Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.
J Virol. 2022 Apr 27;96(8):e0003422. doi: 10.1128/jvi.00034-22. Epub 2022 Apr 6.
With the much-debated exception of the modestly reduced acquisition reported for the RV144 efficacy trial, HIV-1 vaccines have not protected humans against infection, and a vaccine of similar design to that tested in RV144 was not protective in a later trial, HVTN 702. Similar vaccine regimens have also not consistently protected nonhuman primates (NHPs) against viral acquisition. Conversely, experimental vaccines of different designs have protected macaques from viral challenges but then failed to protect humans, while many other HIV-1 vaccine candidates have not protected NHPs. While efficacy varies more in NHPs than humans, vaccines have failed to protect in the most stringent NHP model. Intense investigations have aimed to identify correlates of protection (CoPs), even in the absence of net protection. Unvaccinated animals and humans vary vastly in their susceptibility to infection and in their innate and adaptive responses to the vaccines; hence, merely statistical associations with factors that do not protect are easily found. Systems biological analyses, including artificial intelligence, have identified numerous candidate CoPs but with no clear consistency within or between species. Proposed CoPs sometimes have only tenuous mechanistic connections to immune protection. In contrast, neutralizing antibodies (NAbs) are a central mechanistic CoP for vaccines that succeed against other viruses, including SARS-CoV-2. No HIV-1 vaccine candidate has yet elicited potent and broadly active NAbs in NHPs or humans, but narrow-specificity NAbs against the HIV-1 isolate corresponding to the immunogen do protect against infection by the autologous virus. Here, we analyze why so many HIV-1 vaccines have failed, summarize the outcomes of vaccination in NHPs and humans, and discuss the value and pitfalls of hunting for CoPs other than NAbs. We contrast the failure to find a consistent CoP for HIV-1 vaccines with the identification of NAbs as the principal CoP for SARS-CoV-2.
除了 RV144 疗效试验报告的适度降低的获得性这一备受争议的例外，HIV-1 疫苗未能保护人类免受感染，并且在后来的 RV144 试验中，设计类似的疫苗未能提供保护，HVTN 702 也是如此。类似的疫苗方案也未能一致保护非人类灵长类动物（NHPs）免受病毒感染。相反，不同设计的实验性疫苗保护猕猴免受病毒挑战，但未能保护人类，而许多其他 HIV-1 疫苗候选物未能保护 NHPs。虽然在 NHPs 中功效变化较大，但在最严格的 NHPs 模型中疫苗未能提供保护。尽管没有净保护作用，仍进行了密集的研究以确定保护相关因素（CoPs）。未接种疫苗的动物和人类在感染易感性以及对疫苗的先天和适应性反应方面差异很大；因此，很容易发现与未保护因素的统计关联。系统生物学分析，包括人工智能，已经确定了许多候选 CoPs，但在物种内或物种间没有明确的一致性。提出的 CoPs 与免疫保护的机制联系有时只是很脆弱。相比之下，中和抗体（NAbs）是针对其他病毒（包括 SARS-CoV-2）成功的疫苗的一个核心机制 CoP。到目前为止，还没有任何 HIV-1 疫苗候选物在 NHPs 或人类中引起强大且广泛有效的 NAbs，但针对与免疫原相对应的 HIV-1 分离株的特异性 NAbs 确实可以防止同源病毒感染。在这里，我们分析了为什么如此多的 HIV-1 疫苗会失败，总结了 NHPs 和人类接种疫苗的结果，并讨论了寻找除 NAbs 以外的 CoPs 的价值和陷阱。我们将未能找到一致的 HIV-1 疫苗 CoP 与鉴定 NAbs 作为 SARS-CoV-2 的主要 CoP 进行对比。
