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.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-10-01 Epub Date: 2024-09-04 DOI:10.1016/j.ebiom.2024.105320

Avi Kenny, Janine van Duijn, One Dintwe, Jack Heptinstall, Randy Burnham, Sheetal Sawant, Lu Zhang, Dieter Mielke, Sharon Khuzwayo, Faatima Laher Omar, Sherry Stanfield-Oakley, Taylor Keyes, Brooke Dunn, Derrick Goodman, Youyi Fong, David Benkeser, Rodger Zou, John Hural, Ollivier Hyrien, Michal Juraska, Alex Luedtke, Lars van der Laan, Elena E Giorgi, Craig Magaret, Lindsay N Carpp, Laura Pattacini, Tom van de Kerkhof, Bette Korber, Wouter Willems, Leigh H Fisher, Hanneke Schuitemaker, Edith Swann, James G Kublin, Maria G Pau, Susan Buchbinder, Frank Tomaka, Steven Nijs, Ludo Lavreys, Huub C Gelderblom, Lawrence Corey, Kathryn Mngadi, Glenda E Gray, Erica Borducchi, Jenny Hendriks, Kelly E Seaton, Susan Zolla-Pazner, Dan H Barouch, Guido Ferrari, Stephen C De Rosa, M Juliana McElrath, Erica Andersen-Nissen, Daniel J Stieh, Georgia D Tomaras, Peter B Gilbert

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引用次数: 0

Abstract

Background: 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.

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对南部非洲出生时性别为女性的人群进行的 Imbokodo（HVTN 705/HPX2008）HIV-1 马赛克疫苗疗效试验的免疫相关性分析：一项两阶段病例对照研究。

背景：HVTN 705 Imbokodo 试验在南部非洲进行，共有 2636 名未感染 HIV 且出生时性别为女性的人参加，该试验评估了一种异源 HIV-1 疫苗方案：在第 0、3、6、12 个月接种基于镶嵌腺病毒 26 的疫苗 (Ad26.Mos4.HIV)，在第 6、12 个月接种明矾佐剂 C 支系 gp140。从 7 个月到 24 个月期间，按协议接种疫苗对 HIV-1 诊断的有效率（VE）为 14.1%（95% CI：-22.0% 至 39.5%）。方法：在突破性病例对照队列（n = 52 例病例，246 例非病例）中，对第 7 个月时的体液和细胞免疫反应标记物进行评估，作为风险和保护的免疫相关因素。主要指标包括与疫苗株 gp140 结合的 IgG、与不同 Env 抗原结合的 IgG3（IgG3 Env 广度）、与不同 V1V2 抗原结合的 IgG3（IgG3 V1V2 广度）、针对疫苗株 gp140 的抗体依赖性吞噬作用、Env 特异性 CD4+ 和 CD8+ T 细胞反应以及多表位功能：没有任何免疫标记物与风险有显著的统计学相关性。IgG3 V1V2广度呈反相关趋势：每增加10倍，危险比为0.70（95% CI：0.36至1.35；P = 0.29）；在包含所有主要标记物的Cox模型中，危险比为0.51（95% CI：0.21至1.24；P = 0.14）。在所有 IgG3 V1V2 广度值低于 667 加权几何平均净 MFI 时，VE 估计值为 11.8%（95% CI：-17.9% 至 34.0%）；略高于此值时，VE 估计值急剧增加到 62.6%（95% CI：-17.9% 至 89.6%），在 1471 MFI（标记物分布的第 95 百分位数）时，VE 估计值进一步增加到 80.9%（95% CI：-17.9% 至 99.5%）。通过中介分析，疫苗对该标记物的影响产生了 35.7% 的 VE（95% CI：15.0% 至 51.3%）：IgG3 V1V2抗体广度越大，感染HIV的可能性越低，这一趋势与其他三项HIV疫苗疗效试验中发现的V1V2抗体免疫相关性是一致的，这表明应更加重视将HIV-1包膜中的这一区域作为疫苗免疫原进行研究：国家过敏与传染病研究所和杨森疫苗与预防公司。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.