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。晚期HIV-1 妊娠期诊断、缺乏依从性和母乳喂养期间的急性HIV-1感染仍然存在 在预防母婴传播（MTCT）方面存在重大障碍。因此，为了实现一个 为了实现无艾滋病的一代，我们需要除抗逆转录病毒疗法之外的预防措施。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疫苗 以防止艾滋病毒通过母乳传播。尽管HIV主要通过粘膜途径传播， 少数疫苗策略探索粘膜免疫途径以诱导保护性免疫应答， 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。新生猕猴 用组合的口服（PO）和肌内（IM）DNA-SIV初免接种，并通过组合的 舌下（SL）和IM MVA-SIV具有显著降低的每次暴露风险的口腔SIV感染相比， 仅通过IM途径接种相同疫苗的婴儿。感染风险降低与较高的 粪便标本中SIV Env gp 120和V1 V2特异性IgG抗体。基于这一前提，我们提出了 中心假设，合理设计的SL+亲本疫苗联合方案可以预防口服HIV 婴儿的习得。Waldeyer环丰富的区域淋巴网络提供了一个简单而非 作为全身淋巴网络的固有部分， 通过口服疫苗诱导局部和全身保护性免疫应答。建议的目标 研究的目的是通过合理选择佐剂和HIV Env免疫原来优化我们的儿科疫苗 其可在血浆和粘膜进入部位（如口腔）诱导Env特异性IgG和伊加抗体， 粘膜和肠。我们将用MVA通过SL和皮下（SC）途径免疫婴儿 表达SIVgag、pol和进化枝C HIV C.1086包膜（Env）NFL三聚体加Env NFL三聚体蛋白 并检验SL+SC联合疫苗方案对口服SHIV具有上级有效性的假设 CH 848攻毒与仅通过SC途径接种相比（目的1和2）。Env免疫原和 挑战病毒含有HIV进化枝C的Env，该进化枝在撒哈拉以南非洲最流行， 大多数儿童艾滋病毒感染的发生，强调我们的研究的临床相关性。我们进一步测试 选择新的佐剂来特异性增强粘膜免疫应答， 婴儿树突状细胞的功能。为了确定产生高功能性的细胞所必需的途径， 婴儿中的抗体应答，并与婴儿中对口服SHIV CH 848攻击的保护有关 猕猴，我们将定义决定疫苗诱导的适应性免疫的口服先天分子特征， 激发时的反应，并与激发结果相关（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).