tuberculosis H37Rv to evaluate the protective efficacy. The results showed that rAd-mIL-28B treatment significantly down-regulated the frequency of Tregs at 4 weeks after the last immunization but did not increase the Th1-type immune responses. Moreover, in the regimen of BCG priming and EAMMH boosting, rAd-mIL-28B treatment did not increase the antigen-specific cellular and humoral immune responses, and consequently did not reduce the bacteria load following H37Rv challenge. Instead, it induced more serious pathology reaction. In conclusion, IL-28B down-regulates Tregs following EAMMH vaccination but does not improve the protective immune responses.

  20. Heterologous prime-boost vaccination with DNA and MVA vaccines, expressing HIV-1 subtype C mosaic Gag virus-like particles, is highly immunogenic in mice

    PubMed Central

    Douglass, Nicola; Chege, Gerald; Williamson, Anna-Lise

    2017-01-01

    In an effort to make affordable vaccines suitable for the regions most affected by HIV-1, we have constructed stable vaccines that express an HIV-1 subtype C mosaic Gag immunogen (BCG-GagM, MVA-GagM and DNA-GagM). Mosaic immunogens have been designed to address the tremendous diversity of this virus. Here we have shown that GagM buds from cells infected and transfected with MVA-GagM and DNA-GagM respectively and forms virus-like particles. Previously we showed that a BCG-GagM prime MVA-GagM boost generated strong cellular immune responses in mice. In this study immune responses to the DNA-GagM and MVA-GagM vaccines were evaluated in homologous and heterologous prime-boost vaccinations. The DNA homologous prime boost vaccination elicited predominantly CD8+ T cells while the homologous MVA vaccination induced predominantly CD4+ T cells. A heterologous DNA-GagM prime MVA-GagM boost induced strong, more balanced Gag CD8+ and CD4+ T cell responses and that were predominantly of an effector memory phenotype. The immunogenicity of the mosaic Gag (GagM) was compared to a naturally occurring subtype C Gag (GagN) using a DNA homologous vaccination regimen. DNA-GagN expresses a natural Gag with a sequence that was closest to the consensus sequence of subtype C viruses sampled in South Africa. DNA-GagM homologous vaccination induced cumulative HIV-1 Gag-specific IFN-γ ELISPOT responses that were 6.5-fold higher than those induced by the DNA-GagN vaccination. Similarly, DNA-GagM vaccination generated 7-fold higher levels of cytokine-positive CD8+ T cells than DNA-GagN, indicating that this subtype C mosaic Gag elicits far more potent immune responses than a consensus-type Gag. Cells transfected and infected with DNA-GagM and MVA-GagM respectively, expressed high levels of GagM and produced budding virus-like particles. Our data indicates that a heterologous prime boost regimen using DNA and MVA vaccines expressing HIV-1 subtype C mosaic Gag is highly immunogenic in mice and

  1. Boosting plant immunity with CRISPR/Cas.

    PubMed

    Chaparro-Garcia, Angela; Kamoun, Sophien; Nekrasov, Vladimir

    2015-11-19

    CRISPR/Cas has recently been transferred to plants to make them resistant to geminiviruses, a damaging family of DNA viruses. We discuss the potential and the limitations of this method.See related Research: http://www.genomebiology.com/2015/16/1/238.

  2. Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity".

    PubMed

    Ewer, Katie J; Sierra-Davidson, Kailan; Salman, Ahmed M; Illingworth, Joseph J; Draper, Simon J; Biswas, Sumi; Hill, Adrian V S

    2015-12-22

    Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8(+) T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, "unnatural immunity" comprising immune responses of very high magnitude will need to be induced.

  3. Online Bagging and Boosting

    NASA Technical Reports Server (NTRS)

    Oza, Nikunji C.

    2005-01-01

    Bagging and boosting are two of the most well-known ensemble learning methods due to their theoretical performance guarantees and strong experimental results. However, these algorithms have been used mainly in batch mode, i.e., they require the entire training set to be available at once and, in some cases, require random access to the data. In this paper, we present online versions of bagging and boosting that require only one pass through the training data. We build on previously presented work by presenting some theoretical results. We also compare the online and batch algorithms experimentally in terms of accuracy and running time.

  4. Conjugated anionic PEG-citrate G2 dendrimer with multi-epitopic HIV-1 vaccine candidate enhance the cellular immune responses in mice.

    PubMed

    Abdoli, Asghar; Radmehr, Nina; Bolhassani, Azam; Eidi, Akram; Mehrbod, Parvaneh; Motevalli, Fatemeh; Kianmehr, Zahra; Chiani, Mohsen; Mahdavi, Mehdi; Yazdani, Shaghayegh; Ardestani, Mehdi Shafiee; Kandi, Mohammad Reza; Aghasadeghi, Mohammad Reza

    2017-02-20

    Multi-epitope vaccines might cause immunity against multiple antigenic targets. Four immunodominant epitopes of HIV-1 genome were used to construct a polytope vaccine, formulated by dendrimer. Two regimens of polytopes mixture with dendrimer were utilized to immunize BALB/c mice. Adjuvants were also used to boost immune responses. The conjugated polytope could arouse significant cellular immune responses (P < 0.05) and Th1 response showed higher intensity compared to Th2 (P < 0.05). Our study depicted that conjugated dendrimer with multi-epitopic rHIVtop4 would efficiently induce cell-mediated immune responses and might be considered as promising delivery system for vaccines formulation.

  5. Oxygen boost pump study

    NASA Technical Reports Server (NTRS)

    1975-01-01

    An oxygen boost pump is described which can be used to charge the high pressure oxygen tank in the extravehicular activity equipment from spacecraft supply. The only interface with the spacecraft is the +06 6.205 Pa supply line. The breadboard study results and oxygen tank survey are summarized and the results of the flight-type prototype design and analysis are presented.

  6. Potent immune responses and in vitro pro-inflammatory cytokine suppression by a novel adenovirus vaccine vector based on rare human serotype 28.

    PubMed

    Kahl, Christoph A; Bonnell, Jessica; Hiriyanna, Suja; Fultz, Megan; Nyberg-Hoffman, Cassandra; Chen, Ping; King, C Richter; Gall, Jason G D

    2010-08-09

    Adenovirus vaccine vectors derived from rare human serotypes have been shown to be less potent than serotype 5 (Ad5) at inducing immune responses to encoded antigens. To identify highly immunogenic adenovirus vectors, we assessed pro-inflammatory cytokine expression, binding to the CD46 receptor, and immunogenicity. Species D adenoviruses uniquely suppressed pro-inflammatory cytokines and induced high levels of type I interferon. Thus, it was unexpected that a vector derived from a representative serotype, Ad28, induced significantly higher transgene-specific T cell responses than an Ad35 vector. Prime-boost regimens with Ad28, Ad35, Ad14, or Ad5 significantly boosted T cell and antibody responses. The seroprevalence of Ad28 was confirmed to be <10% in the United States. Together, this shows that a rare human serotype-based vector can elicit strong immune responses, which was not predicted by in vitro results.

  7. StructBoost: Boosting Methods for Predicting Structured Output Variables.

    PubMed

    Chunhua Shen; Guosheng Lin; van den Hengel, Anton

    2014-10-01

    Boosting is a method for learning a single accurate predictor by linearly combining a set of less accurate weak learners. Recently, structured learning has found many applications in computer vision. Inspired by structured support vector machines (SSVM), here we propose a new boosting algorithm for structured output prediction, which we refer to as StructBoost. StructBoost supports nonlinear structured learning by combining a set of weak structured learners. As SSVM generalizes SVM, our StructBoost generalizes standard boosting approaches such as AdaBoost, or LPBoost to structured learning. The resulting optimization problem of StructBoost is more challenging than SSVM in the sense that it may involve exponentially many variables and constraints. In contrast, for SSVM one usually has an exponential number of constraints and a cutting-plane method is used. In order to efficiently solve StructBoost, we formulate an equivalent 1-slack formulation and solve it using a combination of cutting planes and column generation. We show the versatility and usefulness of StructBoost on a range of problems such as optimizing the tree loss for hierarchical multi-class classification, optimizing the Pascal overlap criterion for robust visual tracking and learning conditional random field parameters for image segmentation.

  8. Mucosal prior to systemic application of recombinant adenovirus boosting is more immunogenic than systemic application twice but confers similar protection against SIV-challenge in DNA vaccine-primed macaques

    SciTech Connect

    Schulte, Reiner; Suh, You-Suk; Sauermann, Ulrike; Ochieng, Washingtone; Sopper, Sieghart; Kim, Kwang S.; Ahn, So-Shin; Park, Ki S.; Stolte-Leeb, Nicole; Hunsmann, Gerhard; Sung, Young C. Stahl-Hennig, Christiane

    2009-01-20

    We investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by various routes in the Simian immunodeficiency virus (SIV) rhesus monkey model for AIDS. Twelve animals were immunized with SIV DNA-vectors followed by the application of a recombinant adenovirus (rAd5) expressing the same genes either intramuscularly (i.m.) or by oropharyngeal spray. The second rAd5-application was given i.m. All vaccinees plus six controls were challenged orally with SIVmac239 12 weeks post-final immunization. Both immunization strategies induced strong SIV Gag-specific IFN-{gamma} and T-cell proliferation responses and mediated a conservation of CD4{sup +} memory T-cells and a reduction of viral load during peak viremia following infection. Interestingly, the mucosal group was superior to the systemic group regarding breadth and strength of SIV-specific T-cell responses and exhibited lower vector specific immune responses. Therefore, our data warrant the inclusion of mucosal vector application in a vaccination regimen which makes it less invasive and easier to apply.

  9. Mimotope vaccine efficacy gets a "boost" from native tumor antigens.

    PubMed

    Buhrman, Jonathan D; Slansky, Jill E

    2013-04-01

    Tumor-associated antigen (TAA)-targeting mimotope peptides exert more prominent immunostimulatory functions than unmodified TAAs, with the caveat that some T-cell clones exhibit a relatively low affinity for TAAs. Combining mimotope-based vaccines with native TAAs in a prime-boost setting significantly improves antitumor immunity.

  10. Recombinant measles viruses expressing single or multiple antigens of human immunodeficiency virus (HIV-1) induce cellular and humoral immune responses.

    PubMed

    Liniger, Matthias; Zuniga, Armando; Morin, Teldja Neige Azzouz; Combardiere, Behazine; Marty, Rene; Wiegand, Marian; Ilter, Orhan; Knuchel, Marlyse; Naim, Hussein Y

    2009-05-26

    Recombinant measles viruses (rMV) based on the live attenuated measles vaccine strain (MVb) expressing antigens of HIV-1 clade B were generated by reverse genetics. Recombinants expressing single or double antigens of HIV-1 (rMV-HIV) were genetically highly stable on human diploid cells. The production process of these viruses was essentially similar to the parental MV strain, yielding comparative end titers. Immunization of tg-mice by different regimens and formulations showed potent humoral and cellular immune responses against MV and HIV antigens. Recombinant MV-HIV expressing Gag protein conferred protective immunity in tg-mice after a high-dose pseudochallenge with recombinant vaccinia virus. In addition, rMV-HIV boosted anti-HIV antibodies, in the presence of pre-existing anti-vector antibodies.

  11. Regimen selection in the OPTIONS trial of HIV salvage therapy: drug resistance, prior therapy, and race–ethnicity determine the degree of regimen complexity

    PubMed Central

    Tashima, Karen T.; Mollan, Katie R.; Na, Lumine; Gandhi, Rajesh T.; Klingman, Karin L.; Fichtenbaum, Carl J.; Andrade, Adriana; Johnson, Victoria A.; Eron, Joseph J.; Smeaton, Laura; Haubrich, Richard H.

    2015-01-01

    Background Regimen selection for highly treatment-experienced patients is complicated. Methods Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3–4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression. Results A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR]=2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR=6.2) or boosted protease inhibitor (PI, OR=6.6), prior use of integrase strand transfer inhibitor (INSTI, OR=25), and race–ethnicity (all P≤0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR=0.5) and Hispanic participants from the continental US (OR=0.2) were less likely to start a complex regimen, compared to white non-Hispanics. Conclusions In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race–ethnicity were key factors in decisions to select a more complex regimen. PMID:26212575

  12. Analytic boosted boson discrimination

    DOE PAGES

    Larkoski, Andrew J.; Moult, Ian; Neill, Duff

    2016-05-20

    Observables which discriminate boosted topologies from massive QCD jets are of great importance for the success of the jet substructure program at the Large Hadron Collider. Such observables, while both widely and successfully used, have been studied almost exclusively with Monte Carlo simulations. In this paper we present the first all-orders factorization theorem for a two-prong discriminant based on a jet shape variable, D2, valid for both signal and background jets. Our factorization theorem simultaneously describes the production of both collinear and soft subjets, and we introduce a novel zero-bin procedure to correctly describe the transition region between these limits.more » By proving an all orders factorization theorem, we enable a systematically improvable description, and allow for precision comparisons between data, Monte Carlo, and first principles QCD calculations for jet substructure observables. Using our factorization theorem, we present numerical results for the discrimination of a boosted Z boson from massive QCD background jets. We compare our results with Monte Carlo predictions which allows for a detailed understanding of the extent to which these generators accurately describe the formation of two-prong QCD jets, and informs their usage in substructure analyses. In conclusion, our calculation also provides considerable insight into the discrimination power and calculability of jet substructure observables in general.« less

  13. Analytic boosted boson discrimination

    SciTech Connect

    Larkoski, Andrew J.; Moult, Ian; Neill, Duff

    2016-05-20

    Observables which discriminate boosted topologies from massive QCD jets are of great importance for the success of the jet substructure program at the Large Hadron Collider. Such observables, while both widely and successfully used, have been studied almost exclusively with Monte Carlo simulations. In this paper we present the first all-orders factorization theorem for a two-prong discriminant based on a jet shape variable, D2, valid for both signal and background jets. Our factorization theorem simultaneously describes the production of both collinear and soft subjets, and we introduce a novel zero-bin procedure to correctly describe the transition region between these limits. By proving an all orders factorization theorem, we enable a systematically improvable description, and allow for precision comparisons between data, Monte Carlo, and first principles QCD calculations for jet substructure observables. Using our factorization theorem, we present numerical results for the discrimination of a boosted Z boson from massive QCD background jets. We compare our results with Monte Carlo predictions which allows for a detailed understanding of the extent to which these generators accurately describe the formation of two-prong QCD jets, and informs their usage in substructure analyses. In conclusion, our calculation also provides considerable insight into the discrimination power and calculability of jet substructure observables in general.

  14. Boosted Beta Regression

    PubMed Central

    Schmid, Matthias; Wickler, Florian; Maloney, Kelly O.; Mitchell, Richard; Fenske, Nora; Mayr, Andreas

    2013-01-01

    Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures. PMID:23626706

  15. Ensuring compliance with drug regimens.

    PubMed

    Clarence, M

    This article explores the difficulties patients encounter in complying with prescribed drug regimens, and describes some of the compliance aids which are commonly available. A sensitive understanding of patients' individual difficulties by health care staff is an essential precursor to successful compliance behaviour.

  16. Modulation of Human Immunodeficiency Virus (HIV)-Specific Immune Response by Using Efavirenz, Nelfinavir, and Stavudine in a Rescue Therapy Regimen for HIV-Infected, Drug-Experienced Patients

    PubMed Central

    Trabattoni, Daria; Lo Caputo, Sergio; Biasin, Mara; Seminari, Elena; Di Pietro, Massimo; Ravasi, Giovanni; Mazzotta, Francesco; Maserati, Renato; Clerici, Mario

    2002-01-01

    Analysis of the virologic and immunomodulatory effects of an association of efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) was performed in 18 human immunodeficiency virus (HIV)-infected and highly active antiretroviral therapy (HAART)-experienced patients who failed multiple therapeutic protocols. Patients (<500 CD4+ cells/μl; >10,000 HIV copies/ml) were nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive and were treated for 10 months with EFV (600 mg/day) in association with NFV (750 mg three times daily) and d4T (30 or 40 mg twice daily). Measurement of HIV peptide- and mitogen-stimulated production of interleukin-2 (IL-2), gamma interferon (IFN-γ), IL-4, and IL-10 as well as quantitation of mRNA for the same cytokines in unstimulated peripheral blood mononuclear cells were performed at baseline and 2 weeks (t1), 2 months (t2), and 10 months (t3) into therapy. The results showed that HIV-specific (but not mitogen-stimulated) IL-2 and IFN-γ production was augmented and IL-10 production was reduced in patients who received EFV, NFV, and d4T. Therapy was also associated with a reduction in HIV RNA in plasma and an increase in CD4+ cell count. These changes occurred in the first year of therapy (t2 and t3) and were confirmed by quantitation of cytokine-specific mRNA. Therapy with EFV, NFV, and d4T increases HIV-specific type 1 cytokine production as well as CD4 counts and reduces plasma viremia. This therapeutic regimen may be considered for use in cases of advanced HIV infection. PMID:12204968

  17. Comparison of Antibody Responses Induced by RV144, VAX003, and VAX004 Vaccination Regimens.

    PubMed

    Karnasuta, Chitraporn; Akapirat, Siriwat; Madnote, Sirinan; Savadsuk, Hathairat; Puangkaew, Jiraporn; Rittiroongrad, Surawach; Rerks-Ngarm, Supachai; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Tartaglia, James; Sinangil, Faruk; Francis, Donald P; Robb, Merlin L; de Souza, Mark S; Michael, Nelson L; Excler, Jean-Louis; Kim, Jerome H; O'Connell, Robert J; Karasavvas, Nicos

    2017-01-30

    The RV144 prime-boost regimen demonstrated efficacy against HIV acquisition while VAX003 and VAX004 did not. Although these trials differed by risk groups, immunization regimens, and immunogens, antibody responses may have contributed to the differences observed in vaccine efficacy. We assessed HIV-specific IgG, both total and subclass, and IgA binding to HIV envelope (Env): gp120 proteins and Cyclic V2 (CycV2) and CycV3 peptides and gp70 V1 V2 scaffolds in these 3 HIV vaccine trials. After two protein immunizations, IgG responses to 92TH023 gp120 (contained in ALVAC-HIV vaccine) were significantly higher in RV144 but responses to other Env were higher in the VAX trials lacking ALVAC-HIV. IgG responses declined significantly between vaccinations. All trials induced antibodies to gp70 V1 V2 but VAX004 responses to 92TH023 gp70 V1 V2 were weak. All CycV2 responses were undetectable in VAX004 while 92TH023 gp70 V1 V2 was detected in both RV144 and VAX003 but MN CycV2 was detected only in VAX003. Multiple protein vaccinations in VAX trials did not improve magnitude or durability of V1 V2 and CycV2 antibodies. Herpes simplex virus glycoprotein D (gD) peptide at the N terminus of AIDSVAX(®) B/E and B/B gp120 proteins induced antibodies in all trials, although significantly higher in VAX trials. gD peptide induced IgA, IgG1, IgG2, and IgG3 but not IgG4. Multiple protein vaccinations decreased IgG3 and increased IgG4 changing subclass contribution to total IgG. Although confounded by different modes of HIV transmission, higher Env-specific IgA and IgG4 binding antibodies induced in the VAX trials compared to RV144 raises the hypothesis that these differences may have contributed to different vaccine efficacy results.

  18. Impact of antibody quality and anamnestic response on viremia control post-challenge in a combined Tat/Env vaccine regimen in rhesus macaques

    PubMed Central

    Demberg, Thorsten; Brocca-Cofano, Egidio; Kuate, Seraphin; Aladi, Stanley; Vargas-Inchaustegui, Diego A.; Venzon, David; Kalisz, Irene; Kalyanaraman, V.S.; Lee, Eun Mi; Pal, Ranajit; DiPasquale, Janet; Ruprecht, Ruth M.; Montefiori, David C.; Srivastava, Indresh; Barnett, Susan W.; Robert-Guroff, Marjorie

    2013-01-01

    Previously, priming rhesus macaques with Adenovirus type 5 host range mutant-recombinants encoding Tat and Env and boosting with Tat and Env protein in MPL-SE controlled chronic viremia by 4 logs following homologous intravenous SHIV89.6P challenge. Here we evaluated Tat, Env, and Tat/Env regimens for immunogenicity and protective efficacy using clade C Env, alum adjuvant, and a heterologous intrarectal SHIV1157ipd3N4 challenge. Despite induction of strong cellular and humoral immunity, Tat/Env group T and B-cell memory responses were not significantly enhanced over Tat- or Env-only groups. Lack of viremia control post-challenge was attributed to lower avidity Env antibodies and no anamnestic ADCC response or SHIV1157ipd3N4 neutralizing antibody development post-challenge. Poor biologic activity of the Tat immunogen may have impaired Tat immunity. In the absence of sterilizing immunity, strong anamnestic responses to heterologous virus can help control viremia. Both antibody breadth and optimal adjuvanticity are needed to elicit high-quality antibody for protective efficacy. PMID:23528732

  19. Mucosal immunity induced by adenovirus-based H5N1 HPAI vaccine confers protection against a lethal H5N2 avian influenza virus challenge

    SciTech Connect

    Park, Ki Seok; Lee, Jiyeung; Ahn, So Shin; Byun, Young-Ho; Seong, Baik Lin; Baek, Yun Hee; Song, Min-Suk; Choi, Young Ki; Na, Yun Jeong; Hwang, Inhwan; Sung, Young Chul; Lee, Chang Geun

    2009-12-20

    Development of effective vaccines against highly pathogenic avian influenza (HPAI) H5N1 viruses is a global public health priority. Considering the difficulty in predicting HPAI H5N1 pandemic strains, one strategy used in their design includes the development of formulations with the capacity of eliciting broad cross-protective immunity against multiple viral antigens. To this end we constructed a replication-defective recombinant adenovirus-based avian influenza virus vaccine (rAdv-AI) expressing the codon-optimized M2eX-HA-hCD40L and the M1-M2 fusion genes from HPAI H5N1 human isolate. Although there were no significant differences in the systemic immune responses observed between the intramuscular prime-intramuscular boost regimen (IM/IM) and the intranasal prime-intramuscular boost regimen (IN/IM), IN/IM induced more potent CD8{sup +} T cell and antibody responses at mucosal sites than the IM/IM vaccination, resulting in more effective protection against lethal H5N2 avian influenza (AI) virus challenge. These findings suggest that the strategies used to induce multi-antigen-targeted mucosal immunity, such as IN/IM delivery of rAdv-AI, may be a promising approach for developing broad protective vaccines that may be more effective against the new HPAI pandemic strains.

  20. Host immunity to Bacillus anthracis lethal factor and other immunogens: implications for vaccine design.

    PubMed

    Altmann, Daniel M

    2015-03-01

    Infections of humans with Bacillus anthracis are an issue with respect to the biothreat both to civilians and military personnel, infections of individuals by infected livestock in endemic regions and, recently, infections of intravenous drug users injecting anthrax-contaminated heroin. Existing vaccination regimens are reliant on protective antigen neutralization induced by repeated boosts with the AVA or AVP vaccines. However, there is ongoing interest in updated approaches in light of the intensive booster regime and extent of reactogenicity inherent in the current protocols. Several other immunogens from the B. anthracis proteome have been characterized in recent years, including lethal factor. Lethal factor induces strong CD4 T-cell immunity and encompasses immunodominant epitopes of relevance across diverse HLA polymorphisms. Taken together, recent studies emphasize the potential benefits of vaccines able to confer synergistic immunity to protective antigen and to other immunogens, targeting both B-cell and T-cell repertoires.

  1. Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques

    PubMed Central

    Luo, Kan; Liao, Hua-Xin; Wiehe, Kevin; Gurley, Thaddeus C.; Armand, Lawrence C.; Allen, Ashley A.; Von Holle, Tarra A.; Marshall, Dawn J.; Whitesides, John F.; Pritchett, Jamie; Foulger, Andrew; Hernandez, Giovanna; Parks, Robert; Lloyd, Krissey E.; Stolarchuk, Christina; Sawant, Sheetal; Peel, Jessica; Yates, Nicole L.; Dunford, Erika; Arora, Sabrina; Wang, Amy; Bowman, Cindy M.; Sutherland, Laura L.; Scearce, Richard M.; Xia, Shi-Mao; Bonsignori, Mattia; Pollara, Justin; Edwards, R. Whitney; Santra, Sampa; Letvin, Norman L.; Tartaglia, James; Francis, Donald; Sinangil, Faruk; Lee, Carter; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-ngarm, Supachai; Michael, Nelson L.; Kim, Jerome H.; Alam, S. Munir; Vandergrift, Nathan A.; Ferrari, Guido; Montefiori, David C.; Tomaras, Georgia D.; Haynes, Barton F.; Moody, M. Anthony

    2016-01-01

    The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV‑1 exposures were likely at mucosal surfaces. An immune correlates study demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env‑specific B cell clonal lineages were absent in the terminal ileum. Env‑specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites. PMID:27942585

  2. Assessing the effectiveness of antiretroviral regimens in cohort studies involving HIV-positive injection drug users

    PubMed Central

    Lima, Viviane Dias; Nosyk, Bohdan; Wood, Evan; Kozai, Tsubasa; Zhang, Wendy; Chan, Keith; Montaner, Julio S.G.

    2015-01-01

    Objective We compared the effectiveness of different highly active antiretroviral therapy (HAART) regimens considering, separately, history of injection drug use (IDU) (yes/no). Design, methods A total of 1163 HIV-infected patients initiated HAART between 1 January 2000 and 28 February 2009 in British Columbia, Canada, and were followed until 28 February 2010. HAART effectiveness was measured by the ability to achieve viral suppression below 50 copies/ml at 6 months. We compared HAART regimens containing efavirenz and boosted atazanavir. We developed logistic regression models using different techniques to control for potential confounders. Results Among the 1163 patients, 796 (68%) achieved viral suppression at 6 months (32% reporting a history of IDU). Different confounding models yielded very similar odds ratios for achieving viral suppression. Boosted atazanavir-based HAART demonstrated to be the most effective regimen, showing a surprisingly higher benefit for patients with a history of IDU (odds ratios from different models ranged from 1.74–1.95 to 1.45–1.51). Conclusions The literature has conflicting results regarding the effectiveness of HAART to treat HIV infection among those with a history of IDU. We have shown that most patients, with and without a history of IDU, were able to achieve viral suppression at 6 months. Boosted atazanavir-based HAART was the most resilient regimen and it was more effective than efavirenz-based HAART among IDUs. Given the limited inclusion of IDU in clinical trials of HAART’s efficacy, a randomized clinical trial comparing different first-line HAART regimens among IDU is warranted based on these results. PMID:22555161

  3. Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State

    PubMed Central

    Accolla, Roberto S.; Lombardo, Letizia; Abdallah, Rawan; Raval, Goutham; Forlani, Greta; Tosi, Giovanna

    2014-01-01

    Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes. PMID:24600588

  4. Delivery of DNA HIV-1 Vaccine to the Liver Induces High and Long-lasting Humoral Immune Responses

    PubMed Central

    Raska, Milan; Moldoveanu, Zina; Novak, Jan; Hel, Zdenek; Bozja, Jadranka; Compans, Richard W.; Yang, Chinglai; Mestecky, Jiri

    2008-01-01

    The quality of immune responses induced by DNA vaccination depends on the site of DNA administration, the expression, and the properties of the encoded antigen. In the present study we demonstrate that intravenous hydrodynamic HIV-1 envelope DNA injection resulted in high levels of expression of HIV-1 envelope antigen in the liver. When compared to the administration of DNA by i.n., i.d., i.m., and i.splenic routes, hydrodynamic vaccination induced, upon DNA boosting, 40 times increase of HIV-1 envelope-specific antibodies over the preimmune levels. Hydrodynamic vaccination with 1 μg DNA induced higher humoral responses than 100 μg DNA given intramuscularly in the prime – boost regimen. High levels of envelope-specific IgG and IgA antibodies were induced in genital tract secretions after two doses of DNA followed by intranasal boosting with recombinant HIV-1 gp120 protein. Furthermore, two doses of 100 μg DNA generated interferon-gamma production in ~ 4.3 ± 1.7 % of CD8+ splenocytes after in vitro stimulation with HIV-1 envelope peptides. These results demonstrate that DNA vaccines targeted to tissues with high proteosynthetic activity, such as the liver, results in enhanced immune responses. PMID:18304708

  5. AveBoost2: Boosting for Noisy Data

    NASA Technical Reports Server (NTRS)

    Oza, Nikunj C.

    2004-01-01

    AdaBoost is a well-known ensemble learning algorithm that constructs its constituent or base models in sequence. A key step in AdaBoost is constructing a distribution over the training examples to create each base model. This distribution, represented as a vector, is constructed to be orthogonal to the vector of mistakes made by the pre- vious base model in the sequence. The idea is to make the next base model's errors uncorrelated with those of the previous model. In previous work, we developed an algorithm, AveBoost, that constructed distributions orthogonal to the mistake vectors of all the previous models, and then averaged them to create the next base model s distribution. Our experiments demonstrated the superior accuracy of our approach. In this paper, we slightly revise our algorithm to allow us to obtain non-trivial theoretical results: bounds on the training error and generalization error (difference between training and test error). Our averaging process has a regularizing effect which, as expected, leads us to a worse training error bound for our algorithm than for AdaBoost but a superior generalization error bound. For this paper, we experimented with the data that we used in both as originally supplied and with added label noise-a small fraction of the data has its original label changed. Noisy data are notoriously difficult for AdaBoost to learn. Our algorithm's performance improvement over AdaBoost is even greater on the noisy data than the original data.

  6. Boosted ellipsoid ARTMAP

    NASA Astrophysics Data System (ADS)

    Anagnostopoulos, Georgios C.; Georgiopoulos, Michael; Verzi, Steven J.; Heileman, Gregory L.

    2002-03-01

    Ellipsoid ARTMAP (EAM) is an adaptive-resonance-theory neural network architecture that is capable of successfully performing classification tasks using incremental learning. EAM achieves its task by summarizing labeled input data via hyper-ellipsoidal structures (categories). A major property of EAM, when using off-line fast learning, is that it perfectly learns its training set after training has completed. Depending on the classification problems at hand, this fact implies that off-line EAM training may potentially suffer from over-fitting. For such problems we present an enhancement to the basic Ellipsoid ARTMAP architecture, namely Boosted Ellipsoid ARTMAP (bEAM), that is designed to simultaneously improve the generalization properties and reduce the number of created categories for EAM's off-line fast learning. This is being accomplished by forcing EAM to be tolerant about occasional misclassification errors during fast learning. An additional advantage provided by bEAM's desing is the capability of learning inconsistent cases, that is, learning identical patterns with contradicting class labels. After we present the theory behind bEAM's enhancements, we provide some preliminary experimental results, which compare the new variant to the original EAM network, Probabilistic EAM and three different variants of the Restricted Coulomb Energy neural network on the square-in-a-square classification problem.

  7. Bidirectional buck boost converter

    DOEpatents

    Esser, A.A.M.

    1998-03-31

    A bidirectional buck boost converter and method of operating the same allows regulation of power flow between first and second voltage sources in which the voltage level at each source is subject to change and power flow is independent of relative voltage levels. In one embodiment, the converter is designed for hard switching while another embodiment implements soft switching of the switching devices. In both embodiments, first and second switching devices are serially coupled between a relatively positive terminal and a relatively negative terminal of a first voltage source with third and fourth switching devices serially coupled between a relatively positive terminal and a relatively negative terminal of a second voltage source. A free-wheeling diode is coupled, respectively, in parallel opposition with respective ones of the switching devices. An inductor is coupled between a junction of the first and second switching devices and a junction of the third and fourth switching devices. Gating pulses supplied by a gating circuit selectively enable operation of the switching devices for transferring power between the voltage sources. In the second embodiment, each switching device is shunted by a capacitor and the switching devices are operated when voltage across the device is substantially zero. 20 figs.

  8. Bidirectional buck boost converter

    DOEpatents

    Esser, Albert Andreas Maria

    1998-03-31

    A bidirectional buck boost converter and method of operating the same allows regulation of power flow between first and second voltage sources in which the voltage level at each source is subject to change and power flow is independent of relative voltage levels. In one embodiment, the converter is designed for hard switching while another embodiment implements soft switching of the switching devices. In both embodiments, first and second switching devices are serially coupled between a relatively positive terminal and a relatively negative terminal of a first voltage source with third and fourth switching devices serially coupled between a relatively positive terminal and a relatively negative terminal of a second voltage source. A free-wheeling diode is coupled, respectively, in parallel opposition with respective ones of the switching devices. An inductor is coupled between a junction of the first and second switching devices and a junction of the third and fourth switching devices. Gating pulses supplied by a gating circuit selectively enable operation of the switching devices for transferring power between the voltage sources. In the second embodiment, each switching device is shunted by a capacitor and the switching devices are operated when voltage across the device is substantially zero.

  9. Can you boost your metabolism?

    MedlinePlus

    ... can boost your metabolism. Eating foods like green tea, caffeine, or hot chili peppers will not help ... Randell RK, Jeukendrup AE. The effect of green tea extract on fat oxidation at rest and during ...

  10. Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

    PubMed Central

    Stark, Felicity C.; McCluskie, Michael J.; Krishnan, Lakshmi

    2016-01-01

    Homologous prime-boost vaccinations with live vectors typically fail to induce repeated strong CD8+ T cell responses due to the induction of anti-vector immunity, highlighting the need for alternative delivery vehicles. The unique ether lipids of archaea may be constituted into liposomes, archaeosomes, which do not induce anti-carrier responses, making them an ideal candidate for use in repeat vaccination systems. Herein, we evaluated in mice the maximum threshold of antigen-specific CD8+ T cell responses that may be induced by multiple homologous immunizations with ovalbumin (OVA) entrapped in archaeosomes derived from the ether glycerolipids of the archaeon Methanobrevibacter smithii (MS-OVA). Up to three immunizations with MS-OVA administered in optimized intervals (to allow for sufficient resting of the primed cells prior to boosting), induced a potent anti-OVA CD8+ T cell response of up to 45% of all circulating CD8+ T cells. Additional MS-OVA injections did not add any further benefit in increasing the memory of CD8+ T cell frequency. In contrast, OVA expressed by Listeria monocytogenes (LM-OVA), an intracellular bacterial vector failed to evoke a boosting effect after the second injection, resulting in significantly reduced antigen-specific CD8+ T cell frequencies. Furthermore, repeated vaccination with MS-OVA skewed the response increasingly towards an effector memory (CD62low) phenotype. Vaccinated animals were challenged with B16-OVA at late time points after vaccination (+7 months) and were afforded protection compared to control. Therefore, archaeosomes constituted a robust particulate delivery system to unravel the kinetics of CD8+ T cell response induction and memory maintenance and constitute an efficient vaccination regimen optimized for tumor protection. PMID:27869670

  11. Heterologous prime-boost vaccinations for poverty-related diseases: advantages and future prospects.

    PubMed

    Radosević, Katarina; Rodriguez, Ariane; Lemckert, Angelique; Goudsmit, Jaap

    2009-05-01

    Classical vaccination approaches, based on a single vaccine administered in a homologous prime-boost schedule and optimized to induce primarily neutralizing antibodies, are unlikely to be sufficiently efficacious to prevent TB, malaria or HIV infections. Novel vaccines, capable of inducing a more powerful immune response, in particular T-cell immunity, are desperately needed. Combining different vaccine modalities that are able to complement each other and induce broad and sustainable immunity is a promising approach. This review provides an overview of heterologous prime-boost vaccination modalities currently in development for the 'big three' poverty-related diseases and emphasizes the need for innovative vaccination approaches.

  12. In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

    SciTech Connect

    Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.; Kirschner, Denise E.

    2015-11-14

    Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.

  13. CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria.

    PubMed

    Lau, Lei Shong; Fernandez-Ruiz, Daniel; Mollard, Vanessa; Sturm, Angelika; Neller, Michelle A; Cozijnsen, Anton; Gregory, Julia L; Davey, Gayle M; Jones, Claerwen M; Lin, Yi-Hsuan; Haque, Ashraful; Engwerda, Christian R; Nie, Catherine Q; Hansen, Diana S; Murphy, Kenneth M; Papenfuss, Anthony T; Miles, John J; Burrows, Scott R; de Koning-Ward, Tania; McFadden, Geoffrey I; Carbone, Francis R; Crabb, Brendan S; Heath, William R

    2014-05-01

    To follow the fate of CD8+ T cells responsive to Plasmodium berghei ANKA (PbA) infection, we generated an MHC I-restricted TCR transgenic mouse line against this pathogen. T cells from this line, termed PbT-I T cells, were able to respond to blood-stage infection by PbA and two other rodent malaria species, P. yoelii XNL and P. chabaudi AS. These PbT-I T cells were also able to respond to sporozoites and to protect mice from liver-stage infection. Examination of the requirements for priming after intravenous administration of irradiated sporozoites, an effective vaccination approach, showed that the spleen rather than the liver was the main site of priming and that responses depended on CD8α+ dendritic cells. Importantly, sequential exposure to irradiated sporozoites followed two days later by blood-stage infection led to augmented PbT-I T cell expansion. These findings indicate that PbT-I T cells are a highly versatile tool for studying multiple stages and species of rodent malaria and suggest that cross-stage reactive CD8+ T cells may be utilized in liver-stage vaccine design to enable boosting by blood-stage infections.

  14. Co-Administration of Lipid Nanoparticles and Sub-Unit Vaccine Antigens Is Required for Increase in Antigen-Specific Immune Responses in Mice.

    PubMed

    Thoryk, Elizabeth A; Swaminathan, Gokul; Meschino, Steven; Cox, Kara S; Gindy, Marian; Casimiro, Danilo R; Bett, Andrew J

    2016-12-06

    A vast body of evidence suggests that nanoparticles function as potent immune-modulatory agents. We have previously shown that Merck proprietary Lipid NanoParticles (LNPs) markedly boost B-cell and T-cell responses to sub-unit vaccine antigens in mice. To further evaluate the specifics of vaccine delivery and dosing regimens in vivo, we performed immunogenicity studies in BALB/c and C57BL/6 mice using two model antigens, Hepatitis B Surface Antigen (HBsAg) and Ovalbumin (OVA), respectively. To assess the requirement for co-administration of antigen and LNP for the elicitation of immune responses, we evaluated immune responses after administering antigen and LNP to separate limbs, or administering antigen and LNP to the same limb but separated by 24 h. We also evaluated formulations combining antigen, LNP, and aluminum-based adjuvant amorphous aluminum hydroxylphosphate sulfate (MAA) to look for synergistic adjuvant effects. Analyses of antigen-specific B-cell and T-cell responses from immunized mice revealed that the LNPs and antigens must be co-administered-both at the same time and in the same location-in order to boost antigen-specific immune responses. Mixing of antigen with MAA prior to formulation with LNP did not impact the generation of antigen-specific B-cell responses, but drastically reduced the ability of LNPs to boost antigen-specific T-cell responses. Overall, our data demonstrate that the administration of LNPs and vaccine antigen together enables their immune-stimulatory properties.

  15. Co-Administration of Lipid Nanoparticles and Sub-Unit Vaccine Antigens Is Required for Increase in Antigen-Specific Immune Responses in Mice

    PubMed Central

    Thoryk, Elizabeth A.; Swaminathan, Gokul; Meschino, Steven; Cox, Kara S.; Gindy, Marian; Casimiro, Danilo R.; Bett, Andrew J.

