An effective AIDS vaccine should elicit strong humoral and cellular immune responses while maintaining low levels of CD4⁺ T-cell activation to avoid the generation of target cells for viral infection. The present study investigated two prime-boost regimens, both starting vaccination with single-cycle immunodeficiency virus, followed by two mucosal boosts with either recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 gag/pol and env genes, respectively. Finally, vectors were switched and systemically administered to the reciprocal group of animals. Only mucosal rFWPV immunizations followed by systemic rAd boost significantly protected animals against a repeated low-dose intrarectal challenge with pathogenic SIVmac251, resulting in a vaccine efficacy (i.e., risk reduction per exposure) of 68%. Delayed viral acquisition was associated with higher levels of activated CD8⁺ T cells and Gag-specific gamma interferon (IFN-γ)-secreting CD8⁺ cells, low virus-specific CD4⁺ T-cell responses, and low Env antibody titers. In contrast, the systemic rFWPV boost induced strong virus-specific CD4⁺ T-cell activity. rAd and rFWPV also induced differential patterns of the innate immune responses, thereby possibly shaping the specific immunity. Plasma CXCL10 levels after final immunization correlated directly with virus-specific CD4⁺ T-cell responses and inversely with the number of exposures to infection. Also, the percentage of activated CD69⁺ CD8⁺ T cells correlated with the number of exposures to infection. Differential stimulation of the immune response likely provided the basis for the diverging levels of protection afforded by the vaccine regimen.

IMPORTANCE A failed phase II AIDS vaccine trial led to the hypothesis that CD4⁺ T-cell activation can abrogate any potentially protective effects delivered by vaccination or promote acquisition of the virus because CD4⁺ T helper cells, required for an effective immune response, also represent the target cells for viral infection. We compared two vaccination protocols that elicited similar levels of Gag-specific immune responses in rhesus macaques. Only the animal group that had a low level of virus-specific CD4⁺ T cells in combination with high levels of activated CD8⁺ T cells was significantly protected from infection. Notably, protection was achieved despite the lack of appreciable Env antibody titers. Moreover, we show that both the vector and the route of immunization affected the level of CD4⁺ T-cell responses. Thus, mucosal immunization with FWPV-based vaccines should be considered a potent prime in prime-boost vaccination protocols.

一种有效的艾滋病疫苗应引起强烈的体液和细胞免疫反应，同时保持低水平的 CD4 ⁺ T 细胞活化，以避免产生用于病毒感染的靶细胞。本研究调查了两种初免加强方案，均开始接种单周期免疫缺陷病毒，然后使用表达 SIVmac239 或 SIVmac251 gag/pol和env的重组腺病毒 (rAd) 或禽痘病毒 (rFWPV) 进行两次黏膜加强免疫基因，分别。最后，将载体转换并系统地施用于互惠的动物组。只有粘膜 rFWPV 免疫，然后进行全身性 rAd 加强，才能显着保护动物免受反复低剂量直肠内致病性 SIVmac251 的攻击，从而导致 68% 的疫苗效力（即每次暴露的风险降低）。延迟的病毒获取与较高水平的活化 CD8 ⁺ T 细胞和分泌 Gag 特异性 γ 干扰素 (IFN-γ) 的 CD8 ⁺细胞、低病毒特异性 CD4 ⁺ T 细胞反应和低 Env 抗体滴度有关。相比之下，全身性 rFWPV 加强诱导了强病毒特异性 CD4 ⁺T细胞活性。rAd 和 rFWPV 还诱导了先天免疫反应的不同模式，从而可能形成特异性免疫。最终免疫后的血浆CXCL10水平与病毒特异性 CD4 ⁺ T 细胞反应直接相关，与感染暴露次数成反比。此外，活化的 CD69 ⁺ CD8 ⁺ T 细胞的百分比与接触感染的次数相关。免疫反应的差异刺激可能为疫苗方案提供的不同保护水平提供了基础。

重要性一项失败的 II 期 AIDS 疫苗试验导致了这样的假设，即 CD4 ⁺ T 细胞激活可以消除疫苗接种提供的任何潜在保护作用或促进病毒的获得，因为有效免疫反应所需的CD4 ⁺ T 辅助细胞也代表病毒感染的靶细胞。我们比较了两种在恒河猴中引发相似水平的 Gag 特异性免疫反应的疫苗接种方案。只有具有低水平病毒特异性 CD4 ⁺ T 细胞和高水平活化 CD8 ^{+ T 细胞的动物组}T 细胞被显着保护免受感染。值得注意的是，尽管缺乏明显的 Env 抗体滴度，但仍实现了保护。此外，我们表明载体和免疫途径都会影响 CD4 ⁺ T 细胞反应的水平。因此，使用基于 FWPV 的疫苗进行粘膜免疫应被视为初免-加强疫苗接种方案中的有效初免。