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3M-052-AF 联合 Alum 佐剂在 HIV 三聚体疫苗中的应用诱导人体自身中和抗体。

Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.

机构信息

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Department of Medicine, University of Washington, Seattle, WA, USA.

出版信息

J Exp Med. 2024 Oct 7;221(10). doi: 10.1084/jem.20240604. Epub 2024 Sep 5.

DOI:10.1084/jem.20240604
PMID:39235529
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11380150/
Abstract

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.

摘要

稳定的三聚体保持了类似天然的 HIV 包膜结构，可能是诱导广泛中和抗体（bnAbs）的预防性 HIV 疫苗方案的关键组成部分。我们评估了与新型 TLR7/8 信号佐剂 3M-052-AF/Alum 联合配制的三聚体 BG505 SOSIP.664 gp140，在首次健康成人（n=17）中进行了安全性、佐剂剂量发现和免疫原性的 1 期、随机、安慰剂对照试验（HVTN 137A）。疫苗方案似乎是安全的。在接种后出现了强大的、三聚体特异性的抗体以及 B 细胞和 CD4+T 细胞反应。五名接种者在两到三剂后产生了血清自体 tier 2 nAbs（ID50 滴度，1:28-1:8647），针对电子显微镜和突变假病毒中和分析的 C3/V5 和/或 V1/V2/V3 Env 区域靶向。三聚体特异性、B 细胞衍生的单克隆抗体活性证实了这些结果，并在最强应答者中显示出微弱的异源中和作用。我们的研究结果表明了 3M-052-AF/Alum 佐剂的临床实用性，并支持进一步改进基于三聚体的 Env 免疫原，以将反应集中在多个广泛的 nAb 表位上。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/171dfbf27a14/JEM_20240604_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/43e6808e0a5c/JEM_20240604_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/e061cecf5d18/JEM_20240604_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/6d21e636907a/JEM_20240604_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/fcf67db488dc/JEM_20240604_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/844e26b82f90/JEM_20240604_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/fb3df3f6289b/JEM_20240604_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/e0a6f1f92a70/JEM_20240604_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/171dfbf27a14/JEM_20240604_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/43e6808e0a5c/JEM_20240604_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/e061cecf5d18/JEM_20240604_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/6d21e636907a/JEM_20240604_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/fcf67db488dc/JEM_20240604_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/844e26b82f90/JEM_20240604_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/fb3df3f6289b/JEM_20240604_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/e0a6f1f92a70/JEM_20240604_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e478/11380150/171dfbf27a14/JEM_20240604_FigS3.jpg

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