Tomaras G.D.,Duke Human Vaccine Institute |
Plotkin S.A.,Vaxconsult |
Plotkin S.A.,University of Pennsylvania
Immunological Reviews | Year: 2017
Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine-mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate—thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hinchey J.,Yeshiva University |
Jeon B.Y.,Yonsei University |
Alley H.,Duke Human Vaccine Institute |
Chen B.,Yeshiva University |
And 6 more authors.
PLoS ONE | Year: 2011
Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a major global health problem, despite the widespread use of the M. bovis Bacille Calmette-Guerin (BCG) vaccine and the availability of drug therapies. In recent years, the high incidence of coinfection of M. tuberculosis and HIV, as well as escalating problems associated with drug resistance, has raised ominous concerns with regard to TB control. Vaccination with BCG has not proven highly effective in controlling TB, and also has been associated with increasing concerns about the potential for the vaccine to cause disseminated mycobacterial infection in HIV infected hosts. Thus, the development of an efficacious and safe TB vaccine is generally viewed as a critical to achieving control of the ongoing global TB pandemic. In the current study, we have analyzed the vaccine efficacy of an attenuated M. tuberculosis strain that combines a mutation that enhances T cell priming (ΔsecA2) with a strongly attenuating lysine auxotrophy mutation (ΔlysA). The ΔsecA2 mutant was previously shown to be defective in the inhibition of apoptosis and markedly increased priming of antigen-specific CD8+ T cells in vivo. Similarly, the DsecA2DlysA strain retained enhanced apoptosis and augmented CD8+ T cell stimulatory effects, but with a noticeably improved safety profile in immunosuppressed mice. Thus, the M. tuberculosis DsecA2DlysA mutant represents a live attenuated TB vaccine strain with the potential to deliver increased protection and safety compared to standard BCG vaccination.
Schwartz J.L.,Eastern Virginia Medical School |
Rountree W.,Family Health International FHI |
Rountree W.,Duke Human Vaccine Institute |
Kashuba A.D.M.,University of North Carolina at Chapel Hill |
And 5 more authors.
PLoS ONE | Year: 2011
Background: Tenofovir (TFV) gel is being evaluated as a microbicide with pericoital and daily regimens. To inhibit viral replication locally, an adequate concentration in the genital tract is critical. Methods and Findings: Forty-nine participants entered a two-phase study: single-dose (SD) and multi-dose (MD), were randomized to collection of genital tract samples (endocervical cells [ECC], cervicovaginal aspirate and vaginal biopsies) at one of seven time points [0.5, 1, 2, 4, 6, 8, or 24 hr(s)] post-dose following SD exposure of 4 mL 1% TFV gel and received a single dose. Forty-seven were randomized to once (QD) or twice daily (BID) dosing for 2 weeks and to collection of genital tract samples at 4, 8 or 24 hrs after the final dose, but two discontinued prior to gel application. Blood was collected during both phases at the seven times post-dose. TFV exposure was low in blood plasma for SD and MD; median C max was 4.0 and 3.4 ng/mL, respectively (C≤29 ng/mL). TFV concentrations were high in aspirates and tissue after SD and MD, ranging from 1.2×10 4 to 9.9×10 6 ng/mL and 2.1×10 2 to 1.4×10 6 ng/mL, respectively, and did not noticeably differ between proximal and distal tissue. TFV diphosphate (TFV-DP), the intracellular active metabolite, was high in ECC, ranging from 7.1×10 3 to 8.8×10 6 ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×10 2 to 3.5×10 4 ng/mL. AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID. Conclusions: Single-dose and multiple-dose TFV gel exposure resulted in high genital tract concentrations for at least 24 hours post-dose with minimal systemic absorption. These results support further study of TFV gel for HIV prevention. Trial registration: ClinicalTrials.gov NCT00561496. © 2011 Schwartz et al.
