Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Research Service, James J. Peters VA Medical Center, Bronx, NY, United States.
Front Immunol. 2023 Oct 3;14:1271686. doi: 10.3389/fimmu.2023.1271686. eCollection 2023.
Neutralizing antibodies (Abs) are one of the immune components required to protect against viral infections. However, developing vaccines capable of eliciting neutralizing Abs effective against a broad array of HIV-1 isolates has been an arduous challenge.
This study sought to test vaccines aimed to induce Abs against neutralizing epitopes at the V1V2 apex of HIV-1 envelope (Env).
Four groups of rabbits received a DNA vaccine expressing the V1V2 domain of the CRF01_AE A244 strain on a trimeric 2J9C scaffold (V1V2-2J9C) along with a protein vaccine consisting of an uncleaved prefusion-optimized A244 Env trimer with V3 truncation (UFO-BG.ΔV3) or a V1V2-2J9C protein and their respective immune complexes (ICs). These IC vaccines were made using 2158, a V1V2-specific monoclonal Ab (mAb), which binds the V2i epitope in the underbelly region of V1V2 while allosterically promoting the binding of broadly neutralizing mAb PG9 to its V2 apex epitope .
Rabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.ΔV3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses.
These data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.ΔV3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.ΔV3 complexed with V2i mAb 2158.
中和抗体（Abs）是预防病毒感染所需的免疫成分之一。然而，开发能够诱导针对广泛的 HIV-1 分离株的中和 Abs 的疫苗一直是一项艰巨的挑战。
本研究旨在测试针对 HIV-1 包膜（Env）V1V2 顶点的中和表位诱导 Abs 的疫苗。
四组兔子接受了一种在三聚体 2J9C 支架上表达 CRF01_AE A244 株 V1V2 结构域的 DNA 疫苗（V1V2-2J9C），以及一种由未切割的前融合优化的 A244 Env 三聚体组成的蛋白疫苗，带有 V3 截短（UFO-BG.ΔV3）或 V1V2-2J9C 蛋白及其各自的免疫复合物（IC）。这些 IC 疫苗是使用 2158 制成的，2158 是一种针对 V1V2 的单克隆 Ab（mAb），它结合 V1V2 腹部下方的 V2i 表位，同时变构促进广泛中和 mAb PG9 与其 V2 顶端表位的结合。
接受 DNA 疫苗和未复合或复合 UFO-BG.ΔV3 蛋白（DNA/UFO-UC 或 IC）的兔子组显示出相似的 Env 和 V1V2 结合 Abs 谱，但与接受 DNA 疫苗和未复合或复合 V1V2-2J9C 蛋白（DNA/V1V2-UC 或 IC）的兔子组不同，后者产生了更多的交叉反应性 V1V2 Abs，而没有检测到与 gp120 或 gp140 Env 的结合。值得注意的是，DNA/UFO-UC 疫苗诱导体外中和 Abs 针对来自不同谱系的一些异源 tier 1 和 tier 2 病毒，尽管滴度较低，且仅在部分动物中，但 DNA/V1V2-UC 或 IC 疫苗则没有。与 DNA/UFO-UC 组相比，DNA/UFO-IC 组对 TH023.6 的中和作用呈上升趋势，并且 V1V2 特异性 Ab 依赖性细胞吞噬作用（ADCP）的效力更高，但未能中和异源病毒。
这些数据表明，V1V2-2J9C 编码的 DNA 疫苗与 UFO-BG.ΔV3 结合，而不是与 V1V2-2J9C 蛋白疫苗结合，能够在兔子中诱导同源和异源中和活性。UFO-BG.ΔV3 与 V2i mAb 2158 复合的递送调节了中和和 ADCP 活性的产生。
