The resulting significant increase in funding, and structured collaborative networks, led to important advancements in the understanding of HIV envelope (Env) structural biology, novel approaches to ...immunogen design, the nature of protective immune responses and innovative delivery methods. ...the current imperative for the field is to synthesize the cumulative knowledge gained and use it to define specific critical hypotheses that can be methodically and rigorously tested through small, early-phase, carefully designed experimental studies that can inform the selection of product candidates for efficacy evaluation. ...non-human primate studies have also shown that bnAbs can prevent simian-human immunodeficiency virus (SHIV) infection in monkeys. ...while the diversity of HIV remains daunting, many groups are now focused on vaccine concepts designed to elicit potent and bnAb against conserved viral epitopes. ...it will be vital to know how to generate long-lived plasma cells that can secrete cross-reactive nAbs for at least 5–10 years.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously ...been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectional Anniston Community Health Survey (ACHS) investigates ortho-substituted PCB exposures and health effects near a former PCB manufacturing complex. The rates of obesity, diabetes, and dyslipidemia were previously determined to be high in ACHS. In this study, 738 ACHS participants were categorized by liver disease status using the serum cytokeratin 18 biomarker. Associations between PCB exposures and mechanistic biomarkers of intermediary metabolism, inflammation, and hepatocyte death were determined. The liver disease prevalence was high (60.2%), and 80.7% of these individuals were categorized as having TASH. Sex and race/ethnicity differences were noted. TASH was associated with increased exposures to specific PCB congeners, insulin resistance, dyslipidemia, proinflammatory cytokines, and liver necrosis. These findings are consistent with PCB-related steatohepatitis. ΣPCBs was inversely associated with insulin resistance/production, leptin, and hepatocyte apoptosis, while other adipocytokines were increased. This is possibly the largest environmental liver disease study applying mechanistic biomarkers ever performed and the most comprehensive analysis of PCBs and adipocytokines. It provides insight into the mechanisms of PCB-related endocrine and metabolic disruption in liver disease and diabetes. In the future, associations between additional exposures and liver disease biomarkers will be evaluated in the ACHS and follow-up ACHS-II studies.
PURPOSE OF REVIEWThe purpose of review is to provide an overview of the Pox-Protein Public Private Partnership (P5) and highlight the progress of the P5 program, including an upcoming HIV vaccine ...efficacy trial in South Africa.
RECENT FINDINGSThe RV144 Thai vaccine efficacy trial was the first to demonstrate that an HIV-1 vaccine can prevent HIV acquisition. The P5 vaccine regimen uses an ALVAC prime and protein boost modeled after the RV144 vaccine and adapted for the subtype C virus predominant in the southern African region. This regimen was recently tested in the HIV Vaccine Trials Network 100 phase 1/2a study in South Africa. Based on prospectively defined immunogenicity thresholds, criteria were met to support the launch of an efficacy study in late 2016. The aim of this phase 2b/3 trial will be to improve upon the results of RV144, with increased and more durable vaccine efficacy, to accelerate the potential licensure of a preventive vaccine in southern Africa.
SUMMARYThe planned P5 efficacy trial, HIV Vaccine Trials Network 702, is designed to test and prospectively define correlates of protection, if efficacious. A vaccine with modest efficacy, vaccine efficacy at least 50%, could have substantial public health impact and significantly decrease the incidence of new infections in heavily burdened areas of the world.
The CAVD accelerates research through the open sharing of data, and utilization of central service facilities that include best-in-class B- and T-cell immunology laboratories, sophisticated mouse ...models, a data and statistical management centre and a vaccine product development centre that facilitates the translation of promising concepts from the lab into clinical evaluation 5. Table 1 Partnerships Partnership name Partners Year founded Purpose IAVI www.iavi.org IAVI, Rockefeller Foundation (founding donor), BMGF, USAID, others 1996 Translate scientific discoveries into affordable, globally accessible public health solutions HIV Vaccines Trial Network (HVTN) www.hvtn.org NIH, Fred Hutchinson Cancer Research Center, others 1999 (The AIDS Vaccine Evaluation Group was funded by NIH in 1988 11.) Develop and test the safety and efficacy of interventions designed to prevent the acquisition and transmission of HIV Neutralizing Antibody Consortium IAVI, Scripps Research, NIH Vaccine Research Center (VRC), others 2002–2008 Discover, describe and optimize HIV bnAbs and develop immunogens to elicit them Collaboration for AIDS Vaccine Discovery (CAVD) www.cavd.org BMGF and multiple partners, see 13 2005 Design a variety of novel HIV vaccine candidates and advance the most promising candidates to clinical trials IAVI Neutralizing Antibody Center (NAC) IAVI, Scripps Research, other partners 2008 Discover, describe and optimize HIV bnAbs and develop immunogens to elicit them CHAVI NIH, Duke 2005–2012 Undertake the immunologic research required to tackle the major scientific obstacles in the development of an effective HIV vaccine CHAVI-ID NIH, Duke, Scripps Research 2012–2019 Undertake the immunologic research required to tackle the major scientific obstacles in the development of an effective HIV vaccine IAVI Product Development Center (PDC) IAVI, BMGF, NIH, others 2013 Support investigators with translation research 14 European AIDS Vaccine Initiative (EAVI2020) www.eavi2020.org Imperial College London, University of Oxford, INSERM, others 2015 Advance HIV vaccine concepts that can be moved into clinical