News Article | March 7, 2016
Researchers report that the Zika virus may be linked to a wider variety of "grave outcomes" for developing babies than previously reported - threats that can come at any stage of pregnancy. The findings released Friday are preliminary results from the first study tracking pregnant women in Brazil from the time they were infected, and do not prove that Zika is to blame. But they come as separate laboratory research released Friday strengthens the case that Zika causes a serious birth defect called microcephaly - babies born with abnormally small heads - by targeting embryonic brain cells. "It's much more than microcephaly," said Dr. Karin Nielsen of the University of California, Los Angeles, who led the pregnancy study with colleagues at the Fiocruz Institute in Brazil. "It seems like it can act on multiple fronts." The mosquito-borne virus, which is spreading in Latin America and the Caribbean, normally causes only mild symptoms, if any, in adults. But it raised alarm when Brazilian health officials reported an apparent surge in babies born with microcephaly, which can signal their brains didn't develop properly. Reports have documented traces of the virus in the brains of affected babies who died soon after birth, and in fetal brain tissue after abortion. The study from Brazil, reported Friday in the New England Journal of Medicine, took a closer look during pregnancy. The study so far is tracking 88 otherwise healthy pregnant women who sought care for Zika-like symptoms at a clinic run by the Oswaldo Cruz Foundation in Rio de Janiero between September and last month. Tests showed 72 were actively infected with the virus. Forty-two of the infected women, and all of the presumably non-infected ones, agreed to fetal ultrasound exams. Those ultrasounds found abnormalities in 12 of the infected women, or 29 percent. The non-infected women all had normal ultrasounds. The exams did uncover some abnormal brain development. But they also detected two fetuses that died in utero during the last trimester; poor growth even without microcephaly; problems with the placenta; and one case that prompted an emergency C-section because of low amniotic fluid, Nielsen said. Six live births have occurred so far. One baby has severe microcephaly. Two were born too small for gestational age, one of whom had lesions in the eyes that signal vision problems if not blindness. Two other babies had normal ultrasounds and indeed, appear healthy. The baby delivered by emergency C-section struggled initially but now also appears healthy, Nielsen said. Importantly, the researchers linked problems to infections during each trimester of pregnancy, not just the first trimester that doctors have speculated would be the riskiest. "Unfortunately, we still have many unanswered questions," said Dr. Christopher M. Zahn of the American College of Obstetricians and Gynecologists. But the new findings provide "additional evidence suggesting an association between Zika virus and negative obstetrical outcomes, including birth defects and fetal demise." "We're starting to build the case epidemiologically that maternal infection with this virus is linked to poor fetal outcomes," added Dr. Sallie Permar, a specialist in maternal-fetal infections at the Duke Human Vaccine Institute. In an unrelated study Friday, researchers found that Zika can infect embryonic cells that help form the brain, and harm them in two ways: killing some outright and damaging the ability of others to divide and grow in number. Those cells, when healthy, help build the part of the brain that is affected in microcephaly, said Hengli Tang of Florida State University, a lead author of the work published by the journal Cell Stem Cell. But he stressed that his study does not prove that Zika causes microcephaly, nor that it works by that route. A number of other viruses are known to trigger the condition. Researchers did not take the brain cells from embryos; they created them from stem cells obtained from other sources. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, who did not participate in the research, agreed that the study doesn't prove a link. But "it certainly adds weight to the argument," he said. Researchers also found that infected cells pump out more virus. Dr. Guo-li Ming of Johns Hopkins University, another lead study author, said researchers can now explore questions like how Zika infects the cells. Tang said he is collaborating with other labs to look for substances that will block Zika infection of cells, in hopes of eventually creating a treatment for pregnant women that reduces the risk of passing the infection to their babies.
Jackson K.J.L.,Stanford University |
Jackson K.J.L.,University of New South Wales |
Liu Y.,Stanford University |
Roskin K.M.,Stanford University |
And 23 more authors.