    2016-01-01

    A vast body of evidence suggests that nanoparticles function as potent immune-modulatory agents. We have previously shown that Merck proprietary Lipid NanoParticles (LNPs) markedly boost B-cell and T-cell responses to sub-unit vaccine antigens in mice. To further evaluate the specifics of vaccine delivery and dosing regimens in vivo, we performed immunogenicity studies in BALB/c and C57BL/6 mice using two model antigens, Hepatitis B Surface Antigen (HBsAg) and Ovalbumin (OVA), respectively. To assess the requirement for co-administration of antigen and LNP for the elicitation of immune responses, we evaluated immune responses after administering antigen and LNP to separate limbs, or administering antigen and LNP to the same limb but separated by 24 h. We also evaluated formulations combining antigen, LNP, and aluminum-based adjuvant amorphous aluminum hydroxylphosphate sulfate (MAA) to look for synergistic adjuvant effects. Analyses of antigen-specific B-cell and T-cell responses from immunized mice revealed that the LNPs and antigens must be co-administered—both at the same time and in the same location—in order to boost antigen-specific immune responses. Mixing of antigen with MAA prior to formulation with LNP did not impact the generation of antigen-specific B-cell responses, but drastically reduced the ability of LNPs to boost antigen-specific T-cell responses. Overall, our data demonstrate that the administration of LNPs and vaccine antigen together enables their immune-stimulatory properties. PMID:27929422

  16. New anti-tuberculosis drugs and regimens: 2015 update

    PubMed Central

    D'Ambrosio, Lia; Centis, Rosella; Sotgiu, Giovanni; Pontali, Emanuele; Spanevello, Antonio; Migliori, Giovanni Battista

    2015-01-01

    Over 480 000 cases of multidrug-resistant (MDR) tuberculosis (TB) occur every year globally, 9% of them being affected by extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. The treatment of MDR/XDR-TB is unfortunately long, toxic and expensive, and the success rate largely unsatisfactory (<20% among cases with resistance patterns beyond XDR). The aim of this review is to summarise the available evidence-based updated international recommendations to manage MDR/XDR-TB, and to update the reader on the role of newly developed drugs (delamanid, bedaquiline and pretomanid) as well as repurposed drugs (linezolid and meropenem clavulanate, among others) used to treat these conditions within new regimens. A nonsystematic review based on historical trials results as well as on recent literature and World Health Organization (WHO) guidelines has been performed, with special focus on the approach to managing MDR/XDR-TB. The new, innovative global public health interventions, recently approved by WHO and known as the “End TB Strategy”, support the vision of a TB-free world with zero death, disease and suffering due to TB. Adequate, universally accessed treatment is a pre-requisite to reach TB elimination. New shorter, cheap, safe and effective anti-TB regimens are necessary to boost TB elimination. PMID:27730131

  17. Components of the Goeckerman regimen.

    PubMed

    Le Vine, M J; White, H A; Parrish, J A

    1979-08-01

    Although application of tar products and subsequent exposure to ultraviolet radiation (the Goeckerman regimen) has repeatedly been demonstrated to be effective therapy for psoriasis, the therapeutic role of each component has remained uncertain. Utilizing the bilateral comparison technique in 30 hospitalized patients with chronic stable plaque-type psoriasis vulgaris, we closely monitored the clinical responses to ultraviolet radiation (Westinghouse fluorescent FS40 bulbs, 290--400 nm) and a variety of tar preparations and lubricant vehicles in combination and separately. We found that: 1) 4 weeks of maximally-aggressive exposure to ultraviolet radiation alone will markedly improve, but not completely clear, psoriasis unless combined with a tar preparation or lubricating base; 2) 5% crude coal tar plus ultraviolet radiation offers no clear advantage or benefit over lubricating base plus ultraviolet radiation; and 3) none of the tar preparations tested offered any consistent advantage over any other preparation.

  18. Resolving boosted jets with XCone

    NASA Astrophysics Data System (ADS)

    Thaler, Jesse; Wilkason, Thomas F.

    2015-12-01

    We show how the recently proposed XCone jet algorithm [1] smoothly interpolates between resolved and boosted kinematics. When using standard jet algorithms to reconstruct the decays of hadronic resonances like top quarks and Higgs bosons, one typically needs separate analysis strategies to handle the resolved regime of well-separated jets and the boosted regime of fat jets with substructure. XCone, by contrast, is an exclusive cone jet algorithm that always returns a fixed number of jets, so jet regions remain resolved even when (sub)jets are overlapping in the boosted regime. In this paper, we perform three LHC case studies — dijet resonances, Higgs decays to bottom quarks, and all-hadronic top pairs — that demonstrate the physics applications of XCone over a wide kinematic range.

  19. Prime-boost BCG vaccination with DNA vaccines based in β-defensin-2 and mycobacterial antigens ESAT6 or Ag85B improve protection in a tuberculosis experimental model.

    PubMed

    Cervantes-Villagrana, Alberto R; Hernández-Pando, Rogelio; Biragyn, Arya; Castañeda-Delgado, Julio; Bodogai, Monica; Martínez-Fierro, Margarita; Sada, Eduardo; Trujillo, Valentin; Enciso-Moreno, Antonio; Rivas-Santiago, Bruno

    2013-01-11

    The World Health Organization (WHO) has estimated that there are about 8 million new cases annually of active Tuberculosis (TB). Despite its irregular effectiveness (0-89%), the Bacillus Calmette-Guérin) BCG is the only vaccine available worldwide for prevention of TB; thus, the design is important of novel and more efficient vaccination strategies. Considering that β-defensin-2 is an antimicrobial peptide that induces dendritic cell maturation through the TLR-4 receptor and that both ESAT-6 and Ag85B are immunodominant mycobacterial antigens and efficient activators of the protective immune response, we constructed two DNA vaccines by the fusion of the gene encoding β-defensin-2 and antigens ESAT6 (pDE) and 85B (pDA). After confirming efficient local antigen expression that induced high and stable Interferon gamma (IFN-γ) production in intramuscular (i.m.) vaccinated Balb/c mice, groups of mice were vaccinated with DNA vaccines in a prime-boost regimen with BCG and with BCG alone, and 2 months later were challenged with the mild virulence reference strain H37Rv and the highly virulent clinical isolate LAM 5186. The level of protection was evaluated by survival, lung bacilli burdens, and extension of tissue damage (pneumonia). Vaccination with both DNA vaccines showed similar protection to that of BCG. After the challenge with the highly virulent Mycobacterium tuberculosis strain, animals that were prime-boosted with BCG and then boosted with both DNA vaccines showed significant higher survival and less tissue damage than mice vaccinated only with BCG. These results suggest that improvement of BCG vaccination, such as the prime-boost DNA vaccine, represents a more efficient vaccination scheme against TB.

  20. Priming Immunization with DNA Augments Immunogenicity of Recombinant Adenoviral Vectors for Both HIV-1 Specific Antibody and T-Cell Responses

    PubMed Central

    Koup, Richard A.; Roederer, Mario; Lamoreaux, Laurie; Fischer, Jennifer; Novik, Laura; Nason, Martha C.; Larkin, Brenda D.; Enama, Mary E.; Ledgerwood, Julie E.; Bailer, Robert T.; Mascola, John R.; Nabel, Gary J.; Graham, Barney S.

    2010-01-01

    Background Induction of HIV-1-specific T-cell responses relevant to diverse subtypes is a major goal of HIV vaccine development. Prime-boost regimens using heterologous gene-based vaccine vectors have induced potent, polyfunctional T cell responses in preclinical studies. Methods The first opportunity to evaluate the immunogenicity of DNA priming followed by recombinant adenovirus serotype 5 (rAd5) boosting was as open-label rollover trials in subjects who had been enrolled in prior studies of HIV-1 specific DNA vaccines. All subjects underwent apheresis before and after rAd5 boosting to characterize in depth the T cell and antibody response induced by the heterologous DNA/rAd5 prime-boost combination. Results rAd5 boosting was well-tolerated with no serious adverse events. Compared to DNA or rAd5 vaccine alone, sequential DNA/rAd5 administration induced 7-fold higher magnitude Env-biased HIV-1-specific CD8+ T-cell responses and 100-fold greater antibody titers measured by ELISA. There was no significant neutralizing antibody activity against primary isolates. Vaccine-elicited CD4+ and CD8+ T-cells expressed multiple functions and were predominantly long-term (CD127+) central or effector memory T cells and that persisted in blood for >6 months. Epitopes mapped in Gag and Env demonstrated partial cross-clade recognition. Conclusion Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses. Trial Registration ClinicalTrails.gov NCT00102089, NCT00108654 PMID:20126394

  1. Recombinant BCG prime and PPE protein boost provides potent protection against acute Mycobacterium tuberculosis infection in mice.

    PubMed

    Yang, Enzhuo; Gu, Jin; Wang, Feifei; Wang, Honghai; Shen, Hongbo; Chen, Zheng W

    2016-04-01

    Since BCG, the only vaccine widely used against tuberculosis (TB) in the world, provides varied protective efficacy and may not be effective for inducing long-term cellular immunity, it is in an urgent need to develop more effective vaccines and more potent immune strategies against TB. Prime-boost is proven to be a good strategy by inducing long-term protection. In this study, we tested the protective effect against Mycobacterium tuberculosis (Mtb) challenge of prime-boost strategy by recombinant BCG (rBCG) expressing PPE protein Rv3425 fused with Ag85B and Rv3425. Results showed that the prime-boost strategy could significantly increase the protective efficiency against Mtb infection, characterized by reduction of bacterial load in lung and spleen, attenuation of tuberculosis lesions in lung tissues. Importantly, we found that Rv3425 boost, superior to Ag85B boost, provided better protection against Mtb infection. Further research proved that rBCG prime-Rv3425 boost could obviously increase the expansion of lymphocytes, significantly induce IL-2 production by lymphocytes upon PPD stimulation, and inhibit IL-6 production at an early stage. It implied that rBCG prime-Rv3425 boost opted to induce Th1 immune response and provided a long-term protection against TB. These results implicated that rBCG prime-Rv3425 boost is a potent and promising strategy to prevent acute Mtb infection.

  2. Characterization of Immune Responses Induced by Ebola Virus Glycoprotein (GP) and Truncated GP Isoform DNA Vaccines and Protection Against Lethal Ebola Virus Challenge in Mice

    PubMed Central

    Li, Wenfang; Ye, Ling; Carrion, Ricardo; Mohan, Gopi S.; Nunneley, Jerritt; Staples, Hilary; Ticer, Anysha; Patterson, Jean L.; Compans, Richard W.; Yang, Chinglai

    2015-01-01

    In addition to its surface glycoprotein (GP), Ebola virus directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. We recently reported that sGP actively diverts host antibody responses against the epitopes that it shares with GP and thereby allows itself to absorb anti-GP antibodies, a phenomenon we termed “antigenic subversion.” To investigate the effect of antigenic subversion by sGP on protection against virus infection, we compared immune responses induced by different prime-boost immunization regimens with GP and sGP DNA vaccines in mice and their efficacy against lethal Ebola virus challenge. Similar levels of anti-GP antibodies were induced by 2 immunizations with sGP and GP DNA vaccines. However, 2 immunizations with GP but not sGP DNA vaccine fully protected mice from lethal challenge. Boosting with sGP or GP DNA vaccine in mice that had been primed by GP or sGP DNA vaccine augmented the levels of anti-GP antibody responses and further improved protective efficacy against Ebola virus infection. These results show that both the quality and the levels of anti-GP antibody responses affect the efficacy of protection against Ebola virus infection. PMID:25877553

  3. Characterization of Immune Responses Induced by Ebola Virus Glycoprotein (GP) and Truncated GP Isoform DNA Vaccines and Protection Against Lethal Ebola Virus Challenge in Mice.

    PubMed

    Li, Wenfang; Ye, Ling; Carrion, Ricardo; Mohan, Gopi S; Nunneley, Jerritt; Staples, Hilary; Ticer, Anysha; Patterson, Jean L; Compans, Richard W; Yang, Chinglai

    2015-10-01

    In addition to its surface glycoprotein (GP), Ebola virus directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. We recently reported that sGP actively diverts host antibody responses against the epitopes that it shares with GP and thereby allows itself to absorb anti-GP antibodies, a phenomenon we termed "antigenic subversion." To investigate the effect of antigenic subversion by sGP on protection against virus infection, we compared immune responses induced by different prime-boost immunization regimens with GP and sGP DNA vaccines in mice and their efficacy against lethal Ebola virus challenge. Similar levels of anti-GP antibodies were induced by 2 immunizations with sGP and GP DNA vaccines. However, 2 immunizations with GP but not sGP DNA vaccine fully protected mice from lethal challenge. Boosting with sGP or GP DNA vaccine in mice that had been primed by GP or sGP DNA vaccine augmented the levels of anti-GP antibody responses and further improved protective efficacy against Ebola virus infection. These results show that both the quality and the levels of anti-GP antibody responses affect the efficacy of protection against Ebola virus infection.

  4. Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles

    PubMed Central

    2011-01-01

    Background There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes. Methods Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-γ ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl β-galactosidase assay with primary isolates of HIV-1. Results This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody

  5. Improved anamnestic response among adolescents boosted with a higher dose of the hepatitis B vaccine.

    PubMed

    Chaves, Sandra S; Groeger, Justina; Helgenberger, Louisa; Auerbach, Steven B; Bialek, Stephanie R; Hu, Dale J; Drobeniuc, Jan

    2010-04-01

    Some hepatitis B vaccine booster studies have suggested waning of vaccine-induced immunity in adolescents vaccinated starting at birth. Those studies, however, used a pediatric formulation of the hepatitis B vaccine as a booster to detect anamnestic response. We compared adolescents boosted with an adult dose of hepatitis B vaccine with those boosted with a pediatric dose. Among adolescents who had lost protective antibody levels against hepatitis B, a higher proportion had an anamnestic response when boosted with the adult dose (60.0% vs. 43.8%). Thus, higher antigen concentrations may be required to elicit an adequate immune memory response. Despite improved anamnestic response, our study still raises concerns about whether children immunized in early infancy will remain protected from hepatitis B as they age into adulthood.

  6. Enhancement of immune response to a DNA vaccine against Mycobacterium tuberculosis Ag85B by incorporation of an autophagy inducing system.

    PubMed

    Meerak, Jomkhwan; Wanichwecharungruang, Supason P; Palaga, Tanapat

    2013-01-21

    DNA vaccines are a promising new generation of vaccines that can elicit an immune response using DNA encoding the antigen of interest. The efficacy of these vaccines, however, still needs to be improved. In this study, we investigated the effect of autophagy on increasing the efficacy of a candidate DNA vaccine against Mycobacterium tuberculosis (MTB), a causative agent of tuberculosis. Low molecular weight chitosan was used to encapsulate plasmid DNA containing a gene encoding MTB Antigen 85B (Ag85B), a secreted fibronectin-binding protein. To induce autophagy upon DNA vaccination, the kinase defective mTOR (mTOR-KD) was transfected into cells, and autophagy was detected based on the presence of LC3II. To investigate whether autophagy enhances an immune response upon DNA vaccination, we coencapsualted the Ag85B-containing plasmid with a plasmid encoding mTOR-KD. Plasmids encapsulated by chitosan particles were used for primary subcutaneous immunization and for intranasal boost in mice. After the boost vaccination, sera from the mice were measured for humoral immune response. The DNA vaccine with the autophagy-inducing construct elicited significantly higher Ag85B-specific antibody levels than the control group treated with the Ag85B plasmid alone or with the Ag85B plasmid plus the wild type mTOR construct. Upon in vitro stimulation of splenocytes from mice immunized with recombinant Ag85B, the highest levels of secreted IFN-γ and IL-2 were detected in mice immunized with the autophagy-inducing plasmid, while no differences in IL-4 levels were detected between the groups, suggesting that the DNA vaccine regimen with autophagy induction induced primarily a Th1 immune response. Furthermore, the enhanced proliferation of CD4+ T cells from mice receiving the autophagy-inducing vaccine was observed in vitro. Based on the evidence presented, we conclude that incorporating an autophagy-inducing element into a DNA vaccine may help to improve immune response.

  7. Immunization with recombinant DNA and modified vaccinia virus Ankara (MVA) vectors delivering PSCA and STEAP1 antigens inhibits prostate cancer progression.

    PubMed

    Krupa, Magdalena; Canamero, Marta; Gomez, Carmen E; Najera, Jose L; Gil, Jesus; Esteban, Mariano

    2011-02-04

    Despite recent advances in early detection and improvement of conventional therapies, there is an urgent need for development of additional approaches for prevention and/or treatment of prostate cancer, and the use of immunotherapeutic modalities, such as cancer vaccines, is one of the most promising strategies. In this study, we evaluated the prophylactic efficacy of an active immunization protocol against prostate cancer associated antigens mPSCA and mSTEAP1 in experimental prostate cancer. Two antigen delivery platforms, recombinant DNA and MVA vectors, both encoding either mPSCA or mSTEAP1 were used in diversified DNA prime/MVA boost vaccination protocol. Antitumour activity was evaluated in TRAMP-C1 subcutaneous syngeneic tumour model and TRAMP mice. DNA prime/MVA boost immunization against either mPSCA or mSTEAP1, delayed tumour growth in TRAMP-C1 cells-challenged mice. Furthermore, simultaneous vaccination with both antigens produced a stronger anti-tumour effect against TRAMP-C1 tumours than vaccination with either mPSCA or mSTEAP1 alone. Most importantly, concurrent DNA prime/MVA boost vaccination regimen with those antigens significantly decreased primary tumour burden in TRAMP mice without producing any apparent adverse effects. Histopathological analysis of prostate tumours from vaccinated and control TRAMP mice revealed also that mPSCA/mSTEAP1 based-vaccination was effective at reducing the severity of prostatic lesions and incidence of high-grade poorly differentiated prostate cancer. Suppression of the disease progression in TRAMP mice was correlated with decreased proliferation index and increased infiltration of T-cells in prostate tissue. Active immunization against PSCA and STEAP1 using DNA prime/MVA boost strategy is a promising approach for prevention and/or treatment of prostate cancer.

  8. Representing Arbitrary Boosts for Undergraduates.

    ERIC Educational Resources Information Center

    Frahm, Charles P.

    1979-01-01

    Presented is a derivation for the matrix representation of an arbitrary boost, a Lorentz transformation without rotation, suitable for undergraduate students with modest backgrounds in mathematics and relativity. The derivation uses standard vector and matrix techniques along with the well-known form for a special Lorentz transformation. (BT)

  9. Intranasal immunization with a replication-deficient adenoviral vector expressing the fusion glycoprotein of respiratory syncytial virus elicits protective immunity in BALB/c mice

    SciTech Connect

    Fu, Yuanhui; He, Jinsheng; Zheng, Xianxian; Wu, Qiang; Zhang, Mei; Wang, Xiaobo; Wang, Yan; Xie, Can; Tang, Qian; Wei, Wei; Wang, Min; Song, Jingdong; Qu, Jianguo; Zhang, Ying; Wang, Xin; Hong, Tao

    2009-04-17

    Human respiratory syncytial virus (RSV) is a serious pediatric pathogen of the lower respiratory tract worldwide. There is currently no clinically approved vaccine against RSV infection. Recently, it has been shown that a replication-deficient first generation adenoviral vector (FGAd), which encodes modified RSV attachment glycoprotein (G), elicits long-term protective immunity against RSV infection in mice. The major problem in developing such a vaccine is that G protein lacks MHC-I-restricted epitopes. However, RSV fusion glycoprotein (F) is a major cytotoxic T-lymphocyte epitope in humans and mice, therefore, an FGAd-encoding F (FGAd-F) was constructed and evaluated for its potential as an RSV vaccine in a murine model. Intranasal (i.n.) immunization with FGAd-F generated serum IgG, bronchoalveolar lavage secretory IgA, and RSV-specific CD8+ T-cell responses in BALB/c mice, with characteristic balanced or mixed Th1/Th2 CD4+ T-cell responses. Serum IgG was significantly elevated after boosting with i.n. FGAd-F. Upon challenge, i.n. immunization with FGAd-F displayed an effective protective role against RSV infection. These results demonstrate FGAd-F is able to induce effective protective immunity and is a promising vaccine regimen against RSV infection.

  10. Enhanced immunogenicity and antitumour effects with heterologous prime-boost regime using vaccines based on MG7-Ag mimotope of gastric cancer.

    PubMed

    Lin, T; Liang, S; Meng, F; Han, Q; Guo, C; Sun, L; Chen, Y; Liu, Z; Yu, Z; Xie, H; Ding, J; Fan, D

    2006-05-01

    MG7-Ag, gastric cancer-associated antigen, has been shown to be immunogenic and has been used as marker molecule for prognosis. In a previous study, we developed an oral DNA vaccine based on MG7-Ag mimotope. However, we failed to detect cellular immune response using the oral MG7-Ag mimotope DNA vaccine. To induce significant T cell response, we developed a recombinant adenovirus vaccine based on MG7-Ag mimotope and evaluated the efficacy and protective effects of heterologous prime-boost immunization protocol with an oral DNA vaccine previously developed. We found that both vaccines were able to elicit a significant humoral response against MG7-Ag, while the highest serum titre MG7 antibody was detected in mice immunized with the heterologous prime-boost immunization protocol. Enzyme-linked immunospot (ELISPOT) assay demonstrated that the heterologous prime-boost immunization strategy was more efficient in inducing T cell response than the homologous prime-boost strategy. In the tumour challenge assay, 2 of 5 mice immunized with the heterologous prime-boost protocol were tumour free, while none of the mice in homologous prime-boost groups or control groups was tumour free. Those tumour-bearing mice in the heterologous prime-boost regime had smaller tumour masses than their counterparts in the homologous prime-boost groups or control groups. Therefore, our study suggests that vaccines against MG7-Ag induce significant immune response against gastric cancer, and that the heterologous prime-boost protocol using different types of vaccines could achieve better protective effect than the homologous prime-boost protocol.

  11. Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB.

    PubMed

    Kaveh, Daryan A; Garcia-Pelayo, M Carmen; Webb, Paul R; Wooff, Esen E; Bachy, Véronique S; Hogarth, Philip J

    2016-07-25

    Boosting BCG using heterologous prime-boost represents a promising strategy for improved tuberculosis (TB) vaccines, and adenovirus (Ad) delivery is established as an efficacious boosting vehicle. Although studies demonstrate that intranasal administration of Ad boost to BCG offers optimal protection, this is not currently possible in cattle. Using Ad vaccine expressing the mycobacterial antigen TB10.4 (BCG/Ad-TB10.4), we demonstrate, parenteral boost of BCG immunised mice to induce specific CD8(+) IFN-γ producing T cells via synergistic priming of new epitopes. This induces significant improvement in pulmonary protection against Mycobacterium bovis over that provided by BCG when assessed in a standard 4week challenge model. However, in a stringent, year-long survival study, BCG/Ad-TB10.4 did not improve outcome over BCG, which we suggest may be due to the lack of additional memory cells (IL-2(+)) induced by boosting. These data indicate BCG-prime/parenteral-Ad-TB10.4-boost to be a promising candidate, but also highlight the need for further understanding of the mechanisms of T cell priming and associated memory using Ad delivery systems. That we were able to generate significant improvement in pulmonary protection above BCG with parenteral, rather than mucosal administration of boost vaccine is critical; suggesting that the generation of effective mucosal immunity is possible, without the risks and challenges of mucosal administration, but that further work to specifically enhance sustained protective immunity is required.

  12. Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice.

    PubMed

    Escolano, Amelia; Steichen, Jon M; Dosenovic, Pia; Kulp, Daniel W; Golijanin, Jovana; Sok, Devin; Freund, Natalia T; Gitlin, Alexander D; Oliveira, Thiago; Araki, Tatsuya; Lowe, Sarina; Chen, Spencer T; Heinemann, Jennifer; Yao, Kai-Hui; Georgeson, Erik; Saye-Francisco, Karen L; Gazumyan, Anna; Adachi, Yumiko; Kubitz, Michael; Burton, Dennis R; Schief, William R; Nussenzweig, Michel C

    2016-09-08

    A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope-modified immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2-neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2-neutralizing antibodies resembling the authentic human bNAb. Our data establish that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.

  13. Reweighting with Boosted Decision Trees

    NASA Astrophysics Data System (ADS)

    Rogozhnikov, Alex

    2016-10-01

    Machine learning tools are commonly used in modern high energy physics (HEP) experiments. Different models, such as boosted decision trees (BDT) and artificial neural networks (ANN), are widely used in analyses and even in the software triggers [1]. In most cases, these are classification models used to select the “signal” events from data. Monte Carlo simulated events typically take part in training of these models. While the results of the simulation are expected to be close to real data, in practical cases there is notable disagreement between simulated and observed data. In order to use available simulation in training, corrections must be introduced to generated data. One common approach is reweighting — assigning weights to the simulated events. We present a novel method of event reweighting based on boosted decision trees. The problem of checking the quality of reweighting step in analyses is also discussed.

  14. Interferometric resolution boosting for spectrographs

    SciTech Connect

    Erskine, D J; Edelstein, J

    2004-05-25

    Externally dispersed interferometry (EDI) is a technique for enhancing the performance of spectrographs for wide bandwidth high resolution spectroscopy and Doppler radial velocimetry. By placing a small angle-independent interferometer near the slit of a spectrograph, periodic fiducials are embedded on the recorded spectrum. The multiplication of the stellar spectrum times the sinusoidal fiducial net creates a moir{acute e} pattern, which manifests high detailed spectral information heterodyned down to detectably low spatial frequencies. The latter can more accurately survive the blurring, distortions and CCD Nyquist limitations of the spectrograph. Hence lower resolution spectrographs can be used to perform high resolution spectroscopy and radial velocimetry. Previous demonstrations of {approx}2.5x resolution boost used an interferometer having a single fixed delay. We report new data indicating {approx}6x Gaussian resolution boost (140,000 from a spectrograph with 25,000 native resolving power), taken by using multiple exposures at widely different interferometer delays.

  15. Online boosting for vehicle detection.

    PubMed

    Chang, Wen-Chung; Cho, Chih-Wei

    2010-06-01

    This paper presents a real-time vision-based vehicle detection system employing an online boosting algorithm. It is an online AdaBoost approach for a cascade of strong classifiers instead of a single strong classifier. Most existing cascades of classifiers must be trained offline and cannot effectively be updated when online tuning is required. The idea is to develop a cascade of strong classifiers for vehicle detection that is capable of being online trained in response to changing traffic environments. To make the online algorithm tractable, the proposed system must efficiently tune parameters based on incoming images and up-to-date performance of each weak classifier. The proposed online boosting method can improve system adaptability and accuracy to deal with novel types of vehicles and unfamiliar environments, whereas existing offline methods rely much more on extensive training processes to reach comparable results and cannot further be updated online. Our approach has been successfully validated in real traffic environments by performing experiments with an onboard charge-coupled-device camera in a roadway vehicle.

  16. Chimeric adenovirus type 5/35 vector encoding SIV gag and HIV env genes affords protective immunity against the simian/human immunodeficiency virus in monkeys.

    PubMed

    Someya, Kenji; Xin, Ke-Qin; Ami, Yasushi; Izumi, Yasuyuki; Mizuguchi, Hiroyuki; Ohta, Shinrai; Yamamoto, Naoki; Honda, Mitsuo; Okuda, Kenji

    2007-10-25

    Replication-defective adenovirus type 5 (Ad5) vector-based vaccines are widely known to induce strong immunity against immunodeficiency viruses. To exploit this immunogenicity while overcoming the potential problem of preexisting immunity against human adenoviruses type 5, we developed a recombinant chimeric adenovirus type 5 with type 35 fiber vector (rAd5/35). We initially produced a simian immunodeficiency virus (SIV) gag DNA plasmid (rDNA-Gag), a human immunodeficiency virus type 1 (HIV-1) 89.6 env DNA plasmid (rDNA-Env) and a recombinant Ad5/35 vector encoding the SIV gag and HIV env gene (rAd5/35-Gag and rAd5/35-Env). Prime-boost vaccination with rDNA-Gag and -Env followed by high doses of rAd5/35-Gag and -Env elicited higher levels of cellular immune responses than did rDNAs or rAd5/35s alone. When challenged with a pathogenic simian human immunodeficiency virus (SHIV), animals receiving a prime-boost regimen or rAd5/35s alone maintained a higher number of CD4(+) T cells and remarkably suppressed plasma viral RNA loads. These findings suggest the clinical promise of an rAd5/35 vector-based vaccine.

  17. Gonzalez Regimen (PDQ®)—Patient Version

    Cancer.gov

    Expert-reviewed information summary about the Gonzalez regimen as a treatment for people with cancer. Note: The information in this summary is no longer being updated and is provided for reference purposes only.

  18. Antibody- and cell-mediated immune responses to a synthetic oligosaccharide conjugate vaccine after booster immunization.

    PubMed

    Safari, Dodi; Dekker, Huberta A Th; de Jong, Ben; Rijkers, Ger T; Kamerling, Johannis P; Snippe, Harm

    2011-09-02

    Memory formation to CRM-neoglycoconjugate, a synthetic branched tetrasaccharide of Streptococcus pneumoniae type 14 polysaccharide (Pn14PS) that is conjugated to a CRM197 protein, was investigated using mice models. Mice were first immunized with the CRM-neoglycoconjugate and then boosted with either the same neoglycoconjugate or a native Pn14PS in order to investigate the effect of booster immunization. Boosting with the CRM-neoglycoconjugate resulted in increased levels of interleukin 5 (IL-5) in the serum on Day 1, followed by the appearance of high levels of specific anti-Pn14PS IgG antibodies on Day 7. Boosting with native Pn14PS resulted in neither IL-5 induction nor the generation of anti-Pn14PS IgG antibodies. In vitro (re)stimulation of spleen cells after booster injection with the neoglycoconjugate revealed the presence of IL-4 and IL-5. This was not seen in spleen cells obtained from mice boosted with the polysaccharide. When stimulated with heat-inactivated bacteria, however, the polysaccharide-boosted mice did have higher levels of IFN-γ and lower levels of IL-17 than both the CRM-neoglycoconjugate-boosted mice and the mock-immunized mice. In conclusion, neoglycoconjugate boosting is responsible for the activation of memory cells and the establishment of sustained immunity. Not only is a booster with native polysaccharide ineffective in inducing opsonic antibodies, but it also interferes with several immunoregulatory mechanisms.

  19. A prime/boost PfCS14K(M)/MVA-sPfCS(M) vaccination protocol generates robust CD8(+) T cell and antibody responses to Plasmodium falciparum circumsporozoite protein and protects mice against malaria.

    PubMed

    Vijayan, Aneesh; Mejías-Pérez, Ernesto; Espinosa, Diego A; Raman, Suresh C; Sorzano, Carlos Oscar S; Zavala, Fidel; Esteban, Mariano

    2017-03-15

    Vaccines against the pre-erythrocytic stages of malaria are appealing, since the parasite can be eliminated before disease onset and since they offer the unique possibility of targeting the parasite with both antibodies and T cells. Although the role CD8(+) T cells in pre-erythrocytic malaria stages is well documented, a highly effective T cell-inducing vaccine remains to be advanced. Here we report the development of a prime-boost immunization regimen with the Plasmodium falciparum circumsporozoite protein (PfCS) fused to the oligomer-forming vaccinia virus A27 protein and a modified vaccinia virus Ankara (MVA) vector expressing PfCS. This protocol induced polyfunctional CD8(+) T cells with effector memory phenotype and high PfCS antibody levels. These immune responses correlated with inhibition of liver stage parasitemia in 80% and sterile protection in 40% of mice challenged with a transgenic P. berghei parasite line that expressed PfCS. Our findings underscore the potential of T and B cell immunization strategies in improving protective effectiveness against malaria.

  20. Simultaneous approach using systemic, mucosal and transcutaneous routes of immunization for development of protective HIV-1 vaccines.

    PubMed

    Belyakov, I M; Ahlers, J D

    2011-01-01

    Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4(+) and CD8(+) T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4(+) and CD8(+) responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4(+) and CD8(+) CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8(+) CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti-viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection.

  1. Comparison of different prime-boost regimes with DNA and recombinant Orf virus based vaccines expressing glycoprotein D of pseudorabies virus in pigs.

    PubMed

    van Rooij, E M A; Rijsewijk, F A M; Moonen-Leusen, H W; Bianchi, A T J; Rziha, H-J

    2010-02-17

    Both DNA and Orf virus (ORFV; Parapox virus) based vaccines have shown promise as alternatives for conventional vaccines in pigs against pseudorabies virus (PRV) infection causing Aujeszky's disease. In the present study we evaluated the efficacy of different prime-boost regimes in pigs in terms of immunogenicity and protection against challenge infection with PRV. The different prime-boost regimes consisted of the homologous prime-boost regimes (DNA followed by DNA or ORFV followed by ORFV) and the heterologous prime-boost regimes (DNA followed by ORFV and ORFV followed by DNA), all based on glycoprotein D (gD) of PRV. Moreover, we compared the efficacy of the different prime-boost regimes with the efficacy of a conventional modified live vaccine (MLV). The different prime-boost regimes resulted in different levels of immunity and protection against challenge infection. Most effective was the regime of priming with DNA vaccine followed by boosting with the ORFV based vaccine. This regime resulted in strong antibody responses, comparable to the antibody responses obtained after prime-boost vaccination with a conventional MLV vaccine. Also with regard to protection, the prime DNA-boost ORFV regime performed better than the other prime-boost regimes. This study demonstrates the potential of a heterologous prime-boost vaccination strategy against PRV based on a single antigen, and that in the natural host, the pig.

  2. Electric rockets get a boost

    SciTech Connect

    Ashley, S.

    1995-12-01

    This article reports that xenon-ion thrusters are expected to replace conventional chemical rockets in many nonlaunch propulsion tasks, such as controlling satellite orbits and sending space probes on long exploratory missions. The space age dawned some four decades ago with the arrival of powerful chemical rockets that could propel vehicles fast enough to escape the grasp of earth`s gravity. Today, chemical rocket engines still provide the only means to boost payloads into orbit and beyond. The less glamorous but equally important job of moving vessels around in space, however, may soon be assumed by a fundamentally different rocket engine technology that has been long in development--electric propulsion.

  3. Where boosted significances come from

    NASA Astrophysics Data System (ADS)

    Plehn, Tilman; Schichtel, Peter; Wiegand, Daniel

    2014-03-01

    In an era of increasingly advanced experimental analysis techniques it is crucial to understand which phase space regions contribute a signal extraction from backgrounds. Based on the Neyman-Pearson lemma we compute the maximum significance for a signal extraction as an integral over phase space regions. We then study to what degree boosted Higgs strategies benefit ZH and tt¯H searches and which transverse momenta of the Higgs are most promising. We find that Higgs and top taggers are the appropriate tools, but would profit from a targeted optimization towards smaller transverse momenta. MadMax is available as an add-on to MadGraph 5.

  4. Stochastic approximation boosting for incomplete data problems.

    PubMed

    Sexton, Joseph; Laake, Petter

    2009-12-01

    Boosting is a powerful approach to fitting regression models. This article describes a boosting algorithm for likelihood-based estimation with incomplete data. The algorithm combines boosting with a variant of stochastic approximation that uses Markov chain Monte Carlo to deal with the missing data. Applications to fitting generalized linear and additive models with missing covariates are given. The method is applied to the Pima Indians Diabetes Data where over half of the cases contain missing values.

  5. Immune therapy for hepatitis B.

    PubMed

    Akbar, Sheikh Mohammad Fazle; Al-Mahtab, Mamun; Khan, Md Sakilur Islam; Raihan, Ruksana; Shrestha, Ananta

    2016-09-01

    Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries. Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients. Immune therapy seems to be an alternate therapeutic approach for CHB patients because impaired or distorted or diminished immune responses have been detected in most of these patients. Also, investigators have shown that restoration or induction of proper types of immune responses may have therapeutic implications in CHB. Various immunomodulatory agents have been used to treat patients with CHB around the world and the outcomes of these clinical trials show that the properties of immune modulators and nature and designing of immune therapeutic regimens seem to be highly relevant in the context of treatment of CHB patients. In this review, the general properties and specific features of immune therapy for CHB have been discussed for developing the guidelines of effective regimens of immune therapy for CHB.

  6. Recursive bias estimation and L2 boosting

    SciTech Connect

    Hengartner, Nicolas W; Cornillon, Pierre - Andre; Matzner - Lober, Eric

    2009-01-01

    This paper presents a general iterative bias correction procedure for regression smoothers. This bias reduction schema is shown to correspond operationally to the L{sub 2} Boosting algorithm and provides a new statistical interpretation for L{sub 2} Boosting. We analyze the behavior of the Boosting algorithm applied to common smoothers S which we show depend on the spectrum of I - S. We present examples of common smoother for which Boosting generates a divergent sequence. The statistical interpretation suggest combining algorithm with an appropriate stopping rule for the iterative procedure. Finally we illustrate the practical finite sample performances of the iterative smoother via a simulation study.

  7. Toward the definition of immunosuppressive regimens with antitumor activity.

    PubMed

    Casadio, F; Croci, S; D'Errico Grigioni, A; Corti, B; Grigioni, W F; Landuzzi, L; Lollini, P-L

    2005-06-01

    Immunosuppressive therapies associated with organ transplantation produce an increased risk of cancer development. Malignancies are increased in transplant recipients because of the impaired immune system. Moreover, experimental data point to a tumor-promoting activity of various immunosuppressive agents. In this study, we compared the effects of 4 immunosuppressive agents with different mechanisms of action (cyclosporine, rapamycin, mycophenolic acid, and leflunomide) on the in vitro growth of various tumor cell lines and umbilical vein endothelial cells. To varying degrees rapamycin (10 ng/mL), mycophenolic acid (300 nmol/L), and leflunomide (30 micromol/L) highly inhibited the growth of human rhabdomyosarcoma, hepatocellular carcinoma, colorectal carcinoma, and endothelial cells. In contrast, cyclosporine (100 ng/mL) did not affect their growth. Our data suggest that regimens containing rapamycin, mycophenolic acid, or leflunomide, which have both immunosuppressive and antitumor activities, should be preferred in transplant recipients to minimize the risk of tumors.

  8. Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk

    PubMed Central

    Nelson, Cody S.; Pollara, Justin; Kunz, Erika L.; Jeffries, Thomas L.; Duffy, Ryan; Beck, Charles; Stamper, Lisa; Wang, Minyue; Shen, Xiaoying; Pickup, David J.; Hudgens, Michael G.; Kepler, Thomas B.; Montefiori, David C.; Moody, M. Anthony; Tomaras, Georgia D.; Liao, Hua-Xin; Haynes, Barton F.; Ferrari, Guido; Fouda, Genevieve G. A.

    2016-01-01

    ABSTRACT Maternal vaccination to induce anti-HIV immune factors in breast milk is a potential intervention to prevent postnatal HIV-1 mother-to-child transmission (MTCT). We previously demonstrated that immunization of lactating rhesus monkeys with a modified vaccinia Ankara (MVA) prime/intramuscular (i.m.) protein boost regimen induced functional IgG responses in milk, while MVA prime/intranasal (i.n.) boost induced robust milk Env-specific IgA responses. Yet, recent studies have suggested that prevention of postnatal MTCT may require both Env-specific IgA and functional IgG responses in milk. Thus, to investigate whether both responses could be elicited by a combined systemic/mucosal immunization strategy, animals previously immunized with the MVA prime/i.n. boost regimen received an i.n./i.m. combined C.1086 gp120 boost. Remarkably, high-magnitude Env-specific IgA responses were observed in milk, surpassing those in plasma. Furthermore, 29% of vaccine-elicited Env-specific B cells isolated from breast milk were IgA isotype, in stark contrast to the overwhelming predominance of IgG isotype Env-specific B cells in breast milk of chronically HIV-infected women. A clonal relationship was identified between Env-specific blood and breast milk B cells, suggesting trafficking of that cell population between the two compartments. Furthermore, IgA and IgG monoclonal antibodies isolated from Env-specific breast milk B cells demonstrated diverse Env epitope specificities and multiple effector functions, including tier 1 neutralization, antibody-dependent cellular cytotoxicity (ADCC), infected cell binding, and inhibition of viral attachment to epithelial cells. Thus, maternal i.n./i.m. combined immunization is a novel strategy to enhance protective Env-specific IgA in milk, which is subsequently transferred to the infant via breastfeeding. IMPORTANCE Efforts to increase the availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas

  9. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms.

    PubMed

    Fridlender, Zvi G; Sun, Jing; Singhal, Sunil; Kapoor, Veena; Cheng, Guanjun; Suzuki, Eiji; Albelda, Steven M

    2010-11-01

    The most widely used approach to cancer immunotherapy is vaccines. Unfortunately, the need for multiple administrations of antigens often limits the use of one of the most effective vaccine approaches, immunogene therapy using viral vectors, because neutralizing antibodies are rapidly produced. We hypothesized that after viral immunogene therapy "primed" an initial strong antitumor immune response, subsequent "boosts" could be provided by sequential courses of chemotherapy. Three adenoviral (Ad)-based immunogene therapy regimens were administered to animals with large malignant mesothelioma and lung cancer tumors followed by three weekly administrations of a drug regimen commonly used to treat these tumors (Cisplatin/Gemcitabine). Immunogene therapy followed by chemotherapy resulted in markedly increased antitumor efficacy associated with increased numbers of antigen-specific, activated CD8(+) T-cells systemically and within the tumors. Possible mechanisms included: (i) decreases in immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T-regulatory cells (T-regs), and B-cells, (ii) stimulation of memory cells by intratumoral antigen release leading to efficient cross-priming, (iii) alteration of the tumor microenvironment with production of "danger signals" and immunostimulatory cytokines, and (iv) augmented trafficking of T-cells into the tumors. This approach is currently being tested in a clinical trial and could be applied to other trials of viral immunogene therapy.

  10. Series Connected Buck-Boost Regulator

    NASA Technical Reports Server (NTRS)

    Birchenough, Arthur G. (Inventor)

    2006-01-01

    A Series Connected Buck-Boost Regulator (SCBBR) that switches only a fraction of the input power, resulting in relatively high efficiencies. The SCBBR has multiple operating modes including a buck, a boost, and a current limiting mode, so that an output voltage of the SCBBR ranges from below the source voltage to above the source voltage.

  11. Statistical methods for down-selection of treatment regimens based on multiple endpoints, with application to HIV vaccine trials.

