Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
AIDS Res Hum Retroviruses. 2020 Dec;36(12):984-997. doi: 10.1089/AID.2020.0157. Epub 2020 Oct 27.
Attempts to develop a protective human immunodeficiency virus (HIV) vaccine have had limited success, especially in terms of inducing protective antibodies capable of neutralizing different viral strains. As HIV transmission occurs mainly via mucosal surfaces, HIV replicates significantly in the gastrointestinal tract, and the oral route of vaccination is a very convenient one to implement worldwide, we explored three SIV vaccine modalities administered orally and composed of simian immunodeficiency virus (SIV) DNA priming with different boosting immunogens, with the goal of evaluating whether they could provide lasting humoral and cellular responses, including at mucosal surfaces that are sites of HIV entry. Twenty-four Cynomolgus macaques (CyM) were primed with replication-incompetent SIV DNA provirus and divided into three groups for the following booster vaccinations, all administered in the oral cavity: Group 1 with recombinant SIV gp140 and heat-labile toxin adjuvant dmLT, Group 2 with recombinant SIV-Oral Poliovirus (SIV-OPV), and Group 3 with recombinant SIV-modified vaccinia ankara (SIV-MVA). Cell-mediated responses were measured using blood, lymph node, rectal and vaginal mononuclear cells. Significant levels of systemic and mucosal T-cell responses against Gag and Env were observed in all groups. Some SIV-specific plasma IgG, rectal and salivary IgA antibodies were generated, mainly in animals that received SIV DNA + SIV-MVA, but no vaginal IgA was detected. Susceptibility to infection after SIV challenge was similar in vaccinated and nonvaccinated animals, but acute infection viremia levels were lower in the group that received SIV DNA + SIV-MVA. Nonvaccinated CyM maintained central memory and total CD4 T-cell levels in the normal range during the 5 months of postinfection follow-up as did the vaccinated animals, precluding evaluation of vaccine impact on disease progression. We conclude that the oral cavity vaccination tested in these regimens can stimulate cell-mediated immunity systemically and mucosally, but humoral response stimulation was limited with the doses and the vaccine platforms used.
开发保护性人类免疫缺陷病毒 (HIV) 疫苗的尝试取得了有限的成功，特别是在诱导能够中和不同病毒株的保护性抗体方面。由于 HIV 主要通过黏膜表面传播，HIV 在胃肠道中大量复制，而口服接种疫苗是一种非常方便的全球实施方式，我们探索了三种通过口服途径给予的 SIV 疫苗方式，由不同佐剂增强免疫原的猿猴免疫缺陷病毒 (SIV) DNA 引发，目的是评估它们是否能够提供持久的体液和细胞反应，包括在 HIV 进入的黏膜表面。24 只食蟹猴 (CyM) 用复制缺陷型 SIV DNA 前病毒进行了 priming，并分为三组进行以下增强免疫接种，均通过口腔给予：第 1 组用重组 SIV gp140 和 不耐热肠毒素佐剂 dmLT，第 2 组用重组 SIV-口服脊髓灰质炎病毒 (SIV-OPV)，第 3 组用重组 SIV-改良安卡拉痘苗病毒 (SIV-MVA)。使用血液、淋巴结、直肠和阴道单核细胞测量细胞介导的反应。所有组均观察到针对 Gag 和 Env 的全身性和黏膜 T 细胞反应的显著水平。在接受 SIV DNA+SIV-MVA 的动物中，主要产生了一些 SIV 特异性的血浆 IgG、直肠和唾液 IgA 抗体，但未检测到阴道 IgA。在 SIV 挑战后，接种疫苗和未接种疫苗的动物的感染易感性相似，但接受 SIV DNA+SIV-MVA 的动物的急性感染病毒血症水平较低。未接种疫苗的 CyM 在感染后 5 个月的随访期间保持中央记忆和总 CD4 T 细胞水平在正常范围内，就像接种疫苗的动物一样，从而排除了疫苗对疾病进展的影响的评估。我们的结论是，在这些方案中测试的口腔疫苗接种可以刺激全身和黏膜的细胞介导免疫，但使用所使用的剂量和疫苗平台，对体液反应的刺激有限。