Cell Host and Microbe | Year: 2014
B cells produce a diverse antibody repertoire by undergoing gene rearrangements. Pathogen exposure induces the clonal expansion of B cells expressing antibodies that can bind the infectious agent. To assess human B cell responses to trivalent seasonal influenza and monovalent pandemic H1N1 vaccination, we sequenced gene rearrangements encoding the immunoglobulin heavy chain, a major determinant of epitope recognition. The magnitude of B cell clonal expansions correlates with an individual's secreted antibody response to the vaccine, and the expanded clones are enriched with those expressing influenza-specific monoclonal antibodies. Additionally, B cell responses to pandemic influenza H1N1 vaccination and infection in different people show a prominent family of convergent antibody heavy chain gene rearrangements specific to influenza antigens. These results indicate that microbes can induce specific signatures of immunoglobulin gene rearrangements and that pathogen exposure can potentially be assessed from B cell repertoires. © 2014 Elsevier Inc.
Aussedat B.,Sloan Kettering Institute for Cancer Research |
Vohra Y.,Sloan Kettering Institute for Cancer Research |
Park P.K.,Sloan Kettering Institute for Cancer Research |
Fernandez-Tejada A.,Sloan Kettering Institute for Cancer Research |
And 14 more authors.
Journal of the American Chemical Society | Year: 2013
Critical to the search for an effective HIV-1 vaccine is the development of immunogens capable of inducing broadly neutralizing antibodies (BnAbs). A key first step in this process is to design immunogens that can be recognized by known BnAbs. The monoclonal antibody PG9 is a BnAb that neutralizes diverse strains of HIV-1 by targeting a conserved carbohydrate-protein epitope in the variable 1 and 2 (V1V2) region of the viral envelope. Important for recognition are two closely spaced N-glycans at Asn160 and Asn156. Glycopeptides containing this synthetically challenging bis-N-glycosylated motif were prepared by convergent assembly, and were shown to be antigenic for PG9. Synthetic glycopeptides such as these may be useful for the development of HIV-1 vaccines based on the envelope V1V2 BnAb epitope. © 2013 American Chemical Society.
Barrigan L.M.,University of North Carolina at Chapel Hill |
Barrigan L.M.,University of Arizona |
Tuladhar S.,University of Arizona |
Brunton J.C.,University of North Carolina at Chapel Hill |
And 7 more authors.
Infection and Immunity | Year: 2013
Bacterial attenuation is typically thought of as reduced bacterial growth in the presence of constant immune pressure. Infection with Francisella tularensis elicits innate and adaptive immune responses. Several in vivo screens have identified F. tularensis genes necessary for virulence. Many of these mutations render F. tularensis defective for intracellular growth. However, some mutations have no impact on intracellular growth, leading us to hypothesize that these F. tularensis mutants are attenuated because they induce an altered host immune response. We were particularly interested in the F. tularensis LVS (live vaccine strain) clpB (FTL_0094) mutant because this strain was attenuated in pneumonic tularemia yet induced a protective immune response. The attenuation of LVS clpB was not due to an intracellular growth defect, as LVS clpB grew similarly to LVS in primary bone marrow-derived macrophages and a variety of cell lines. We therefore determined whether LVS clpB induced an altered immune response compared to that induced by LVS in vivo. We found that LVS clpB induced proinflammatory cytokine production in the lung early after infection, a process not observed during LVS infection. LVS clpB provoked a robust adaptive immune response similar in magnitude to that provoked by LVS but with increased gamma interferon (IFN-γ) and interleukin-17A (IL- 17A) production, as measured by mean fluorescence intensity. Altogether, our results indicate that LVS clpB is attenuated due to altered host immunity and not an intrinsic growth defect. These results also indicate that disruption of a nonessential gene(s) that is involved in bacterial immune evasion, like F. tularensis clpB, can serve as a model for the rational design of attenuated vaccines. © 2013, American Society for Microbiology.