    PubMed

    Huang, Ying; Gilbert, Peter B; Fu, Rong; Janes, Holly

    2016-09-20

    SummaryBiomarker endpoints measuring vaccine-induced immune responses are essential to HIV vaccine development because of their potential to predict the effect of a vaccine in preventing HIV infection. A vaccine's immune response profile observed in phase I immunogenicity studies is a key factor in determining whether it is advanced for further study in phase II and III efficacy trials. The multiplicity of immune variables and scientific uncertainty in their relative importance, however, pose great challenges to the development of formal algorithms for selecting vaccines to study further. Motivated by the practical need to identify a set of promising vaccines from a pool of candidate regimens for inclusion in an upcoming HIV vaccine efficacy trial, we propose a new statistical framework for the selection of vaccine regimens based on their immune response profile. In particular, we propose superiority and non-redundancy criteria to be achieved in down-selection, and develop novel statistical algorithms that integrate hypothesis testing and ranking for selecting vaccine regimens satisfying these criteria. Performance of the proposed selection algorithms are evaluated through extensive numerical studies. We demonstrate the application of the proposed methods through the comparison of immune responses between several HIV vaccine regimens. The methods are applicable to general down-selection applications in clinical trials.

  12. Boost-phase discrimination research

    NASA Technical Reports Server (NTRS)

    Langhoff, Stephen R.; Feiereisen, William J.

    1993-01-01

    The final report describes the combined work of the Computational Chemistry and Aerothermodynamics branches within the Thermosciences Division at NASA Ames Research Center directed at understanding the signatures of shock-heated air. Considerable progress was made in determining accurate transition probabilities for the important band systems of NO that account for much of the emission in the ultraviolet region. Research carried out under this project showed that in order to reproduce the observed radiation from the bow shock region of missiles in their boost phase it is necessary to include the Burnett terms in the constituent equation, account for the non-Boltzmann energy distribution, correctly model the NO formation and rotational excitation process, and use accurate transition probabilities for the NO band systems. This work resulted in significant improvements in the computer code NEQAIR that models both the radiation and fluid dynamics in the shock region.

  13. Fecal Bacterial Communities in treated HIV infected individuals on two antiretroviral regimens

    PubMed Central

    Pinto-Cardoso, Sandra; Lozupone, Catherine; Briceño, Olivia; Alva-Hernández, Selma; Téllez, Norma; Adriana, Aguilar; Murakami-Ogasawara, Akio; Reyes-Terán, Gustavo

    2017-01-01

    Intestinal microbiome changes that occur in HIV positive individuals on different antiretroviral therapy (ART) regimens are important to understand, as they are potentially linked with chronic inflammation and microbiome-linked comorbidities that occur at increased incidence in this population. We conducted a cross-sectional study comparing the fecal microbiomes of HIV-uninfected (HIV SN) to HIV-infected individuals on long-term ART (HIV+ LTART) from Mexico using 16S ribosomal RNA (16sRNA) targeted sequencing. These individuals were on two ART regimens based on either Non-Nucleoside Reverse Transcriptase Inhibitors (EFV) or ritonavir-boosted Protease Inhibitors (PI) with the same backbone of Nucleoside Reverse Transcriptase Inhibitors. Microbiome diversity was reduced in treated HIV infection compared to HIV SN (p < 0.05). Several operational taxonomic units (OTUs) related to the Ruminococcaceae family including Faecalibacterium prausnitzii were depleted in EFV and PI compared to HIV SN and negatively correlated with intestinal gut dysfunction as measured by the intestinal fatty binding protein (p < 0.05). This is the first report to address the fecal bacterial communities in HIV-infected individuals on two ARV regimens from Mexico. PMID:28262770

  14. Fecal Bacterial Communities in treated HIV infected individuals on two antiretroviral regimens.

    PubMed

    Pinto-Cardoso, Sandra; Lozupone, Catherine; Briceño, Olivia; Alva-Hernández, Selma; Téllez, Norma; Adriana, Aguilar; Murakami-Ogasawara, Akio; Reyes-Terán, Gustavo

    2017-03-06

    Intestinal microbiome changes that occur in HIV positive individuals on different antiretroviral therapy (ART) regimens are important to understand, as they are potentially linked with chronic inflammation and microbiome-linked comorbidities that occur at increased incidence in this population. We conducted a cross-sectional study comparing the fecal microbiomes of HIV-uninfected (HIV SN) to HIV-infected individuals on long-term ART (HIV+ LTART) from Mexico using 16S ribosomal RNA (16sRNA) targeted sequencing. These individuals were on two ART regimens based on either Non-Nucleoside Reverse Transcriptase Inhibitors (EFV) or ritonavir-boosted Protease Inhibitors (PI) with the same backbone of Nucleoside Reverse Transcriptase Inhibitors. Microbiome diversity was reduced in treated HIV infection compared to HIV SN (p < 0.05). Several operational taxonomic units (OTUs) related to the Ruminococcaceae family including Faecalibacterium prausnitzii were depleted in EFV and PI compared to HIV SN and negatively correlated with intestinal gut dysfunction as measured by the intestinal fatty binding protein (p < 0.05). This is the first report to address the fecal bacterial communities in HIV-infected individuals on two ARV regimens from Mexico.

  15. Orthodontics Align Crooked Teeth and Boost Self-Esteem

    MedlinePlus

    ... desktop! more... Orthodontics Align Crooked Teeth and Boost Self- esteem Article Chapters Orthodontics Align Crooked Teeth and Boost Self- esteem Orthodontics print full article print this chapter email ...

  16. Immunizations for foreign travel.

    PubMed Central

    Hill, D. R.

    1992-01-01

    One of the most important aspects of preparing travelers for destinations throughout the world is providing them with immunizations. Before administering any vaccines, however, a careful health and immunization history and travel itinerary should be obtained in order to determine vaccine indications and contraindications. There are three categories of immunizations for foreign travel. The first category includes immunizations which are routinely recommended whether or not the individual is traveling. Many travelers are due for primary vaccination or boosting against tetanus-diphtheria, measles-mumps-rubella, pneumococcal pneumonia, and influenza, for example, and the pre-travel visit is an ideal time to administer these. The second category are immunizations which might be required by a country as a condition for entry; these are yellow fever and cholera. The final category contains immunizations which are recommended because there is a risk of acquiring a particular disease during travel. Typhoid fever, meningococcal disease, rabies, and hepatitis are some examples. Travelers who are pregnant or who are infected with the human immunodeficiency virus require special consideration. Provision of appropriate immunizations for foreign travel is an important aspect of preventing illness in travelers. PMID:1337807

  17. Riemann curvature of a boosted spacetime geometry

    NASA Astrophysics Data System (ADS)

    Battista, Emmanuele; Esposito, Giampiero; Scudellaro, Paolo; Tramontano, Francesco

    2016-10-01

    The ultrarelativistic boosting procedure had been applied in the literature to map the metric of Schwarzschild-de Sitter spacetime into a metric describing de Sitter spacetime plus a shock-wave singularity located on a null hypersurface. This paper evaluates the Riemann curvature tensor of the boosted Schwarzschild-de Sitter metric by means of numerical calculations, which make it possible to reach the ultrarelativistic regime gradually by letting the boost velocity approach the speed of light. Thus, for the first time in the literature, the singular limit of curvature, through Dirac’s δ distribution and its derivatives, is numerically evaluated for this class of spacetimes. Moreover, the analysis of the Kretschmann invariant and the geodesic equation shows that the spacetime possesses a “scalar curvature singularity” within a 3-sphere and it is possible to define what we here call “boosted horizon”, a sort of elastic wall where all particles are surprisingly pushed away, as numerical analysis demonstrates. This seems to suggest that such “boosted geometries” are ruled by a sort of “antigravity effect” since all geodesics seem to refuse to enter the “boosted horizon” and are “reflected” by it, even though their initial conditions are aimed at driving the particles toward the “boosted horizon” itself. Eventually, the equivalence with the coordinate shift method is invoked in order to demonstrate that all δ2 terms appearing in the Riemann curvature tensor give vanishing contribution in distributional sense.

  18. Long-term efficacy and toxicity of abacavir/lamivudine/nevirapine compared to the most prescribed ARV regimens before 2013 in a French Nationwide Cohort Study.

    PubMed

    de Boissieu, Paul; Dramé, Moustapha; Raffi, François; Cabie, André; Poizot-Martin, Isabelle; Cotte, Laurent; Garraffo, Rodolphe; Delobel, Pierre; Huleux, Thomas; Rey, David; Bani-Sadr, Firouzé

    2016-09-01

    Data on the long-term efficacy and safety of abacavir/lamivudine (ABC/3TC) and nevirapine (NVP) are scarce. This combination has the advantage of simplifying treatment and improving long-term tolerance. The aim of this study was to compare the rate of any discontinuation of antiretroviral (ARV) regimen because of virologic failure (VF), and/or adverse drug reaction (ADR) among patients receiving stable ARV regimens for at least 6 months.ABC/3TC/NVP was compared to ABC/3TC with either ritonavir-boosted darunavir (DRV/r) or ritonavir-boosted atazanavir (ATV/r), unboosted ATV, or tenofovir/emtricitabine (TDF/FTC) with either one of the following: ATV/r, unboosted ATV, DRV/r, efavirenz (EFV), or NVP, in the French prospective multicenter Dat'AIDS cohort.The study enrolled 16,511 patients treated with following ARV regimens: ABC/3TC/NVP (n = 1089), TDF/FTC/NVP (n = 1542), ABC/3TC/DRV/r (n = 1065), ABC/3TC/ATV/r (n = 1847), ABC/3TC/ATV (n = 563), TDF/FTC/ATV/r (n = 3519), TDF/FTC/DRV/r (n = 2767), TDF/FTC/ATV (n = 419), and TDF/FTC/EFV (n = 3700). Mean follow-up was 36 ± 24 months. Patients treated with ABC/3TC/NVP received this regimen as a switch regimen in 97% of cases. By multivariable analysis, the risk of treatment discontinuation due to VF was similar between ABC/3TC/NVP and other ARV regimens, except for TDF/FTC/ATV and ABC/3TC/ATV, which were associated with a higher risk of treatment interruption due to VF (hazard ratio [HR] 1.99; 95% confidence interval [CI] 1.29-3.06 and HR 2.19; 95% CI 1.51-3.18, respectively). Treatment discontinuation due to ADR was lowest with the ABC/3TC/NVP regimen. Other ARV regimens were associated with a 1.80- to 3.19-fold increase in the risk of treatment discontinuation due to ADR (P < 0.0001 for all comparisons).ABC/3TC/NVP as a simplification regimen is a long-term effective regimen with lower discontinuation due to long-term toxicity compared with other standard ARV regimens.

  19. Why to start the concomitant boost in accelerated radiotherapy for advanced laryngeal cancer in week 3

    SciTech Connect

    Terhaard, Chris H.J. . E-mail: C.H.J.Terhaard@AZU.nl; Kal, Henk B.; Hordijk, Gerrit-Jan

    2005-05-01

    Purpose: We analyzed toxicity and the local control rates for advanced laryngeal cancer, treated with two accelerated fractionation schedules. The main difference between the schedules was the onset of the concomitant boost, in Week 3 or Week 4. Overall treatment time and total dose were equivalent. Methods and Materials: In a prospective, nonrandomized study of T{sub 3}, T{sub 4}, and advanced T{sub 2} laryngeal cancer, concomitant boost schedules were used in 100 patients. Thirty patients received a schedule of twice daily 1.2 Gy in Weeks 1-3, followed by twice daily 1.7 Gy in Weeks 4 and 5; total dose was 70 Gy (the hyperfractionated accelerated schedule [HAS] regimen). Seventy patients were treated with 5 times 2 Gy in Weeks 1 and 2, followed by daily 1.8 Gy and 1.5 Gy (boost) in Weeks 3-5; total dose 69.5 Gy (the accelerated schedule only [ASO] regimen). Distribution of T stage was 47%, 40%, and 12% for T{sub 2}, T{sub 3}, and T{sub 4}, respectively. In 24% of the patients, lymph nodes were positive. Pretreatment tracheotomy or stridor or both occurred in 8 patients. The distribution of prognostic factors was not significantly different between the two fractionation schedules. Acute and late toxicity was assessed. Results were estimated by the use of actuarial methods. For late toxicity and local control univariate and multivariate analyses were performed. Tumor control probability analysis was used to model cure rate differences. Results: Overall acute mucositis score was equal for both schedules. Acute mucositis started and decreased significantly earlier in the HAS regimen. In all patients acute mucositis healed completely. The treatment was completed within 38 days in all patients. The regional control rate was 100% for clinical N{sub 0}, and 75% for the clinical N{sub +} patients. The 3-year local control rate was 59% and 78% for the HAS and ASO regimens, respectively (p = 0.05); the ultimate local control was 80% and 94%, respectively. In multivariate

  20. Boosting Wigner's nj-symbols

    NASA Astrophysics Data System (ADS)

    Speziale, Simone

    2017-03-01

    We study the SL (2 ,ℂ ) Clebsch-Gordan coefficients appearing in the Lorentzian EPRL spin foam amplitudes for loop quantum gravity. We show how the amplitudes decompose into SU(2) nj- symbols at the vertices and integrals over boosts at the edges. The integrals define edge amplitudes that can be evaluated analytically using and adapting results in the literature, leading to a pure state sum model formulation. This procedure introduces virtual representations which, in a manner reminiscent of virtual momenta in Feynman amplitudes, are off-shell of the simplicity constraints present in the theory, but with the integrands that peak at the on-shell values. We point out some properties of the edge amplitudes which are helpful for numerical and analytical evaluations of spin foam amplitudes, and suggest among other things a simpler model useful for calculations of certain lowest order amplitudes. As an application, we estimate the large spin scaling behaviour of the simpler model, on a closed foam with all 4-valent edges and Euler characteristic χ , to be Nχ -5 E +V /2. The paper contains a review and an extension of the results on SL (2 ,ℂ ) Clebsch-Gordan coefficients among unitary representations of the principal series that can be useful beyond their application to quantum gravity considered here.

  1. Prophylactic antibiotic regimens in tumour surgery (PARITY)

    PubMed Central

    Investigators, The PARITY

    2015-01-01

    Objective Clinical studies of patients with bone sarcomas have been challenged by insufficient numbers at individual centres to draw valid conclusions. Our objective was to assess the feasibility of conducting a definitive multi-centre randomised controlled trial (RCT) to determine whether a five-day regimen of post-operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours. Methods We performed a pilot international multi-centre RCT. We used central randomisation to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens. Results We screened 96 patients and enrolled 60 participants (44 men and 16 women) across 21 sites from four countries over 24 months (mean 2.13 participants per site per year, standard deviation 2.14). One participant was lost to follow-up and one withdrew consent. Complete data were obtained for 98% of eligible patients at two weeks, 83% at six months, and 73% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post-operatively, but 93% of all post-operative doses were administered per protocol. Conclusions It is feasible to conduct a definitive multi-centre RCT of post-operative antibiotic regimens in patients with bone sarcomas, but further expansion of our collaborative network will be critical. We have demonstrated an ability to coordinate in multiple countries, enrol participants, maintain protocol adherence, and minimise losses to follow-up. Cite this article: Bone Joint Res;4:154–162 PMID:26423584

  2. Relativistic projection and boost of solitons

    SciTech Connect

    Wilets, L.

    1991-12-31

    This report discusses the following topics on the relativistic projection and boost of solitons: The center of mass problem; momentum eigenstates; variation after projection; and the nucleon as a composite. (LSP).

  3. Relativistic projection and boost of solitons

    SciTech Connect

    Wilets, L.

    1991-01-01

    This report discusses the following topics on the relativistic projection and boost of solitons: The center of mass problem; momentum eigenstates; variation after projection; and the nucleon as a composite. (LSP).

  4. Boosting Manufacturing through Modular Chemical Process Intensification

    SciTech Connect

    2016-12-09

    Manufacturing USA's Rapid Advancement in Process Intensification Deployment Institute will focus on developing breakthrough technologies to boost domestic energy productivity and energy efficiency by 20 percent in five years through manufacturing processes.

  5. Boosting Manufacturing through Modular Chemical Process Intensification

    ScienceCinema

    None

    2017-01-06

    Manufacturing USA's Rapid Advancement in Process Intensification Deployment Institute will focus on developing breakthrough technologies to boost domestic energy productivity and energy efficiency by 20 percent in five years through manufacturing processes.

  6. Boosting BCG with inert spores improves immunogenicity and induces specific IL-17 responses in a murine model of bovine tuberculosis.

    PubMed

    Garcia-Pelayo, M Carmen; Kaveh, Daryan A; Sibly, Laura; Webb, Paul R; Bull, Naomi C; Cutting, Simon M; Hogarth, Philip J

    2016-05-01

    Tuberculosis (TB) remains a global pandemic, in both animals and man, and novel vaccines are urgently required. Heterologous prime-boost of BCG represents a promising strategy for improved TB vaccines, with respiratory delivery the most efficacious to date. Such an approach may be an ideal vaccination strategy against bovine TB (bTB), but respiratory vaccination presents a technical challenge in cattle. Inert bacterial spores represent an attractive vaccine vehicle. Therefore we evaluated whether parenterally administered spores are efficacious when used as a BCG boost in a murine model of immunity against Mycobacterium bovis. Here we report the use of heat-killed, TB10.4 adsorbed, Bacillus subtilis spores delivered via subcutaneous injection to boost immunity primed by BCG. We demonstrate that this approach improves the immunogenicity of BCG. Interestingly, this associated with substantial boosting of IL-17 responses; considered to be important in protective immunity against TB. These data demonstrate that parenteral delivery of spores represents a promising vaccine vehicle for boosting BCG, and identifies potential for optimisation for use as a vaccine for bovine TB.

  7. Centaur liquid oxygen boost pump vibration test

    NASA Technical Reports Server (NTRS)

    Tang, H. M.

    1975-01-01

    The Centaur LOX boost pump was subjected to both the simulated Titan Centaur proof flight and confidence demonstration vibration test levels. For each test level, both sinusoidal and random vibration tests were conducted along each of the three orthogonal axes of the pump and turbine assembly. In addition to these tests, low frequency longitudinal vibration tests for both levels were conducted. All tests were successfully completed without damage to the boost pump.

  8. Protective effect of a prime-boost strategy with plasmid DNA followed by recombinant adenovirus expressing TgAMA1 as vaccines against Toxoplasma gondii infection in mice.

    PubMed

    Yu, Longzheng; Yamagishi, Junya; Zhang, Shoufa; Jin, Chunmei; Aboge, Gabriel Oluga; Zhang, Houshuang; Zhang, Guohong; Tanaka, Tetsuya; Fujisaki, Kozo; Nishikawa, Yoshifumi; Xuan, Xuenan

    2012-09-01

    A heterologous prime-boost strategy with priming plasmid DNA followed by recombinant virus expressing relevant antigens is known to stimulate protective immunity against intracellular parasites. In this study, we have evaluated a heterologous prime-boost strategy for immunizing mice against Toxoplasma gondii infection. Our results revealed that the prime-boost strategy using both plasmid DNA and adenoviral vector encoding TgAMA1 may stimulate both humoral and Th1/Th2 cellular immune responses specific for TgAMA1. Moreover, C57BL/6 mice immunized with the pAMA1/Ad5Null, pNull/Ad5AMA1, and pAMA1/Ad5AMA1 constructs showed survival rates of 12.5%, 37.5%, and 50%, respectively. In contrast, all the pNull/Ad5Null immunized mice died after infection with the PLK-GFP strain of T. gondii. Brain cyst burden was reduced by 23% in mice immunized with pAMA1/Ad5AMA1 compared with the pNull/Ad5AMA1 immunized mice. These results demonstrate that the heterologous DNA priming and recombinant adenovirus boost strategy may provide protective immunity against T. gondii infection.

  9. Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity

    PubMed Central

    Gu, Yang-Zhuo; Fan, Chuan-Wen; Lu, Ran; Shao, Bin; Sang, Ya-Xiong; Huang, Qiao-Rong; Li, Xue; Meng, Wen-Tong; Mo, Xian-Ming; Wei, Yu-Quan

    2016-01-01

    Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4+ and CD8+ T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4+ and CD8+ effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8+ effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens. PMID:27571893

  10. Comparative impact of antiretroviral drugs on markers of inflammation and immune activation during the first two years of effective therapy for HIV-1 infection: an observational study

    PubMed Central

    2014-01-01

    Background Few studies have compared the impact of different antiretroviral regimens on residual immune activation and inflammation with discordant results. Aim of the study was to investigate the impact of various antiretroviral regimens on markers of immune activation and inflammation during the first two years of effective therapy. Methods We studied HIV-infected antiretroviral-naïve patients who began cART with either abacavir/lamivudine or tenofovir/emtricitabine, combined with ritonavir-boosted lopinavir (LPV/r), atazanavir (ATV/r) or efavirenz (EFV). All the patients had a virological response within 6 months, which was maintained for 2 years with no change in their ART regimen. C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), monokine induced by interferon-γ (MIG) and interferon-γ-inducible protein-10 (IP-10) were measured in stored plasma obtained at cART initiation and 24 months later. Mean changes from baseline were analyzed on loge-transformed values and multivariable linear regression models were used to study the effect of the treatment components, after adjusting for factors that might have influenced the choice of ART regimen or biomarker levels. Differences were expressed as the mean fold change percentage difference (Δ). Results Seventy-eight patients (91% males) with a median age of 43 years met the inclusion criteria. Their median baseline CD4 cell count was 315/mm3 and HIV-1 RNA level 4.6 log10 copies/ml. During the 2-years study period, IL-6, IP-10 and MIG levels fell significantly, while hs-CRP and sCD14 levels remained stable. IP-10 and MIG levels declined significantly less strongly with ATV/r than with EFV (IP-10Δ -57%, p = 0.011; MIGΔ -136%, p = 0.007), while no difference was noted between LPV/r and EFV. The decline in IL-6 did not differ significantly across the different treatment components. Conclusions After the first 2 years of successful cART, IL-6, IP-10 and MIG fell markedly while hs

  11. Boosted Jets at the LHC

    NASA Astrophysics Data System (ADS)

    Larkoski, Andrew

    2015-04-01

    Jets are collimated streams of high-energy particles ubiquitous at any particle collider experiment and serve as proxy for the production of elementary particles at short distances. As the Large Hadron Collider at CERN continues to extend its reach to ever higher energies and luminosities, an increasingly important aspect of any particle physics analysis is the study and identification of jets, electroweak bosons, and top quarks with large Lorentz boosts. In addition to providing a unique insight into potential new physics at the tera-electron volt energy scale, high energy jets are a sensitive probe of emergent phenomena within the Standard Model of particle physics and can teach us an enormous amount about quantum chromodynamics itself. Jet physics is also invaluable for lower-level experimental issues including triggering and background reduction. It is especially important for the removal of pile-up, which is radiation produced by secondary proton collisions that contaminates every hard proton collision event in the ATLAS and CMS experiments at the Large Hadron Collider. In this talk, I will review the myriad ways that jets and jet physics are being exploited at the Large Hadron Collider. This will include a historical discussion of jet algorithms and the requirements that these algorithms must satisfy to be well-defined theoretical objects. I will review how jets are used in searches for new physics and ways in which the substructure of jets is being utilized for discriminating backgrounds from both Standard Model and potential new physics signals. Finally, I will discuss how jets are broadening our knowledge of quantum chromodynamics and how particular measurements performed on jets manifest the universal dynamics of weakly-coupled conformal field theories.

  12. Oral immunization of mice with gamma-irradiated Brucella neotomae induces protection against intraperitoneal and intranasal challenge with virulent B. abortus 2308.

    PubMed

    Dabral, Neha; Martha-Moreno-Lafont; Sriranganathan, Nammalwar; Vemulapalli, Ramesh

    2014-01-01

    Brucella spp. are Gram-negative, facultative intracellular coccobacilli that cause one of the most frequently encountered zoonosis worldwide. Humans naturally acquire infection through consumption of contaminated dairy and meat products and through direct exposure to aborted animal tissues and fluids. No vaccine against brucellosis is available for use in humans. In this study, we tested the ability of orally inoculated gamma-irradiated B. neotomae and B. abortus RB51 in a prime-boost immunization approach to induce antigen-specific humoral and cell mediated immunity and protection against challenge with virulent B. abortus 2308. Heterologous prime-boost vaccination with B. abortus RB51 and B. neotomae and homologous prime-boost vaccination of mice with B. neotomae led to the production of serum and mucosal antibodies specific to the smooth LPS. The elicited serum antibodies included the isotypes of IgM, IgG1, IgG2a, IgG2b and IgG3. All oral vaccination regimens induced antigen-specific CD4(+) and CD8(+) T cells capable of secreting IFN-γ and TNF-α. Upon intra-peritoneal challenge, mice vaccinated with B. neotomae showed the highest level of resistance against virulent B. abortus 2308 colonization in spleen and liver. Experiments with different doses of B. neotomae showed that all tested doses of 10(9), 10(10) and 10(11) CFU-equivalent conferred significant protection against the intra-peritoneal challenge. However, a dose of 10(11) CFU-equivalent of B. neotomae was required for affording protection against intranasal challenge as shown by the reduced bacterial colonization in spleens and lungs. Taken together, these results demonstrate the feasibility of using gamma-irradiated B. neotomae as an effective and safe oral vaccine to induce protection against respiratory and systemic infections with virulent Brucella.

  13. Exercise, nutrition and immune function.

    PubMed

    Gleeson, Michael; Nieman, David C; Pedersen, Bente K

    2004-01-01

    Strenuous bouts of prolonged exercise and heavy training are associated with depressed immune cell function. Furthermore, inadequate or inappropriate nutrition can compound the negative influence of heavy exertion on immunocompetence. Dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction. An adequate intake of iron, zinc and vitamins A, E, B6 and B12 is particularly important for the maintenance of immune function, but excess intakes of some micronutrients can also impair immune function and have other adverse effects on health. Immune system depression has also been associated with an excess intake of fat. To maintain immune function, athletes should eat a well-balanced diet sufficient to meet their energy requirements. An athlete exercising in a carbohydrate-depleted state experiences larger increases in circulating stress hormones and a greater perturbation of several immune function indices. Conversely, consuming 30-60 g carbohydrate x h(-1) during sustained intensive exercise attenuates rises in stress hormones such as cortisol and appears to limit the degree of exercise-induced immune depression. Convincing evidence that so-called 'immune-boosting' supplements, including high doses of antioxidant vitamins, glutamine, zinc, probiotics and Echinacea, prevent exercise-induced immune impairment is currently lacking.

  14. Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine.

    PubMed

    Pouliot, Kimberly; Buglione-Corbett, Rachel; Marty-Roix, Robyn; Montminy-Paquette, Sara; West, Kim; Wang, Shixia; Lu, Shan; Lien, Egil

    2014-09-03

    Recombinant protein vaccines are commonly formulated with an immune-stimulatory compound, or adjuvant, to boost immune responses to a particular antigen. Recent studies have shown that, through recognition of molecular motifs, receptors of the innate immune system are involved in the functions of adjuvants to generate and direct adaptive immune responses. However, it is not clear to which degree those receptors are also important when the adjuvant is used as part of a novel heterologous prime-boost immunization process in which the priming and boosting components are not the same type of vaccines. In the current study, we compared the immune responses elicited by a pentavalent HIV-1 DNA prime-protein boost vaccine in mice deficient in either Toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88) to wildtype mice. HIV gp120 protein administered in the boost phase was formulated with either monophosphoryl lipid A (MPLA), QS-21, or Al(OH)3. Endpoint antibody titer, serum cytokine response and T-cell memory response were assessed. Neither TLR4 nor MyD88 deficiency had a significant effect on the immune response of mice given vaccine formulated with QS-21 or Al(OH)3. However, TLR4- and MyD88-deficiency decreased both the antibody and T-cell responses in mice administered HIV gp120 formulated with MPLA. These results further our understanding of the activation of TLR4 and MyD88 by MPLA in the context of a DNA prime/protein boost immunization strategy.

  15. Immune System

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Immune System KidsHealth > For Teens > Immune System A A A ... could put us out of commission. What the Immune System Does The immune (pronounced: ih-MYOON) system, which ...

  16. Protective efficacy and immune responses by homologous prime-booster immunizations of a novel inactivated Salmonella Gallinarum vaccine candidate

    PubMed Central

    2016-01-01

    Purpose Salmonella enterica serovar Gallinarum (SG) ghost vaccine candidate was recently constructed. In this study, we evaluated various prime-boost vaccination strategies using the candidate strain to optimize immunity and protection efficacy against fowl typhoid. Materials and Methods The chickens were divided into five groups designated as group A (non-immunized control), group B (orally primed and boosted), group C (primed orally and boosted intramuscularly), group D (primed and boosted intramuscularly), and group E (primed intramuscularly and boosted orally). The chickens were primed with the SG ghost at 7 days of age and were subsequently boosted at the fifth week of age. Post-immunization, the plasma IgG and intestinal secretory IgA (sIgA) levels, and the SG antigen-specific lymphocyte stimulation were monitored at weekly interval and the birds were subsequently challenged with a virulent SG strain at the third week post-second immunization. Results Chickens in group D showed an optimized protection with significantly increased plasma IgG, sIgA, and lymphocyte stimulation response compared to all groups. The presence of CD4+ and CD8+ T cells and monocyte/macrophage (M/M) in the spleen, and splenic expression of cytokines such as interferon γ (IFN-γ) and interleukin 6 (IL-6) in the immunized chickens were investigated. The prime immunization induced significantly higher splenic M/M population and mRNA levels of IFN-γ whereas the booster showed increases of splenic CD4+ and CD8+ T-cell population and IL-6 cytokine in mRNA levels. Conclusion Our results indicate that the prime immunization with the SG ghost vaccine induced Th1 type immune response and the booster elicited both Th1- and Th2-related immune responses. PMID:27489805

  17. Reduction in Radiation-Induced Morbidity by Use of an Intercurrent Boost in the Management of Early-Stage Breast Cancer

    SciTech Connect

    Trombetta, Mark; Julian, Thomas B.; Valakh, Vladimir; Greenberg, Larisa; Labban, George; Khalid, Mian K.; Werts, E. Day; Parda, David

    2010-08-01

    Purpose: Electron or photon boost immediately following whole-breast irradiation performed after conservation surgery for early-stage breast cancer is the accepted standard of care. This regimen frequently results in Grade III dermatitis, causing discomfort or treatment interruption. Herein, we compare patients treated with whole-breast irradiation followed by boost compared with a cohort with a planned intercurrent radiation boost. Methods and Materials: The records of 650 consecutive breast cancer patients treated at Allegheny General Hospital (AGH) between 2000 and 2008 were reviewed. Selected for this study were 327 patients with T1 or T2 tumors treated with external beam radiotherapy postlumpectomy. One hundred and sixty-nine patients were treated by whole-breast radiotherapy (WBRT) followed by boost at completion. One hundred fifty-eight were treated with a planned intercurrent boost (delivered following 3,600 cGy WBRT). The mean whole breast radiation dose in the conventionally treated group was 5,032 cGy (range, 4500-5400 cGy), and the mean whole breast dose was 5,097 cGy (range, 4860-5040 cGy) in the group treated with a planned intercurrent boost. Results: The occurrence of Grade III dermatitis was significantly reduced in the WBRT/intercurrent boost group compared with the WBRT/boost group (0.6% vs. 8.9%), as was the incidence of treatment interruption (1.9% vs. 14.2%). With a median follow-up of 32 months and 27 months, respectively, no significant difference in local control was identified. Conclusions: Patients treated with intercurrent boost developed less Grade III dermatitis and unplanned treatment interruptions with similar local control.

  18. Tracking down hyper-boosted top quarks

    NASA Astrophysics Data System (ADS)

    Larkoski, Andrew J.; Maltoni, Fabio; Selvaggi, Michele

    2015-06-01

    The identification of hadronically decaying heavy states, such as vector bosons, the Higgs, or the top quark, produced with large transverse boosts has been and will continue to be a central focus of the jet physics program at the Large Hadron Collider (LHC). At a future hadron collider working at an order-of-magnitude larger energy than the LHC, these heavy states would be easily produced with transverse boosts of several TeV. At these energies, their decay products will be separated by angular scales comparable to individual calorimeter cells, making the current jet substructure identification techniques for hadronic decay modes not directly employable. In addition, at the high energy and luminosity projected at a future hadron collider, there will be numerous sources for contamination including initial- and final-state radiation, underlying event, or pile-up which must be mitigated. We propose a simple strategy to tag such "hyper-boosted" objects that defines jets with radii that scale inversely proportional to their transverse boost and combines the standard calorimetric information with charged track-based observables. By means of a fast detector simulation, we apply it to top quark identification and demonstrate that our method efficiently discriminates hadronically decaying top quarks from light QCD jets up to transverse boosts of 20 TeV. Our results open the way to tagging heavy objects with energies in the multi-TeV range at present and future hadron colliders.

  19. Tracking down hyper-boosted top quarks

    SciTech Connect

    Larkoski, Andrew J.; Maltoni, Fabio; Selvaggi, Michele

    2015-06-05

    The identification of hadronically decaying heavy states, such as vector bosons, the Higgs, or the top quark, produced with large transverse boosts has been and will continue to be a central focus of the jet physics program at the Large Hadron Collider (LHC). At a future hadron collider working at an order-of-magnitude larger energy than the LHC, these heavy states would be easily produced with transverse boosts of several TeV. At these energies, their decay products will be separated by angular scales comparable to individual calorimeter cells, making the current jet substructure identification techniques for hadronic decay modes not directly employable. In addition, at the high energy and luminosity projected at a future hadron collider, there will be numerous sources for contamination including initial- and final-state radiation, underlying event, or pile-up which must be mitigated. We propose a simple strategy to tag such "hyper-boosted" objects that defines jets with radii that scale inversely proportional to their transverse boost and combines the standard calorimetric information with charged track-based observables. By means of a fast detector simulation, we apply it to top quark identification and demonstrate that our method efficiently discriminates hadronically decaying top quarks from light QCD jets up to transverse boosts of 20 TeV. Lastly, our results open the way to tagging heavy objects with energies in the multi-TeV range at present and future hadron colliders.

  20. Tracking down hyper-boosted top quarks

    DOE PAGES

    Larkoski, Andrew J.; Maltoni, Fabio; Selvaggi, Michele

    2015-06-05

    The identification of hadronically decaying heavy states, such as vector bosons, the Higgs, or the top quark, produced with large transverse boosts has been and will continue to be a central focus of the jet physics program at the Large Hadron Collider (LHC). At a future hadron collider working at an order-of-magnitude larger energy than the LHC, these heavy states would be easily produced with transverse boosts of several TeV. At these energies, their decay products will be separated by angular scales comparable to individual calorimeter cells, making the current jet substructure identification techniques for hadronic decay modes not directlymore » employable. In addition, at the high energy and luminosity projected at a future hadron collider, there will be numerous sources for contamination including initial- and final-state radiation, underlying event, or pile-up which must be mitigated. We propose a simple strategy to tag such "hyper-boosted" objects that defines jets with radii that scale inversely proportional to their transverse boost and combines the standard calorimetric information with charged track-based observables. By means of a fast detector simulation, we apply it to top quark identification and demonstrate that our method efficiently discriminates hadronically decaying top quarks from light QCD jets up to transverse boosts of 20 TeV. Lastly, our results open the way to tagging heavy objects with energies in the multi-TeV range at present and future hadron colliders.« less

  1. An adenovirus-simian immunodeficiency virus env vaccine elicits humoral, cellular, and mucosal immune responses in rhesus macaques and decreases viral burden following vaginal challenge.

    PubMed Central

    Buge, S L; Richardson, E; Alipanah, S; Markham, P; Cheng, S; Kalyan, N; Miller, C J; Lubeck, M; Udem, S; Eldridge, J; Robert-Guroff, M

    1997-01-01

    Six female rhesus macaques were immunized orally and intranasally at 0 weeks and intratracheally at 12 weeks with an adenovirus type 5 host range mutant (Ad5hr)-simian immunodeficiency virus SIVsm env recombinant and at 24 and 36 weeks with native SIVmac251 gp120 in Syntex adjuvant. Four macaques received the Ad5hr vector and adjuvant alone; two additional controls were naive. In vivo replication of the Ad5hr wild-type and recombinant vectors occurred with detection of Ad5 DNA in stool samples and/or nasal secretions in all macaques and increases in Ad5 neutralizing antibody in 9 of 10 macaques following Ad administrations. SIV-specific neutralizing antibodies appeared after the second recombinant immunization and rose to titers > 10,000 following the second subunit boost. Immunoglobulin G (IgG) and IgA antibodies able to bind gp120 developed in nasal and rectal secretions, and SIV-specific IgGs were also observed in vaginal secretions and saliva. T-cell proliferative responses to SIV gp140 and T-helper epitopes were sporadically detected in all immunized macaques. Following vaginal challenge with SIVmac251, transient or persistent infection resulted in both immunized and control monkeys. The mean viral burden in persistently infected immunized macaques was significantly decreased in the primary infection period compared to that of control macaques. These results establish in vivo use of the Ad5hr vector, which overcomes the host range restriction of human Ads for rhesus macaques, thereby providing a new model for evaluation of Ad-based vaccines. In addition, they show that a vaccine regimen using the Ad5hr-SIV env recombinant and gp120 subunit induces strong humoral, cellular, and mucosal immunity in rhesus macaques. The reduced viral burden achieved solely with an env-based vaccine supports further development of Ad-based vaccines comprising additional viral components for immune therapy and AIDS vaccine development. PMID:9343211

  2. Boost breaking in the EFT of inflation

    NASA Astrophysics Data System (ADS)

    Delacrétaz, Luca V.; Noumi, Toshifumi; Senatore, Leonardo

    2017-02-01

    If time-translations are spontaneously broken, so are boosts. This symmetry breaking pattern can be non-linearly realized by either just the Goldstone boson of time translations, or by four Goldstone bosons associated with time translations and boosts. In this paper we extend the Effective Field Theory of Multifield Inflation to consider the case in which the additional Goldstone bosons associated with boosts are light and coupled to the Goldstone boson of time translations. The symmetry breaking pattern forces a coupling to curvature so that the mass of the additional Goldstone bosons is predicted to be equal to √2H in the vast majority of the parameter space where they are light. This pattern therefore offers a natural way of generating self-interacting particles with Hubble mass during inflation. After constructing the general effective Lagrangian, we study how these particles mix and interact with the curvature fluctuations, generating potentially detectable non-Gaussian signals.

  3. Comparative analysis of the magnitude, quality, phenotype, and protective capacity of simian immunodeficiency virus gag-specific CD8+ T cells following human-, simian-, and chimpanzee-derived recombinant adenoviral vector immunization.

    PubMed

    Quinn, Kylie M; Da Costa, Andreia; Yamamoto, Ayako; Berry, Dana; Lindsay, Ross W B; Darrah, Patricia A; Wang, Lingshu; Cheng, Cheng; Kong, Wing-Pui; Gall, Jason G D; Nicosia, Alfredo; Folgori, Antonella; Colloca, Stefano; Cortese, Riccardo; Gostick, Emma; Price, David A; Gomez, Carmen E; Esteban, Mariano; Wyatt, Linda S; Moss, Bernard; Morgan, Cecilia; Roederer, Mario; Bailer, Robert T; Nabel, Gary J; Koup, Richard A; Seder, Robert A

    2013-03-15

    Recombinant adenoviral vectors (rAds) are the most potent recombinant vaccines for eliciting CD8(+) T cell-mediated immunity in humans; however, prior exposure from natural adenoviral infection can decrease such responses. In this study we show low seroreactivity in humans against simian- (sAd11, sAd16) or chimpanzee-derived (chAd3, chAd63) compared with human-derived (rAd5, rAd28, rAd35) vectors across multiple geographic regions. We then compared the magnitude, quality, phenotype, and protective capacity of CD8(+) T cell responses in mice vaccinated with rAds encoding SIV Gag. Using a dose range (1 × 10(7)-10(9) particle units), we defined a hierarchy among rAd vectors based on the magnitude and protective capacity of CD8(+) T cell responses, from most to least, as: rAd5 and chAd3, rAd28 and sAd11, chAd63, sAd16, and rAd35. Selection of rAd vector or dose could modulate the proportion and/or frequency of IFN-γ(+)TNF-α(+)IL-2(+) and KLRG1(+)CD127(-)CD8(+) T cells, but strikingly ∼30-80% of memory CD8(+) T cells coexpressed CD127 and KLRG1. To further optimize CD8(+) T cell responses, we assessed rAds as part of prime-boost regimens. Mice primed with rAds and boosted with NYVAC generated Gag-specific responses that approached ∼60% of total CD8(+) T cells at peak. Alternatively, priming with DNA or rAd28 and boosting with rAd5 or chAd3 induced robust and equivalent CD8(+) T cell responses compared with prime or boost alone. Collectively, these data provide the immunologic basis for using specific rAd vectors alone or as part of prime-boost regimens to induce CD8(+) T cells for rapid effector function or robust long-term memory, respectively.

