Texas Biomedical Research Institute, San Antonio, TX, United States.
Department of Pulmonary Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
Front Immunol. 2022 Feb 22;13:788619. doi: 10.3389/fimmu.2022.788619. eCollection 2022.
A virosomal vaccine inducing systemic/mucosal anti-HIV-1 gp41 IgG/IgA had previously protected Chinese-origin rhesus macaques (RMs) against vaginal SHIV challenges. Here, we assessed its efficacy in Indian-origin RMs by intramuscular priming/intranasal boosting (n=12/group). Group K received virosome-P1-peptide alone (harboring the Membrane Proximal External Region), Group L combined virosome-rgp41 plus virosome-P1, and Group M placebo virosomes. Vaccination induced plasma binding but no neutralizing antibodies. Five weeks after boosting, all RMs were challenged intravaginally with low-dose SHIV until persistent systemic infection developed. After SHIV challenge #7, six controls were persistently infected versus only one Group L animal (vaccine efficacy 87%; =0.0319); Group K was not protected. After a 50% SHIV dose increase starting with challenge #8, protection in Group L was lost. Plasmas/sera were analyzed for IgG phenotypes and effector functions; the former revealed that protection in Group L was significantly associated with increased binding to FcγR2/3(A/B) across several time-points, as were some IgG measurements. Vaginal washes contained low-level anti-gp41 IgGs and IgAs, representing a 1-to-5-fold excess over the SHIV inoculum's gp41 content, possibly explaining loss of protection after the increase in challenge-virus dose. Virosomal gp41-vaccine efficacy was confirmed during the initial seven SHIV challenges in Indian-origin RMs when the SHIV inoculum had at least 100-fold more HIV RNA than acutely infected men's semen. Vaccine protection by virosome-induced IgG and IgA parallels the cooperation between systemically administered IgG1 and mucosally applied dimeric IgA2 monoclonal antibodies that as single-agents provided no/low protection - but when combined, prevented mucosal SHIV transmission in all passively immunized RMs.
一种基于病毒体的疫苗能够诱导系统性/黏膜性抗 HIV-1 gp41 IgG/IgA，此前已被证明能保护中国来源的恒河猴（RMs）免受阴道 SHIV 挑战。在此，我们通过肌肉注射初免/鼻内加强免疫（每组 12 只）评估了其在印度来源的 RMs 中的功效。K 组仅接受病毒体-P1 肽（携带膜近外部区域），L 组接受病毒体-rgp41 加病毒体-P1，M 组接受安慰剂病毒体。接种诱导了血浆结合抗体，但没有中和抗体。加强免疫后 5 周，所有 RMs 均经阴道接受低剂量 SHIV 挑战，直至出现持续性全身感染。在 SHIV 挑战 #7 后，6 只对照动物持续感染，而 L 组只有 1 只动物（疫苗功效 87%；=0.0319）；K 组未得到保护。从第 8 次挑战开始增加 SHIV 剂量的 50%后，L 组的保护作用丧失。分析血浆/血清中的 IgG 表型和效应功能；前者表明，L 组的保护作用与多个时间点对 FcγR2/3(A/B)的结合增加显著相关，一些 IgG 测量结果也有类似情况。阴道冲洗液中含有低水平的抗 gp41 IgG 和 IgA，与 SHIV 接种物的 gp41 含量相比，其含量高出 1 至 5 倍，这可能解释了在挑战病毒剂量增加后保护作用丧失的原因。在印度来源的 RMs 中进行的最初 7 次 SHIV 挑战期间，病毒体 gp41 疫苗的功效得到了证实，当时 SHIV 接种物的 HIV RNA 比急性感染男性精液中的 HIV RNA 多 100 倍。病毒体诱导的 IgG 和 IgA 疫苗保护作用与系统给予 IgG1 和黏膜应用二聚体 IgA2 单克隆抗体之间的合作相平行，这些单克隆抗体作为单一制剂不能提供高保护率 - 但当联合使用时，可防止所有被动免疫的 RMs 发生黏膜 SHIV 传播。