Excler J.-L.,Us Military Hiv Research Program Mhrp |
Tomaras G.D.,Duke Human Vaccine Institute |
Tomaras G.D.,Duke University |
Russell N.D.,Bill and Melinda Gates Foundation
Current Opinion in HIV and AIDS | Year: 2013
Purpose of Review: Considerable HIV-1 vaccine development efforts have been deployed over the past decade. Put into perspective, the results from efficacy trials and the identification of correlates of risk have opened large and unforeseen avenues for vaccine development. Recent Findings: The Thai efficacy trial, RV144, provided the first evidence that HIV-1 vaccine protection against HIV-1 acquisition could be achieved. The correlate of risk analysis showed that IgG antibodies against the gp120 V2 loop inversely correlated with a decreased risk of infection, whereas Env-specific IgA directly correlated with risk. Further clinical trials will focus on testing new envelope subunit proteins formulated with adjuvants capable of inducing higher and more durable functional antibody responses (both binding and broadly neutralizing antibodies). Moreover, vector-based vaccine regimens that can induce cell-mediated immune responses in addition to humoral responses remain a priority. Summary: Future efficacy trials will focus on prevention of HIV-1 transmission in heterosexual population in Africa and MSM in Asia. The recent successes leading to novel directions in HIV-1 vaccine development are a result of collaboration and commitment among vaccine manufacturers, funders, scientists and civil society stakeholders. Sustained and broad collaborative efforts are required to advance new vaccine strategies for higher levels of efficacy. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Haynes B.F.,Duke Human Vaccine Institute |
Liao H.-X.,Duke Human Vaccine Institute |
Tomaras G.D.,Duke Human Vaccine Institute |
Tomaras G.D.,Duke University
Current Opinion in HIV and AIDS | Year: 2010
Purpose of review: This review discusses select recent data that suggest that indeed it is possible to make a clinically useful preventive vaccine for HIV-1 and outlines some of the remaining obstacles that stand in the way of success. Recent Findings: Passive protection studies, with broad neutralizing antibodies for mucosal simian-HIV challenges, in nonhuman primates have suggested that lower doses of neutralizing antibodies than previously thought may be effective in preventing HIV-1 infection. The use of recombinant antibody technology coupled with the ability to culture single memory B cells has yielded new broad neutralizing antibodies and new targets for vaccine design. The success of the RV144 Thai HIV-1 efficacy trials with a replication-defective recombinant canarypox vector (ALVAC)/gp120 prime, clade B/E recombinant gp120 protein boost showing 31% efficacy has given hope that indeed a protective HIV-1 vaccine can be made. Summary: Recent data in the last year have provided new hope that a clinically useful preventive HIV-1 vaccine can potentially be made. The path forward will require development of improved immunogens, understanding the correlates of protection to HIV-1, and development of immunogens to induce antibodies that can prevent the initial stages of HIV-1 infection at mucosal sites, in order to improve on the RV144 trial results. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Roberts L.M.,University of Arizona |
Davies J.S.,University of Arizona |
Sempowski G.D.,Duke Human Vaccine Institute |
Frelinger J.A.,University of Arizona
Vaccine | Year: 2014
IL-17 and IFN-γ production by Th17 and Th1 cells, respectively, is critical for survival during primary respiratory infection with the pathogenic bacterium, Francisella tularensis Live Vaccine Strain (LVS). The importance, however, of these T cell subsets and their soluble mediators is not well understood during a secondary or memory response. We measured the number of CD4+ T cells producing IFN-γ or IL-17 in the spleen and lungs of vaccinated mice on day four of the secondary response using intracellular cytokine staining in order to identify protective T cell subsets participating in the memory response. Few bacteria were present in spleens of vaccinated mice on day four and a T cell response was not observed. In the lung, where more bacteria were present, there was a robust Th1 response in vaccinated mice but Th17 cells were not present at higher numbers in vaccinated mice compared to unvaccinated mice. These data show that the lung is the dominant site of the secondary immune response and suggest that Th17 cells are not required for survival during secondary challenge. To further investigate the importance of IFN-γ and IL-17 during the secondary response to F. tularensis, we neutralized either IFN-γ or IL-17 in vivo using monoclonal antibody treatment. Vaccinated mice treated with anti-IFN-γ lost more weight and had higher bacterial burdens compared to vaccinated mice treated with isotype control antibody. In contrast, treatment with anti-IL-17A antibody did not alter weight loss profiles or bacterial burdens compared to mice treated with isotype control antibody. Together, these results suggested that IFN-γ is required during both primary and secondary respiratory F. tularensis infection. IL-17, on the other hand, is only critical during the primary response to respiratory F. tularensis but dispensable during the secondary response. © 2014 Elsevier Ltd.