  4. Boosting Access to Government Rocket Science

    DTIC Science & Technology

    2014-10-01

    September–October 2014 8 with MSFC, through an SAA signed in 2012, using Marshall’s expertise and resources to perform wind tunnel testing on various...Defense AT&L: September–October 2014 6 Boosting Access to Government Rocket Science John F. Rice Defense AT&L: September–October 2014 6 Report...REPORT TYPE 3. DATES COVERED 00-00-2014 to 00-00-2014 4. TITLE AND SUBTITLE Boosting Access to Government Rocket Science 5a. CONTRACT NUMBER

  5. Durable cytotoxic immune responses against gp120 elicited by recombinant SV40 vectors encoding HIV-1 gp120 +/- IL-15.

    PubMed

    McKee, Hayley J; T'sao, Patricia Y; Vera, Maria; Fortes, Puri; Strayer, David S

    2004-08-23

    BACKGROUND: A vaccine that elicits durable, powerful anti-HIV immunity remains an elusive goal. In these studies we tested whether multiple treatments with viral vector-delivered HIV envelope antigen (gp120), with and without IL-15, could help to approach that goal. For this purpose, we used recombinant Tag-deleted SV40-derived vectors (rSV40s), since they do not elicit neutralizing antibody responses, and so can be given multiply without loss of transduction efficiency. METHODS: SV(gp120) carried the coding sequences for HIV-1NL4-3 Env, and SV(mIL-15) carried the cDNA for mouse IL-15. Singly, and in combination, these two vectors were given monthly to BALB/cJ mice. Cytotoxic immunity and cytotoxic memory were tested in direct cytotoxicity assays using unselected effector cells. Antibody vs. gp120 was measured in a binding assay. In both cases, targets were P815 cells that were stably transfected with gp120. RESULTS: Multiple injections of SV(gp120) elicited powerful anti-gp120 cytolytic activity (>70% specific lysis) by unselected spleen cells. Cells from multiply-immunized mice that were rested 1 year after their last injections still showed >60% gp120-specific lysis. Anti-gp120 antibody was first detected after 2 monthly injections of SV(gp120) and remained elevated thereafter. Adding SV(mIL-15) to the immunization regimen dramatically accelerated the development of memory cytolytic responses, with >/= 50% specific lysis seen 1 month after two treatments. IL-15 did not alter the development of antibody responses. CONCLUSIONS: Thus, rSV40s encoding antigens and immunostimulatory cytokines may be useful tools for priming and/or boosting immune responses against HIV.

  6. How Psychological States Affect the Immune System: Implications for Interventions in the Context of HIV.

    ERIC Educational Resources Information Center

    Littrell, Jill

    1996-01-01

    Discusses the psychological states associated with enhanced immune system functioning and those associated with suppressed immune functioning. Reviews studies of psychological and behavioral interventions to boost the immune systems of people who are HIV positive. Suggests that group interventions can enhance psychological states associated with…

  7. A Comparison of Breast Cancer Treatment Regimens by Demographic Characteristics

    DTIC Science & Technology

    1998-10-01

    Cancer Treatment Regimens by Demographic Characteristics PRINCIPAL INVESTIGATOR: Marianne E. Ulcickas Yood, M.P.H. CONTRACTING ORGANIZATION: Henry...NUMBERS A Comparison of Breast Cancer Treatment Regimens by Demographic Characteristics DAMD17-97-1-7302 6. AUTHOR(S) Marianne E. Ulcickas Yood, M.P.H. 7... Cancer Treatment Regimens by Demographic Characteristics (DAMD17-97-1-7302), Annual Report October, 1998 TABLE OF CONTENTS Introduction

  8. The Attentional Boost Effect and Context Memory

    ERIC Educational Resources Information Center

    Mulligan, Neil W.; Smith, S. Adam; Spataro, Pietro

    2016-01-01

    Stimuli co-occurring with targets in a detection task are better remembered than stimuli co-occurring with distractors--the attentional boost effect (ABE). The ABE is of interest because it is an exception to the usual finding that divided attention during encoding impairs memory. The effect has been demonstrated in tests of item memory but it is…

  9. Concomitant GRID boost for Gamma Knife radiosurgery

    SciTech Connect

    Ma Lijun; Kwok, Young; Chin, Lawrence S.; Simard, J. Marc; Regine, William F.

    2005-11-15

    We developed an integrated GRID boost technique for Gamma Knife radiosurgery. The technique generates an array of high dose spots within the target volume via a grid of 4-mm shots. These high dose areas were placed over a conventional Gamma Knife plan where a peripheral dose covers the full target volume. The beam weights of the 4-mm shots were optimized iteratively to maximize the integral dose inside the target volume. To investigate the target volume coverage and the dose to the adjacent normal brain tissue for the technique, we compared the GRID boosted treatment plans with conventional Gamma Knife treatment plans using physical and biological indices such as dose-volume histogram (DVH), DVH-derived indices, equivalent uniform dose (EUD), tumor control probabilities (TCP), and normal tissue complication probabilities (NTCP). We found significant increase in the target volume indices such as mean dose (5%-34%; average 14%), TCP (4%-45%; average 21%), and EUD (2%-22%; average 11%) for the GRID boost technique. No significant change in the peripheral dose coverage for the target volume was found per RTOG protocol. In addition, the EUD and the NTCP for the normal brain adjacent to the target (i.e., the near region) were decreased for the GRID boost technique. In conclusion, we demonstrated a new technique for Gamma Knife radiosurgery that can escalate the dose to the target while sparing the adjacent normal brain tissue.

  10. Schools Enlisting Defense Industry to Boost STEM

    ERIC Educational Resources Information Center

    Trotter, Andrew

    2008-01-01

    Defense contractors Northrop Grumman Corp. and Lockheed Martin Corp. are joining forces in an innovative partnership to develop high-tech simulations to boost STEM--or science, technology, engineering, and mathematics--education in the Baltimore County schools. The Baltimore County partnership includes the local operations of two major military…

  11. The Attentional Boost Effect with Verbal Materials

    ERIC Educational Resources Information Center

    Mulligan, Neil W.; Spataro, Pietro; Picklesimer, Milton

    2014-01-01

    Study stimuli presented at the same time as unrelated targets in a detection task are better remembered than stimuli presented with distractors. This attentional boost effect (ABE) has been found with pictorial (Swallow & Jiang, 2010) and more recently verbal materials (Spataro, Mulligan, & Rossi-Arnaud, 2013). The present experiments…

  12. Energy Boost. Q & A with Steve Kiesner.

    ERIC Educational Resources Information Center

    Schneider, Jay W.

    2002-01-01

    Presents an interview with the director of national accounts for the Edison Electric Institute in Washington, DC about the association, its booklet on energy conservation within education facilities, and ways in which educational facilities can reduce costs by boosting energy conservation. (EV)

  13. Mediterranean Diet Plus Olive Oil a Boost to Heart Health?

    MedlinePlus

    ... gov/news/fullstory_163557.html Mediterranean Diet Plus Olive Oil a Boost to Heart Health? It enhances ... HealthDay News) -- A Mediterranean diet high in virgin olive oil may boost the protective effects of "good" ...

  14. A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host

    PubMed Central

    Rai, Pradeep K; Chodisetti, Sathi Babu; Nadeem, Sajid; Maurya, Sudeep K; Gowthaman, Uthaman; Zeng, Weiguang; Janmeja, Ashok K; Jackson, David C; Agrewala, Javed N

    2016-01-01

    Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ+TNF-α+ polyfunctional Th1 cells and IL-17A+IFN-γ+ Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime. PMID:27052185

  15. A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host.

    PubMed

    Rai, Pradeep K; Chodisetti, Sathi Babu; Nadeem, Sajid; Maurya, Sudeep K; Gowthaman, Uthaman; Zeng, Weiguang; Janmeja, Ashok K; Jackson, David C; Agrewala, Javed N

    2016-04-07

    Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ(+)TNF-α(+) polyfunctional Th1 cells and IL-17A(+)IFN-γ(+) Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime.

  16. Prevalence of inappropriate tuberculosis treatment regimens: a systematic review

    PubMed Central

    Langendam, M.W.; van der Werf, M.J.; Huitric, E.; Manissero, D.

    2012-01-01

    A potential threat to the success of new tuberculosis (TB) drugs is the development of resistance. Using drugs in appropriate regimens, such as those recommended in the World Health Organization (WHO) treatment guidelines, prevents the development of resistance. We performed a systematic review to assess the prevalence of inappropriate prescription of TB drugs for the treatment of TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Observational studies published from 2000 that included TB patients receiving treatment were selected. A treatment regimen was considered inappropriate if the regimen was not a WHO recommended regimen. 37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies. The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%. In 19 studies the quality of treatment regimen reporting was low. Despite the fact that assessment of inappropriate treatment was hampered by low quality of reporting, our data indicate a reasonable amount of inappropriate prescription of TB treatment regimens. Thus, there is a risk that new drugs will be used in inappropriate treatment regimens, even with WHO guidelines in place, introducing the risk of resistance development. This article highlights the need to improve implementation of the WHO treatment of TB guidelines. PMID:22005923

  17. Immune Thrombocytopenia

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Immune Thrombocytopenia? Immune thrombocytopenia (THROM-bo-si-toe-PE-ne- ... from one person to another. Types of Immune Thrombocytopenia The two types of ITP are acute (temporary ...

  18. Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection.

    PubMed

    Mehta, Rohtesh S; Rezvani, Katayoun

    2016-11-16

    Infection is the leading cause of non-relapse mortality after allogeneic haematopoietic cell transplantation (HCT). This occurs as a result of dysfunction to the host immune system from the preparative regimen used prior to HCT, combined with a delay in reconstitution of the donor-derived immune system after HCT. In this article, we elaborate on the process of immune reconstitution post-HCT that begins with the innate system and is followed by recovery of adaptive immunity. Simultaneously, we describe how the tempo of immune reconstitution influences the risk of various infections. We explain some of the key differences in immune reconstitution and the consequent risk of infections in recipients of peripheral blood stem cell, bone marrow or umbilical cord blood grafts. Other factors that impact on immune recovery are also highlighted. Finally, we allude to various strategies that are being tested to enhance immune reconstitution post-HCT.

  19. HIF transcription factors, inflammation, and immunity.

    PubMed

    Palazon, Asis; Goldrath, Ananda W; Nizet, Victor; Johnson, Randall S

    2014-10-16

    The hypoxic response in cells and tissues is mediated by the family of hypoxia-inducible factor (HIF) transcription factors; these play an integral role in the metabolic changes that drive cellular adaptation to low oxygen availability. HIF expression and stabilization in immune cells can be triggered by hypoxia, but also by other factors associated with pathological stress: e.g., inflammation, infectious microorganisms, and cancer. HIF induces a number of aspects of host immune function, from boosting phagocyte microbicidal capacity to driving T cell differentiation and cytotoxic activity. Cellular metabolism is emerging as a key regulator of immunity, and it constitutes another layer of fine-tuned immune control by HIF that can dictate myeloid cell and lymphocyte development, fate, and function. Here we discuss how oxygen sensing in the immune microenvironment shapes immunological response and examine how HIF and the hypoxia pathway control innate and adaptive immunity.

  20. Photodynamic immune modulation (PIM)

    NASA Astrophysics Data System (ADS)

    North, John R.; Hunt, David W. C.; Simkin, Guillermo O.; Ratkay, Leslie G.; Chan, Agnes H.; Lui, Harvey; Levy, Julia G.

    1999-09-01

    Photodynamic Therapy (PDT) is accepted for treatment of superficial and lumen-occluding tumors in regions accessible to activating light and is now known to be effective in closure of choroidal neovasculature in Age Related Macular Degeneration. PDT utilizes light absorbing drugs (photosensitizers) that generate the localized formation of reactive oxygen species after light exposure. In a number of systems, PDT has immunomodulatory effects; Photodynamic Immune Modulation (PIM). Using low- intensity photodynamic regimens applied over a large body surface area, progression of mouse autoimmune disease could be inhibited. Further, this treatment strongly inhibited the immunologically- medicated contact hypersensitivity response to topically applied chemical haptens. Immune modulation appears to result from selective targeting of activated T lymphocytes and reduction in immunostimulation by antigen presenting cells. Psoriasis, an immune-mediated skin condition, exhibits heightened epidermal cell proliferation, epidermal layer thickening and plaque formation at different body sites. In a recent clinical trial, approximately one-third of patients with psoriasis and arthritis symptoms (psoriatic arthritis) displayed a significant clinical improvement in several psoriasis-related parameters after four weekly whole-body PIM treatments with verteporfin. The safety profile was favorable. The capacity of PIM to influence other human immune disorders including rheumatoid arthritis is under extensive evaluation.

  1. Auto immune hepatitis.

    PubMed

    van Gerven, Nicole Mf; de Boer, Ynto S; Mulder, Chris Jj; van Nieuwkerk, Carin Mj; Bouma, Gerd

    2016-05-21

    To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: "auto immune hepatitis", "clinical presentation", "symptoms", "signs", "diagnosis", "auto antibodies", "laboratory values", "serology", "histopathology", "histology", "genetics", "HLA genes", "non-HLA genes", "environment", "epidemiology", "prevalence", "incidence", "demographics", "complications", "HCC", "PBC", "PSC", "corticosteroid", "therapy", "treatment", "alternative treatment". English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.

  2. Enhancing Commitment Improves Adherence to a Medical Regimen.

    ERIC Educational Resources Information Center

    Putnam, Dana E.; And Others

    1994-01-01

    Evaluated commitment-based intervention for improvement of adherence to 10-day antibiotic regimen. Subjects were 60 college students. Experimental subjects made verbal and written commitments for adherence and completed tasks designed to increase their investment in medication regimen. Controls performed similarly structured tasks unrelated to…

  3. Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data.

    PubMed

    Makanga, Michael; Premji, Zul; Falade, Catherine; Karbwang, Juntra; Mueller, Edgar A; Andriano, Kim; Hunt, Philip; De Palacios, Patricia Ibarra

    2006-06-01

    Patient data from eight clinical trials were pooled and analyzed to study the efficacy and safety of the six-dose versus four-dose regimen of artemether-lumefantrine (coartemether; Coartem) in children weighing 5-25 kg. A total of 544 patients with uncomplicated P. falciparum malaria (six-dose: 343; four-dose: 201), matched for demographic and baseline characteristics and individual coartemether doses were included in the analysis. Analysis of day 28 cure rate based on the intention-to-treat and evaluable populations yielded corrected cure rates for the six-dose regimen of 93% and 96% compared with 61% and 76%, respectively, for the four-dose regimen (P < 0.0001 for both comparisons). Similarly high cure rates were achieved with the six-dose regimen in non-immune infants weighing as little as 5 kg. The six- and four-dose regimens were equally well tolerated. The main finding of this analysis is that the six-dose regimen of coartemether is safe and more efficacious than the four-dose regimen in children.

  4. Mucosal Vaccination Overcomes the Barrier to Recombinant Vaccinia Immunization Caused by Preexisting Poxvirus Immunity

    NASA Astrophysics Data System (ADS)

    Belyakov, Igor M.; Moss, Bernard; Strober, Warren; Berzofsky, Jay A.

    1999-04-01

    Overcoming preexisting immunity to vaccinia virus in the adult population is a key requirement for development of otherwise potent recombinant vaccinia vaccines. Based on our observation that s.c. immunization with vaccinia induces cellular and antibody immunity to vaccinia only in systemic lymphoid tissue and not in mucosal sites, we hypothesized that the mucosal immune system remains naive to vaccinia and therefore amenable to immunization with recombinant vaccinia vectors despite earlier vaccinia exposure. We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses. These responses occurred not only in mucosal but also in systemic lymphoid tissue, whereas systemic immunization was ineffective under these circumstances. In this context, intrarectal immunization was more effective than intranasal immunization. Boosting with a second dose of recombinant vaccinia was also more effective via the mucosal route. The systemic HIV-specific cytotoxic T lymphocyte response was enhanced by coadministration of IL-12 at the mucosal site. These results also demonstrate the independent compartmentalization of the mucosal versus systemic immune systems and the asymmetric trafficking of lymphocytes between them. This approach to circumvent previous vaccinia immunity may be useful for induction of protective immunity against infectious diseases and cancer in the sizable populations with preexisting immunity to vaccinia from smallpox vaccination.

  5. OASL – a new player in controlling antiviral innate immunity

    PubMed Central

    Zhu, Jianzhong; Ghosh, Arundhati; Sarkar, Saumendra N.

    2015-01-01

    The cellular innate immune system plays a critical role in mounting the initial resistance to virus infection. It is comprised of various pattern-recognition receptors that induce type I interferon production, which further shapes the adaptive immunity. However, to overcome this resistance and promote replication, viruses have evolved mechanisms to evade this host innate immune response. Here we discuss a recently described mechanism of boosting the innate immunity by oligoadenylate synthetase-like (OASL) protein, which can potentially be used to overcome viral evasion and enhance innate immunity. PMID:25676874

  6. Individualizing phenytoin dosage regimens using a programmable calculator.

    PubMed

    Ng, P K

    1980-04-01

    A programmable calculator procedure for the determination of individualized phenytoin dosage regimens is described. The calculator is programmed based on a one-compartment, open model using the Michaelis-Menten equation. A detailed description of the programs and user instructions are presented. The programs allow calculation of oral dosage regimens and steady-state phenytoin levels. The first two programs require a given dose and one corresponding steady-state minimum concentration point to estimate a dosage regimen and steady-state serum level. The second two programs, which provide a more accurate prediction of dosage regimen and steady-state serum levels, require two dose and steady-state minimum concentration poits. The calculator programs provide a rapid and reliable means of estimating a patient's phenytoin dosage regimens and steady-state serum levels.

  7. Voltage-Boosting Driver For Switching Regulator

    NASA Technical Reports Server (NTRS)

    Trump, Ronald C.

    1990-01-01

    Driver circuit assures availability of 10- to 15-V gate-to-source voltage needed to turn on n-channel metal oxide/semiconductor field-effect transistor (MOSFET) acting as switch in switching voltage regulator. Includes voltage-boosting circuit efficiently providing gate voltage 10 to 15 V above supply voltage. Contains no exotic parts and does not require additional power supply. Consists of NAND gate and dual voltage booster operating in conjunction with pulse-width modulator part of regulator.

  8. Gradient Boosting for Conditional Random Fields

    DTIC Science & Technology

    2014-09-23

    Information Processing Systems 26 ( NIPS ’13), pages 647–655. 2013. [4] J. Friedman. Greedy function approximation: a gradient boosting machine. Annals of...and phrases and their compositionality. In Advances in Neural Information Processing Systems 26 ( NIPS ’13), pages 3111–3119. 2013. [15] A. Quattoni, M...Collins, and T. Darrell. Conditional random fields for object recognition. In Advances in Neural Information Processing Systems 17 ( NIPS ’04), pages

  9. Sculpting humoral immunity through dengue vaccination to enhance protective immunity

    PubMed Central

    Crill, Wayne D.; Hughes, Holly R.; Trainor, Nicole B.; Davis, Brent S.; Whitney, Matt T.; Chang, Gwong-Jen J.

    2012-01-01

    Dengue viruses (DENV) are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF). Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1) DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT) with this cross-reactivity reduced (CRR) vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naїve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine-induced immune responses. PMID

  10. Boosted Random Ferns for Object Detection.

    PubMed

    Villamizar, Michael; Andrade-Cetto, Juan; Sanfeliu, Alberto; Moreno-Noguer, Francesc

    2017-03-01

    In this paper we introduce the Boosted Random Ferns (BRFs) to rapidly build discriminative classifiers for learning and detecting object categories. At the core of our approach we use standard random ferns, but we introduce four main innovations that let us bring ferns from an instance to a category level, and still retain efficiency. First, we define binary features on the histogram of oriented gradients-domain (as opposed to intensity-), allowing for a better representation of intra-class variability. Second, both the positions where ferns are evaluated within the sliding window, and the location of the binary features for each fern are not chosen completely at random, but instead we use a boosting strategy to pick the most discriminative combination of them. This is further enhanced by our third contribution, that is to adapt the boosting strategy to enable sharing of binary features among different ferns, yielding high recognition rates at a low computational cost. And finally, we show that training can be performed online, for sequentially arriving images. Overall, the resulting classifier can be very efficiently trained, densely evaluated for all image locations in about 0.1 seconds, and provides detection rates similar to competing approaches that require expensive and significantly slower processing times. We demonstrate the effectiveness of our approach by thorough experimentation in publicly available datasets in which we compare against state-of-the-art, and for tasks of both 2D detection and 3D multi-view estimation.

  11. A Phase III Comparative Study of the Efficacy and Tolerability of Three Non-Nucleoside Reverse Transcriptase Inhibitor-Sparing Antiretroviral Regimens for Treatment-Naïve HIV-1-Infected Volunteers: A Randomized, Controlled Trial

    PubMed Central

    Lennox, Jeffrey L.; Landovitz, Raphael J.; Ribaudo, Heather J.; Ofotokun, Ighovwerha; Na, Lumine H.; Godfrey, Catherine; Kuritzkes, Daniel R.; Sagar, Manish; Brown, Todd T.; Cohn, Susan E.; McComsey, Grace A.; Aweeka, Francesca; Fichtenbaum, Carl J.; Presti, Rachel M.; Koletar, Susan L.; Haas, David W.; Patterson, Kristine B.; Benson, Constance A.; Baugh, Bryan P.; Leavitt, Randi Y.; Rooney, James F.; Seekins, Daniel; Currier, Judith S.

    2015-01-01

    Background Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naïve HIV-infected persons. Objective Perform a rigorous evaluation of three NNRTI-sparing initial antiretroviral regimens to demonstrate equivalence for virologic efficacy and tolerability. Design Phase-III, 1:1:1 randomized, open label, >96 week study. Setting Fifty-seven sites in United States and Puerto Rico. Patients Treatment naïve, ≥18 years, HIV-1 RNA >1000 copies/mL, no nucleoside reverse transcriptase or protease inhibitor resistance. Intervention Atazanavir 300 mg with ritonavir 100 mg, daily; or raltegravir 400 mg twice daily; or darunavir 800 mg with ritonavir 100 mg, daily; plus emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg daily. Measurements Virologic failure defined as confirmed HIV-1 RNA >1000 copies/mL between 16 and 24 weeks, or >200 copies/mL at or after 24 weeks; tolerability failure defined as discontinuation of atazanavir, raltegravir or darunavir for toxicity. A secondary endpoint was a combination of virologic efficacy and tolerability. Results Among 1,809 participants all pairwise comparisons of incidence of virologic failure over 96-weeks demonstrated equivalence within ±10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and a 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir respectively, primarily due to hyperbilirubinemia. For combined virologic efficacy and tolerability ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at time of virologic failure was rare but more likely with raltegravir. Limitations Open label; ritonavir not provided Conclusions Over 2 years all three regimens attain high and equivalent rates of virologic control. Regimens

  12. Enhancement of Protective Efficacy through Adenoviral Vectored Vaccine Priming and Protein Boosting Strategy Encoding Triosephosphate Isomerase (SjTPI) against Schistosoma japonicum in Mice

    PubMed Central

    Dai, Yang; Wang, Xiaoting; Tang, Jianxia; Zhao, Song; Xing, Yuntian; Dai, Jianrong; Jin, Xiaolin; Zhu, Yinchang

    2015-01-01

    Background Schistosomiasis japonica is a zoonotic parasitic disease; developing transmission blocking veterinary vaccines are urgently needed for the prevention and control of schistosomiasis in China. Heterologous prime-boost strategy, a novel vaccination approach, is more effective in enhancing vaccine efficacy against multiple pathogens. In the present study, we established a novel heterologous prime-boost vaccination strategy, the rAdV-SjTPI.opt intramuscular priming and rSjTPI subcutaneous boosting strategy, and evaluated its protective efficacy against Schistosoma japonicum in mice. Methodology/Principal Findings Adenoviral vectored vaccine (rAdV-SjTPI.opt) and recombinant protein vaccine (rSjTPI) were prepared and used in different combinations as vaccines in a mouse model. The specific immune responses and protective efficacies were evaluated. Furthermore, the longevity of protective efficacy was also determined. Results showed that the rAdV-SjTPI.opt priming-rSjTPI boosting strategy elicited higher levels of specific IgG responses and broad-spectrum specific cellular immune responses. The protective efficacy could reach up to nearly 70% and 50% of protection could be observed at 10 weeks after the last immunization in mice. Conclusions/Significance The rAdV-SjTPI.opt intramuscular priming-rSjTPI subcutaneous boosting vaccination strategy is a novel, highly efficient, and stable approach to developing vaccines against Schistosoma japonicum infections in China. PMID:25793406

  13. Integrated Immune

    NASA Technical Reports Server (NTRS)

    Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarnece

    2010-01-01

    This slide presentation reviews the program to replace several recent studies about astronaut immune systems with one comprehensive study that will include in-flight sampling. The study will address lack of in-flight data to determine the inflight status of immune systems, physiological stress, viral immunity, to determine the clinical risk related to immune dysregulation for exploration class spaceflight, and to determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

  14. Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients

    PubMed Central

    Cholongitas, Evangelos; Pipili, Chrysoula; Papatheodoridis, George

    2015-01-01

    The goal of therapy in chronic hepatitis C virus (HCV) infection is sustained virological response (SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of direct-acting antivirals (DAAs) including sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. Carefully selected combinations of these DAAs offer the potential for highly effective all-oral safe regimens even for patients with decompensated cirrhosis or liver transplant (LT) recipients. Like all current protease inhibitors, simeprevir and paritaprevir should not be used in patients with Child C cirrhosis, while sofosbuvir and ledipasvir/sofosbuvir should not be given in patients with severe renal impairment and glomerular filtration rate less than 30 mL/min. Drug-drug interactions may still occur with the current DAAs particularly in post-LT patients, in whom simeprevir should not be co-administered with cyclosporine and dose adjustments of calcineurin inhibitors are required in case of regimens including the ritonavir boosted paritaprevir. Phase II clinical trials and real life cohort studies have shown that sofosbuvir based combinations are safe and can achieve improvements of clinical status, high SVR rates and even prevention of post-LT HCV recurrence in patients with decompensated cirrhosis or LT-candidates. In the post-LT setting, sofosbuvir based regimens and the combination of paritaprevir/ombitasvir and dasabuvir have been reported to be safe and achieve high SVR rates, similar to those in non-transplant patients, being effective even in cases with cholestatic fibrosing hepatitis. Ongoing clinical trials and rapidly emerging real life data will further clarify the safety and efficacy of the new regimens in these settings. PMID:26327760

  15. Deletion of specific immune-modulatory genes from modified vaccinia virus Ankara-based HIV vaccines engenders improved immunogenicity in rhesus macaques.

    PubMed

    Garber, David A; O'Mara, Leigh A; Gangadhara, Sailaja; McQuoid, Monica; Zhang, Xiugen; Zheng, Rui; Gill, Kiran; Verma, Meena; Yu, Tianwei; Johnson, Brent; Li, Bing; Derdeyn, Cynthia A; Ibegbu, Chris; Altman, John D; Hunter, Eric; Feinberg, Mark B

    2012-12-01

    Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1β receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVAΔ4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVAΔ5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 × 10(8) PFU) or low-dose (1 × 10(7) PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates.

  16. CD8+-T-Cell-Dependent Control of Trypanosoma cruzi Infection in a Highly Susceptible Mouse Strain after Immunization with Recombinant Proteins Based on Amastigote Surface Protein 2

    PubMed Central

    Araújo, Adriano F. S.; de Alencar, Bruna C. G.; Vasconcelos, José Ronnie C.; Hiyane, Meire I.; Marinho, Cláudio R. F.; Penido, Marcus L. O.; Boscardin, Silvia B.; Hoft, Daniel F.; Gazzinelli, Ricardo T.; Rodrigues, Mauricio M.

    2005-01-01

    We previously described that DNA vaccination with the gene encoding amastigote surface protein 2 (ASP-2) protects approximately 65% of highly susceptible A/Sn mice against the lethal Trypanosoma cruzi infection. Here, we explored the possibility that bacterial recombinant proteins of ASP-2 could be used to improve the efficacy of vaccinations. Initially, we compared the protective efficacy of vaccination regimens using either a plasmid DNA, a recombinant protein, or both sequentially (DNA priming and protein boosting). Survival after the challenge was not statistically different among the three mouse groups and ranged from 53.5 to 75%. The fact that immunization with a recombinant protein alone induced protective immunity revealed the possibility that this strategy could be pursued for vaccination. We investigated this possibility by using six different recombinant proteins representing distinct portions of ASP-2. The vaccination of mice with glutathione S-transferase fusion proteins representing amino acids 261 to 500 or 261 to 380 of ASP-2 in the presence of the adjuvants alum and CpG oligodeoxynucleotide 1826 provided remarkable immunity, consistently protecting 100% of the A/Sn mice. Immunity was completely reversed by the in vivo depletion of CD8+ T cells, but not CD4+ T cells, and was associated with the presence of CD8+ T cells specific for an epitope located between amino acids 320 and 327 of ASP-2. We concluded that a relatively simple formulation consisting of a recombinant protein with a selected portion of ASP-2, alum, and CpG oligodeoxynucleotide 1826 might be used to cross-prime strong CD8+-T-cell-dependent protective immunity against T. cruzi infection. PMID:16113322

  17. Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

    PubMed Central

    Zarnitsyna, Veronika I.; Ellebedy, Ali H.; Davis, Carl; Jacob, Joshy; Ahmed, Rafi; Antia, Rustom

    2015-01-01

    The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza's main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stem of HA, which are attractive targets for a ‘universal vaccine’. We develop multi-epitope models to explore how pre-existing immunity modulates the immune response to new strains following immunization. Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics of OAS and limited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for how pre-existing antibodies to an epitope on HA decrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains. PMID:26194761

  18. Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients

    Cancer.gov

    A four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer.

  19. Gonzalez Regimen (PDQ®)—Health Professional Version

    Cancer.gov

    Expert-reviewed information summary about the Gonzalez regimen as a treatment for people with cancer. Note: The information in this summary is no longer being updated and is provided for reference purposes only.

  20. What to Start: Selecting a First HIV Regimen

    MedlinePlus

    ... medicines to treat HIV infection is called antiretroviral therapy (ART). People on ART take a combination of HIV ... treat HIV infection. HIV treatment (also called antiretroviral therapy or ART) begins with choosing an HIV regimen. People on ...

  1. Controlled-protein dietary regimens for Parkinson's disease.

    PubMed

    Cereda, Emanuele; Barichella, Michela; Pezzoli, Gianni

    2010-02-01

    Continuous levodopa replacement still is the most efficacious treatment for patients with Parkinson's disease. Unfortunately, the neutral aromatic amino acids contained in dietary proteins may compete with this drug for intestinal absorption and transport across the blood-brain barrier, thus limiting its efficacy and being responsible for the occurrence of motor fluctuations. Current guidelines recommend low-protein dietary regimens with protein redistribution, as shifting protein intake to the evening has proved to ameliorate the response to levodopa. However, adherence to this dietary regimen does not seem to be satisfactory and response is variable. Recent studies have shown that low-protein products designed for chronic renal failure patients are safe, tasty, well-tolerated and useful in improving both adherence to low-protein dietary regimens and levodopa-related motor fluctuations. However, there still is the need to define the selection criteria for the patients who may benefit the most from adherence to this regimen.

  2. Boost matrix converters in clean energy systems

    NASA Astrophysics Data System (ADS)

    Karaman, Ekrem

    This dissertation describes an investigation of novel power electronic converters, based on the ultra-sparse matrix topology and characterized by the minimum number of semiconductor switches. The Z-source, Quasi Z-source, Series Z-source and Switched-inductor Z-source networks were originally proposed for boosting the output voltage of power electronic inverters. These ideas were extended here on three-phase to three-phase and three-phase to single-phase indirect matrix converters. For the three-phase to three-phase matrix converters, the Z-source networks are placed between the three-switch input rectifier stage and the output six-switch inverter stage. A brief shoot-through state produces the voltage boost. An optimal pulse width modulation technique was developed to achieve high boosting capability and minimum switching losses in the converter. For the three-phase to single-phase matrix converters, those networks are placed similarly. For control purposes, a new modulation technique has been developed. As an example application, the proposed converters constitute a viable alternative to the existing solutions in residential wind-energy systems, where a low-voltage variable-speed generator feeds power to the higher-voltage fixed-frequency grid. Comprehensive analytical derivations and simulation results were carried out to investigate the operation of the proposed converters. Performance of the proposed converters was then compared between each other as well as with conventional converters. The operation of the converters was experimentally validated using a laboratory prototype.

  3. Immunization Coverage

    MedlinePlus

    ... and afford to pay for them. World Immunization Week The last week of April each year is marked by WHO and partners as World Immunization Week. It aims to accelerate action to increase awareness ...

  4. Moving East: the Euro-Lupus Nephritis regimen in Asia.

    PubMed

    Houssiau, Frédéric A

    2016-01-01

    Treatment of lupus nephritis is more evidenced-based than ever. Yet many areas of uncertainty persist. The article by Rathi et al. brings a piece to the puzzle by comparing, in a group of Indian patients, the Euro-Lupus low-dose i.v. cyclophosphamide regimen with mycophenolate mofetil. Although some caveats must be raised, the results suggest that, after crossing the Atlantic, the Euro-Lupus regimen may well be moving East.

  5. [Principles of organizing efficient work and rest regimens for crews on prolonged space flights].

    PubMed

    Litsov, A N; Bulyko, V I

    1983-01-01

    The work-rest cycles of Salyut-6 crews were investigated. Several modifications were detected: 24-hour static regimens (65-70%) and altered regimens (35-30%) with longer or shorter work-rest cycles. It is concluded that in prolonged space flights two regimens are allowed: principal regimens (normal static regimens of work and rest) used throughout the flight, and operational regimens (differing from 24-hour ones) used no more than once every 7-10 days.

  6. Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses

    PubMed Central

    Tomusange, Khamis; Wijesundara, Danushka; Gummow, Jason; Wesselingh, Steve; Suhrbier, Andreas; Gowans, Eric J.; Grubor-Bauk, Branka

    2016-01-01

    Mucosal immunity is deemed crucial to control sexual transmission of human immunodeficiency virus (HIV). Herein we report the efficacy of a mucosal HIV vaccine strategy comprising intranasal (IN) vaccination with a cocktail of live recombinant human rhinoviruses (HRVs) encoding overlapping fragments of HIV Gag and full length Tat (rHRV-Gag/Tat) followed by intradermal (ID) vaccination with DNA vaccines encoding HIV Gag and Tat (pVAX-Gag-Tat). This heterologous prime-boost strategy will be referred to hereafter as rHRV-DNA. As a control, IN vaccination with wild type (wt)-HRV-A1 followed by a single ID dose of pVAX (wt-HRV-A1/pVAX vaccination) was included. rHRV-DNA vaccination elicited superior multi-functional CD8+T cell responses in lymphocytes harvested from mesenteric lymph nodes and spleens, and higher titres of Tat-specific antibodies in blood and vaginal lavages, and reduced the viral load more effectively after challenge with EcoHIV, a murine HIV challenge model, in peritoneal macrophages, splenocytes and blood compared compared with wt-HRV-A1/pVAX vaccination or administration of 3 ID doses of pVAX-Gag-Tat (3X pVAX-Gag-Tat vaccination). These data provide the first evidence that a rHRV-DNA vaccination regimen can induce HIV-specific immune responses in the gut, vaginal mucosa and systemically, and supports further testing of this regimen in the development of an effective mucosally-targeted HIV-1 vaccine. PMID:27853256

  7. Precision Jet Substructure from Boosted Event Shapes

    NASA Astrophysics Data System (ADS)

    Feige, Ilya; Schwartz, Matthew D.; Stewart, Iain W.; Thaler, Jesse

    2012-08-01

    Jet substructure has emerged as a critical tool for LHC searches, but studies so far have relied heavily on shower Monte Carlo simulations, which formally approximate QCD at the leading-log level. We demonstrate that systematic higher-order QCD computations of jet substructure can be carried out by boosting global event shapes by a large momentum Q and accounting for effects due to finite jet size, initial-state radiation (ISR), and the underlying event (UE) as 1/Q corrections. In particular, we compute the 2-subjettiness substructure distribution for boosted Z→qq¯ events at the LHC at next-to-next-to-next-to-leading-log order. The calculation is greatly simplified by recycling known results for the thrust distribution in e+e- collisions. The 2-subjettiness distribution quickly saturates, becoming Q independent for Q≳400GeV. Crucially, the effects of jet contamination from ISR/UE can be subtracted out analytically at large Q without knowing their detailed form. Amusingly, the Q=∞ and Q=0 distributions are related by a scaling by e up to next-to-leading-log order.

  8. Domain adaptive boosting method and its applications

    NASA Astrophysics Data System (ADS)

    Geng, Jie; Miao, Zhenjiang

    2015-03-01

    Differences of data distributions widely exist among datasets, i.e., domains. For many pattern recognition, nature language processing, and content-based analysis systems, a decrease in performance caused by the domain differences between the training and testing datasets is still a notable problem. We propose a domain adaptation method called domain adaptive boosting (DAB). It is based on the AdaBoost approach with extensions to cover the domain differences between the source and target domains. Two main stages are contained in this approach: source-domain clustering and source-domain sample selection. By iteratively adding the selected training samples from the source domain, the discrimination model is able to achieve better domain adaptation performance based on a small validation set. The DAB algorithm is suitable for the domains with large scale samples and easy to extend for multisource adaptation. We implement this method on three computer vision systems: the skin detection model in single images, the video concept detection model, and the object classification model. In the experiments, we compare the performances of several commonly used methods and the proposed DAB. Under most situations, the DAB is superior.

  9. A multiview boosting approach to tissue segmentation

    NASA Astrophysics Data System (ADS)

    Kwak, Jin Tae; Xu, Sheng; Pinto, Peter A.; Turkbey, Baris; Bernardo, Marcelino; Choyke, Peter L.; Wood, Bradford J.

    2014-04-01

    Digitized histopathology images have a great potential for improving or facilitating current assessment tools in cancer pathology. In order to develop accurate and robust automated methods, the precise segmentation of histologic objects such epithelium, stroma, and nucleus is necessary, in the hopes of information extraction not otherwise obvious to the subjective eye. Here, we propose a multivew boosting approach to segment histology objects of prostate tissue. Tissue specimen images are first represented at different scales using a Gaussian kernel and converted into several forms such HSV and La*b*. Intensity- and texture-based features are extracted from the converted images. Adopting multiview boosting approach, we effectively learn a classifier to predict the histologic class of a pixel in a prostate tissue specimen. The method attempts to integrate the information from multiple scales (or views). 18 prostate tissue specimens from 4 patients were employed to evaluate the new method. The method was trained on 11 tissue specimens including 75,832 epithelial and 103,453 stroma pixels and tested on 55,319 epithelial and 74,945 stroma pixels from 7 tissue specimens. The technique showed 96.7% accuracy, and as summarized into a receiver operating characteristic (ROC) plot, the area under the ROC curve (AUC) of 0.983 (95% CI: 0.983-0.984) was achieved.

  10. Centaur boost pump turbine icing investigation

    NASA Technical Reports Server (NTRS)

    Rollbuhler, R. J.

    1976-01-01

    An investigation was conducted to determine if ice formation in the Centaur vehicle liquid oxygen boost pump turbine could prevent rotation of the pump and whether or not this phenomenon could have been the failure mechanism for the Titan/Centaur vehicle TC-1. The investigation consisted of a series of tests done in the LeRC Space Power Chamber Facility to evaluate evaporative cooling behavior patterns in a turbine as a function of the quantity of water trapped in the turbine and as a function of the vehicle ascent pressure profile. It was found that evaporative freezing of water in the turbine housing, due to rapid depressurization within the turbine during vehicle ascent, could result in the formation of ice that would block the turbine and prevent rotation of the boost pump. But for such icing conditions to exist it would be necessary to have significant quantities of water in the turbine and/or its components, and the turbine housing temperature would have to be colder than 40 F at vehicle liftoff.

  11. Non-boost-invariant dissipative hydrodynamics

    NASA Astrophysics Data System (ADS)

    Florkowski, Wojciech; Ryblewski, Radoslaw; Strickland, Michael; Tinti, Leonardo

    2016-12-01

    The one-dimensional non-boost-invariant evolution of the quark-gluon plasma, presumably produced during the early stages of heavy-ion collisions, is analyzed within the frameworks of viscous and anisotropic hydrodynamics. We neglect transverse dynamics and assume homogeneous conditions in the transverse plane but, differently from Bjorken expansion, we relax longitudinal boost invariance in order to study the rapidity dependence of various hydrodynamical observables. We compare the results obtained using several formulations of second-order viscous hydrodynamics with a recent approach to anisotropic hydrodynamics, which treats the large initial pressure anisotropy in a nonperturbative fashion. The results obtained with second-order viscous hydrodynamics depend on the particular choice of the second-order terms included, which suggests that the latter should be included in the most complete way. The results of anisotropic hydrodynamics and viscous hydrodynamics agree for the central hot part of the system, however, they differ at the edges where the approach of anisotropic hydrodynamics helps to control the undesirable growth of viscous corrections observed in standard frameworks.

