Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.
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2024-10
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The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models.Methods
Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions.Findings
No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker.Interpretation
The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen.Funding
National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.Type
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Kenny, Avi, Janine van Duijn, One Dintwe, Jack Heptinstall, Randy Burnham, Sheetal Sawant, Lu Zhang, Dieter Mielke, et al. (2024). Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study. EBioMedicine, 108. p. 105320. 10.1016/j.ebiom.2024.105320 Retrieved from https://hdl.handle.net/10161/33625.
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Scholars@Duke
Avi Kenny
Avi Kenny is an Assistant Professor in the Department of Biostatistics and Bioinformatics at Duke University, with a secondary appointment at the Duke Global Health Institute. He holds a PhD in biostatistics from the University of Washington, where he developed statistical methods for immune correlates analysis of vaccine clinical trial data. Prior to this, he worked for five years in Liberia as the Director of Research, Monitoring, and Evaluation at Last Mile Health. His current research interests include statistical methods to handle treatment effect heterogeneity in cluster randomized trials, survival analysis using machine learning tools, evaluation of global health programs, and data quality assurance in low-resource settings.
Guido Ferrari
The activities of the Ferrari Laboratory are based on both independent basic research and immune monitoring studies. The research revolves around three main areas of interest: class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity (ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation along with many other productive collaborations within and outside of Duke, the Ferrari Lab has expanded its focus of research to include the ontogeny of HIV-1 specific immune responses that work by eliminating HIV-1 infected cells and how these can be induced by AIDS vaccine candidates.
Georgia Doris Tomaras
Dr. Georgia Tomaras is a tenured Professor of Surgery, Professor of Immunology, Professor of Molecular Genetics and Microbiology and is a Fellow of the American Academy of Microbiology (AAM) and a Fellow of the American Association for the Advancement of Science (AAAS). Dr. Tomaras is Co-Director of the Center for Human Systems Immunology (CHSI) Duke University and Director of the Duke Center for AIDS Research (CFAR). Her national and international leadership roles include: Executive Management Team (EMT) leader and mPI for the HIV Vaccine Trials Network (HVTN); Director of Lab Sciences (HVTN); and Chair of NIH Vaccine Research Center (VRC) Board of Scientific Counselors. Her prior leadership roles include serving as the Director of Research, Duke Human Vaccine Institute (DHVI); Director of the DHVI Training Program; Associate Director of DHVI Research; Co-Director of the Interdisciplinary Research Training Program in AIDS (IRTPA) Duke; Chair of the National Institutes of Health (NIH) AIDS Vaccine Research Subcommittee (AVRS), and Advisory Counsel member of the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID). Dr. Tomaras’ primary research focus is deciphering mechanisms of protective human immunity and identification of immune correlates of protection to further development of effective vaccines against infectious diseases.
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