trials in a 5-year window using an experimental medicine research model ADVANCE www.iavi.org USAID, IAVI, CRC partners in five African countries and India, others 2016 (with prior, sustained USAID investments starting in 2001) Support researchers in Africa and India to become leaders in global efforts to identify, evaluate and implement HIV biomedical prevention products CHAVD www.chavd.org (Scripps) www.dhvi.duke.edu (Duke) NIH, Duke, Scripps Research 2019 Develop and down select HIV immunogens and regimens that induce bnAb responses for clinical testing European HIV Vaccine Alliance (EHVA) www.ehv-a.eu Horizon 2020, INSERM, Swiss Vaccine Research Institute at the Lausanne University Hospital, others 2016 Develop platforms for HIV vaccine research and engage African scientists to prepare for clinical evaluation of EHVA vaccine candidates Collaborative HIV Immunogen Project (CHIP) NIH, BMGF, Scripps CHAVD, Duke CHAVD, HVTN, NIAID Vaccine Research Center, IAVI 2019 Coordinate groups developing HIV vaccine candidates designed to lead to the production of bnAbs 9 Abbreviations: ADVANCE, Accelerate the Development of Vaccines and New Technologies to Combat the AIDS Epidemic; BMGF, Bill & Melinda Gates Foundation; CHAVI, Center for HIV/AIDS Vaccine Immunology; CHAVI-ID, Centers for HIV-AIDS Vaccine Immunology and Immunogen Discovery; CRC, clinical research centre; INSERM, Institut national de la santé et de la recherche médicale; NIAID, National Institute of Allergy and Infectious Diseases; NIH, National Institutes of Health. Clinical trial networks, such as the HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network, along with other clinical development activities funded by USAID and the European and Developing Countries Clinical Trials Partnership, have enabled the conduct of clinical trials among those most at risk of HIV acquisition.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
PURPOSE OF REVIEWConsiderable 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 FINDINGSThe 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.
SUMMARYFuture 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.
There is evidence in both simian immunodeficiency virus and human immunodeficiency virus (HIV) type 1 infection that class I major histocompatibility complex–restricted CD8+ cytotoxic T lymphocytes ...play a pivotal role in controlling infection and, potentially, in protecting by immunization. Progress has been made in designing strategies to elicit these responses with HIV-1 vaccines, but methods to reproducibly quantify them have posed difficulties. An interferon-γ enzyme-linked immunospot assay, using peptide pools spanning the HIV-1 genes, was developed and standardized. This method is rapid (2 days), sensitive (threshold of detection, ⩾0.005%), quantitative, feasible using cryopreserved cells, and able to define epitope specificities. When this assay was applied to 36 HIV-1–seropositive and 10 HIV-1–seronegative subjects, it proved to be robust (specificity, 100%). When responses in natural infection were compared with vaccine-induced responses, vaccine recipient responses were ⩾1 log lower, which confirms the importance of using this sensitive assay as an initial screen in vaccine protocols
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Highlights ► HIV, the etiologic agent that causes AIDS, is the fourth largest killer in the world today. ► The rate of new HIV infections continues to outpace efforts on HIV prevention and control. ► ...The development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
BACKGROUND:A goal of T-cell HIV vaccines is to define the correlation between a vaccine-induced immune response and protection from HIV infection. We conducted a phase 2 trial to determine if a ...canarypox vaccine candidate (vCP1452) administered with rgp120 subunit protein would “qualify” for a trial to define a correlate of efficacy.
METHODS:A total of 330 healthy volunteers were enrolled into 4 groups120 received vCP1452 alone (0, 1, 3, and 6 months), 120 received vCP1452 with 2 different regimens of rgp120 coadministration, and 90 received placebo. HIV-specific antibody responses were measured by enzyme-linked immunoassay (ELISA) and neutralizing activity. T-cell responses were measured by chromium release and interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay.
RESULTS:Significant neutralizing antibody responses to the HIV MN strain were detected in all vaccine groups, with net responses ranging from 57% (95% confidence interval CI40% to 71%) to 94% (95% CI85% to 99%). Net cumulative HIV-specific CD8 IFNγ ELISpot assay responses were 13% (95% CI−1% to 26%) for recipients of vCP1452 alone and 16% (95% CI2% to 29%) for recipients of vCP1452 plus rgp120.
CONCLUSIONS:Overall, the HIV-specific CD8 cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8 CTL frequency of 30%.
Summary We evaluated EP HIV-1090 vaccine, a DNA plasmid encoding 21 cytotoxic T-lymphocyte (CTL) epitopes of human immunodeficiency virus type 1 (HIV-1) and the pan-DR helper T-lymphocyte epitope ...(PADRE), in a dose escalation, randomized, double-blinded, placebo-controlled Phase 1 trial. Vaccine, at 0.5, 2.0, or 4.0 mg doses, or placebo was injected four times over 6 months. Forty-two healthy, HIV-1-uninfected adults were enrolled. Using an interferon-γ ELISPOT assay, a response to PADRE was detected in one vaccine recipient. Three vaccine recipients raised anti-HIV-1 CD8+ CTL measured by chromium-release assay. The vaccine was safe and well-tolerated, but only weakly immunogenic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were ...randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 μg), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 μg). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P ≤ 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452)+LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452)+LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. The clinical trial is registered on ClinicalTrials.gov with registry number NCT00076063.
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