  12. Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine

    PubMed Central

    2014-01-01

    The severity and longevity of the current Ebola outbreak highlight the need for a fast-acting yet long-lasting vaccine for at-risk populations (medical personnel and rural villagers) where repeated prime-boost regimens are not feasible. While recombinant adenovirus (rAd)-based vaccines have conferred full protection against multiple strains of Ebola after a single immunization, their efficacy is impaired by pre-existing immunity (PEI) to adenovirus. To address this important issue, a panel of formulations was evaluated by an in vitro assay for their ability to protect rAd from neutralization. An amphiphilic polymer (F16, FW ∼39,000) significantly improved transgene expression in the presence of anti-Ad neutralizing antibodies (NAB) at concentrations of 5 times the 50% neutralizing dose (ND50). In vivo performance of rAd in F16 was compared with unformulated virus, virus modified with poly(ethylene) glycol (PEG), and virus incorporated into poly(lactic-co-glycolic) acid (PLGA) polymeric beads. Histochemical analysis of lung tissue revealed that F16 promoted strong levels of transgene expression in naive mice and those that were exposed to adenovirus in the nasal cavity 28 days prior to immunization. Multiparameter flow cytometry revealed that F16 induced significantly more polyfunctional antigen-specific CD8+ T cells simultaneously producing IFN-γ, IL-2, and TNF-α than other test formulations. These effects were not compromised by PEI. Data from formulations that provided partial protection from challenge consistently identified specific immunological requirements necessary for protection. This approach may be useful for development of formulations for other vaccine platforms that also employ ubiquitous pathogens as carriers like the influenza virus. PMID:25549696

  13. Topical CpG Adjuvantation of a Protein-Based Vaccine Induces Protective Immunity to Listeria monocytogenes

    PubMed Central

    Cheng, Wing Ki; Wee, Kathleen; Kollmann, Tobias R.

    2014-01-01

    Robust CD8+ T cell responses are essential for immune protection against intracellular pathogens. Using parenteral administration of ovalbumin (OVA) protein as a model antigen, the effect of the Toll-like receptor 9 (TLR9) agonist, CpG oligodeoxynucleotide (ODN) 1826, as an adjuvant delivered either topically, subcutaneously, or intramuscularly on antigen-specific CD8+ T cell responses in a mouse model was evaluated. Topical CpG adjuvant increased the frequency of OVA-specific CD8+ T cells in the peripheral blood and in the spleen. The more effective strategy to administer topical CpG adjuvant to enhance CD8+ T cell responses was single-dose administration at the time of antigen injection with a prime-boost regimen. Topical CpG adjuvant conferred both rapid and long-lasting protection against systemic challenge with recombinant Listeria monocytogenes expressing the cytotoxic T lymphocyte (CTL) epitope of OVA257–264 (strain Lm-OVA) in a TLR9-dependent manner. Topical CpG adjuvant induced a higher proportion of CD8+ effector memory T cells than parenteral administration of the adjuvant. Although traditional vaccination strategies involve coformulation of antigen and adjuvant, split administration using topical adjuvant is effective and has advantages of safety and flexibility. Split administration of topical CpG ODN 1826 with parenteral protein antigen is superior to other administration strategies in enhancing both acute and memory protective CD8+ T cell immune responses to subcutaneous protein vaccines. This vaccination strategy induces rapid and persistent protective immune responses against the intracellular organism L. monocytogenes. PMID:24391136

  14. Novel calcium infusion regimen after parathyroidectomy for renal hyperparathyroidism

    PubMed Central

    Tan, Jih Huei; Tan, Henry Chor Lip; Arulanantham, Sarojah A/P

    2017-01-01

    Abstract Aim Calcium infusion is used after parathyroid surgery for renal hyperparathyroidism to treat postoperative hypocalcaemia. We compared a new infusion regimen to one commonly used in Malaysia based on 2003 K/DOQI guidelines. Methods Retrospective data on serum calcium and infusion rates was collected from 2011–2015. The relationship between peak calcium efflux (PER) and time was determined using a scatterplot and linear regression. A comparison between regimens was made based on treatment efficacy (hypocalcaemia duration, total infusion amount and time) and calcium excursions (outside target range, peak and trough calcium) using bar charts and an unpaired t‐test. Results Fifty‐one and 34 patients on the original and new regimens respectively were included. Mean PER was lower (2.16 vs 2.56 mmol/h; P = 0.03) and occurred earlier (17.6 vs 23.2 h; P = 0.13) for the new regimen. Both scatterplot and regression showed a large correlation between PER and time (R‐square 0.64, SE 1.53, P < 0.001). The new regimen had shorter period of hypocalcaemia (28.9 vs 66.4 h, P = 0.04), and required less calcium infusion (67.7 vs 127.2 mmol, P = 0.02) for a shorter duration (57.3 vs 102.9 h, P = 0.001). Calcium excursions, peak and trough calcium were not significantly different between regimens. Early postoperative high excursions occurred when the infusion was started in spite of elevated peri‐operative calcium levels. Conclusion The new infusion regimen was superior to the original in that it required a shorter treatment period and resulted in less hypocalcaemia. We found that early aggressive calcium replacement is unnecessary and raises the risk of rebound hypercalcemia. PMID:26952689

  15. Molecular view on PRR cross-talk in antifungal immunity.

    PubMed

    Hontelez, S; Sanecka, A; Netea, M G; van Spriel, A B; Adema, G J

    2012-04-01

    The identification of a major class of innate immune receptors, termed pattern recognition receptors (PRRs), has boosted research on innate pathogen recognition. The immune response to a specific pathogen is not restricted to the recognition by one type of PRR or activation of a single cell type, but instead comprises complex collaborations between different receptors, cells and signal mediators. Here we will discuss the cross-talk between PRRs involved in fungal recognition, focusing on the molecular interactions occurring at the plasma membrane.

  16. Exercise, Immunity, and Susceptibility to Infection: A J-Shaped Relationship?

    ERIC Educational Resources Information Center

    Shephard, Roy J.; Shek, Pang N.

    1999-01-01

    Epidemiologic data suggest that regular moderate exercise boosts immunity, but intense training may reduce it. Objective data do not clearly show a J-shaped relationship between exercise and immune function. Nutritional, hygienic, exercise, environmental, and pharmacologic strategies can minimize risks of infection. Practical measures to reduce…

  17. Enhancing the Immune Response to Recombinant Plague Antigens

    DTIC Science & Technology

    2006-05-01

    parvovirus (CPMV). In those studies, animals primed IN and boosted SC developed significantly higher serum anti-CPMV IgG2a responses than did animals...Wakelin. 2003. Effect of priming/booster immunisation protocols on immune response to canine parvovirus peptide induced by vaccination with a chimaeric

  18. Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

    PubMed Central

    Patterson, L. Jean; Robert-Guroff, Marjorie

    2008-01-01

    Background In the last few years the HIV vaccine field has moved forward a number of promising vaccine candidates into human clinical trials. Objective In this review we briefly discuss the advances made in vaccine development and HIV pathogenesis and give an overview of the body of work our lab has generated in multiple animal models on replication-competent Ad recombinant vaccines. Methods Emphasis is placed on comparative examination of vaccine components, routes of immunization and challenge models using replicating Ad vectors. Results/conclusion The overall findings make the case that replicating Ad vectors are superior in priming multiple arms of the immune system, and in conjunction with protein boosting, have resulted in dramatic protective efficacy leading to their advancement to phase 1 trials. Implications of the recent halting of the Merck Ad5-HIV phase 2b clinical trial for our vaccine approach and other vectored vaccines are discussed. PMID:18694354

  19. Behavior Analysis in Distance Education by Boosting Algorithms

    ERIC Educational Resources Information Center

    Zang, Wei; Lin, Fuzong

    2006-01-01

    Student behavior analysis is an active research topic in distance education in recent years. In this article, we propose a new method called Boosting to investigate students' behaviors. The Boosting Algorithm can be treated as a data mining method, trying to infer from a large amount of training data the essential factors and their relations that…

  20. Development of antibiotic regimens using graph based evolutionary algorithms.

    PubMed

    Corns, Steven M; Ashlock, Daniel A; Bryden, Kenneth M

    2013-12-01

    This paper examines the use of evolutionary algorithms in the development of antibiotic regimens given to production animals. A model is constructed that combines the lifespan of the animal and the bacteria living in the animal's gastro-intestinal tract from the early finishing stage until the animal reaches market weight. This model is used as the fitness evaluation for a set of graph based evolutionary algorithms to assess the impact of diversity control on the evolving antibiotic regimens. The graph based evolutionary algorithms have two objectives: to find an antibiotic treatment regimen that maintains the weight gain and health benefits of antibiotic use and to reduce the risk of spreading antibiotic resistant bacteria. This study examines different regimens of tylosin phosphate use on bacteria populations divided into Gram positive and Gram negative types, with a focus on Campylobacter spp. Treatment regimens were found that provided decreased antibiotic resistance relative to conventional methods while providing nearly the same benefits as conventional antibiotic regimes. By using a graph to control the information flow in the evolutionary algorithm, a variety of solutions along the Pareto front can be found automatically for this and other multi-objective problems.

  1. Targeting immune checkpoints in malignant glioma

    PubMed Central

    Li, Tete; Liu, Yong-Jun; Chen, Wei; Chen, Jingtao

    2017-01-01

    Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the bodys anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered immune privileged and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma. PMID:27756892

  2. Immunological function restoration with lopinavir/ritonavir versus efavirenz containing regimens in HIV-infected patients: a randomized clinical trial.

    PubMed

    Torres, Berta; Rallón, Norma I; Loncá, Montserrat; Díaz, Alba; Alós, Llucia; Martínez, Esteban; Cruceta, Anna; Arnaiz, Joan Albert; Leal, Lorna; Lucero, Constanza; León, Agathe; Sánchez, Marcelo; Negredo, Eugenia; Clotet, Bonaventura; Gatell, José M; Benito, José M; Garcia, Felipe

    2014-05-01

    CD4(+) count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4(+) count have not been assessed in a randomized clinical trial. Fifty antiretroviral treatment (cART) naïve HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine for 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, interleukin (IL)-7-receptor/IL-7 system, thymic volume, and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Both groups experienced a CD4(+) count increase that was higher in the EFV group (ΔCD4(+) 88 vs. 315 cells/μl LPV/r vs. EFV, respectively, p<0.001). Despite this difference in CD4(+) gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion, and apoptosis on CD4(+) and CD8(+) T cells (p<0.001 for all) and a significant increase in markers of thymic function, IL-7 receptor, and in the levels of central memory CD4(+) T cells and naive subsets of CD8(+) T cells (p<0.001 for all) with respect to baseline values were observed without any difference between groups. These data indicate that the differences in CD4(+) gain with different cART regimens are not immunologically meaningful and might explain the similar clinical efficacy of these regimens.

  3. Immunological Function Restoration with Lopinavir/Ritonavir Versus Efavirenz Containing Regimens in HIV-Infected Patients: A Randomized Clinical Trial

    PubMed Central

    Rallón, Norma I.; Loncá, Montserrat; Díaz, Alba; Alós, Llucia; Martínez, Esteban; Cruceta, Anna; Arnaiz, Joan Albert; Leal, Lorna; Lucero, Constanza; León, Agathe; Sánchez, Marcelo; Negredo, Eugenia; Clotet, Bonaventura; Gatell, José M.; Benito, José M.; Garcia, Felipe

    2014-01-01

    Abstract CD4+ count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4+ count have not been assessed in a randomized clinical trial. Fifty antiretroviral treatment (cART) naïve HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine for 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, interleukin (IL)-7-receptor/IL-7 system, thymic volume, and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Both groups experienced a CD4+ count increase that was higher in the EFV group (ΔCD4+ 88 vs. 315 cells/μl LPV/r vs. EFV, respectively, p<0.001). Despite this difference in CD4+ gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion, and apoptosis on CD4+ and CD8+ T cells (p<0.001 for all) and a significant increase in markers of thymic function, IL-7 receptor, and in the levels of central memory CD4+ T cells and naive subsets of CD8+ T cells (p<0.001 for all) with respect to baseline values were observed without any difference between groups. These data indicate that the differences in CD4+ gain with different cART regimens are not immunologically meaningful and might explain the similar clinical efficacy of these regimens. PMID:24380397

  4. Boosting jet power in black hole spacetimes.

    PubMed

    Neilsen, David; Lehner, Luis; Palenzuela, Carlos; Hirschmann, Eric W; Liebling, Steven L; Motl, Patrick M; Garrett, Travis

    2011-08-02

    The extraction of rotational energy from a spinning black hole via the Blandford-Znajek mechanism has long been understood as an important component in models to explain energetic jets from compact astrophysical sources. Here we show more generally that the kinetic energy of the black hole, both rotational and translational, can be tapped, thereby producing even more luminous jets powered by the interaction of the black hole with its surrounding plasma. We study the resulting Poynting jet that arises from single boosted black holes and binary black hole systems. In the latter case, we find that increasing the orbital angular momenta of the system and/or the spins of the individual black holes results in an enhanced Poynting flux.

  5. Inflammation boosts bacteriophage transfer between Salmonella spp.

    PubMed

    Diard, Médéric; Bakkeren, Erik; Cornuault, Jeffrey K; Moor, Kathrin; Hausmann, Annika; Sellin, Mikael E; Loverdo, Claude; Aertsen, Abram; Ackermann, Martin; De Paepe, Marianne; Slack, Emma; Hardt, Wolf-Dietrich

    2017-03-17

    Bacteriophage transfer (lysogenic conversion) promotes bacterial virulence evolution. There is limited understanding of the factors that determine lysogenic conversion dynamics within infected hosts. A murine Salmonella Typhimurium (STm) diarrhea model was used to study the transfer of SopEΦ, a prophage from STm SL1344, to STm ATCC14028S. Gut inflammation and enteric disease triggered >55% lysogenic conversion of ATCC14028S within 3 days. Without inflammation, SopEΦ transfer was reduced by up to 10(5)-fold. This was because inflammation (e.g., reactive oxygen species, reactive nitrogen species, hypochlorite) triggers the bacterial SOS response, boosts expression of the phage antirepressor Tum, and thereby promotes free phage production and subsequent transfer. Mucosal vaccination prevented a dense intestinal STm population from inducing inflammation and consequently abolished SopEΦ transfer. Vaccination may be a general strategy for blocking pathogen evolution that requires disease-driven transfer of temperate bacteriophages.

  6. Boosting jet power in black hole spacetimes

    PubMed Central

    Neilsen, David; Lehner, Luis; Palenzuela, Carlos; Hirschmann, Eric W.; Liebling, Steven L.; Motl, Patrick M.; Garrett, Travis

    2011-01-01

    The extraction of rotational energy from a spinning black hole via the Blandford–Znajek mechanism has long been understood as an important component in models to explain energetic jets from compact astrophysical sources. Here we show more generally that the kinetic energy of the black hole, both rotational and translational, can be tapped, thereby producing even more luminous jets powered by the interaction of the black hole with its surrounding plasma. We study the resulting Poynting jet that arises from single boosted black holes and binary black hole systems. In the latter case, we find that increasing the orbital angular momenta of the system and/or the spins of the individual black holes results in an enhanced Poynting flux. PMID:21768341

  7. Boost type PWM HVDC transmission system

    SciTech Connect

    Ooi, B.T.; Wang, X. . Dept. of Electrical Engineering)

    1991-10-01

    This paper reports that conventional HVdc is built around the mercury arc rectifier or the thyristor which requires line commutation. The advances of fast, high power GTO's and future devices such as MCT's with turn off capabilities, are bringing PWM techniques within the range of HVdc applications. By combining PWM techniques to the boost type bridge topology, one has an alternate system of HVdc Transmission. On the ac side, the converter station has active controls over: the voltage amplitude, the voltage angle and the frequency. On the dc side, parallel connections facilitate multi-terminal load sharing by simple local controls so that redundant communication channels are not required. Bidirectional power through each station is accomplished by the reversal of the direction of dc current flow. These claims have been substantiated by experimental results from laboratory size multi-terminal models.

  8. Giving top quark effective operators a boost

    NASA Astrophysics Data System (ADS)

    Englert, Christoph; Moore, Liam; Nordström, Karl; Russell, Michael

    2016-12-01

    We investigate the prospects to systematically improve generic effective field theory-based searches for new physics in the top sector during LHC run 2 as well as the high luminosity phase. In particular, we assess the benefits of high momentum transfer final states on top EFT-fit as a function of systematic uncertainties in comparison with sensitivity expected from fully-resolved analyses focusing on t t bar production. We find that constraints are typically driven by fully-resolved selections, while boosted top quarks can serve to break degeneracies in the global fit. This demystifies and clarifies the importance of high momentum transfer final states for global fits to new interactions in the top sector from direct measurements.

  9. The Chimeric Protein Domain III-Capsid of Dengue Virus Serotype 2 (DEN-2) Successfully Boosts Neutralizing Antibodies Generated in Monkeys upon Infection with DEN-2▿

    PubMed Central

    Valdés, Iris; Gil, Lázaro; Romero, Yaremis; Castro, Jorge; Puente, Pedro; Lazo, Laura; Marcos, Ernesto; Guzmán, María G.; Guillén, Gerardo; Hermida, Lisset

    2011-01-01

    Use of a heterologous prime-boost strategy based on a combination of nonreplicative immunogens and candidate attenuated virus vaccines against dengue virus in the same schedule is an attractive approach. These combinations may result in a condensed immunization regime for humans, thus reducing the number of doses with attenuated virus and the time spacing. The present work deals with the evaluation of the heterologous prime-boost strategy combining a novel chimeric protein (domain III-capsid) of dengue virus serotype 2 (DEN-2) and the infective homologous virus in the same immunization schedule in monkeys. Primed monkeys received one dose of infective DEN-2 and were then vaccinated with the recombinant protein. We found that animals developed a neutralizing antibody response after the infective dose and were notably boosted with a second dose of the chimeric protein 3 months later. The neutralizing antibodies induced were long lasting, and animals also showed the ability to induce a specific cellular response 6 months after the booster dose. As a conclusion, we can state that the domain III region, when it is properly presented as a fusion protein to the immune system, is able to recall the neutralizing antibody response elicited following homologous virus infection in monkeys. Further prime-boost approaches can be performed in a condensed regime combining the chimeric domain III-capsid protein and candidate live attenuated vaccines against DEN-2. PMID:21209159

  10. Boosting for multi-graph classification.

    PubMed

    Wu, Jia; Pan, Shirui; Zhu, Xingquan; Cai, Zhihua

    2015-03-01

    In this paper, we formulate a novel graph-based learning problem, multi-graph classification (MGC), which aims to learn a classifier from a set of labeled bags each containing a number of graphs inside the bag. A bag is labeled positive, if at least one graph in the bag is positive, and negative otherwise. Such a multi-graph representation can be used for many real-world applications, such as webpage classification, where a webpage can be regarded as a bag with texts and images inside the webpage being represented as graphs. This problem is a generalization of multi-instance learning (MIL) but with vital differences, mainly because instances in MIL share a common feature space whereas no feature is available to represent graphs in a multi-graph bag. To solve the problem, we propose a boosting based multi-graph classification framework (bMGC). Given a set of labeled multi-graph bags, bMGC employs dynamic weight adjustment at both bag- and graph-levels to select one subgraph in each iteration as a weak classifier. In each iteration, bag and graph weights are adjusted such that an incorrectly classified bag will receive a higher weight because its predicted bag label conflicts to the genuine label, whereas an incorrectly classified graph will receive a lower weight value if the graph is in a positive bag (or a higher weight if the graph is in a negative bag). Accordingly, bMGC is able to differentiate graphs in positive and negative bags to derive effective classifiers to form a boosting model for MGC. Experiments and comparisons on real-world multi-graph learning tasks demonstrate the algorithm performance.

  11. Ventriculogram segmentation using boosted decision trees

    NASA Astrophysics Data System (ADS)

    McDonald, John A.; Sheehan, Florence H.

    2004-05-01

    Left ventricular status, reflected in ejection fraction or end systolic volume, is a powerful prognostic indicator in heart disease. Quantitative analysis of these and other parameters from ventriculograms (cine xrays of the left ventricle) is infrequently performed due to the labor required for manual segmentation. None of the many methods developed for automated segmentation has achieved clinical acceptance. We present a method for semi-automatic segmentation of ventriculograms based on a very accurate two-stage boosted decision-tree pixel classifier. The classifier determines which pixels are inside the ventricle at key ED (end-diastole) and ES (end-systole) frames. The test misclassification rate is about 1%. The classifier is semi-automatic, requiring a user to select 3 points in each frame: the endpoints of the aortic valve and the apex. The first classifier stage is 2 boosted decision-trees, trained using features such as gray-level statistics (e.g. median brightness) and image geometry (e.g. coordinates relative to user supplied 3 points). Second stage classifiers are trained using the same features as the first, plus the output of the first stage. Border pixels are determined from the segmented images using dilation and erosion. A curve is then fit to the border pixels, minimizing a penalty function that trades off fidelity to the border pixels with smoothness. ED and ES volumes, and ejection fraction are estimated from border curves using standard area-length formulas. On independent test data, the differences between automatic and manual volumes (and ejection fractions) are similar in size to the differences between two human observers.

  12. DNA Immunization

    PubMed Central

    Wang, Shixia; Lu, Shan

    2013-01-01

    DNA immunization was discovered in early 1990s and its use has been expanded from vaccine studies to a broader range of biomedical research, such as the generation of high quality polyclonal and monoclonal antibodies as research reagents. In this unit, three common DNA immunization methods are described: needle injection, electroporation and gene gun. In addition, several common considerations related to DNA immunization are discussed. PMID:24510291

  13. Design of initial dosage regimen using a programmable calculator.

    PubMed

    Ritschel, W A; Eldon, M A

    1985-07-01

    A programmable calculator procedure for the determination of dosage regimens to achieve desired steady state concentrations is described. The dosage regimen prediction is based on data from the literature on pharmacokinetic parameters of drugs and correction factors specific for the patient's condition, such as renal failure, geriatric patient and congestive heart failure. The program is designed to generate dosage regimens based on desired steady state trough level, desired steady state peak level, desired mean steady state level, or to fluctuate between desired steady state peak and trough levels. The program can be used for I.V. and extravascular route of administration. A detailed program description and user instructions are presented and illustrated by three examples.

  14. The reach for charged Higgs bosons with boosted bottom and boosted top jets

    NASA Astrophysics Data System (ADS)

    Sullivan, Zack; Pedersen, Keith

    2017-01-01

    At moderate values of tan(β) , a supersymmetric charged Higgs boson H+/- is expected to be difficult to find due its small cross section and large backgrounds. Using the new μx boosted bottom jet tag, and measured boosted top tagging rates from the CERN LHC, we examine the reach for TeV-scale charged Higgs bosons at 14 TeV and 100 TeV colliders in top-Higgs associated production, where the charged Higgs decays to a boosted top and bottom quark pair. We conclude that the cross section for charged Higgs bosons is indeed too small to observe at the LHC in the moderate tan(β) ``wedge region,'' but it will be possible to probe charged Higgs bosons at nearly all tan(β) up to 6 TeV at a 100 TeV collider. This work was supported by the U.S. Department of Energy under award No. DE-SC0008347.

  15. Principles for designing future regimens for multidrug-resistant tuberculosis.

    PubMed

    Brigden, Grania; Nyang'wa, Bern-Thomas; du Cros, Philipp; Varaine, Francis; Hughes, Jennifer; Rich, Michael; Horsburgh, C Robert; Mitnick, Carole D; Nuermberger, Eric; McIlleron, Helen; Phillips, Patrick P J; Balasegaram, Manica

    2014-01-01

    Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.

  16. Nonmyeloablative Conditioning Regimen to Increase Engraftment of Gene-modified Hematopoietic Stem Cells in Young Rhesus Monkeys

    PubMed Central

    Tarantal, Alice F; Giannoni, Francesca; I Lee, C Chang; Wherley, Jennifer; Sumiyoshi, Teiko; Martinez, Michele; Kahl, Christoph A; Elashoff, David; Louie, Stan G; Kohn, Donald B

    2012-01-01

    Immune responses to transgene products may lead to rejection of transduced cells, limiting successful gene therapy for genetic diseases. While moderate dosages of chemotherapeutic agents such as busulfan may increase hematopoietic stem cells (HSC) engraftment, they are not immune suppressive and do not abrogate immune responses to transgene products. Studies focused on nonmyeloablative conditioning with busulfan ± fludarabine in a clinically relevant monkey model to induce immune suppression to allow cells expressing a foreign transgene product to persist. Bone marrow CD34+ HSC were transduced in two equal fractions using simian immunodeficiency virus (SIV)-based lentiviral vectors carrying a nonexpressed DNA sequence tag (NoN) and the green fluorescent protein (GFP) reporter gene. Post-transplant there was no evidence of elimination of cells containing the potentially immunogenic GFP gene; several recipients had stable persistence of cells, and no differences were detected with fludarabine, which was rapidly cleared. Antibodies and cellular immune responses to GFP developed in recipients with the highest levels of GFP-marked cells, although these cells were not eliminated. These studies establish a clinically relevant pediatric primate model to assess the effects of conditioning regimens on the engraftment of transduced HSC and the immune responses to cells expressing a foreign gene product. PMID:22294147

  17. Adjuvant, neoadjuvant, and experimental regimens in overcoming pancreatic ductal adenocarcinoma

    PubMed Central

    Wysocka, Olga; Kulbacka, Julita; Saczko, Jolanta

    2016-01-01

    Pancreatic cancer is one of the most aggressive and deadly malignancies. Despite better understanding of its biology and pathogenesis, contemporary treatment regimens are still insufficient. Along with the introduction of new treatment agents and combination therapy, the response rates are increasing, but these scores do not go with overall survival, and results are frequently conflicting. Therefore, contemporary medicine faces the challenge of expanding the knowledge base and practice on all grounds – pathology, factor risk, diagnosis, and finally surgical and palliative treatment of this disease. This paper provides a review of current adjuvant and neoadjuvant regimens and the role of experimental therapies in pancreatic ductal adenocarcinoma. PMID:27713776

  18. Hepatitis C Virus Infection: Looking for Interferon Free Regimens

    PubMed Central

    González-Moreno, J.; Payeras-Cifre, A.

    2013-01-01

    Recent developments of new drugs' combinations are changing the treatment paradigm in hepatitis C virus infection. Due to the side effect profile of pegylated interferons, interferon-sparing regimens have become the main target in chronic hepatitis C treatment research. Recent proofs of concept studies have suggested that cure of chronic hepatitis C can be achieved without interferon. The purpose of this paper is to provide an overview of the clinical results recently reported for the treatment of hepatitis C virus infection with interferon-free regimens, focusing on the most promising new compounds and combinations. PMID:23710151

  19. Zagreb Regimen, an Abbreviated Intramuscular Schedule for Rabies Vaccination

    PubMed Central

    Ren, Jiangping; Yao, Linong; Sun, Jimin

    2014-01-01

    The Zagreb regimen, an abbreviated intramuscular schedule for rabies vaccination, was developed by I. Vodopija and colleagues of the Zagreb Institute of Public Health in Croatia in the 1980s. It was recommended by WHO as one of the intramuscular (IM) schedules for rabies vaccination in 2010. We reviewed the literature on the immunogenicity, safety, economic burden, and compliance of the Zagreb 2-1-1 regimen. Compared to Essen, another IM schedule recommended by WHO, Zagreb has higher compliance, lower medical cost, and better immunogenicity at an early stage. PMID:25392012

  20. Enhancement of antimycobacterial Th1-cell responses by a Mycobacterium bovis BCG prime-protein boost vaccination strategy.

    PubMed

    Lu, Miao; Xia, Zhi Yang; Bao, Lang

    2013-01-01

    Tuberculosis is a major global health problem, and the only available vaccine Bacille Calmette-Guérin (BCG) is not sufficiently effective against the disease. It is extremely urgent to develop novel vaccine approaches. Previous research demonstrated that there were several Regions of Difference (RD1-16) between the substrains of BCG and Mycobacterium tuberculosis or Mycobacterium bovis. The ORFs Rv1769 and Rv1772 are located in the RD14 deletions and have not been major targets of study. However, some studies have demonstrated that the two genes (Rv1769 and Rv1772) are excellent T cell antigens, which might induce an immune response. What kind of role these ORFs might play in anti-mycobacterial immunity, however, is still unknown. In our research we used the BCG prime-protein boost strategy to immunize BALB/c mice and evaluated its immunogenicity. Our data suggest that our novel BCG-P+PRO69 vaccine could elicit the most long-lasting and strongest Th1 type cellular immune responses. This response is characterized by a strong antibody response, the proliferation rate of splenocytes, a high percentage of CD4+ and CD8+ T cells and high levels of IFN-γ in antigen-stimulated splenocyte cultures. These results indicate that prime-boost is a potent strategy and the protein of gene Rv1769 is a potential antigen or subunit vaccine to TB for further study.

  1. Immune System

    EPA Science Inventory

    A properly functioning immune system is essential to good health. It defends the body against infectious agents and in some cases tumor cells. Individuals with immune deficiencies resulting from genetic defects, diseases (e.g., AIDS, leukemia), or drug therapies are more suscepti...

  2. Influence of Route of Administration on Immediate and Extended Protection in Rats Immunized with Escherichia coli Heat-Labile Enterotoxin

    PubMed Central

    Klipstein, Frederick A.; Engert, Richard F.

    1980-01-01

    The effect of route of administration, dosage, and number of boosts employed during immunization with the polymyxin-release form of Escherichia coli heat-labile (LT) enterotoxin on the degree and duration of protection afforded was evaluated in rats which were challenged by the ligated loop technique. Increasing the boosting dosage by fivefold from 50 to 250 μg resulted in a marked increase in protection against challenge with toxin in rats immunized either just by the parenteral route (i.p./i.p.) or by a parenteral prime, followed by peroral boosts (i.p./p.o.) in rats pretreated with cimetidine to ablate gastric secretions; such was not the case, however, even with a 50-fold increase in dosage in rats immunized just by the peroral route (p.o./p.o.). Four weekly peroral boosts were required to achieve the strongest degree of protection. Increasing the boosting dosage also increased the degree of protection against challenge with viable LT+/ST− and LT+/ST+ strains (ST indicates heat-stable enterotoxin) in rats immunized by the i.p./p.o., but not by the i.p./i.p., route; no protection was evident against an LT−/ST+ strain. Protection was lost within 3 weeks after immunization in rats immunized by the i.p./i.p. route. In contrast, protection was extended over the 3-month observation period in those immunized by the i.p./p.o. route; the degree of protection was enhanced in rats which received an additional boost at 2 months. These observations establish the fact that immunization with LT is similar to that with cholera toxin in that arousal of the local immune intestinal response by means of peroral immunization provides maximal extended protection. PMID:6987180

  3. Series-Connected Buck Boost Regulators

    NASA Technical Reports Server (NTRS)

    Birchenough, Arthur G.

    2005-01-01

    A series-connected buck boost regulator (SCBBR) is an electronic circuit that bucks a power-supply voltage to a lower regulated value or boosts it to a higher regulated value. The concept of the SCBBR is a generalization of the concept of the SCBR, which was reported in "Series-Connected Boost Regulators" (LEW-15918), NASA Tech Briefs, Vol. 23, No. 7 (July 1997), page 42. Relative to prior DC-voltage-regulator concepts, the SCBBR concept can yield significant reductions in weight and increases in power-conversion efficiency in many applications in which input/output voltage ratios are relatively small and isolation is not required, as solar-array regulation or battery charging with DC-bus regulation. Usually, a DC voltage regulator is designed to include a DC-to-DC converter to reduce its power loss, size, and weight. Advances in components, increases in operating frequencies, and improved circuit topologies have led to continual increases in efficiency and/or decreases in the sizes and weights of DC voltage regulators. The primary source of inefficiency in the DC-to-DC converter portion of a voltage regulator is the conduction loss and, especially at high frequencies, the switching loss. Although improved components and topology can reduce the switching loss, the reduction is limited by the fact that the converter generally switches all the power being regulated. Like the SCBR concept, the SCBBR concept involves a circuit configuration in which only a fraction of the power is switched, so that the switching loss is reduced by an amount that is largely independent of the specific components and circuit topology used. In an SCBBR, the amount of power switched by the DC-to-DC converter is only the amount needed to make up the difference between the input and output bus voltage. The remaining majority of the power passes through the converter without being switched. The weight and power loss of a DC-to-DC converter are determined primarily by the amount of power

  4. Polio inactivated vaccine costs into routine childhood immunization in Brazil

    PubMed Central

    Sartori, Ana Marli Christovam; Vicentine, Margarete Paganotti; Gryninger, Lígia Castelloni Figueiredo; de Soárez, Patricia Coelho; Novaes, Hillegonda Maria Dutilh

    2015-01-01

    OBJECTIVE To analyze the costs of vaccination regimens for introducing inactivated polio vaccine in routine immunization in Brazil. METHODS A cost analysis was conducted for vaccines in five vaccination regimens, including inactivated polio vaccine, compared with the oral polio vaccine-only regimen. The costs of the vaccines were estimated for routine use and for the “National Immunization Days”, during when the oral polio vaccine is administered to children aged less than five years, independent of their vaccine status, and the strategic stock of inactivated polio vaccine. The presented estimated costs are of 2011. RESULTS The annual costs of the oral vaccine-only program (routine and two National Immunization Days) were estimated at US$19,873,170. The incremental costs of inclusion of the inactivated vaccine depended on the number of vaccine doses, presentation of the vaccine (bottles with single dose or ten doses), and number of “National Immunization Days” carried out. The cost of the regimen adopted with two doses of inactivated vaccine followed by three doses of oral vaccine and one “National Immunization Day” was estimated at US$29,653,539. The concomitant replacement of the DTPw/Hib and HepB vaccines with the pentavalent vaccine enabled the introduction of the inactivated polio without increasing the number of injections or number of visits needed to complete the vaccination. CONCLUSIONS The introduction of the inactivated vaccine increased the annual costs of the polio vaccines by 49.2% compared with the oral vaccine-only regimen. This increase represented 1.13% of the expenditure of the National Immunization Program on the purchase of vaccines in 2011. PMID:25741645

  5. Recombinant Poxvirus and the Tumor Microenvironment: Oncolysis, Immune Regulation and Immunization

    PubMed Central

    Sharp, Daniel W.; Lattime, Edmund C.

    2016-01-01

    Oncolytic viruses (OVs) are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by encoding and delivering immunostimulatory molecules. This combination makes them an effective platform for the development of immunotherapeutic strategies beyond their primary lytic function. Engineering the viruses to also express tumor-associated antigens (TAAs) allows them to simultaneously serve as therapeutic vaccines, targeting and amplifying an immune response to TAAs. Our group and others have shown that vaccinating intratumorally with a poxvirus that encodes TAAs, in addition to immune stimulatory molecules, can modulate the tumor microenvironment, overcome immune inhibitory pathways, and drive both local and systemic tumor specific immune responses. PMID:28191451

  6. Sleep after vaccination boosts immunological memory.

    PubMed

    Lange, Tanja; Dimitrov, Stoyan; Bollinger, Thomas; Diekelmann, Susanne; Born, Jan

    2011-07-01

    Sleep regulates immune functions. We asked whether sleep can influence immunological memory formation. Twenty-seven healthy men were vaccinated against hepatitis A three times, at weeks 0, 8, and 16 with conditions of sleep versus wakefulness in the following night. Sleep was recorded polysomnographically, and hormone levels were assessed throughout the night. Vaccination-induced Th cell and Ab responses were repeatedly monitored for 1 y. Compared with the wake condition, sleep after vaccination doubled the frequency of Ag-specific Th cells and increased the fraction of Th1 cytokine-producing cells in this population. Moreover, sleep markedly increased Ag-specific IgG1. The effects were followed up for 1 y and were associated with high sleep slow-wave activity during the postvaccination night as well as with accompanying levels of immunoregulatory hormones (i.e., increased growth hormone and prolactin but decreased cortisol release). Our findings provide novel evidence that sleep promotes human Th1 immune responses, implicating a critical role for slow-wave sleep in this process. The proinflammatory milieu induced during this sleep stage apparently acts as adjuvant that facilitates the transfer of antigenic information from APCs to Ag-specific Th cells. Like the nervous system, the immune system takes advantage of the offline conditions during sleep to foster adaptive immune responses resulting in improved immunological memory.

  7. Successful Treatment of Mixed Hepatitis C Genotypes in a Cirrhotic Patient With an All-Oral, Interferon-Free Regimen

    PubMed Central

    Ahmed Sakr, Ayman; Hanifi, Jasmine M.

    2017-01-01

    Mixed hepatitis C virus (HCV) genotype infection is emerging with improved methods of detection. It is commonly seen in hemodialysis patients and intravenous drug users due to repeated HCV exposure and absence of protective immunity, and can contribute to treatment failure. Direct-acting antiviral regimens have been extensively studied in patients with different individual HCV genotypes; however, there are no reported data on their use in patients with mixed HCV genotype. We present a case of mixed HCV genotype 1a and 2 infection in a decompensated cirrhotic patient treated successfully with sofosbuvir, ledipasvir, and ribavirin. PMID:28184373

  8. Are calcineurin inhibitors-free regimens ready for prime time?

    PubMed

    Vincenti, Flavio

    2012-11-01

    The goal of research in transplant therapeutics is to achieve safe and effective immunosuppression strategies that allow durable engraftment free of toxicities. The calcineurin inhibitors (CNIs) regimens, because of their inherent toxicities (including nephrotoxicity), have been unable to meet these promises. Over the past decade acute cellular rejection decreased dramatically with a concomitant robust increase in 1-year graft survival; however, long-term graft outcome showed only modest improvement. This is due in part to the toxicities of the immunosuppressive drugs. The quest for a toxicity-free-CNI-free regimen has been both intense and frustrating. A turning point in CNIs-free therapy may have occurred with the recent approval of belatacept, which represents a new paradigm in immunosuppression: biological therapy for chronic immunosuppression devoid of the usual toxicities associated with the CNIs. Belatacept, a fusion receptor protein, blocks costimulation signals necessary for the activation of T cells. Although costimulation blockade has not been shown to induce tolerance, it can provide safe and effective immunosuppression without renal or cardiovascular toxicities. The approval of belatacept in both the United States and Europe for use in renal transplantation will finally push CNI-free regimens into prime time. Novel biologics such as ASKP1240 (a human anti-CD40 monoclonal antibody) and one small molecule, tofacitinib, may advance further the use of CNI-free regimens in organ transplantation.

  9. Tuberculosis 2: exploring methods of diagnosis, treatment regimens and concordance.

    PubMed

    Jarvis, Miles

    The second in this two part unit on tuberculosis examines diagnosis and treatment options. Part I outlined background on epidemiology and control of this disease. This part draws on the guidance set out by the National Institute for Health and Clinical Excellence. Diagnostic methods are discussed and the standard treatment regimen is outlined.

  10. Roughage level and limited maximum intake regimens for feedlot steers.

    PubMed

    Bartle, S J; Preston, R L

    1992-11-01

    Hereford steers (n = 280, BW = 371 +/- 29 kg; 40 pens) were used to evaluate two alternatives to ad libitum access to feed and constant roughage levels in finishing diets. The eight treatments were as follows: two treatments in which intake was limited to a multiple of the maintenance (MM) energy requirement (2.1, 2.3, 2.5, and 2.7, [2.7MM] and 2.3, 2.5, 2.7, and 2.9 [2.9MM] times maintenance for wk 1, 2, 3, and 4 and thereafter, respectively) and six roughage regimen and grain source treatments (10% roughage equivalent [RE] fed during the mid- and late-finishing periods [10/10], respectively, 2% RE followed by 10% RE [2/10], and 10% RE followed by 2% RE [10/2] fed with steam-flaked sorghum grain [SFSG] or whole-shelled corn [WSC]). The 2.7MM treatment tended to improve ADG (6%, P = .08) and gain efficiency (4%, P = .15) relative to ad libitum access to feed. The 2.9MM treatment was intermediate. Steers fed WSC diets consumed approximately 12% more DM (9.2 vs 8.2 kg/d) and gained 4% more (1.45 vs 1.39 kg/d, P < .05) but had lower gain efficiency (7%, 159 and 170 g/kg, P < .001) than steers fed SFSG diets. For SFSG diets, the 2/10 regimen resulted in similar gains, a 3.6% decrease (P = .10) in DMI, an 8.6% improvement (P < .01) in gain efficiency, and reduced roughage use (40 kg per steer) compared with the 10/10 regimen. With WSC diets, the 2/10 regimen did not (P > .2) affect gain efficiency but did reduce roughage use (48 kg) compared with the 10/10 regimen. The 10/2 regimen did not differ (P > .2) from the 10/10 regimen. Few differences in carcass characteristics were noted among treatments. Roughage use and cost of gain can be reduced by feeding 2% roughage during the mid-finishing period followed by a return to 10% roughage.

