Development of a maternal vaccine to protect infants against clade C HIV-1

摘要：项目1 如果要实现没有艾滋病毒-1的一代，就必须实现艾滋病毒-1的母婴传播 被根除了。虽然抗逆转录病毒预防策略有效地预防了母婴传播，但它们并不能消除 在高危环境中的传播，如急性孕产妇感染、母亲产生抗药性 变种，以及缺乏抗逆转录病毒药物的获取或坚持。一个有吸引力的解决方案是开发 对母婴传播的免疫干预，如疫苗。项目1将侧重于开发一种母体 通过胎盘转移免疫球蛋白和粘膜注射免疫婴儿的接种策略 母乳抗体。母体疫苗的开发得到了我们最近的发现的支持，这些发现表明 母体对HIV-1的高强度抗体反应可以预测母体感染母婴传播的风险降低 包膜(Env)可变环3(V3)和1级异源病毒的中和。此外，我们还展示了 给孕期和幼年恒河猴接种猴免疫缺陷病毒疫苗可以 部分保护婴儿口腔SIV感染。最后，我们证明了HIV-1 Env MVA PRIME/Protein加强免疫对哺乳猴的免疫效果：既能产生强效的环境特异性IgA，又能中和 母乳中的抗体反应。重要的是，这些发现表明，产妇接种疫苗可以 增强易诱发的环境特异性抗体应答可通过以下途径预防经口感染HIV-1 在婴儿早期进行母乳喂养，这是婴儿接种疫苗无法提供保护的时间点。因此，我们 假设母体疫苗接种采用优化的Env Prime/Boost策略，以获得强大的、潜在的- 保护性环境特异性母体抗体反应将有效减少口服猿猴/人 免疫缺陷病毒(SIV)在新生幼猴中的获取。在这项提案的第一个目标中，我们将 已鉴定的母乳来源HIV-1环境特异性免疫球蛋白和免疫球蛋白A的特异性和功能比较 母体MVA Prime/Env T/F 1086.C激发的抗体加强免疫以确定潜在的益处 母乳抗体反应的诱导。在目标2中，我们将确定母体位置 转移或母乳衍生疫苗诱导的抗体对急性口腔志贺病具有保护作用 在婴儿中挑战，模拟哺乳期的急性母体感染。最后，在目标3中，我们将确定 这种母体环境免疫策略是否能增强潜在的保护性母体抗体 感染新城疫病毒并接受抗逆转录病毒治疗的怀孕猴的反应，并确定它们减少口服的能力 暴露于SIV的婴儿中的自体SIV获取。这是一项免疫原性和免疫功能的临床前研究 母体HIV-1环境免疫对减少婴儿病毒感染的有效性将决定 母体HIV-1免疫用于消除儿童HIV-1感染的可行性。

ABSTRACT: Project 1 If an HIV-1-free generation is to be achieved, mother-to-child HIV-1 transmission (MTCT) of HIV-1 must be eradicated. While antiretroviral prophylaxis strategies effectively prevent MTCT, they do not eliminate transmission in high-risk settings such as acute maternal infection, development of maternal drug-resistant variants, and lack of antiretroviral drug access or adherence. An attractive solution is the development of immunologic interventions for MTCT, such as vaccines. Project 1 will focus on developing a maternal vaccination strategy to passively immunize the infant via placental transfer of IgG and mucosal delivery of breast milk antibody. The development of a maternal vaccine is supported by our recent findings, which show that reduced risk of MTCT can be predicted by high magnitude maternal antibody responses against the HIV-1 Envelope (Env) variable loop 3 (V3) and neutralization of tier 1 heterologous viruses. In addition, we showed that vaccination of pregnant and infant rhesus monkeys against Simian Immunodeficiency Virus (SIV) can partially protect against infant oral SIV acquisition. Finally, we demonstrated that HIV-1 Env MVA prime/protein boost immunization of lactating monkeys elicits both robust Env-specific IgA and neutralizing antibody responses in maternal breast milk. Importantly, these findings suggest that maternal vaccination to enhance easy-to-elicit Env-specific antibody responses could protect against oral HIV-1 acquisition via breastfeeding in early infancy, a time point when infant vaccination cannot offer protection. Thus, we hypothesize that maternal vaccination with an Env prime/boost strategy optimized to elicit robust, potentially- protective Env-specific maternal antibody responses will effectively reduce oral simian/human immunodeficiency virus (SHIV) acquisition in neonatal infant monkeys. In the first Aim of this proposal, we will compare the specificity and function of previously-identified breast milk-derived HIV-1 Env-specific IgG and IgA antibodies elicited by maternal MVA prime/Env T/F 1086.C boost immunization to define the potential benefits of breast milk antibody response induction. In Aim 2, we will determine whether maternal placentally transferred or breast milk-derived vaccine-elicited antibodies confer protection against acute oral SHIV challenge in infants, simulating acute maternal infection during lactation. Finally, in Aim 3, we will determine whether this maternal Env immunization strategy can enhance potentially protective maternal antibody responses in SHIV-infected, antiretroviral-treated pregnant monkeys and define their ability to reduce oral autologous SHIV acquisition in the SHIV-exposed infant. This preclinical study of the immunogenicity and effectiveness of maternal HIV-1 Env immunization for reduction of infant virus acquisition will define the feasibility of maternal HIV-1 immunization for elimination of pediatric HIV-1 infections.