Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants

摘要 全球每天约有400名婴儿感染HIV-1，其中绝大多数是通过母乳传播的。晚期HIV-1 怀孕期间的诊断、缺乏依从性和哺乳期间的急性艾滋病毒-1感染仍然存在 预防母婴传播(母婴传播)的重大障碍。因此，要实现一个 对于没有艾滋病的一代，我们除了抗逆转录病毒疗法(ART)外，还需要预防措施。一种艾滋病毒疫苗 是这些努力的核心组成部分。我们的长期目标是开发一种儿科艾滋病毒疫苗 以防止母乳传播艾滋病毒。尽管艾滋病毒主要通过粘膜途径传播， 很少有疫苗策略探索粘膜免疫途径来诱导保护性免疫反应 潜在的粘膜进入部位，包括婴儿的口腔粘膜。为了缩小这些差距，我们开始探索 口服疫苗在预防母乳传播艾滋病毒方面的潜力。初生猕猴 口服(PO)和肌肉注射(IM)DNA-SIV联合疫苗和联合加强免疫 与舌下(SL)和IM MVA-SIV相比，每暴露一次口腔SIV感染的风险显著降低 仅通过IM途径接种相同疫苗的婴儿。较低的感染风险与较高的 粪便标本中SIV env gp120和V1V2特异性抗体。基于这一前提，我们提出了 中心假设合理设计的SL双亲联合疫苗方案可以预防口腔HIV 婴儿的获得性。Waldeyer‘s环丰富的区域淋巴网络提供了一种简单和非 口服疫苗摄取的侵入性门户，作为全身淋巴网络的固有部分，使 口服疫苗诱导局部和系统保护性免疫反应。建议的目标是 研究是通过合理选择佐剂和HIV环境免疫原来优化我们的儿科疫苗 可以在血浆和粘膜进入部位(如口腔)诱导Env特异性的IgG和IgA抗体 粘膜和肠道。我们将通过SL和皮下(SC)途径为婴儿接种MVA 表达SIVgag、Poll及C分支HIV C.1086囊膜NFL三聚体和NFL三聚体蛋白 并检验SL SC联合疫苗方案对口服志贺氏菌病具有优越疗效的假设 CH848挑战与仅通过SC途径接种疫苗进行比较(目标1和2)。环境免疫原和 挑战病毒包含HIV C分支的env，该分支在撒哈拉以南非洲最流行，在那里 大多数儿童艾滋病毒感染都发生了，强调了我们研究的临床相关性。我们进一步测试 被选择来特异性增强粘膜免疫反应和引发的新型佐剂 婴幼儿树突状细胞的功能。确定对高功能细胞的产生至关重要的途径 婴儿中的抗体反应与婴儿口服新城疫病毒CH848攻击的保护性相关 猕猴，我们将定义决定疫苗诱导适应性免疫的口服先天分子签名 挑战时的反应，并与挑战结果相关(目标3)。

ABSTRACT Every day, about 400 infants acquire HIV-1 globally, the vast majority by breast milk transmission. Late HIV-1 diagnosis in pregnancy, lack of adherence, and acute HIV-1 infection during the breastfeeding period remain significant hurdles in the prevention of mother-to-child-transmission (MTCT). Thus, to achieve the goal of an AIDS-free generation, we need preventive measures in addition to antiretroviral therapy (ART). An HIV vaccine represents a core component of these efforts. Our long-term goal is the development of a pediatric HIV vaccine to protect against breastmilk transmission of HIV. Despite HIV being transmitted primarily by mucosal routes, few vaccine strategies explored mucosal routes of immunization to induce protective immune responses at potential mucosal entry sites, including the oral mucosa in infants. To close these gaps, we started to explore the potential of oral vaccination in the protection against breastmilk transmission of HIV. Newborn macaques vaccinated with a combined oral (PO) and intramuscular (IM) DNA-SIV prime and boosted by combined sublingual (SL) and IM MVA-SIV had a significantly reduced per-exposure-risk of oral SIV infection compared to infants receiving the same vaccine by the IM route alone. Reduced infection risk was associated with higher SIV Env gp120 and V1V2 specific IgG antibodies in fecal specimens. Based on this premise, we present the central hypothesis that a rationally designed combined SL+parental vaccine regimen can prevent oral HIV acquisition in infants. The rich regional lymphatic network of the Waldeyer’s Ring provides an easy and non- invasive portal for oral vaccine uptake, and, as an intrinsic part of the systemic lymphatic network, enables the induction of local and systemic protective immune responses by oral vaccines. The objective of the proposed studies is to optimize our pediatric vaccine through rational selection of adjuvants and HIV Env immunogens that can induce Env-specific IgG and IgA antibodies in plasma and at mucosal entry sites, such as the oral mucosa and the intestine. We will immunize infants by the SL and subcutaneous (SC) route with MVA expressing SIVgag, pol and the clade C HIV C.1086 envelope (Env) NFL trimer plus Env NFL trimer protein and test the hypothesis that a combined SL+SC vaccine regimen provides superior efficacy against oral SHIV CH848 challenge compared to vaccination by only the SC route (Aims 1 and 2). Both Env immunogen and challenge virus contain Envs of HIV clade C, the clade most prevalent in sub-Saharan Africa where the majority of pediatric HIV infections occur, emphasizing the clinical relevance of our studies. We further test novel adjuvants that were selected to specifically enhance mucosal immune responses and the priming function of infant dendritic cells. To identify pathways that are essential for the generation of highly functional antibody responses in infants and are associated with protection against oral SHIV CH848 challenge in infant macaques, we will define oral innate molecular signatures that determine vaccine-induced adaptive immune responses at the time of challenge and are correlated with challenge outcome (Aim 3).