  11. Innate immunity.

    PubMed

    Revillard, Jean-Pierre

    2002-01-01

    For more than half a century immunological research has been almost exclusively orientated towards the acquired immune response and the mechanisms of immune tolerance. Major discoveries have enabled us to better understand the functioning of the specific immune system: the structure of antibody molecules, the genetic mechanisms leading to the molecular diversity of B (BCR) and T (TCR) lymphocyte antigen receptors, the biological function of major histocompatibility complex (MHC) molecules in the presentation of peptides to alpha/beta receptor bearing T lymphocytes, the processes of positive and negative selection of lymphocytes during the course of their differentiation. The major role of specific or acquired immunity has been shown by the rapidly lethal character of severe combined immune deficiency diseases and various alterations in the mechanisms of tolerance have been proposed to explain the chronic inflammatory illnesses which are considered to be auto-immune. Natural or innate immunity has been known since the first description of an inflammatory reaction attributed to Cornelius Celsus. It entered into the scientific era at the end of the 19th century with the discovery of phagocytes by Metchnikoff and of the properties of the complement system by Bordet [1] but due to the vastness of the field and its lack of clear definition, it failed to excite the interest of researchers. The discovery of cytokines and progress in knowledge of the mechanisms of the inflammatory reaction have certainly helped to banish preconceived ideas about natural immunity, which was wrongly labelled as non-specific. This has led to the proposition of a wider role for immune functions beyond the level of the cell or the organism [2] and to a better understanding of the importance of the immediate defence mechanisms and their role in the later orientation of the acquired response.

  12. Maternal Immunization

    PubMed Central

    Chu, Helen Y.; Englund, Janet A.

    2014-01-01

    Maternal immunization has the potential to protect the pregnant woman, fetus, and infant from vaccine-preventable diseases. Maternal immunoglobulin G is actively transported across the placenta, providing passive immunity to the neonate and infant prior to the infant's ability to respond to vaccines. Currently inactivated influenza, tetanus toxoid, and acellular pertussis vaccines are recommended during pregnancy. Several other vaccines have been studied in pregnancy and found to be safe and immunogenic and to provide antibody to infants. These include pneumococcus, group B Streptococcus, Haemophilus influenzae type b, and meningococcus vaccines. Other vaccines in development for potential maternal immunization include respiratory syncytial virus, herpes simplex virus, and cytomegalovirus vaccines. PMID:24799324

  13. Boosting nitrification by membrane-attached biofilm.

    PubMed

    Wu, C Y; Ushiwaka, S; Horii, H; Yamagiwa, K

    2006-01-01

    Nitrification is a key step for reliable biological nitrogen removal. In order to enhance nitrification in the activated sludge (AS) process, membrane-attached biofilm (MAB) was incorporated in a conventional activated sludge tank. Simultaneous organic carbon removal and nitrification of the MAB incorporated activated sludge (AS + MAB) process was investigated with continuous wastewater treatment. The effluent TOC concentration of AS and the AS + MAB processes were about 6.3 mg/L and 7.9 mg/L, respectively. The TOC removal efficiency of both AS and AS + MAB were above 95% during the wastewater treatment, indicating excellent organic carbon removal performance in both processes. Little nitrification occurred in the AS process. On the contrary, successful nitrification was obtained with the AS + MAB process with nitrification efficiency of about 90%. The volumetric and surface nitrification rates were about 0.14 g/Ld and 6.5 g/m2d, respectively. The results clearly demonstrated that nitrification in the conventional AS process was boosted by MAB. Furthermore, the microfaunal population in the AS + MAB process was different from that in the AS process. The high concentration of rotifers in the AS + MAB process was expected to decrease the generation of excess sludge in the process.

  14. Acetonitrile boosts conductivity of imidazolium ionic liquids.

    PubMed

    Chaban, Vitaly V; Voroshylova, Iuliia V; Kalugin, Oleg N; Prezhdo, Oleg V

    2012-07-05

    We apply a new methodology in the force field generation (Phys. Chem. Chem. Phys.2011, 13, 7910) to study binary mixtures of five imidazolium-based room-temperature ionic liquids (RTILs) with acetonitrile (ACN). Each RTIL is composed of tetrafluoroborate (BF(4)) anion and dialkylimidazolium (MMIM) cations. The first alkyl group of MIM is methyl, and the other group is ethyl (EMIM), butyl (BMIM), hexyl (HMIM), octyl (OMIM), and decyl (DMIM). Upon addition of ACN, the ionic conductivity of RTILs increases by more than 50 times. It significantly exceeds an impact of most known solvents. Unexpectedly, long-tailed imidazolium cations demonstrate the sharpest conductivity boost. This finding motivates us to revisit an application of RTIL/ACN binary systems as advanced electrolyte solutions. The conductivity correlates with a composition of ion aggregates simplifying its predictability. Addition of ACN exponentially increases diffusion and decreases viscosity of the RTIL/ACN mixtures. Large amounts of ACN stabilize ion pairs, although they ruin greater ion aggregates.

  15. Boosted Regression Tree Models to Explain Watershed ...

    EPA Pesticide Factsheets

    Boosted regression tree (BRT) models were developed to quantify the nonlinear relationships between landscape variables and nutrient concentrations in a mesoscale mixed land cover watershed during base-flow conditions. Factors that affect instream biological components, based on the Index of Biotic Integrity (IBI), were also analyzed. Seasonal BRT models at two spatial scales (watershed and riparian buffered area [RBA]) for nitrite-nitrate (NO2-NO3), total Kjeldahl nitrogen, and total phosphorus (TP) and annual models for the IBI score were developed. Two primary factors — location within the watershed (i.e., geographic position, stream order, and distance to a downstream confluence) and percentage of urban land cover (both scales) — emerged as important predictor variables. Latitude and longitude interacted with other factors to explain the variability in summer NO2-NO3 concentrations and IBI scores. BRT results also suggested that location might be associated with indicators of sources (e.g., land cover), runoff potential (e.g., soil and topographic factors), and processes not easily represented by spatial data indicators. Runoff indicators (e.g., Hydrological Soil Group D and Topographic Wetness Indices) explained a substantial portion of the variability in nutrient concentrations as did point sources for TP in the summer months. The results from our BRT approach can help prioritize areas for nutrient management in mixed-use and heavily impacted watershed

  16. Exploiting tRNAs to Boost Virulence.

    PubMed

    Albers, Suki; Czech, Andreas

    2016-01-19

    Transfer RNAs (tRNAs) are powerful small RNA entities that are used to translate nucleotide language of genes into the amino acid language of proteins. Their near-uniform length and tertiary structure as well as their high nucleotide similarity and post-transcriptional modifications have made it difficult to characterize individual species quantitatively. However, due to the central role of the tRNA pool in protein biosynthesis as well as newly emerging roles played by tRNAs, their quantitative assessment yields important information, particularly relevant for virus research. Viruses which depend on the host protein expression machinery have evolved various strategies to optimize tRNA usage-either by adapting to the host codon usage or encoding their own tRNAs. Additionally, several viruses bear tRNA-like elements (TLE) in the 5'- and 3'-UTR of their mRNAs. There are different hypotheses concerning the manner in which such structures boost viral protein expression. Furthermore, retroviruses use special tRNAs for packaging and initiating reverse transcription of their genetic material. Since there is a strong specificity of different viruses towards certain tRNAs, different strategies for recruitment are employed. Interestingly, modifications on tRNAs strongly impact their functionality in viruses. Here, we review those intersection points between virus and tRNA research and describe methods for assessing the tRNA pool in terms of concentration, aminoacylation and modification.

  17. Exploiting tRNAs to Boost Virulence

    PubMed Central

    Albers, Suki; Czech, Andreas

    2016-01-01

    Transfer RNAs (tRNAs) are powerful small RNA entities that are used to translate nucleotide language of genes into the amino acid language of proteins. Their near-uniform length and tertiary structure as well as their high nucleotide similarity and post-transcriptional modifications have made it difficult to characterize individual species quantitatively. However, due to the central role of the tRNA pool in protein biosynthesis as well as newly emerging roles played by tRNAs, their quantitative assessment yields important information, particularly relevant for virus research. Viruses which depend on the host protein expression machinery have evolved various strategies to optimize tRNA usage—either by adapting to the host codon usage or encoding their own tRNAs. Additionally, several viruses bear tRNA-like elements (TLE) in the 5′- and 3′-UTR of their mRNAs. There are different hypotheses concerning the manner in which such structures boost viral protein expression. Furthermore, retroviruses use special tRNAs for packaging and initiating reverse transcription of their genetic material. Since there is a strong specificity of different viruses towards certain tRNAs, different strategies for recruitment are employed. Interestingly, modifications on tRNAs strongly impact their functionality in viruses. Here, we review those intersection points between virus and tRNA research and describe methods for assessing the tRNA pool in terms of concentration, aminoacylation and modification. PMID:26797637

  18. Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: an observational cohort study

    PubMed Central

    Cesar, Carina; Jenkins, Cathy A.; Shepherd, Bryan E.; Padgett, Denis; Mejía, Fernando; Ribeiro, Sayonara Rocha; Cortes, Claudia P.; Pape, Jean W.; Madero, Juan Sierra; Fink, Valeria; Sued, Omar; McGowan, Catherine; Cahn, Pedro

    2015-01-01

    Background Access to combination antiretroviral therapy (cART) is expanding in Latin America and the Caribbean (LAC). There is little information in this region regarding incidence of and factors associated with regimen failure and regimen change. Methods Antiretroviral-naïve adults starting cART from 2000-2014 at sites in seven countries throughout LAC were included. Cumulative incidence of virologic failure and major regimen change were estimated with death considered a competing event. Findings 14,027 cART initiators (60% male, median age 37 years, median CD4 156 cells/mm3, median HIV-RNA 5·0 log10 copies/mL, and 28% with clinical AIDS) were followed for a median of 3·9 years. 1,719 patients presented virologic failure and 1,955 had a major regimen change. Excluding GHESKIO-Haiti (which did not regularly measure HIV-RNA), cumulative incidence of virologic failure was 7·8%, 19·2%, and 25·8% at one, three, and five years after cART initiation, respectively; cumulative incidence of major regimen change was 5·9%, 12·7%, and 18·2%. Incidence of major regimen change at GHESKIO-Haiti at five years was 10·7%. Virologic failure was associated with younger age (adjusted hazard ratio[aHR]=2·03 for 20 vs. 40 years; 95% confidence interval[CI] 1·68-2·44), infection through injection-drug use (IDU) (aHR=1·60; 95%CI 1·02-2·52), initiation in earlier calendar years (aHR=1·28 for 2002 vs. 2006; 95%CI 1·13-1·46), and starting with a boosted protease inhibitor (aHR=1·17 vs. non-nucleoside reverse transcriptase inhibitor; 95%CI 1·00-1·64). Interpretation Incidence of virologic failure was generally lower than in North America/Europe. Our results suggest the need to design strategies to reduce failure and major regimen change among younger patients and those with a history of IDU. Funding US National Institutes of Health: U01 AI069923. PMID:26520929

  19. Adherence to treatment of chronic hepatitis C: from interferon containing regimens to interferon and ribavirin free regimens

    PubMed Central

    Younossi, Zobair M.; Stepanova, Maria; Henry, Linda; Nader, Fatema; Younossi, Youssef; Hunt, Sharon

    2016-01-01

    Abstract Patients’ experience during treatment may affect treatment adherence. Our aim was to assess the impact of patient-reported outcomes (PROs) on adherence to different anti-hepatitis C virus (HCV) regimens. Clinical, demographic, and PRO data (short form-36 [SF-36], chronic liver disease questionnaire-hepatitis C version [CLDQ-HCV], functional assessment of chronic illness therapy-fatigue [FACIT-F], work productivity and activity impairment: specific health problem [WPAI:SHP]) from 13 multinational clinical trials of anti-HCV treatment were available. Treatment adherence was defined as >80% of prescribed doses taken. Included were 4825 HCV patients. Regimens were grouped into: interferon- and ribavirin (RBV)-containing (±sofosbuvir [SOF]), interferon-free RBV-containing (RBV + SOF ± ledipasvir [LDV]), and interferon-free RBV-free (LDV/SOF). The adherence to these regimens were 77.6%, 84.3%, and 96.2%, respectively (P < 0.0001). Nonadherent patients were more likely to be unemployed and to have a greater PRO impairment at baseline (up to −5.3% lower PRO scores, P < 0.0001). During treatment with interferon- or RBV-based regimens, nonadherent patients experienced lower PROs and had larger decrements from their baseline PRO scores. In contrast, there were no significant declines in PRO scores (all P > 0.05) for the small number of patients who were nonadherent to LDV/SOF. In multivariate analysis, being treatment-naive, longer treatment duration, and receiving an interferon- or RBV-containing regimen were associated with a lower likelihood of adherence (all P < 0.003). Better baseline and on-treatment PRO scores were associated with a higher likelihood of adherence to interferon and RBV. The use of interferon and/or RBV, longer duration of treatment, and lower baseline and on-treatment PRO scores were linked to a decreased likelihood of being adherent to interferon + RBV-containing or interferon-free RBV-containing antiviral

  20. Cutting Salt a Health Boost for Kidney Patients

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_163628.html Cutting Salt a Health Boost for Kidney Patients Blood pressure ... Encouraging people with kidney disease to reduce their salt intake may help improve blood pressure and cut ...

  1. Did El Nino Weather Give Zika a Boost?

    MedlinePlus

    ... fullstory_162611.html Did El Nino Weather Give Zika a Boost? Climate phenomenon could have helped infection- ... might have aided the explosive spread of the Zika virus throughout South America, a new study reports. ...

  2. High-temperature alloys: Single-crystal performance boost

    NASA Astrophysics Data System (ADS)

    Schütze, Michael

    2016-08-01

    Titanium aluminide alloys are lightweight and have attractive properties for high-temperature applications. A new growth method that enables single-crystal production now boosts their mechanical performance.

  3. Xanax, Valium May Boost Pneumonia Risk in Alzheimer's Patients

    MedlinePlus

    ... html Xanax, Valium May Boost Pneumonia Risk in Alzheimer's Patients Researchers suspect people may breathe saliva or ... 10, 2017 MONDAY, April 10, 2017 (HealthDay News) -- Alzheimer's patients given sedatives such as Valium or Xanax ...

  4. Lung-Sparing Surgery May Boost Mesothelioma Survival

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_162720.html Lung-Sparing Surgery May Boost Mesothelioma Survival Treatment nearly ... 23, 2016 (HealthDay News) -- Surgery that preserves the lung, when combined with other therapies, appears to extend ...

  5. Autism Greatly Boosts Kids' Injury Risk, Especially for Drowning

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_164198.html Autism Greatly Boosts Kids' Injury Risk, Especially for Drowning ... TUESDAY, March 21, 2017 (HealthDay News) -- Children with autism are at extremely high risk of drowning compared ...

  6. Trauma as A Teen May Boost Depression Risk Around Menopause

    MedlinePlus

    ... 164355.html Trauma as a Teen May Boost Depression Risk Around Menopause Likelihood was more than twice ... during their teens have a greater risk of depression during the years leading into menopause, a new ...

  7. A Lengthy, Stable Marriage May Boost Stroke Survival

    MedlinePlus

    ... 162542.html A Lengthy, Stable Marriage May Boost Stroke Survival Lifelong singles fared the worst, study finds ... 14, 2016 WEDNESDAY, Dec. 14, 2016 (HealthDay News) -- Stroke patients may have better odds of surviving if ...

  8. Immune response

    MedlinePlus Videos and Cool Tools

    The immune system includes specialized white blood cells, called lymphocytes that adapt themselves to fight specific foreign invaders. These cells develop into two groups in the bone marrow. From the bone ...

  9. SCALING OF THE ANOMALOUS BOOST IN RELATIVISTIC JET BOUNDARY LAYER

    SciTech Connect

    Zenitani, Seiji; Hesse, Michael; Klimas, Alex

    2010-04-01

    We investigate the one-dimensional interaction of a relativistic jet and an external medium. Relativistic magnetohydrodynamic simulations show an anomalous boost of the jet fluid in the boundary layer, as previously reported. We describe the boost mechanism using an ideal relativistic fluid and magnetohydrodynamic theory. The kinetic model is also examined for further understanding. Simple scaling laws for the maximum Lorentz factor are derived, and verified by the simulations.

  10. The Immune System in Cancer Prevention, Development and Therapy.

    PubMed

    Candeias, Serge M; Gaipl, Udo S

    2016-01-01

    The immune system plays a pivotal role in the maintenance of the integrity of an organism. Besides the protection against pathogens, it is strongly involved in cancer prevention, development and defense. This review focuses on how the immune system protects against infections and trauma and on its role in cancer development and disease. Focus is set on the interactions of the innate and adaptive immune system and tumors. The role of IFN-γ as a pleiotropic cytokine that plays a very important role at the interface of innate and adaptive immune systems in tumor development and induction of anti-tumor immune responses is outlined. Further, immune cells as prognostic and predictive markers of cancer will be discussed. Data are provided that even the brain as immune privileged organ is subjected to immune surveillance and consequently also brain tumors. Immune therapeutic approaches for glioblastoma multiforme, the most frequent and malignant brain tumor, based on vaccination with dendritic cells are outlined and application of hyperthermia in form of magnetic nanoparticles is discussed. We conclude that the immune system and developing tumors are intimately intertwined. Anti-tumor immune responses can be prominently boosted by multimodal therapies aiming on the one hand to induce immunogenic tumor cell death forms and on the other hand to actively counteract the immune suppressive microenvironment based on the tumor itself.

  11. In vivo effects of monoclonal anti-L3T4 antibody on immune responsiveness of mice infected with Schistosoma mansoni. Reduction of irradiated cercariae-induced resistance

    SciTech Connect

    Kelly, E.A.; Colley, D.G.

    1988-04-15

    Mice can be partially protected against challenge infections of Schistosoma mansoni cercariae by either single or multiple exposure to irradiated cercariae (x-cerc). The participation of L3T4+ lymphocytes on this resistance phenomenon was evaluated by selectively depleting this cell population through in vivo administration of mAb anti-L3T4 at three different times in relationship to the challenge infections. Treatment with anti-L3T4 before challenge such that depletion was effective during the time of cercarial skin penetration and dermal/s.c. residence significantly reduced the level of resistance induced by x-cerc sensitization. When treatment was delayed until after challenge, depletion of L3T4+ cells coincided with either the lung or post-lung/liver phases of schistosomular migration, and normal levels of x-cerc-induced resistance were induced. In contrast to once-immunized mice, mice hyperimmunized by five exposures to x-cerc and then depleted of L3T4+ cells at the time of challenge still expressed resistance to the challenge. These data suggest that when mice are sensitized only once with x-cerc the challenge infection provides a necessary immunologic boost which requires L3T4+ cells for effective expression of resistance. The requirement for this anamnestic effect by the challenge infection can be circumvented by hyperimmunization. Evaluation of the immune response of one-time sensitized or hyperimmunized mice demonstrated that cellular Ag-specific proliferative responses and mitogen-induced lymphokine production were abrogated after any of the various in vivo regimens of anti-L3T4 antibody. In contrast, immunoblot analysis of humoral responsiveness revealed a correlation between the expression of resistance and the ability of sera from immunized and anti-L3T4 treated mice to recognize a 75-kDa parasite antigenic component.

  12. Role of lipid structure in the humoral immune response in mice to covalent lipid-peptides from the membrane proximal region of HIV-1 gp41

    PubMed Central

    Watson, Douglas S.; Szoka, Francis C.

    2009-01-01

    The membrane proximal region (MPR) of HIV-1 gp41 is a desirable target for development of a vaccine that elicits neutralizing antibodies since the patient-derived monoclonal antibodies, 2F5 and 4E10, bind to the MPR and neutralize primary HIV isolates. The 2F5 and 4E10 antibodies cross-react with lipids and structural studies suggest that MPR immunogens may be presented in a membrane environment. We hypothesized that covalent attachment of lipid anchors would enhance the humoral immune response to MPR-derived peptides presented in liposomal bilayers. In a comparison of eight lipids conjugated to an extended 2F5 epitope peptide, a sterol, cholesterol hemisuccinate (CHEMS), was found to promote the strongest anti-peptide IgG titers (6.4 × 104) in sera of BALB/C mice. Two lipid anchors, palmitic acid and phosphatidylcholine, failed to elicit a detectable serum anti-peptide IgG response. Association with the liposomal vehicle contributed to the ability of a lipopeptide to elicit anti-peptide antibodies, but no other single factor, such as position of the lipid anchor, peptide helical content, lipopeptide partition coefficient, or presence of phosphate on the anchor clearly determined lipopeptide potency. Conjugation to CHEMS also rendered a 4E10 epitope peptide immunogenic (5.6 × 102 IgG titer in serum). Finally, attachment of CHEMS to a peptide spanning both the 2F5 and 4E10 epitopes elicited serum IgG antibodies that bound to each of the individual epitopes as well as to recombinant gp140. Further research into the mechanism of how structure influences the immune response to the MPR may lead to immunogens that could be useful in prime-boost regimens for focusing the immune response in an HIV vaccine. PMID:19520200

  13. Protection against Mycobacterium tuberculosis challenge in mice by DNA vaccine Ag85A-ESAT-6-IL-21 priming and BCG boosting.

    PubMed

    Dou, J; Wang, Y; Yu, F; Yang, H; Wang, J; He, X; Xu, W; Chen, J; Hu, K

    2012-04-01

    Tuberculosis (TB) is one of most important chronic infectious diseases caused by Mycobacterium tuberculosis and remains a major global health problem. In the study, we developed the DNA vaccine encoding fusion protein of antigen 85 A and 6 kDa early secretory antigen target of M. tuberculosis as well as the cytokine IL-21 to investigate its immune protective efficacy against M. tuberculosis challenge in mice after the DNA vaccine priming and Bacille Calmette-Guérin (BCG) boosting. Compared with the different control groups, the intranasal DNA vaccine priming twice and BCG boosting once markedly increased the cytotoxicities of natural killer cells and splenocytes and enhanced the interferon-γ level in the splenocyte supernatant as well as sIgA level in bronchoalveolar lavage in the vaccinated mice. Importantly, this heterologous prime-boost strategy significantly decreased the bacterial load in the mouse lungs in contrast to that of intranasal or subcutaneous BCG immunization alone. These findings provide further approaches for mucosal-targeted prime-boost vaccination to fight against TB.

  14. Prime-boost vaccinations using recombinant flavivirus replicon and vaccinia virus vaccines: an ELISPOT analysis.

    PubMed

    Rattanasena, Paweena; Anraku, Itaru; Gardner, Joy; Le, Thuy T; Wang, Xiang Ju; Khromykh, Alexander A; Suhrbier, Andreas

    2011-03-01

    Recombinant Kunjin replicon virus-like particle (VLP), vaccinia virus (rVV) and DNA vaccines were tested in a large series of prime-boost vaccinations using interferon (IFN)γ ELISPOT assays that reflected effector (E), effector memory (EM) and central memory (CM) responses. All vaccine constructs encoded the murine polytope immunogen and responses to four CD8 T-cell epitopes (TYQRTRALV, SYIPSAEKI, YPHFMPTNL and RPQASGVYM) were measured. VLP/rVV out performed (by 14- to 20-fold) DNA/rVV for induction of CM responses, whereas EM responses were only marginally increased. DNA/VLP induced more EM, but not CM responses, than VLP alone, illustrating that DNA priming is not universally beneficial. rVV/VLP gave comparable results to VLP/rVV combinations, although the former induced approximately threefold more E responses, illustrating the utility of poxvirus priming in this setting. Although higher doses of VLP and rVV increased responses after single immunizations, such dose increases provided only marginal benefit in heterologous prime-boost settings. Triple combinations also provided no benefit over two vaccinations. DNA vaccination was associated with broad CM, but not EM responses, and the breadth of EM and E responses was significantly improved by increasing viral vector dose. VLP/rVV, rather than DNA priming, induced T cells with consistently high IFNγ secretion profiles across all ELISPOT measures. Vector-specific CD8 T-cell responses generally correlated well with immunogen-specific responses, although, as expected, single use of each vector reduced the relative levels of vector-specific responses. These experiments illustrate the utility of replicons in heterologous prime-boost vaccinations, and illustrate the diversity of data that can be obtained from ELISPOT analyses.

  15. High Variability of Plasma Drug Concentrations in Dual Protease Inhibitor Regimens

    PubMed Central

    Guiard-Schmid, Jean-Baptiste; Poirier, Jean-Marie; Meynard, Jean-Luc; Bonnard, Philippe; Gbadoe, Ayi Hola; Amiel, Corinne; Calligaris, Frédérique; Abraham, Bruno; Pialoux, Gilles; Girard, Pierre-Marie; Jaillon, Patrice; Rozenbaum, Willy

    2003-01-01

    Ritonavir (RTV) strongly increases the concentrations of protease inhibitors (PIs) in plasma in patients given a combination of RTV and another PI. This pharmacological interaction is complex and poorly characterized and shows marked inter- and intraindividual variations. In addition, RTV interacts differently with saquinavir (SQV), indinavir (IDV), amprenavir (APV), and lopinavir (LPV). In this retrospective study on 542 human immunodeficiency virus-infected patients, we compared inter- and intraindividual variability of plasma PI concentrations and correlations between the Cmin (minimum concentration of drug in plasma) values for RTV and the coadministered PI Cmin values. Mean RTV Cmins are significantly lower in patients receiving combinations containing APV or LPV than in combinations with SQV or IDV. With the most common PI dose regimens (600 mg of IDV twice a day [BID], 800 mg of SQV BID, and 400 mg of LPV BID), the interindividual Cmin variability of patients treated with a PI and RTV seemed to be lower with APV and LPV than with IDV and SQV. As regards intraindividual variability, APV also differed from the other PIs, exhibiting lower Cmin variability than with the other combinations. Significant positive correlations between RTV Cmin and boosted PI Cmin were observed with IDV, SQV, and LPV, but not with APV. Individual dose adjustments must take into account the specificity the pharmacological interaction of each RTV/PI combination and the large inter- and intraindividual variability of plasma PI levels to avoid suboptimal plasma drug concentrations which may lead to treatment failure and too high concentrations which may induce toxicity and therefore reduce patient compliance. PMID:12604531

  16. Our intraoperative boost radiotherapy experience and applications

    PubMed Central

    Günay, Semra; Alan, Ömür; Yalçın, Orhan; Türkmen, Aygen; Dizdar, Nihal

    2016-01-01

    Objective: To present our experience since November 2013, and case selection criteria for intraoperative boost radiotherapy (IObRT) that significantly reduces the local recurrence rate after breast conserving surgery in patients with breast cancer. Material and Methods: Patients who were suitable for IObRT were identified within the group of patients who were selected for breast conserving surgery at our breast council. A MOBETRON (mobile linear accelerator for IObRT) was used for IObRt during surgery. Results: Patients younger than 60 years old with <3 cm invasive ductal cancer in one focus (or two foci within 2 cm), with a histologic grade of 2–3, and a high possibility of local recurrence were admitted for IObRT application. Informed consent was obtained from all participants. Lumpectomy and sentinel lymph node biopsy was performed and advancement flaps were prepared according to the size and inclination of the conus following evaluation of tumor size and surgical margins by pathology. Distance to the thoracic wall was measured, and a radiation oncologist and radiation physicist calculated the required dose. Anesthesia was regulated with slower ventilation frequency, without causing hypoxia. The skin and incision edges were protected, the field was radiated (with 6 MeV electron beam of 10 Gy) and the incision was closed. In our cases, there were no major postoperative surgical or early radiotherapy related complications. Conclusion: The completion of another stage of local therapy with IObRT during surgery positively effects sequencing of other treatments like chemotherapy, hormonotherapy and radiotherapy, if required. IObRT increases disease free and overall survival, as well as quality of life in breast cancer patients. PMID:26985156

  17. Boosting BCG-primed mice with chimeric DNA vaccine HG856A induces potent multifunctional T cell responses and enhanced protection against Mycobacterium tuberculosis.

    PubMed

    Ji, Ping; Hu, Zhi-Dong; Kang, Han; Yuan, Qin; Ma, Hui; Wen, Han-Li; Wu, Juan; Li, Zhong-Ming; Lowrie, Douglas B; Fan, Xiao-Yong

    2016-02-01

    The tuberculosis pandemic continues to rampage despite widespread use of the current Bacillus Calmette-Guerin (BCG) vaccine. Because DNA vaccines can elicit effective antigen-specific immune responses, including potent T cell-mediated immunity, they are promising vehicles for antigen delivery. In a prime-boost approach, they can supplement the inadequate anti-TB immunological memory induced by BCG. Based on this, a chimeric DNA vaccine HG856A encoding Mycobacterium tuberculosis (M. tuberculosis) immunodominant antigen Ag85A plus two copies of ESAT-6 was constructed. Potent humoral immune responses, as well as therapeutic effects induced by this DNA vaccine, were observed previously in M. tuberculosis-infected mice. In this study, we further evaluated the antigen-specific T cell immune responses and showed that repeated immunization with HG856A gave modest protection against M. tuberculosis challenge infection and significantly boosted the immune protection primed by BCG vaccination. Enhanced protection was accompanied by increased multifunctional Th1 CD4(+) T cell responses, most notably by an elevated frequency of M. tuberculosis antigen-specific IL-2-producing CD4(+) T cells post-vaccination. These data confirm the potential of chimeric DNA vaccine HG856A as an anti-TB vaccine candidate.

  18. Intensified hemodialysis regimens: neglected treatment options for children and adolescents.

    PubMed

    Müller, Dominik; Zimmering, Miriam; Chan, Christopher T; McFarlane, Philip A; Pierratos, Andreas; Querfeld, Uwe

    2008-10-01

    During recent years, the importance of intensified dialysis regimens has gathered increasing interest, especially after the Hemodialysis (HEMO) Study Group reported that a higher dose of thrice-weekly hemodialysis failed to improve clinical outcomes. Long nocturnal hemodialysis (three to six times per week) or short daily hemodialysis are the currently used forms of intensified dialysis. There is substantial evidence for cardiovascular and quality-of-life improvements as well as financial benefits with intensified hemodialysis. Preliminary experience with daily hemodialysis and hemodiafiltration in children has been reported. Given the continuing shortage of donor organs for kidney transplantation, the increasing incidence of end-stage renal disease (ESRD) and recognition of the deleterious effects of long-lasting ESRD, growth retardation, and poor social rehabilitation, more intensified dialysis regimens are a much-needed therapeutical option in both adults and children.

  19. Initial dosage regimens of gentamicin in patients with burns.

    PubMed

    Zaske, D E; Chin, T; Kohls, P R; Solem, L D; Strate, R G

    1991-01-01

    For 95 patients with burns the gentamicin dosage regimen necessary to achieve optimal serum concentrations was determined. Individual elimination rates and distribution volumes for gentamicin were determined and correlated with renal function parameters and age. In patients with burns who had normal serum creatinine levels (less than 1.5 mg/dl), gentamicin clearance and thus dosage regimens can be stratified by age. Gentamicin's clearance decreased inversely with age. Initial dosage guidelines were calculated for different age groups of patients with normal levels of serum creatinine. The guidelines were developed to assist the clinician in attaining therapeutic concentrations with initial doses of gentamicin. Therapeutic serum concentrations were reached in most patients with burns dosed by these guidelines. Serum gentamicin concentrations should always be monitored during therapy, and dosages should be adjusted to ensure optimal concentrations during the course of therapy.

  20. Basis for selecting optimum antibiotic regimens for secondary peritonitis.

    PubMed

    Maseda, Emilio; Gimenez, Maria-Jose; Gilsanz, Fernando; Aguilar, Lorenzo

    2016-01-01

    Adequate management of severely ill patients with secondary peritonitis requires supportive therapy of organ dysfunction, source control of infection and antimicrobial therapy. Since secondary peritonitis is polymicrobial, appropriate empiric therapy requires combination therapy in order to achieve the needed coverage for both common and more unusual organisms. This article reviews etiological agents, resistance mechanisms and their prevalence, how and when to cover them and guidelines for treatment in the literature. Local surveillances are the basis for the selection of compounds in antibiotic regimens, which should be further adapted to the increasing number of patients with risk factors for resistance (clinical setting, comorbidities, previous antibiotic treatments, previous colonization, severity…). Inadequate antimicrobial regimens are strongly associated with unfavorable outcomes. Awareness of resistance epidemiology and of clinical consequences of inadequate therapy against resistant bacteria is crucial for clinicians treating secondary peritonitis, with delicate balance between optimization of empirical therapy (improving outcomes) and antimicrobial overuse (increasing resistance emergence).

  1. Migratory common blackbirds have lower innate immune function during autumn migration than resident conspecifics.

    PubMed

    Eikenaar, Cas; Hegemann, Arne

    2016-03-01

    Animals need a well-functioning immune system to protect themselves against pathogens. The immune system, however, is costly and resource trade-offs with other demands exist. For migratory animals several (not mutually exclusive) hypotheses exist. First, migrants reduce immune function to be able to allocate resources to migration. Second, migrants boost immune function to cope with more and/or novel pathogens encountered during migration. Third, migrants reallocate resources within the immune system. We tested these hypotheses by comparing baseline immune function in resident and migratory common blackbirds (Turdus merula), both caught during the autumn migration season on the island of Helgoland, Germany. Indices of baseline innate immune function (microbial killing capacity and haptoglobin-like activity) were lower in migrants than in residents. There was no difference between the groups in total immunoglobulins, a measure of baseline acquired immune function. Our study on a short-distance avian migrant supports the hypothesis that innate immune function is compromised during migration.

  2. Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

    PubMed Central

    Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

    2015-01-01

    The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID:25692350

  3. Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study.

    PubMed

    Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

    2015-01-01

    The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

  4. [Malaria and life at sea: prophylactic regimens on merchant ships].

    PubMed

    Michot, S

    2011-02-01

    The purpose of this article is to describe requirements for protection/treatment of malaria on merchant ships. The first part of the article reviews recent data on the incidence of malaria in seagoing personnel. The second part provides advice on mosquito-bite prevention on merchant ships. The third part presents the most important information on prophylaxis for seafarers working in malarial risk areas. Several regimens are proposed. The last part of the article discusses curative treatment for malaria on merchant ships.

  5. “Rescue” regimens after Helicobacter pylori treatment failure

    PubMed Central

    Gisbert, Javier P

    2008-01-01

    Helicobacter pylori (H pylori) infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. After more than 20 years of experience in H pylori treatment, in my opinion, the ideal regimen to treat this infection is still to be found. Currently, apart from having to know first-line eradication regimens well, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a “rescue” treatment depends on which treatment is used initially. If a clarithromycin-based regimen was used initially, a subsequent metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin-based combination would be a third “rescue” option. Alternatively, it has recently been suggested that levofloxacin-based rescue therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, a quadruple regimen may be reserved as a third-line rescue option. Finally, rifabutin-based rescue therapy constitutes an encouraging empirical fourth-line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H pylori eradication can finally be achieved in almost all patients if several rescue therapies are consecutively given. Therefore, the attitude in H pylori eradication therapy failure, even after two or more unsuccessful attempts, should be to fight and not to surrender. PMID:18803350

  6. Bowel preparation regimens for colon capsule endoscopy: a review

    PubMed Central

    Nigar, Sofia; Paleti, Vani; Lane, Devin; Duddempudi, Sushil

    2014-01-01

    Colon capsule endoscopy (CCE) is being actively evaluated as an emerging complementary or alternative procedure for evaluation of the colon. The yield of CCE is significantly dependent on the quality of bowel preparation. In addition to achieving a stool-free colon the bowel preparation protocols need to decrease bubble effect and aid propulsion of the capsule. An extensive English literature search was done using PubMed with search terms of colon capsule endoscopy, PillCam and bowel preparation. Full-length articles which met the criteria were included for review. A total of 12 studies including 1149 patients were reviewed. There was significant variability in the type of bowel preparation regimens. Large-volume (3–4 liters) polyethylene glycol (PEG) was the most widely used laxative. Lower volumes of PEG showed comparable results but larger studies are needed to determine efficacy. Sodium phosphate was used as an effective booster in most studies. Magnesium citrate and ascorbic acid are emerging as promising boosters to replace sodium phosphate when it is contraindicated. The potential benefit of prokinetics needs further evaluation. Over the past decade there has been significant improvement in the bowel preparation regimens for CCE. Further experience and studies are likely to standardize the bowel preparation regimens before CCE is adopted into routine clinical practice. PMID:24790642

  7. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time

    PubMed Central

    Lee, Bai-Yu; Clemens, Daniel L.; Silva, Aleidy; Dillon, Barbara Jane; Masleša-Galić, Saša; Nava, Susana; Ding, Xianting; Ho, Chih-Ming; Horwitz, Marcus A.

    2017-01-01

    The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis. PMID:28117835

  8. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time.

    PubMed

    Lee, Bai-Yu; Clemens, Daniel L; Silva, Aleidy; Dillon, Barbara Jane; Masleša-Galić, Saša; Nava, Susana; Ding, Xianting; Ho, Chih-Ming; Horwitz, Marcus A

    2017-01-24

    The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.

  9. Nutritional strategies to optimize dairy cattle immunity.

    PubMed

    Sordillo, L M

    2016-06-01

    Dairy cattle are susceptible to increased incidence and severity of both metabolic and infectious diseases during the periparturient period. A major contributing factor to increased health disorders is alterations in bovine immune mechanisms. Indeed, uncontrolled inflammation is a major contributing factor and a common link among several economically important infectious and metabolic diseases including mastitis, retained placenta, metritis, displaced abomasum, and ketosis. The nutritional status of dairy cows and the metabolism of specific nutrients are critical regulators of immune cell function. There is now a greater appreciation that certain mediators of the immune system can have a reciprocal effect on the metabolism of nutrients. Thus, any disturbances in nutritional or immunological homeostasis can provide deleterious feedback loops that can further enhance health disorders, increase production losses, and decrease the availability of safe and nutritious dairy foods for a growing global population. This review will discuss the complex interactions between nutrient metabolism and immune functions in periparturient dairy cattle. Details of how either deficiencies or overexposure to macro- and micronutrients can contribute to immune dysfunction and the subsequent development of health disorders will be presented. Specifically, the ways in which altered nutrient metabolism and oxidative stress can interact to compromise the immune system in transition cows will be discussed. A better understanding of the linkages between nutrition and immunity may facilitate the design of nutritional regimens that will reduce disease susceptibility in early lactation cows.

  10. Enhanced Priming of Adaptive Immunity by Mycobacterium smegmatis Mutants with High-Level Protein Secretion

    PubMed Central

    Taylor, Natalie; Bahunde, Faith; Thompson, Afton; Yu, Jae-Sung; Jacobs, William R.; Letvin, Norm L.; Haynes, Barton F.

    2012-01-01

    Mycobacteria have features that make them attractive as potential vaccine vectors. The nonpathogenic and rapidly growing Mycobacterium smegmatis can express both Mycobacterium tuberculosis antigens and heterologous antigens from other pathogens, and it has been used as a viable vector for the development of live vaccines. In order to further improve antigen-specific immunogenicity of M. smegmatis, we screened a random transposon mutant library for mutants displaying enhanced efficiency of protein secretion (“high secretors”) and isolated 61 mutants showing enhanced endogenic and transgenic protein secretion. Sequence analysis identified a total of 54 genes involved in optimal secretion of insert proteins, as well as multiple independent transposon insertions localized within the same genomic loci and operons. The majority of transposon insertions occurred in genes that have no known protein secretion function. These transposon mutants were shown to prime antigen-specific CD8+ T cell responses better than the parental strain. Specifically, upon introducing the simian immunodeficiency virus (SIV) gag gene into these transposon mutant strains, we observed that they primed SIV Gag-specific CD8+ T cell responses significantly better than the control prime immunization in a heterologous prime/boost regimen. Our results reveal a dependence on bacterial secretion of mycobacterial and foreign antigens for the induction of antigen-specific CD8+ T cells in vivo. The data also suggest that these M. smegmatis transposon mutants could be used as novel live attenuated vaccine strains to express foreign antigens, such as those of human immunodeficiency virus type 1 (HIV-1), and induce strong antigen-specific T cell responses. PMID:22787192

  11. Toxicities of different first-line chemotherapy regimens in the treatment of advanced ovarian cancer

    PubMed Central

    Qu, Chang-Ping; Sun, Gui-Xia; Yang, Shao-Qin; Tian, Jun; Si, Jin-Ge; Wang, Yi-Feng

    2017-01-01

    Abstract Background: Ovarian cancer (OC) is the 5th leading cause of cancer-related deaths around the world, and several chemotherapy regimens have been applied in the treatment of OC. We aim to compare toxicities of different chemotherapy regimens in the treatment of advanced ovarian cancer (AOC) using network meta-analysis. Methods: Literature research in Cochrane Library, PubMed, and EMBASE was performed up to November 2015. Eligible randomized controlled trials (RCTs) of different chemotherapy regimens were included. Network meta-analysis combined direct and indirect evidence to assess pooled odds ratios (ORs) and draw the surface under the cumulative ranking (SUCRA) curves. Results: Thirteen eligible RCTs were included in this network meta-analysis, including 8 chemotherapy regimens (paclitaxel + carboplatin [PC], pegylated liposomal doxorubicin [PLD] + carboplatin, carboplatin, gemcitabine + carboplatin, paclitaxel, PC + epirubicin, PC + topotecan, docetaxel + carboplatin). Gemcitabine + carboplatin regimen exerted higher incidence of anemia when compared with carboplatin and paclitaxel regimens. The incidence of febrile neutropenia of gemcitabine + carboplatin regimen was higher than that of PC, PLD + carboplatin, carboplatin, and PC + topotecan regimens. Topotecan PC + epirubicin regimen had a higher toxicity, comparing with PC, PLD + carboplatin, and PC + topotecan regimens. As for thrombocytopenia, gemcitabine + carboplatin chemotherapy regimen produced an obviously higher toxicity than PC and carboplatin. As for nausea, PLD + carboplatin chemotherapy regimen had a significantly higher toxicity than that of carboplatin chemotherapy regimen. Moreover, when compared with PC and carboplatin chemotherapy regimens, the toxicity of PC + epirubicin was greatly higher to patients with AOC. Conclusion: The nonhematologic toxicity of PLD + carboplatin regimen was higher than other regimens, which

  12. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis

    PubMed Central

    Wang, Yini; Huang, Wenqiu; Hu, Liangding; Cen, Xinan; Li, Lihong; Wang, Jijun; Shen, Jianliang; Wei, Na

    2015-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a refractory immune disorder with a significant risk of death. Although standard therapy has dramatically improved survival in HLH patients, approximately 30%, especially adults, show no response to current treatment strategies. This prospective study aimed to investigate the efficacy of liposomal doxorubicin treatment combined with etoposide and methylprednisolone (doxorubicin-etoposide-methylprednisolone; DEP) as a salvage therapy for adult refractory HLH. Adult patients who did not achieve at least partial response 2 weeks after initial standard HLH therapy were enrolled in this study between June 2013 and June 2014. Response to salvage therapy was assessed at 2 and 4 weeks after initiation of DEP therapy and patients were followed until death or until November 2014. Sixty-three refractory HLH patients were enrolled, including 29 cases of lymphoma-associated HLH, 22 cases of Epstein-Barr virus–associated HLH, and 4 cases of familial HLH. There were 8 cases with unknown underlying diseases. Seventeen cases (27.0%) achieved complete response and 31 cases (49.2%) achieved partial response. The overall response was 76.2% (48/63). Patients who showed no response to DEP died within 4 weeks after salvage therapy. Twenty-nine of the 48 patients who achieved partial or complete response survived to subsequent chemotherapy, allogenic hematopoietic stem cell transplantation, or splenectomy. Our study suggests that DEP regimen is an effective salvage regimen for adult refractory HLH, which can prolong patient survival as we continue to understand the responsible mechanisms and bridge the gap between HLH and its underlying diseases. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR-IPC-14005514. PMID:26289641

  13. Boosted Fast Flux Loop Final Report

    SciTech Connect

    Boosted Fast Flux Loop Project Staff

    2009-09-01

    The Boosted Fast Flux Loop (BFFL) project was initiated to determine basic feasibility of designing, constructing, and installing in a host irradiation facility, an experimental vehicle that can replicate with reasonable fidelity the fast-flux test environment needed for fuels and materials irradiation testing for advanced reactor concepts. Originally called the Gas Test Loop (GTL) project, the activity included (1) determination of requirements that must be met for the GTL to be responsive to potential users, (2) a survey of nuclear facilities that may successfully host the GTL, (3) conceptualizing designs for hardware that can support the needed environments for neutron flux intensity and energy spectrum, atmosphere, flow, etc. needed by the experimenters, and (4) examining other aspects of such a system, such as waste generation and disposal, environmental concerns, needs for additional infrastructure, and requirements for interfacing with the host facility. A revised project plan included requesting an interim decision, termed CD-1A, that had objectives of' establishing the site for the project at the Advanced Test Reactor (ATR) at the Idaho National Laboratory (INL), deferring the CD 1 application, and authorizing a research program that would resolve the most pressing technical questions regarding GTL feasibility, including issues relating to the use of booster fuel in the ATR. Major research tasks were (1) hydraulic testing to establish flow conditions through the booster fuel, (2) mini-plate irradiation tests and post-irradiation examination to alleviate concerns over corrosion at the high heat fluxes planned, (3) development and demonstration of booster fuel fabrication techniques, and (4) a review of the impact of the GTL on the ATR safety basis. A revised cooling concept for the apparatus was conceptualized, which resulted in renaming the project to the BFFL. Before the subsequent CD-1 approval request could be made, a decision was made in April 2006

  14. How Vein Sealing Boosts Fracture Opening

    NASA Astrophysics Data System (ADS)

    Nüchter, Jens-Alexander

    2015-04-01

    an increase in the fracture opening rates. (4) At constant strain rates, the rate of fracture opening increases with increasing strain. These results suggest that vein sealing boosts the rate of fracture opening, and contributes to development of low-aspect ratio veins.

  15. Synthesis of biodegradable polymer-mesoporous silica composite microspheres for DNA prime-protein boost vaccination.

    PubMed

    Ho, Jenny; Huang, Yi; Danquah, Michael K; Wang, Huanting; Forde, Gareth M

    2010-03-18

    DNA vaccines or proteins are capable of inducing specific immunity; however, the translation to the clinic has generally been problematic, primarily due to the reduced magnitude of immune response and poor pharmacokinetics. Herein we demonstrate a composite microsphere formulation, composed of mesoporous silica spheres (MPS) and poly(D,L-lactide-co-glycolide) (PLGA), enables the controlled delivery of a prime-boost vaccine via the encapsulation of plasmid DNA (pDNA) and protein in different compartments. Method with modified dual-concentric-feeding needles attached to a 40 kHz ultrasonic atomizer was studied. These needles focus the flow of two different solutions, which passed through the ultrasonic atomizer. The process synthesis parameters, which are important to the scale-up of composite microspheres, were also studied. These parameters include polymer concentration, feed flowrate, and volumetric ratio of polymer and pDNA-PEI/MPS-BSA. This fabrication technique produced composite microspheres with mean D[4,3] ranging from 6 to 34 microm, depending upon the microsphere preparation. The resultant physical morphology of composite microspheres was largely influenced by the volumetric ratio of pDNA-PEI/MPS-BSA to polymer, and this was due to the precipitation of MPS at the surface of the microspheres. The encapsulation efficiencies were predominantly in the range of 93-98% for pDNA and 46-68% for MPS. In the in vitro studies, the pDNA and protein showed different release kinetics in a 40 day time frame. The dual-concentric-feeding in ultrasonic atomization was shown to have excellent reproducibility. It was concluded that this fabrication technique is an effective method to prepare formulations containing a heterologous prime-boost vaccine in a single delivery system.

  16. The two faces of heterologous immunity: protection or immunopathology.

    PubMed

    Sharma, Shalini; Thomas, Paul G

    2014-03-01

    Immunity to previously encountered viruses can alter responses to unrelated pathogens. This phenomenon, which is known as heterologous immunity, has been well established in animal model systems. Heterologous immunity appears to be relatively common and may be beneficial by boosting protective responses. However, heterologous reactivity can also result in severe immunopathology. The key features that define heterologous immune modulation include alterations in the CD4(+) and CD8(+) T cell compartments and changes in viral dynamics and disease progression. In this review, we discuss recent advances and the current understanding of antiviral immunity in heterologous infections. The difficulties of studying these complex heterologous infections in humans are discussed, with special reference to the variations in HLA haplotypes and uncertainties about individuals' infection history. Despite these limitations, epidemiological analyses in humans and the data from mouse models of coinfection can be applied toward advancing the design of therapeutics and vaccination strategies.

  17. Single-cell technologies to study the immune system.

    PubMed

    Proserpio, Valentina; Mahata, Bidesh

    2016-02-01

    The immune system is composed of a variety of cells that act in a coordinated fashion to protect the organism against a multitude of different pathogens. The great variability of existing pathogens corresponds to a similar high heterogeneity of the immune cells. The study of individual immune cells, the fundamental unit of immunity, has recently transformed from a qualitative microscopic imaging to a nearly complete quantitative transcriptomic analysis. This shift has been driven by the rapid development of multiple single-cell technologies. These new advances are expected to boost the detection of less frequent cell types and transient or intermediate cell states. They will highlight the individuality of each single cell and greatly expand the resolution of current available classifications and differentiation trajectories. In this review we discuss the recent advancement and application of single-cell technologies, their limitations and future applications to study the immune system.

  18. Physical Theory of the Competition that Allows HIV to Escape from the Immune System

    NASA Astrophysics Data System (ADS)

    Wang, Guanyu; Deem, Michael W.

    2006-11-01

    Competition within the immune system may degrade immune control of viral infections. We formalize the evolution that occurs in both HIV-1 and the immune system quasispecies. Inclusion of competition in the immune system leads to a novel balance between the immune response and HIV-1, in which the eventual outcome is HIV-1 escape rather than control. The analytical model reproduces the three stages of HIV-1 infection. We propose a vaccine regimen that may be able to reduce competition between T cells, potentially eliminating the third stage of HIV-1.

  19. A Physical Theory of the Competition that Allows HIV to Escape from the Immune System

    NASA Astrophysics Data System (ADS)

    Deem, Michael

    2007-03-01

    Competition within the immune system may degrade immune control of viral infections. We formalize the evolution that occurs in both HIV-1 and the immune system quasispecies [1]. Inclusion of competition in the immune system leads to a novel balance between the immune response and HIV-1, in which the eventual outcome is HIV-1 escape rather than control. The analytical model reproduces the three stages of HIV-1 infection. We propose a vaccine regimen that may be able to reduce competition between T cells, potentially eliminating the third stage of HIV-1. 1) G. Wang and M. W. Deem, Phys. Rev. Lett. 97 (2006) 188106.

  20. Improved semi-supervised online boosting for object tracking

    NASA Astrophysics Data System (ADS)

    Li, Yicui; Qi, Lin; Tan, Shukun

    2016-10-01

    The advantage of an online semi-supervised boosting method which takes object tracking problem as a classification problem, is training a binary classifier from labeled and unlabeled examples. Appropriate object features are selected based on real time changes in the object. However, the online semi-supervised boosting method faces one key problem: The traditional self-training using the classification results to update the classifier itself, often leads to drifting or tracking failure, due to the accumulated error during each update of the tracker. To overcome the disadvantages of semi-supervised online boosting based on object tracking methods, the contribution of this paper is an improved online semi-supervised boosting method, in which the learning process is guided by positive (P) and negative (N) constraints, termed P-N constraints, which restrict the labeling of the unlabeled samples. First, we train the classification by an online semi-supervised boosting. Then, this classification is used to process the next frame. Finally, the classification is analyzed by the P-N constraints, which are used to verify if the labels of unlabeled data assigned by the classifier are in line with the assumptions made about positive and negative samples. The proposed algorithm can effectively improve the discriminative ability of the classifier and significantly alleviate the drifting problem in tracking applications. In the experiments, we demonstrate real-time tracking of our tracker on several challenging test sequences where our tracker outperforms other related on-line tracking methods and achieves promising tracking performance.

  1. Maximizing boosted top identification by minimizing N-subjettiness

    NASA Astrophysics Data System (ADS)

    Thaler, Jesse; van Tilburg, Ken

    2012-02-01

    N -subjettiness is a jet shape designed to identify boosted hadronic objects such as top quarks. Given N subjet axes within a jet, N-subjettiness sums the angular distances of jet constituents to their nearest subjet axis. Here, we generalize and improve on N -subjettiness by minimizing over all possible subjet directions, using a new variant of the k-means clustering algorithm. On boosted top benchmark samples from the BOOST2010 workshop, we demonstrate that a simple cut on the 3-subjettiness to 2-subjettiness ratio yields 20% (50%) tagging efficiency for a 0.23% (4.1%) fake rate, making N -subjettiness a highly effective boosted top tagger. N-subjettiness can be modified by adjusting an angular weighting exponent, and we find that the jet broadening measure is preferred for boosted top searches. We also explore multivariate techniques, and show that additional improvements are possible using a modified Fisher discriminant. Finally, we briefly mention how our minimization procedure can be extended to the entire event, allowing the event shape N-jettiness to act as a fixed N cone jet algorithm.

  2. Phase I Trial of Preoperative Hypofractionated Intensity-Modulated Radiotherapy with Incorporated Boost and Oral Capecitabine in Locally Advanced Rectal Cancer

    SciTech Connect

    Freedman, Gary M. . E-mail: G_Freedman@FCCC.edu; Meropol, Neal J.; Sigurdson, Elin R.; Hoffman, John; Callahan, Elaine; Price, Robert; Cheng, Jonathan; Cohen, Steve; Lewis, Nancy; Watkins-Bruner, Deborah; Rogatko, Andre; Konski, Andre

    2007-04-01

    Purpose: To determine the safety and efficacy of preoperative hypofractionated radiotherapy using intensity-modulated radiotherapy (IMRT) and an incorporated boost with concurrent capecitabine in patients with locally advanced rectal cancer. Methods and Materials: The eligibility criteria included adenocarcinoma of the rectum, T3-T4 and/or N1-N2 disease, performance status 0 or 1, and age {>=}18 years. Photon IMRT and an incorporated boost were used to treat the whole pelvis to 45 Gy and the gross tumor volume plus 2 cm to 55 Gy in 25 treatments within 5 weeks. The study was designed to escalate the dose to the gross tumor volume in 5-Gy increments in 3-patient cohorts. Capecitabine was given orally 825 mg/m{sup 2} twice daily for 7 days each week during RT. The primary endpoint was the maximal tolerated radiation dose, and the secondary endpoints were the pathologic response and quality of life. Results: Eight patients completed RT at the initial dose level of 55 Gy. The study was discontinued because of toxicity-six Grade 3 toxicities occurred in 3 (38%) of 8 patients. All patients went on to definitive surgical resection, and no patient had a pathologically complete response. Conclusion: This regimen, using hypofractionated RT with an incorporated boost, had unacceptable toxicity despite using standard doses of capecitabine and IMRT. Additional research is needed to determine whether IMRT is able to reduce the side effects during and after pelvic RT with conventional dose fractionation.

  3. Plant Immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plants are faced with defending themselves against a multitude of pathogens, including bacteria, fungi, viruses, nematodes, etc. Immunity is multi-layered and complex. Plants can induce defenses when they recognize small peptides, proteins or double-stranded RNA associated with pathogens. Recognitio...

  4. Safety and Immunogenicity Study of Multiclade HIV-1 Adenoviral Vector Vaccine Alone or as Boost following a Multiclade HIV-1 DNA Vaccine in Africa

    PubMed Central

    Allen, Susan; Than, Soe; Adams, Elizabeth M.; Graham, Barney S.; Koup, Richard A.; Bailer, Robert T.; Smith, Carol; Dally, Len; Tarragona-Fiol, Tony; Bergin, Philip J.; Hayes, Peter; Ho, Martin; Loughran, Kelley; Komaroff, Wendy; Stevens, Gwynneth; Thomson, Helen; Boaz, Mark J.; Cox, Josephine H.; Schmidt, Claudia; Gilmour, Jill; Nabel, Gary J.; Fast, Patricia

    2010-01-01

    Background We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults. Methodology/Principal Findings Volunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1×1010 or 1×1011 particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector® 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-γ) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-γ ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone. Conclusions/Significance The HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints. Trial

  5. Boosted Fast Flux Loop Alternative Cooling Assessment

    SciTech Connect

    Glen R. Longhurst; Donna Post Guillen; James R. Parry; Douglas L. Porter; Bruce W. Wallace

    2007-08-01

    The Gas Test Loop (GTL) Project was instituted to develop the means for conducting fast neutron irradiation tests in a domestic radiation facility. It made use of booster fuel to achieve the high neutron flux, a hafnium thermal neutron absorber to attain the high fast-to-thermal flux ratio, a mixed gas temperature control system for maintaining experiment temperatures, and a compressed gas cooling system to remove heat from the experiment capsules and the hafnium thermal neutron absorber. This GTL system was determined to provide a fast (E > 0.1 MeV) flux greater than 1.0E+15 n/cm2-s with a fast-to-thermal flux ratio in the vicinity of 40. However, the estimated system acquisition cost from earlier studies was deemed to be high. That cost was strongly influenced by the compressed gas cooling system for experiment heat removal. Designers were challenged to find a less expensive way to achieve the required cooling. This report documents the results of the investigation leading to an alternatively cooled configuration, referred to now as the Boosted Fast Flux Loop (BFFL). This configuration relies on a composite material comprised of hafnium aluminide (Al3Hf) in an aluminum matrix to transfer heat from the experiment to pressurized water cooling channels while at the same time providing absorption of thermal neutrons. Investigations into the performance this configuration might achieve showed that it should perform at least as well as its gas-cooled predecessor. Physics calculations indicated that the fast neutron flux averaged over the central 40 cm (16 inches) relative to ATR core mid-plane in irradiation spaces would be about 1.04E+15 n/cm2-s. The fast-to-thermal flux ratio would be in excess of 40. Further, the particular configuration of cooling channels was relatively unimportant compared with the total amount of water in the apparatus in determining performance. Thermal analyses conducted on a candidate configuration showed the design of the water coolant and

  6. The Washington Regimen: rehabilitation of the hand following flexor tendon injuries.

    PubMed

    Dovelle, S; Heeter, P K

    1989-12-01

    This article describes the use of the "Washington Regimen" of early controlled motion in the rehabilitation of flexor tendon injuries of the hand. This regimen is derived from a combination of Kleinert's controlled active extension with rubber-hand passive flexion, Duran's controlled passive techniques, and the modification of the Kleinert orthosis that uses a palmar pulley system. Based on results of clinical investigations, this regimen of early controlled motion appears effective in inhibiting peritendinous scarring, joint contractures, and other complications that commonly occur secondary to flexor tendon repairs. A six-week staged regimen of postoperative rehabilitation is presented. Splint design, exercise regimen, and rationale for treatment are reviewed.

  7. A DNA vaccine encoding the E protein of West Nile virus is protective and can be boosted by recombinant domain DIII.

    PubMed

    Schneeweiss, Anne; Chabierski, Stefan; Salomo, Mathias; Delaroque, Nicolas; Al-Robaiy, Samiya; Grunwald, Thomas; Bürki, Kurt; Liebert, Uwe G; Ulbert, Sebastian

    2011-08-26

    West Nile Virus (WNV) is an emerging pathogenic flavivirus with increasing distribution worldwide. Birds are the natural host of the virus, but also mammals, including humans, can be infected. In some cases, a WNV infection can be associated with severe neurological symptoms. All currently available WNV vaccines are in the veterinary sector, and there is a need to develop safe and effective immunization technologies, which can also be used in humans. An alternative to current vaccination methods is DNA immunization. Most current DNA vaccine candidates against flaviviruses simultaneously express the viral envelope (E) and membrane (prM) proteins, which leads to the formation of virus-like particles. Here we generated a DNA plasmid, which expresses only the E-protein ectodomain. Vaccination of mice stimulated anti-WNV T-cell responses and neutralizing antibodies that were higher than those obtained after immunizing with a recombinant protein previously shown to be a protective WNV vaccine. A single dose of the plasmid was sufficient to protect animals from a lethal challenge with the virus. Moreover, immunogenicity could be boosted when DNA injection was followed by immunization with recombinant domain DIII of the E-protein. This resulted in significantly enhanced neutralizing antibody titers and a more prominent cellular immune response. The results suggest that the WNV E-protein is sufficient as a protective antigen in DNA vaccines and that protection can be significantly improved by adding a recombinant protein boost to the DNA prime.

  8. Conditional Random Field (CRF)-Boosting: Constructing a Robust Online Hybrid Boosting Multiple Object Tracker Facilitated by CRF Learning

    PubMed Central

    Yang, Ehwa; Gwak, Jeonghwan; Jeon, Moongu

    2017-01-01

    Due to the reasonably acceptable performance of state-of-the-art object detectors, tracking-by-detection is a standard strategy for visual multi-object tracking (MOT). In particular, online MOT is more demanding due to its diverse applications in time-critical situations. A main issue of realizing online MOT is how to associate noisy object detection results on a new frame with previously being tracked objects. In this work, we propose a multi-object tracker method called CRF-boosting which utilizes a hybrid data association method based on online hybrid boosting facilitated by a conditional random field (CRF) for establishing online MOT. For data association, learned CRF is used to generate reliable low-level tracklets and then these are used as the input of the hybrid boosting. To do so, while existing data association methods based on boosting algorithms have the necessity of training data having ground truth information to improve robustness, CRF-boosting ensures sufficient robustness without such information due to the synergetic cascaded learning procedure. Further, a hierarchical feature association framework is adopted to further improve MOT accuracy. From experimental results on public datasets, we could conclude that the benefit of proposed hybrid approach compared to the other competitive MOT systems is noticeable. PMID:28304366

  9. Successful Treatment of Disseminated Bacillus Calmette-Guérin Disease in an HIV-Infected Child with a Linezolid-Containing Regimen

    PubMed Central

    Dickson, Drusia; Miše, Branko; Katalinić-Janković, Vera; Rutherford, George

    2016-01-01

    Upon HIV infection diagnosis, an 8-month-old boy was transferred for evaluation of worsening respiratory distress requiring mechanical ventilation. Pneumocystis jirovecii pneumonia (PCP) was diagnosed; the boy also had a nonhealing ulcer at the site of vaccination with Statens Serum Institut (Danish strain) Bacillus Calmette-Guérin (BCG) vaccine and associated axillary lymphadenopathy. PCP treatment resulted in weaning from mechanical ventilation. Antimycobacterial treatment was immediately attempted but was discontinued because of hepatotoxicity. Over several months, he developed splenic lesions and then disseminated skin and cystic bone lesions. M. bovis was repeatedly cultured from both skin and bone lesions despite various multidrug antimycobacterial regimens which included linezolid. Eventually, treatment with a regimen of rifabutin, isoniazid, ethambutol, and linezolid led to definitive cure. Clinicians should consider a linezolid-containing regimen for treatment of severe disseminated BCG infection, especially if other drug regimens have failed. Although drug toxicity is a particular concern for young children, this patient received linezolid for 13 months without serious toxicity. This case also highlights the need for universal screening among pregnant women to prevent vertical transmission of HIV. Finally, routine immunization with BCG vaccine at birth should be questioned in countries with low and declining burden of tuberculosis. PMID:27803824

  10. A Phase I/II adaptive design to determine the optimal treatment regimen from a set of combination immunotherapies in high-risk melanoma.

    PubMed

    Wages, Nolan A; Slingluff, Craig L; Petroni, Gina R

    2015-03-01

    In oncology, vaccine-based immunotherapy often investigates regimens that demonstrate minimal toxicity overall and higher doses may not correlate with greater immune response. Rather than determining the maximum tolerated dose, the goal of the study becomes locating the optimal biological dose, which is defined as a safe dose demonstrating the greatest immunogenicity, based on some predefined measure of immune response. Incorporation of adjuvants, new or optimized peptide vaccines, and combining vaccines with immune modulators may enhance immune response, with the aim of improving clinical response. Innovative dose escalation strategies are needed to establish the safety and immunogenicity of new immunologic combinations. We describe the implementation of an adaptive design for identifying the optimal treatment strategy in a multi-site, FDA-approved, phase I/II trial of a novel vaccination approach using long-peptides plus TLR agonists for resected stage IIB-IV melanoma. Operating characteristics of the design are demonstrated under various possible true scenarios via simulation studies. Overall performance indicates that the design is a practical Phase I/II adaptive method for use with combined immunotherapy agents. The simulation results demonstrate the method's ability to effectively recommend optimal regimens in a high percentage of trials with manageable sample sizes. The numerical results presented in this work include the type of simulation information that aid review boards in understanding design performance, such as average sample size and frequency of early trial termination, which we hope will augment early-phase trial design in cancer immunotherapy.

  11. Combined prime-boost vaccination against tick-borne encephalitis (TBE) using a recombinant vaccinia virus and a bacterial plasmid both expressing TBE virus non-structural NS1 protein

    PubMed Central

    Aleshin, SE; Timofeev, AV; Khoretonenko, MV; Zakharova, LG; Pashvykina, GV; Stephenson, JR; Shneider, AM; Altstein, AD

    2005-01-01

    Background Heterologous prime-boost immunization protocols using different gene expression systems have proven to be successful tools in protecting against various diseases in experimental animal models. The main reason for using this approach is to exploit the ability of expression cassettes to prime or boost the immune system in different ways during vaccination procedures. The purpose of the project was to study the ability of recombinant vaccinia virus (VV) and bacterial plasmid, both carrying the NS1 gene from tick-borne encephalitis (TBE) virus under the control of different promoters, to protect mice against lethal challenge using a heterologous prime-boost vaccination protocol. Results The heterologous prime-boost vaccination protocol, using a VV recombinant and bacterial plasmid, both containing the NS1 TBE virus protein gene under the control of different promoters, achieved a high level of protection in mice against lethal challenge with a highly pathogenic TBE virus strain. No signs of pronounced TBE infection were detected in the surviving animals. Conclusion Heterologous prime-boost vaccination protocols using recombinant VV and bacterial plasmids could be used for the development of flavivirus vaccines. PMID:16076390

  12. Management of patients using unproven regimens for arthritis.

    PubMed

    Wolman, P G

    1987-09-01

    Such treatments as vegetarian diets, fresh or raw diets, allergy diets, no-dairy-products diets, fasting, vitamin and mineral supplementation, apple cider vinegar, and honey drinks are touted in the popular press as effective for the treatment of arthritis. In contrast to conventional therapies, the unproven treatments promise not only relief from symptoms but freedom from the disease as long as the diet regimen is followed. Several of the remedies appear to be harmless, but others are dangerous, especially if followed for prolonged periods. Nutrition professionals should be aware of the nature of these treatments and be prepared to offer sound, scientifically based but nonjudgmental care and information.

  13. Rifaximin Plus Levofloxacin-Based Rescue Regimen for the Eradication of Helicobacter pylori

    PubMed Central

    Yun, Sang-Pil; Seon, Han Gyung; Ok, Chang Soo; Yoo, Kwang Ho; Kang, Min Kyung; Kim, Won Hee; Kwon, Chang Il; Ko, Kwang Hyun; Hwang, Seong Gyu; Park, Pil Won

    2012-01-01

    Background/Aims This study assessed the efficacy of a rifaximin plus levofloxacin-based rescue regimen in patients that had failed both triple and quadruple standard regimens for the eradication of Helicobacter pylori. Methods We treated patients for H. pylori between August 2009 and April 2011. The triple regimen consisted of combined treatment with amoxicillin, clarithromycin, and pantoprazole for 1 week. For failed cases, a quadruple regimen of tetracycline, metronidazole, bismuth dicitrate, and lansoprazole for 1 week was administered. The rescue regimen for persistently refractory cases was rifaximin 200 mg t.i.d., levofloxacin 500 mg q.d., and lansoprazole 15 mg b.i.d. for 1 week. Results In total, 482 patients were enrolled in this study. The eradication rates associated with the first and second regimens were 58% and 60%, respectively. Forty-seven out of 58 patients who failed with the second-line regimen received rifaximin plus levofloxacin-based third-line therapy. The eradication rate for the third regimen was 65%. The cumulative eradication rates were 58%, 85%, and 96% for each regimen, respectively. Conclusions A rifaximin plus levofloxacin-based regimen could be an alternative rescue therapy in patients with resistance to both triple and quadruple regimens for the eradication of H. pylori. PMID:23170149

  14. Immunogenicity of a vaccine regimen composed of simian immunodeficiency virus DNA, rMVA, and viral particles administered to female rhesus macaques via four different mucosal routes.

    PubMed

    Manrique, Mariana; Kozlowski, Pamela A; Cobo-Molinos, Antonio; Wang, Shainn-Wei; Wilson, Robert L; Montefiori, David C; Carville, Angela; Aldovini, Anna

    2013-04-01

    A comparative evaluation of the immunity stimulated with a vaccine regimen that includes simian immunodeficiency virus (SIV), interleukin 2 (IL-2), and IL-15 DNAs, recombinant modified vaccinia virus Ankara (rMVA), and inactivated SIVmac239 particles administered into the oral and nasal cavities, small intestine, and vagina was carried out in female rhesus macaques to determine the best route to induce diverse anti-SIV immunity that may be critical to protection from SIV infection and disease. All four immunizations generated mucosal SIV-specific IgA. Oral immunization was as effective as vaginal immunization in inducing SIV-specific IgA in vaginal secretions and generated greater IgA responses in rectal secretions and saliva samples compared to the other immunization routes. All four immunizations stimulated systemic T-cell responses against Gag and Env, albeit to a different extent, with oral immunization providing greater magnitude and nasal immunization providing wider functional heterogeneity. SIV-specific T cells producing gamma interferon (IFN-γ) dominated these responses. Limited levels of SIV-specific IgG antibodies were detected in plasma samples, and no SIV-specific IgG antibodies were detected in secretions. Vaccination also induced CD4(+) and CD8(+) T-cell responses in the rectal and vaginal mucosa with greater functional heterogeneity than in blood samples. Rectal T-cell responses were significantly greater in the orally vaccinated animals than in the other animals. The most balanced, diverse, and higher-magnitude vaginal T-cell responses were observed after intestinal vaccination. Significantly higher CD8(+) granzyme B-positive T-cell responses were observed systemically after intestinal vaccination and in rectal cells after oral immunization. The majority of SIV-specific T cells that produced granzyme B did not produce cytokines. Of the immunization routes tested, oral vaccination provided the most diverse and significant response to the vaccine.

  15. A methodology for boost-glide transport technology planning

    NASA Technical Reports Server (NTRS)

    Repic, E. M.; Olson, G. A.; Milliken, R. J.

    1974-01-01

    A systematic procedure is presented by which the relative economic value of technology factors affecting design, configuration, and operation of boost-glide transport can be evaluated. Use of the methodology results in identification of first-order economic gains potentially achievable by projected advances in each of the definable, hypersonic technologies. Starting with a baseline vehicle, the formulas, procedures and forms which are integral parts of this methodology are developed. A demonstration of the methodology is presented for one specific boost-glide system.

  16. Boosted Objects: A Probe of Beyond the Standard Model Physics

    SciTech Connect

    Abdesselam, A.; Kuutmann, E.Bergeaas; Bitenc, U.; Brooijmans, G.; Butterworth, J.; Bruckman de Renstrom, P.; Buarque Franzosi, D.; Buckingham, R.; Chapleau, B.; Dasgupta, M.; Davison, A.; Dolen, J.; Ellis, S.; Fassi, F.; Ferrando, J.; Frandsen, M.T.; Frost, J.; Gadfort, T.; Glover, N.; Haas, A.; Halkiadakis, E.; /more authors..

    2012-06-12

    We present the report of the hadronic working group of the BOOST2010 workshop held at the University of Oxford in June 2010. The first part contains a review of the potential of hadronic decays of highly boosted particles as an aid for discovery at the LHC and a discussion of the status of tools developed to meet the challenge of reconstructing and isolating these topologies. In the second part, we present new results comparing the performance of jet grooming techniques and top tagging algorithms on a common set of benchmark channels. We also study the sensitivity of jet substructure observables to the uncertainties in Monte Carlo predictions.

  17. Buck-boost converter feedback controller design via evolutionary search

    NASA Astrophysics Data System (ADS)

    Sundareswaran, K.; Devi, V.; Nadeem, S. K.; Sreedevi, V. T.; Palani, S.

    2010-11-01

    Buck-boost converters are switched power converters. The model of the converter system varies from the ON state to the OFF state and hence traditional methods of controller design based on approximate transfer function models do not yield good dynamic response at different operating points of the converter system. This article attempts to design a feedback controller for a buck-boost type dc-dc converter using a genetic algorithm. The feedback controller design is perceived as an optimisation problem and a robust controller is estimated through an evolutionary search. Extensive simulation and experimental results provided in the article show the effectiveness of the new approach.

  18. Quantum AdaBoost algorithm via cluster state

    NASA Astrophysics Data System (ADS)

    Li, Yuan

    2017-03-01

    The principle and theory of quantum computation are investigated by researchers for many years, and further applied to improve the efficiency of classical machine learning algorithms. Based on physical mechanism, a quantum version of AdaBoost (Adaptive Boosting) training algorithm is proposed in this paper, of which purpose is to construct a strong classifier. In the proposed scheme with cluster state in quantum mechanism is to realize the weak learning algorithm, and then update the corresponding weight of examples. As a result, a final classifier can be obtained by combining efficiently weak hypothesis based on measuring cluster state to reweight the distribution of examples.

  19. Immunization Schedules for Adults

    MedlinePlus

    ... ACIP Vaccination Recommendations Why Immunize? Vaccines: The Basics Immunization Schedules for Adults in Easy-to-read Formats ... previous immunizations. View or Print a Schedule Recommended Immunizations for Adults (19 Years and Older) by Age ...

  20. Immune System (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Immune System KidsHealth > For Parents > Immune System A A A ... can lead to illness and infection. About the Immune System The immune system is the body's defense against ...

  1. Logistics of therapy with the ibritumomab tiuxetan regimen

    SciTech Connect

    Meredith, Ruby F. . E-mail: rmeredith@uabmc.edu

    2006-10-01

    Radioimmunotherapy is an important new modality for treating patients with B-cell non-Hodgkin's lymphoma (NHL). Clinical trials have shown the safety and efficacy of agents that deliver radiation directly to malignant cells by attaching the {sup 131}I or {sup 9}Y radionuclide to monoclonal antibodies against CD20. In clinical trials, {sup 9}Y ibritumomab tiuxetan has produced rates of response as high as 83% in patients with relapsed or refractory CD20+ NHL. The ibritumomab tiuxetan regimen is conveniently given in an outpatient setting over the course of 7-9 days. This article describes the logistics for initiating treatment, coordinating a multidisciplinary team, identifying eligible patients, and delivering the imaging and therapeutic doses of ibritumomab tiuxetan. The standard radiation safety procedures to protect family members and healthcare professionals involved in the care of patients treated with {sup 9}Y ibritumomab tiuxetan are also reviewed. Treatment with the ibritumomab tiuxetan regimen involves only standard precautions needed to minimize radiation exposure to other persons.

  2. Remission-Induction Regimens in Acute Nonlymphocytic Leukemia

    PubMed Central

    Brennan, Donald C.; Lewis, Jerry P.

    1980-01-01

    A sequential study was carried out involving 40 adults with acute nonlymphocytic leukemia (ANLL). The first 20 patients were treated with cytarabine (Ara-C) and 6-thioguanine (6-TG), the second 20 with a regimen that added a three-day course of daunomycin (DNM) to the Ara-C and 6-TG therapy. With both groups well matched for age, patients in the DNM-treated group had a higher complete remission (CR) rate but failed to survive longer than those in the Ara-C and 6-TG treatment group. In a comprehensive literature review of various treatments for adult ANLL, a higher CR rate but not significantly better survival for patients initially treated with DNM-combined regimens was found. Our analysis of cases and literature review suggest that while DNM is a very active drug, its use in the initial treatment of adult ANLL has not produced a significant improvement in overall survival or in survival of those brought into complete remission. PMID:7347042

  3. HIV-1-Specific Antibody Response and Function after DNA Prime and Recombinant Adenovirus 5 Boost HIV Vaccine in HIV-Infected Subjects

    PubMed Central

    Gach, Johannes S.; Gorlani, Andrea; Dotsey, Emmanuel Y.; Becerra, Juan C.; Anderson, Chase T. M.; Berzins, Baiba; Felgner, Philip L.; Forthal, Donald N.; Deeks, Steven G.; Wilkin, Timothy J.; Casazza, Joseph P.; Koup, Richard A.; Katlama, Christine; Autran, Brigitte; Murphy, Robert L.; Achenbach, Chad J.

    2016-01-01

    Little is known about the humoral immune response against DNA prime-recombinant adenovirus 5 (rAd5) boost HIV vaccine among HIV-infected patients on long-term suppressive antiretroviral therapy (ART). Previous studies emphasized cellular immune responses; however, current research suggests both cellular and humoral responses are likely required for a successful therapeutic vaccine. Thus, we aimed to understand antibody response and function induced by vaccination of ART-treated HIV-1-infected patients with immune recovery. All subjects participated in EraMune 02, an open-label randomized clinical trial of ART intensification followed by a six plasmid DNA prime (envA, envB, envC, gagB, polB, nefB) and rAd5 boost HIV vaccine with matching inserts. Antibody binding levels were determined with a recently developed microarray approach. We also analyzed neutralization efficiency and antibody-dependent cellular cytotoxicity (ADCC). We found that the DNA prime-rAd5 boost vaccine induced a significant cross-clade HIV-specific antibody response, which correlated with antibody neutralization efficiency. However, despite the increase in antibody binding levels, the vaccine did not significantly stimulate neutralization or ADCC responses. This finding was also reflected by a lack of change in total CD4+ cell associated HIV DNA in those who received the vaccine. Our results have important implications for further therapeutic vaccine design and administration, especially in HIV-1 infected patients, as boosting of preexisting antibody responses are unlikely to lead to clearance of latent proviruses in the HIV reservoir. PMID:27500639

  4. Prime-boost bacillus Calmette-Guérin vaccination with lentivirus-vectored and DNA-based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice.

    PubMed

    Xu, Ying; Yang, Enzhuo; Wang, Jianguang; Li, Rui; Li, Guanghua; Liu, Guoyuan; Song, Na; Huang, Qi; Kong, Cong; Wang, Honghai

    2014-10-01

    To prevent the global spread of tuberculosis (TB), more effective vaccines and vaccination strategies are urgently needed. As a result of the success of bacillus Calmette-Guérin (BCG) in protecting children against miliary and meningeal TB, the majority of individuals will have been vaccinated with BCG; hence, boosting BCG-primed immunity will probably be a key component of future vaccine strategies. In this study, we compared the ability of DNA-, protein- and lentiviral vector-based vaccines that express the antigens Ag85B and Rv3425 to boost the effects of BCG in the context of immunity and protection against Mycobacterium tuberculosis in C57BL/6 mice. Our results demonstrated that prime-boost BCG vaccination with a lentiviral vector expressing the antigens Ag85B and Rv3425 significantly enhanced immune responses, including T helper type 1 and CD8(+) cytotoxic T lymphocyte responses, compared with DNA- and protein-based vaccines. However, lentivirus-vectored and DNA-based vaccines greatly improved the protective efficacy of BCG against M. tuberculosis, as indicated by a lack of weight loss and significantly reduced bacterial loads and histological damage in the lung. Our study suggests that the use of lentiviral or DNA vaccines containing the antigens Ag85B and Rv3425 to boost BCG is a good choice for the rational design of an efficient vaccination strategy against TB.

  5. Long-term CD4+ T-cell count evolution after switching from regimens including HIV nucleoside reverse transcriptase inhibitors (NRTI) plus protease inhibitors to regimens containing NRTI plus non-NRTI or only NRTI

    PubMed Central

    2011-01-01

    not seem to impair CD4+ trend over long-term follow-up. Although the greater CD4+ increases in patients who switched to the NRTI-only regimen was due to higher CD4+ counts before the switch, several statistical analyses consistently showed that switching to this regimen did not damage the ongoing immune-reconstitution. Lastly, the observation that CD4+ T-cell counts remained low or decreased in the long term despite virological success merits further investigation. PMID:21266068

  6. Monoclonal antibody against mouse CAR following genetic immunization.

    PubMed

    Carson, Steven D; Switzer, Barbara L; Tracy, Steven M; Chapman, Nora M

    2004-02-01

    To broaden our repertoire of monoclonal antibodies against CAR (coxsackievirus and adenovirus receptor), we inoculated mice with an expression vector containing the cDNA encoding human CAR extracellular and transmembrane sequence, and boosted the response by inoculation with soluble human CAR protein produced in E. coli. Of the hybridomas obtained following this immunization protocol, one secreted IgG with exceptional reactivity against mouse CAR. Since CAR has been shown to form dimers, expression of human CAR in cells that express mouse CAR may have stimulated the host immune system to recognize endogenous CAR in heterodimers.

  7. Repetitive peptide boosting progressively enhances functional memory CTLs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Induction of functional memory CTLs holds promise for fighting critical infectious diseases through vaccination, but so far, no effective regime has been identified. We show here that memory CTLs can be enhanced progressively to high levels by repetitive intravenous boosting with peptide and adjuvan...

  8. Real-World Connections Can Boost Journalism Program.

    ERIC Educational Resources Information Center

    Schrier, Kathy; Bott, Don; McGuire, Tim

    2001-01-01

    Describes various ways scholastic journalism advisers have attempted to make real-world connections to boost their journalism programs: critiques of student publications by invited guest speakers (professional journalists); regional workshops where professionals offer short presentations; local media offering programming or special sections aimed…

  9. Boost compensator for use with internal combustion engine with supercharger

    SciTech Connect

    Asami, T.

    1988-04-12

    A boost compensator for controlling the position of a control rack of a fuel injection pump to supply fuel to an internal combustion with a supercharger in response to a boost pressure to be applied to the engine is described. The control rack is movable in a first direction increasing an amount of fuel to be supplied by the fuel injection pump to the engine and in a second direction, opposite to the first direction, decreasing the amount of fuel. The boost compensator comprises: a push rod disposed for forward and rearward movement in response to the boost pressure; a main lever disposed for angular movement about a first pivot; an auxiliary lever disposed for angular movement about a second pivot; return spring means associated with the first portion of the auxiliary lever for resiliently biasing same in one direction about the second pivot; and abutment means mounted on the second portion of the auxiliary lever and engageable with the second portion of the main lever.

  10. Balance-Boosting Footwear Tips for Older People

    MedlinePlus

    ... Home » Learn About Feet » Tips for Healthy Feet Balance-Boosting Footwear Tips for Older People Balance in all aspects of life is a good ... mental equilibrium isn't the only kind of balance that's important in life. Good physical balance can ...

  11. Graph ensemble boosting for imbalanced noisy graph stream classification.

    PubMed

    Pan, Shirui; Wu, Jia; Zhu, Xingquan; Zhang, Chengqi

    2015-05-01

    Many applications involve stream data with structural dependency, graph representations, and continuously increasing volumes. For these applications, it is very common that their class distributions are imbalanced with minority (or positive) samples being only a small portion of the population, which imposes significant challenges for learning models to accurately identify minority samples. This problem is further complicated with the presence of noise, because they are similar to minority samples and any treatment for the class imbalance may falsely focus on the noise and result in deterioration of accuracy. In this paper, we propose a classification model to tackle imbalanced graph streams with noise. Our method, graph ensemble boosting, employs an ensemble-based framework to partition graph stream into chunks each containing a number of noisy graphs with imbalanced class distributions. For each individual chunk, we propose a boosting algorithm to combine discriminative subgraph pattern selection and model learning as a unified framework for graph classification. To tackle concept drifting in graph streams, an instance level weighting mechanism is used to dynamically adjust the instance weight, through which the boosting framework can emphasize on difficult graph samples. The classifiers built from different graph chunks form an ensemble for graph stream classification. Experiments on real-life imbalanced graph streams demonstrate clear benefits of our boosting design for handling imbalanced noisy graph stream.

  12. Boost glycemic control in teen diabetics through 'family focused teamwork'.

    PubMed

    2003-09-01

    While family conflict during the teenaged years is typical, it can have long-term health consequences when it involves an adolescent with diabetes. However, researchers at Joslin Diabetes Center in Boston have developed a low-cost intervention that aims to remove conflict from disease management responsibilities--and a new study shows that it can boost glycemic control as well.

  13. Early Boost and Slow Consolidation in Motor Skill Learning

    ERIC Educational Resources Information Center

    Hotermans, Christophe; Peigneux, Philippe; de Noordhout, Alain Maertens; Moonen, Gustave; Maquet, Pierre

    2006-01-01

    Motor skill learning is a dynamic process that continues covertly after training has ended and eventually leads to delayed increments in performance. Current theories suggest that this off-line improvement takes time and appears only after several hours. Here we show an early transient and short-lived boost in performance, emerging as early as…

  14. Intravenous immune globulin in chronic lymphocytic leukaemia.

    PubMed Central

    Gamm, H; Huber, C; Chapel, H; Lee, M; Ries, F; Dicato, M A

    1994-01-01

    The most common complication of chronic lymphocytic leukaemia (CLL) is infection, which occurs mainly in advanced stages of disease or in those patients with hypogammaglobulinaemia. Intravenous immune globulin (IVIG) has been shown to be a useful prophylactic therapy against infections in such patients. A randomized, double-blind study on 36 patients receiving either 500 mg/kg or 250 mg/kg IVIG every 4 weeks was undertaken to determine the dose regimen required. There was no significant difference in the two treatment groups and we found that CLL patients were equally protected with low-dose IVIG. PMID:8033428

  15. A Nonadjuvanted Transcutaneous Tetanus Patch Is Effective in Boosting Anti-Tetanus Toxoid Immune Responses

    PubMed Central

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

    2014-01-01

    Dry tetanus toxoid (TTx) patches were formulated without any adjuvant, with excipients to impart antigen stabilization and to enhance skin delivery. The booster effects of the TTx patches were assessed using a guinea pig model. The study revealed significant rises in TTx IgG titers induced by the TTx patches after a low-dose subcutaneous (s.c.) prime with TTx adsorbed to aluminum hydroxide. The TTx patch can therefore be considered an effective alternative to a subcutaneous booster. PMID:24334688

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

    PubMed

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

    2014-02-01

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

  17. Benefit of Radiation Boost After Whole-Breast Radiotherapy

    SciTech Connect

    Livi, Lorenzo; Borghesi, Simona; Saieva, Calogero; Fambrini, Massimiliano; Iannalfi, Alberto; Greto, Daniela; Paiar, Fabiola; Scoccianti, Silvia; Simontacchi, Gabriele; Bianchi, Simonetta; Cataliotti, Luigi; Biti, Giampaolo

    2009-11-15

    Purpose: To determine whether a boost to the tumor bed after breast-conserving surgery (BCS) and radiotherapy (RT) to the whole breast affects local control and disease-free survival. Methods and Materials: A total of 1,138 patients with pT1 to pT2 breast cancer underwent adjuvant RT at the University of Florence. We analyzed only patients with a minimum follow-up of 1 year (range, 1-20 years), with negative surgical margins. The median age of the patient population was 52.0 years (+-7.9 years). The breast cancer relapse incidence probability was estimated by the Kaplan-Meier method, and differences between patient subgroups were compared by the log rank test. Cox regression models were used to evaluate the risk of breast cancer relapse. Results: On univariate survival analysis, boost to the tumor bed reduced breast cancer recurrence (p < 0.0001). Age and tamoxifen also significantly reduced breast cancer relapse (p = 0.01 and p = 0.014, respectively). On multivariate analysis, the boost and the medium age (45-60 years) were found to be inversely related to breast cancer relapse (hazard ratio [HR], 0.27; 95% confidence interval [95% CI], 0.14-0.52, and HR 0.61; 95% CI, 0.37-0.99, respectively). The effect of the boost was more evident in younger patients (HR, 0.15 and 95% CI, 0.03-0.66 for patients <45 years of age; and HR, 0.31 and 95% CI, 0.13-0.71 for patients 45-60 years) on multivariate analyses stratified by age, although it was not a significant predictor in women older than 60 years. Conclusion: Our results suggest that boost to the tumor bed reduces breast cancer relapse and is more effective in younger patients.

  18. The Successful Application of a National Peer Advisory Committee for Physicians Who Provide Salvage Regimens to Heavily Antiretroviral-Experienced Patients in Mexican Human Immunodeficiency Virus Clinics

    PubMed Central

    Calva, Juan J.; Sierra-Madero, Juan; Soto-Ramírez, Luis E.; Aguilar-Salinas, Pedro

    2014-01-01

    Background  Designing optimal antiretroviral (ARV) salvage regimens for multiclass drug-resistant, human immunodeficiency virus (HIV)-infected patients demands specific clinical skills. Our aim was to assess the virologic and immunologic effects of the treatment recommendations drafted by a peer advisory board to physicians caring for heavily ARV-experienced patients. Methods  We conducted a nationwide, HIV clinic-based, cohort study in Mexico. Adults infected with HIV were assessed for a median of 33 months (interquartile range [IQR] = 22–43 months). These patients had experienced the virologic failure of at least 2 prior ARV regimens and had detectable viremia while currently being treated; their physicians had received therapeutic advice, by a panel of experts, regarding the ARV salvage regimen. The primary endpoint was the incidence of loss of virologic response (plasma HIV-RNA levels of <200 copies per mL, followed by levels above this threshold) during the follow-up assessment using an observed-failure competing risks regression analysis. Results  A total of 611 patients were observed (median ARV therapy exposure = 10.5 years; median prior regimens = 4). The probabilities of virologic failure were 11.9%, 14.4%, 16.9%, and 19.4% at the 12-, 24-, 36-, and 48-month follow-up assessments, respectively. Of the 531 patients who achieved a confirmed plasma HIV-RNA level below 200 copies per mL, the median increase in blood CD4+ T-cell count was 162 cells per mL (IQR = 45–304 cells per mL). Conclusions  In routine practice, a high rate of patients with extensive ARV experience, who received an optimized salvage regimen recommended by a peer advisory committee, achieved a long-term sustained virologic response and immune reconstitution. PMID:25734149

  19. 14 CFR 27.695 - Power boost and power-operated control system.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Systems § 27.695 Power boost and power-operated control system. (a) If a power boost or power-operated... failure of all engines. (b) Each alternate system may be a duplicate power portion or a manually operated... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Power boost and power-operated...

  20. 14 CFR 29.695 - Power boost and power-operated control system.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Systems § 29.695 Power boost and power-operated control system. (a) If a power boost or power-operated... failure of all engines. (b) Each alternate system may be a duplicate power portion or a manually operated... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Power boost and power-operated...

  1. Gefitinib, Fluorouracil, Oxaliplatin, and Leucovorin (IFOX) Regimen for Colorectal Cancer

    PubMed Central

    Chen, Alicia S.; Solimando, Dominic A.; Waddell, J. Aubrey

    2013-01-01

    The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID:24474830

  2. Comparison of different regimens for surgical hand preparation.

    PubMed

    Larson, E L; Aiello, A E; Heilman, J M; Lyle, C T; Cronquist, A; Stahl, J B; Della-Latta, P

    2001-02-01

    Twenty surgical staff members participated in a clinical trial to compare the microbiology and skin condition of hands when using a traditional surgical scrub (TSS) with a detergent-based antiseptic containing 4% chlorhexidine gluconate (CHG) and a short application without scrub of a waterless hand preparation (HP) containing 61% ethyl alcohol, 1% CHG, and emollients. The HP was associated with less skin damage (P = .002) and lower microbial counts postscrub at days five (P = .002) and 19 (P = .02). The HP protocol had shorter contact time (HP mean [M] = 80.7 seconds; TSS M = 144.9 seconds; P < .0001), and more subjects preferred the HP regimen (P = .001). The HP performed better than the TSS, was less costly, and should be evaluated in larger trials and considered for widespread implementation.

  3. Levothyroxine Treatment in Pregnancy: Indications, Efficacy, and Therapeutic Regimen

    PubMed Central

    Klubo-Gwiezdzinska, Joanna; Burman, Kenneth D.; Van Nostrand, Douglas; Wartofsky, Leonard

    2011-01-01

    The prevalence of overt and subclinical hypothyroidism during pregnancy is estimated to be 0.3–0.5% and 2–3%, respectively. Thyroid autoantibodies are found in 5–18% of women in the childbearing age. The aim of this review is to underscore the clinical significance of these findings on the health of both the mother and her offspring. Methods of evaluation of thyroid function tests (TFTs) during pregnancy are described as are the threshold values for the diagnosis of overt and subclinical hypothyroidism or hypothyroxinemia. Anticipated differences in TFTs in iodine-sufficient and iodine-deficient areas are discussed and data are provided on potential complications of hypothyroidism/hypothyroxinemia and autoimmune thyroid disease during pregnancy and adverse effects for the offspring. The beneficial effects of levothyroxine therapy on pregnancy outcomes and offspring development are discussed with a proposed treatment regimen and follow up strategy. PMID:21876837

  4. Current regimens and novel agents for mantle cell lymphoma.

    PubMed

    Chen, Yiming; Wang, Michael; Romaguera, Jorge

    2014-10-01

    Mantle cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes.

  5. Dilemma of first line regimens in metastatic pancreatic adenocarcinoma

    PubMed Central

    Ghosn, Marwan; Ibrahim, Tony; Assi, Tarek; El Rassy, Elie; Kourie, Hampig Raphael; Kattan, Joseph

    2016-01-01

    Pancreatic cancer is one of the deadliest cancers, ranking fourth among cancer-related deaths. Despite all the major molecular advances and treatment breakthroughs, mainly targeted therapies, the cornerstone treatment of metastatic pancreatic cancer (mPC) remains cytotoxic chemotherapy. In 2016, more than 40 years after the introduction of gemcitabine in the management of mPC, the best choice for first-line treatment has not yet been fully elucidated. Two main strategies have been adopted to enhance treatment efficacy. The first strategy is based on combining non-cross resistant drugs, while the second option includes the development of newer generations of chemotherapy. More recently, two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel (GNP), have both been shown to improve overall survival in comparison with gemcitabine alone, at the cost of increased toxicity. Therefore, the best choice for first line therapy is a matter of debate. For some authors, FOLFIRINOX should be the first choice in patients with an Eastern Cooperative Oncology Group score (0-1) given its lower hazard ratio. However, others do not share this opinion. In this paper, we review the main comparison points between FOLFIRINOX and GNP. We analyze the two pivotal trials to determine the similarities and differences in study design. In addition, we compare the toxicity profile of the two regimens as well as the impact on quality of life. Finally, we present studies revealing real life experiences and review the advantages and disadvantages of possible second-line therapies including their cost effectiveness. PMID:28028360

  6. Superiority of Interferon-Free Regimens for Chronic Hepatitis C

    PubMed Central

    Younossi, Zobair M.; Stepanova, Maria; Esteban, Rafael; Jacobson, Ira; Zeuzem, Stefan; Sulkowski, Mark; Henry, Linda; Nader, Fatema; Cable, Rebecca; Afendy, Mariam; Hunt, Sharon

    2017-01-01

    Abstract Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients. Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy—Fatigue, Chronic Liver Disease Questionnaire— HCV, Work Productivity and Activity—Specific Health Problem) before, during, and after treatment. A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to −24.4% by treatment week 12, up to −8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to −7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs. IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores. PMID:28207507

  7. A study of parenteral iron regimens in hemodialysis patients.

    PubMed

    Besarab, A; Kaiser, J W; Frinak, S

    1999-07-01

    The administration of parenteral iron dextran to hemodialysis patients is typically intermittent. We sought to determine the most appropriate intervals for sampling iron parameters during intermittent need-based and continuous maintenance regimens and to quantify differences in efficacy between such regimens during long-term therapy. After a single course of 10 consecutive 100-mg iron doses administered to 14 patients on 16 occasions, transferrin saturation (TSAT) and ferritin were unreliable indices of iron status for the next 2 and 6 weeks, respectively. TSAT and ferritin levels at 1 week were virtually identical to those at 2 weeks after the administration of a single 50-mg or 100-mg iron dextran dose to 16 other patients. Twelve patients on maintenance iron therapy (25 to 100 mg/wk; TSAT, 30% to 50%) had a statistically significant decrease in the amount of recombinant human erythropoietin (rHuEPO) needed to maintain hemoglobin (Hb) levels between 10 and 11 g/dL compared with 12 patients receiving intermittent need-based dosing, an effect that persisted from week 16 to week 72 of the study. Maintenance iron was feasible even in a third group of eight patients targeted to sustain an Hb level of 14 g/dL. In both iron maintenance groups, iron indices could be measured at weekly intervals, and ferritin levels did not progressively increase over time. Continuous maintenance iron dextran used to maintain TSATs of 30% to 50% significantly reduced rHuEPO requirements and resulted in no adverse side effects in chronic hemodialysis patients. After weekly maintenance 25- to 100-mg iron dextran doses, iron indices can be measured after 1 week; a delay of 2 weeks is not necessary.

  8. Integrated Circuit Immunity

    NASA Technical Reports Server (NTRS)

    Sketoe, J. G.; Clark, Anthony

    2000-01-01

    This paper presents a DOD E3 program overview on integrated circuit immunity. The topics include: 1) EMI Immunity Testing; 2) Threshold Definition; 3) Bias Tee Function; 4) Bias Tee Calibration Set-Up; 5) EDM Test Figure; 6) EMI Immunity Levels; 7) NAND vs. and Gate Immunity; 8) TTL vs. LS Immunity Levels; 9) TP vs. OC Immunity Levels; 10) 7805 Volt Reg Immunity; and 11) Seventies Chip Set. This paper is presented in viewgraph form.

  9. Extended regimen combined oral contraception: A review of evolving concepts and acceptance by women and clinicians

    PubMed Central

    Nappi, Rossella E.; Kaunitz, Andrew M.; Bitzer, Johannes

    2016-01-01

    ABSTRACT Objectives: The clinical utility of extended regimen combined oral contraceptives (COCs) is increasingly being recognised. Our objective was to understand the attitudes of women and clinicians about the use of these regimens. We present the rationale for extended regimen COCs from a historical perspective, and trace their evolution and growing popularity in light of their clinical benefits. We conclude by offering potential strategies for counselling women about extended regimen COC options. Methods: We conducted a MEDLINE search to identify and summarise studies of extended regimen COCs, focusing on attitudes of women and clinicians regarding efficacy, safety/tolerability and fewer scheduled bleeding episodes and other potential benefits. Results: The body of contemporary literature on extended regimen COCs suggests that their contraceptive efficacy is comparable to that of conventional 28-day (i.e., 21/7) regimens. For women seeking contraception that allows infrequent scheduled bleeding episodes, particularly those who suffer from hormone withdrawal symptoms and cyclical symptoms (e.g., headache, mood changes, dysmenorrhoea, heavy menstrual bleeding), extended regimen COCs are an effective and safe option. Although satisfaction with extended regimen COCs in clinical trials is high, misperceptions about continuous hormone use may still limit the widespread acceptance of this approach. Conclusions: Despite the widespread acceptance among clinicians of extended regimen COCs as an effective and safe contraceptive option, these regimens are underused, likely due to a lack of awareness about their availability and utility among women. Improved patient education and counselling regarding the safety and benefits of extended regimen COCs may help women make more informed contraceptive choices. PMID:26572318

  10. Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria.

    PubMed

    Falade, Catherine; Makanga, Michael; Premji, Zul; Ortmann, Christine-Elke; Stockmeyer, Marlies; de Palacios, Patricia Ibarra

    2005-06-01

    Approximately one million children die from malaria each year. A recently approved artemisinin-based tablet, Coartem (co-artemether), comprising artemether 120 mg plus lumefantrine 20 mg, given in four doses, provides effective antimalarial treatment for children in many sub-Saharan countries. However, this regimen is considered insufficient for non-immune infants and in areas where multidrug-resistant Plasmodium falciparum predominates. This open-label study assessed the efficacy and safety of co-artemether administered to 310 African children weighing 5-25 kg, with acute, uncomplicated falciparum malaria. Six doses of co-artemether were given over 3 days, with follow-up at 7, 14 and 28 days. Treatment rapidly cleared parasitemia and fever. The overall 28-day cure rate was 86.5%, and 93.9% when corrected by PCR for reinfection. Cure rates at 7 and 14 days exceeded 97.0% (uncorrected) and, on day 28, were similar in infants (5-<10 kg) previously exposed to malaria infection (partially immune: 88.6% uncorrected; 93.3% corrected), and in those who were non-immune (82.5% uncorrected; 95.0% corrected). Adverse events were mostly mild. There was no electrocardiographic evidence of cardiotoxicity. The co-artemether six-dose regimen, treating acute uncomplicated falciparum malaria in African children, achieved rapid parasite clearance and a high cure rate. Treatment was generally safe and well tolerated.

  11. A Randomized Study Comparing the Efficacy of Three Hepatitis B Vaccine Induction Regimens in Adult Patients with Hematological Malignancies

    PubMed Central

    Özkurt, Zübeyde Nur; Suyanı, Elif; Haznedar, Rauf; Yağcı, Münci

    2016-01-01

    Objective: Non-responsiveness to hepatitis B virus (HBV) vaccines is not rare in hemato-oncological patients due to disease-associated or treatment-induced immune suppression. Although different strategies have been employed to improve the response rates, to date there is not an approved schedule for HBV immunization in patients with hematological malignancies. We designed a prospective randomized study to evaluate the efficacy of 3 different induction regimens for HBV vaccination. Materials and Methods: In the standard-dose (SD) group, total vaccine dose delivered was 40 µg and patients were vaccinated with 20 µg at weeks 0 and 4. In the high-dose dose-intensive (HDDI) group, total vaccine dose delivered was 80 µg and patients were vaccinated with 40 µg at weeks 0 and 4. In the high-dose time-intensive (HDTI) group, total vaccine dose delivered was 80 µg and patients were vaccinated with 20 µg at weeks 0, 2, 4, and 6. Results: In a cohort of 114 patients, 38.6% responded to HBV vaccination. The response rate in the SD arm, HDDI arm, and HDTI arm was 26.2%, 29.7%, and 44.4%, respectively (p>0.05). Age was the only variable identified as having a negative impact on response. Conclusion: Short of achieving statistical significance, a higher response rate was observed in the HDTI arm. Therefore, this study supports a high-dose, time-intensive HBV vaccine induction regimen in patients with hematological malignancies who are not on chemotherapy. PMID:27094506

  12. Treatment regimens and health care utilization in children with persistent asthma symptoms.

    PubMed

    Yoos, H Lorrie; Kitzman, Harriet; Halterman, Jill S; Henderson, Charles; Sidora-Arcoleo, Kimberly; McMullen, Ann

    2006-01-01

    This study evaluated the anti-inflammatory medication regimens in children with persistent asthma, determined their health care utilization patterns, and evaluated factors associated with failure to seek and/or receive appropriate treatment. Parents of 68% of children who qualified for anti-inflammatory medications by National Asthma Education and Prevention Program (NAEPP) guidelines reported their use. However, only 14% received an optimal regimen (mild intermittent symptoms), while 55% were still symptomatic despite reported medications (suboptimal regimen). Nearly half of symptomatic children did not have a health care visit; of those who did, 61% had no corrective action documented. Factors contributing to variations in regimen and utilization are discussed.

  13. Randomized Open Trial Comparing 2-Dose Regimens of the Human Papillomavirus 16/18 AS04-Adjuvanted Vaccine in Girls Aged 9–14 Years Versus a 3-Dose Regimen in Women Aged 15–25 Years

    PubMed Central

    Puthanakit, Thanyawee; Huang, Li-Min; Chiu, Cheng-Hsun; Tang, Ren-Bin; Schwarz, Tino F.; Esposito, Susanna; Frenette, Louise; Giaquinto, Carlo; McNeil, Shelly; Rheault, Paul; Durando, Paolo; Horn, Michael; Klar, Maximilian; Poncelet, Sylviane; De Simoni, Stéphanie; Friel, Damien; De Muynck, Benoit; Suryakiran, Pemmaraju V.; Hezareh, Marjan; Descamps, Dominique; Thomas, Florence; Struyf, Frank

    2016-01-01

    Background. This randomized, open trial compared regimens including 2 doses (2D) of human papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine in girls aged 9–14 years with one including 3 doses (3D) in women aged 15–25 years. Methods. Girls aged 9–14 years were randomized to receive 2D at months 0 and 6 (M0,6; (n = 550) or months 0 and 12 (M0,12; n = 415), and women aged 15–25 years received 3D at months 0, 1, and 6 (n = 482). End points included noninferiority of HPV-16/18 antibodies by enzyme-linked immunosorbent assay for 2D (M0,6) versus 3D (primary), 2D (M0,12) versus 3D, and 2D (M0,6) versus 2D (M0,12); neutralizing antibodies; cell-mediated immunity; reactogenicity; and safety. Limits of noninferiority were predefined as <5% difference in seroconversion rate and <2-fold difference in geometric mean antibody titer ratio. Results. One month after the last dose, both 2D regimens in girls aged 9–14 years were noninferior to 3D in women aged 15–25 years and 2D (M0,12) was noninferior to 2D (M0,6). Geometric mean antibody titer ratios (3D/2D) for HPV-16 and HPV-18 were 1.09 (95% confidence interval, .97–1.22) and 0.85 (.76–.95) for 2D (M0,6) versus 3D and 0.89 (.79–1.01) and 0.75 (.67–.85) for 2D (M0,12) versus 3D. The safety profile was clinically acceptable in all groups. Conclusions. The 2D regimens for the HPV-16/18 AS04-adjuvanted vaccine in girls aged 9–14 years (M0,6 or M0,12) elicited HPV-16/18 immune responses that were noninferior to 3D in women aged 15–25 years. Clinical Trials Registration. NCT01381575. PMID:26908726

  14. Stress hyperglycemia, insulin treatment, and innate immune cells.

    PubMed

    Xiu, Fangming; Stanojcic, Mile; Diao, Li; Jeschke, Marc G

    2014-01-01

    Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

  15. Spacecraft boost and abort guidance and control systems requirement study, boost dynamics and control analysis study. Exhibit A: Boost dynamics and control anlaysis

    NASA Technical Reports Server (NTRS)

    Williams, F. E.; Price, J. B.; Lemon, R. S.

    1972-01-01

    The simulation developments for use in dynamics and control analysis during boost from liftoff to orbit insertion are reported. Also included are wind response studies of the NR-GD 161B/B9T delta wing booster/delta wing orbiter configuration, the MSC 036B/280 inch solid rocket motor configuration, the MSC 040A/L0X-propane liquid injection TVC configuration, the MSC 040C/dual solid rocket motor configuration, and the MSC 049/solid rocket motor configuration. All of the latest math models (rigid and flexible body) developed for the MSC/GD Space Shuttle Functional Simulator, are included.

  16. Immunization with heat-killed Francisella tularensis LVS elicits protective antibody-mediated immunity.

    PubMed

    Lavine, Christy L; Clinton, Shawn R; Angelova-Fischer, Irena; Marion, Tony N; Bina, Xiaowen R; Bina, James E; Whitt, Michael A; Miller, Mark A

    2007-11-01

    Francisella tularensis (FT) has been classified by the CDC as a category A pathogen because of its high virulence and the high mortality rate associated with infection via the aerosol route. Because there is no licensed vaccine available for FT, development of prophylactic and therapeutic regimens for the prevention/treatment of infection is a high priority. In this report, heat-killed FT live vaccine strain (HKLVS) was employed as a vaccine immunogen, either alone or in combination with an adjuvant, and was found to elicit protective immunity against high-dose FT live vaccine strain (FTLVS) challenge. FT-specific antibodies produced in response to immunization with HKLVS alone were subsequently found to completely protect naive mice against high-dose FT challenge in both infection-interference and passive immunization experiments. Additional passive immunization trials employing serum collected from mice immunized with a heat-killed preparation of an O-antigen-deficient transposon mutant of FTLVS (HKLVS-OAg(neg)) yielded similar results. These findings demonstrated that FT-specific antibodies alone can confer immunity against high-dose FTLVS challenge, and they reveal that antibody-mediated protection is not dependent upon production of LPS-specific antibodies.

  17. A phase II trial of accelerated radiotherapy using weekly stereotactic conformal boost for supratentorial glioblastoma multiforme: RTOG 0023

    SciTech Connect

    Cardinale, Robert; Choucair, Ali; Gillin, Michael; Chakravarti, Arnab; Schultz, Christopher; Souhami, Luis; Chen, Allan; Pham, Huong; Mehta, Minesh

    2006-08-01

    Purpose: This phase II trial was performed to assess the feasibility, toxicity, and efficacy of dose-intense accelerated radiation therapy using weekly fractionated stereotactic radiotherapy (FSRT) boost for patients with glioblastoma multiforme (GBM). Methods and Materials: Patients with histologically confirmed GBM with postoperative enhancing tumor plus tumor cavity diameter <60 mm were enrolled. A 50-Gy dose of standard radiation therapy (RT) was given in daily 2-Gy fractions. In addition, patients received four FSRT treatments, once weekly, during Weeks 3 to 6. FSRT dosing of either 5 Gy or 7 Gy per fraction was given for a cumulative dose of 70 or 78 Gy in 29 (25 standard RT + 4 FSRT) treatments over 6 weeks. After the RT course, carmustine (BCNU) at 80 mg/m{sup 2} was given for 3 days, every 8 weeks, for 6 cycles. Results: A total of 76 patients were analyzed. Toxicity included: 3 Grade 4 chemotherapy, 3 acute Grade 4 radiotherapy, and 1 Grade 3 late. The median survival time was 12.5 months. No survival difference is seen when compared with the RTOG historical database. Patients with gross total resection (41%) had a median survival time of 16.6 months vs. 12.0 months for historic controls with gross total resection (p = 0.14). Conclusion: This first, multi-institutional FSRT boost trial for GBM was feasible and well tolerated. There is no significant survival benefit using this dose-intense RT regimen. Subset analysis revealed a trend toward improved outcome for GTR patients suggesting that patients with minimal disease burden may benefit from this form of accelerated RT.

  18. DNA immunization as a technology platform for monoclonal antibody induction

    PubMed Central

    Liu, Shuying; Wang, Shixia; Lu, Shan

    2016-01-01

    To combat the threat of many emerging infectious diseases, DNA immunization offers a unique and powerful approach to the production of high-quality monoclonal antibodies (mAbs) against various pathogens. Compared with traditional protein-based immunization approaches, DNA immunization is efficient for testing novel immunogen designs, does not require the production or purification of proteins from a pathogen or the use of recombinant protein technology and is effective at generating mAbs against conformation-sensitive targets. Although significant progress in the use of DNA immunization to generate mAbs has been made over the last two decades, the literature does not contain an updated summary of this experience. The current review provides a comprehensive analysis of the literature, including our own work, describing the use of DNA immunization to produce highly functional mAbs, in particular, those against emerging infectious diseases. Critical factors such as immunogen design, delivery approach, immunization schedule, use of immune modulators and the role of final boost immunization are discussed in detail. PMID:27048742

  19. Biparental immune priming in the pipefish Syngnathus typhle.

    PubMed

    Beemelmanns, Anne; Roth, Olivia

    2016-08-01

    The transfer of immunity from parents to offspring (trans-generational immune priming (TGIP)) boosts offspring immune defence and parasite resistance. TGIP is usually a maternal trait. However, if fathers have a physical connection to their offspring, and if offspring are born in the paternal parasitic environment, evolution of paternal TGIP can become adaptive. In Syngnathus typhle, a sex-role reversed pipefish with male pregnancy, both parents invest into offspring immune defence. To connect TGIP with parental investment, we need to know how parents share the task of TGIP, whether TGIP is asymmetrically distributed between the parents, and how the maternal and paternal effects interact in case of biparental TGIP. We experimentally investigated the strength and differences but also the costs of maternal and paternal contribution, and their interactive biparental influence on offspring immune defence throughout offspring maturation. To disentangle maternal and paternal influences, two different bacteria were used in a fully reciprocal design for parental and offspring exposure. In offspring, we measured gene expression of 29 immune genes, 15 genes associated with epigenetic regulation, immune cell activity and life-history traits. We identified asymmetric maternal and paternal immune priming with a dominating, long-lasting paternal effect. We could not detect an additive adaptive biparental TGIP impact. However, biparental TGIP harbours additive costs as shown in delayed sexual maturity. Epigenetic regulation may play a role both in maternal and paternal TGIP.

  20. DNA immunization as a technology platform for monoclonal antibody induction.

    PubMed

    Liu, Shuying; Wang, Shixia; Lu, Shan

    2016-04-06

    To combat the threat of many emerging infectious diseases, DNA immunization offers a unique and powerful approach to the production of high-quality monoclonal antibodies (mAbs) against various pathogens. Compared with traditional protein-based immunization approaches, DNA immunization is efficient for testing novel immunogen designs, does not require the production or purification of proteins from a pathogen or the use of recombinant protein technology and is effective at generating mAbs against conformation-sensitive targets. Although significant progress in the use of DNA immunization to generate mAbs has been made over the last two decades, the literature does not contain an updated summary of this experience. The current review provides a comprehensive analysis of the literature, including our own work, describing the use of DNA immunization to produce highly functional mAbs, in particular, those against emerging infectious diseases. Critical factors such as immunogen design, delivery approach, immunization schedule, use of immune modulators and the role of final boost immunization are discussed in detail.

  1. High Temperature Boost (HTB) Power Processing Unit (PPU) Formulation Study

    NASA Technical Reports Server (NTRS)

    Chen, Yuan; Bradley, Arthur T.; Iannello, Christopher J.; Carr, Gregory A.; Mohammad, Mojarradi M.; Hunter, Don J.; DelCastillo, Linda; Stell, Christopher B.

    2013-01-01

    This technical memorandum is to summarize the Formulation Study conducted during fiscal year 2012 on the High Temperature Boost (HTB) Power Processing Unit (PPU). The effort is authorized and supported by the Game Changing Technology Division, NASA Office of the Chief Technologist. NASA center participation during the formulation includes LaRC, KSC and JPL. The Formulation Study continues into fiscal year 2013. The formulation study has focused on the power processing unit. The team has proposed a modular, power scalable, and new technology enabled High Temperature Boost (HTB) PPU, which has 5-10X improvement in PPU specific power/mass and over 30% in-space solar electric system mass saving.

  2. Black brane entropy and hydrodynamics: The boost-invariant case

    SciTech Connect

    Booth, Ivan; Heller, Michal P.; Spalinski, Michal

    2009-12-15

    The framework of slowly evolving horizons is generalized to the case of black branes in asymptotically anti-de Sitter spaces in arbitrary dimensions. The results are used to analyze the behavior of both event and apparent horizons in the gravity dual to boost-invariant flow. These considerations are motivated by the fact that at second order in the gradient expansion the hydrodynamic entropy current in the dual Yang-Mills theory appears to contain an ambiguity. This ambiguity, in the case of boost-invariant flow, is linked with a similar freedom on the gravity side. This leads to a phenomenological definition of the entropy of black branes. Some insights on fluid/gravity duality and the definition of entropy in a time-dependent setting are elucidated.

  3. Boost capacity, slash LWBS rate with POD triage system.

    PubMed

    2011-04-01

    With bottlenecks boosting ED wait times as well as the LWBS rate, Methodist Hospital of Sacramento decided to boost its triage capacity by taking over six beds that were being used for fast-track patients, and by taking advantage of waiting-room space for patients who don't need to be placed in beds. Within a month of implementing the new approach, the LWBS rate dropped to less than 2%, and door-to-doc time was slashed by 20 minutes. Under the POD system, providers have 15 minutes to determine whether patients should be discharged, sent back to the waiting room while tests are conducted, or placed in an ED bed where they can be monitored. To implement the approach, no alterations in physician staffing were needed, but the hospital added a triage nurse and a task nurse to manage patient flow of the triage POD.

  4. Development of a high speed parallel hybrid boost bearing

    NASA Technical Reports Server (NTRS)

    Winn, L. W.; Eusepi, M. W.

    1973-01-01

    The analysis, design, and testing of the hybrid boost bearing are discussed. The hybrid boost bearing consists of a fluid film bearing coupled in parallel with a rolling element bearing. This coupling arrangement makes use of the inherent advantages of both the fluid film and rolling element bearing and at the same time minimizes their disadvantages and limitations. The analytical optimization studies that lead to the final fluid film bearing design are reported. The bearing consisted of a centrifugally-pressurized planar fluid film thrust bearing with oil feed through the shaft center. An analysis of the test ball bearing is also presented. The experimental determination of the hybrid bearing characteristics obtained on the basis of individual bearing component tests and a combined hybrid bearing assembly is discussed and compared to the analytically determined performance characteristics.

  5. IMM tracking of a theater ballistic missile during boost phase

    NASA Astrophysics Data System (ADS)

    Hutchins, Robert G.; San Jose, Anthony

    1998-09-01

    Since the SCUD launches in the Gulf War, theater ballistic missile (TBM) systems have become a growing concern for the US military. Detection, tracking and engagement during boost phase or shortly after booster cutoff are goals that grow in importance with the proliferation of weapons of mass destruction. This paper addresses the performance of tracking algorithms for TBMs during boost phase and across the transition to ballistic flight. Three families of tracking algorithms are examined: alpha-beta-gamma trackers, Kalman-based trackers, and the interactive multiple model (IMM) tracker. In addition, a variation on the IMM to include prior knowledge of a booster cutoff parameter is examined. Simulated data is used to compare algorithms. Also, the IMM tracker is run on an actual ballistic missile trajectory. Results indicate that IMM trackers show significant advantage in tracking through the model transition represented by booster cutoff.

  6. High Efficient Universal Buck Boost Solar Array Regulator SAR Module

    NASA Astrophysics Data System (ADS)

    Kimmelmann, Stefan; Knorr, Wolfgang

    2014-08-01

    The high efficient universal Buck Boost Solar Array Regulator (SAR) module concept is applicable for a wide range of input and output voltages. The single point failure tolerant SAR module contains 3 power converters for the transfer of the SAR power to the battery dominated power bus. The converters are operating parallel in a 2 out of 3 redundancy and are driven by two different controllers. The output power of one module can be adjusted up to 1KW depending on the requirements. The maximum power point tracker (MPPT) is placed on a separate small printed circuit board and can be used if no external tracker signal is delivered. Depending on the mode and load conditions an efficiency of more than 97% is achievable. The stable control performance is achieved by implementing the magnetic current sense detection. The sensed power coil current is used in Buck and Boost control mode.

  7. Externally Dispersed Interferometry for Resolution Boosting and Doppler Velocimetry

    SciTech Connect

    Erskine, D J

    2003-12-01

    Externally dispersed interferometry (EDI) is a rapidly advancing technique for wide bandwidth spectroscopy and radial velocimetry. By placing a small angle-independent interferometer near the slit of an existing spectrograph system, periodic fiducials are embedded on the recorded spectrum. The multiplication of the stellar spectrum times the sinusoidal fiducial net creates a moire pattern, which manifests high detailed spectral information heterodyned down to low spatial frequencies. The latter can more accurately survive the blurring, distortions and CCD Nyquist limitations of the spectrograph. Hence lower resolution spectrographs can be used to perform high resolution spectroscopy and radial velocimetry (under a Doppler shift the entire moir{acute e} pattern shifts in phase). A demonstration of {approx}2x resolution boosting (100,000 from 50,000) on the Lick Obs. echelle spectrograph is shown. Preliminary data indicating {approx}8x resolution boost (170,000 from 20,000) using multiple delays has been taken on a linear grating spectrograph.

  8. Dendritic cells and immunity against cancer

    PubMed Central

    Palucka, Karolina; Ueno, Hideki; Fay, Joseph; Banchereau, Jacques

    2010-01-01

    SUMMARY T cells can reject established tumors when adoptively transferred into patients, thereby demonstrating the power of the immune system for cancer therapy. However, it has proven difficult to maintain adoptively transferred T cells in the long term. Vaccines have the potential to induce tumor-specific effector and memory T cells. However, clinical efficacy of current vaccines is limited, possibly because tumors skew the immune system by means of myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of cancer vaccines in patients with metastatic disease, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the dendritic cell (DC) system, including the existence of distinct DC subsets which respond differentially to distinct activation signals, (functional plasticity), both contributing to the generation of unique adaptive immune responses. We foresee that these novel cancer vaccines will be used as monotherapy in patients with resected disease, and in combination with drugs targeting regulatory/suppressor pathways in patients with metastatic disease. PMID:21158979

  9. Efficient control of chronic LCMV infection by a CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model.

    PubMed

    He, Ran; Yang, Xinxin; Liu, Cheng; Chen, Xiangyu; Wang, Lin; Xiao, Minglu; Ye, Jianqiang; Wu, Yuzhang; Ye, Lilin

    2017-03-13

    CD4(+) T cells are essential for sustaining CD8(+) T cell responses during a chronic infection. The adoptive transfer of virus-specific CD4(+) T cells has been shown to efficiently rescue exhausted CD8(+) T cells. However, the question of whether endogenous virus-specific CD4(+) T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8(+) T cells remains unexplored. In this study, we developed a CD4(+) T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We primed chronically LCMV-infected mice with a Listeria monocytogenes vector that expressed the LCMV glycoprotein-specific I-A(b)-restricted CD4(+) T cell epitope GP61-80 (LM-GP61) and subsequently boosted the primed mice with an influenza virus A (PR8 strain) vector that expressed the same CD4(+) T cell epitope (IAV-GP61). This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4(+) T cell responses, which further improved both the quantity and quality of the virus-specific CD8(+) T cells and led to better control of the viral loads. The combination of this strategy and the blockade of the programmed cell death-1 (PD-1) inhibitory pathway further enhanced the anti-viral CD8(+) T cell responses and viral clearance. Thus, a heterologous prime-boost immunization that selectively induces virus-specific CD4(+) T cell responses in conjunction with blockade of the inhibitory pathway may represent a promising therapeutic approach to treating patients with chronic viral infections.Cellular & Molecular Immunology advance online publication, 13 March 2017; doi:10.1038/cmi.2017.3.

  10. The immune system and overtraining in athletes: clinical implications.

    PubMed

    Hackney, Anthony C; Koltun, Kristen J

    2012-12-01

    The primary objective of this review is to provide an overview of how overtraining and the overtraining syndrome (OTS) affect the immune system of athletes. A secondary objective is to provide sports medicine clinicians with guidance as to how best to prevent and/or treat some of the health consequences of overtraining and the OTS as related to the development of a compromised immune system associated with exercise training. The OTS is a physically debilitating condition that results in athletes being totally compromised in their capacity to perform and compete. Many physiological systems are affected by the process of overtraining and the OTS; but one system in particular, the immune, is highly susceptible to degradation resulting in a reduction in overall health and performance. Monitoring of an athlete's exercise training load and other life stresses is critical to the determination of when their training regimen may be excessive, thereby increasing the risk of OTS developing. Taking steps to mitigate prolonged exposure to extreme stress (training + life or otherwise) in athletes as well as promoting a healthy immune system can significantly aid in the advancement of an athlete's training regimen progression and ultimate physical performance and overall health. In this light, this review provides approaches to aid sports medicine clinicians in promoting a healthy immune system in athletes.

  11. Motivating quantum field theory: the boosted particle in a box

    NASA Astrophysics Data System (ADS)

    Vutha, Amar C.

    2013-07-01

    It is a maxim often stated, yet rarely illustrated, that the combination of special relativity and quan