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

摘要：项目1 如果要实现无HIV-1的一代，就必须控制HIV-1的母婴传播（MTCT）。 被消灭了虽然抗逆转录病毒预防战略有效地预防了母婴传播，但它们并不能消除 在高危环境中传播，如急性孕产妇感染、孕产妇抗药性的发展 变异，以及缺乏抗逆转录病毒药物的获得或坚持。一个有吸引力的解决方案是开发 预防母婴传播的免疫干预措施，如疫苗。项目1将侧重于发展一个产妇 通过IgG的胎盘转移和IgG的粘膜递送被动免疫婴儿的疫苗接种策略 母乳抗体我们最近的发现支持了母体疫苗的发展， 母婴传播风险的降低可以通过对HIV-1的高强度母体抗体反应来预测 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 对怀孕和婴儿恒河猴进行猴免疫缺陷病毒（SIV）疫苗接种， 部分防止婴儿口腔SIV感染。最后，我们证明了HIV-1 Env MVA 哺乳期猴的初次/蛋白质加强免疫既增强了Env特异性伊加， 母乳中的抗体反应。重要的是，这些发现表明，母亲接种疫苗， 增强易于引发的Env特异性抗体应答可以通过以下途径防止口服HIV-1感染： 在婴儿早期进行母乳喂养，此时婴儿接种疫苗不能提供保护。因此我们 假设用Env初免/加强策略优化母体疫苗接种以引起稳健的、潜在的- 保护性Env特异性母源抗体应答将有效降低口服猿猴/人 免疫缺陷病毒（SHIV）在新生猴中的获得。在本建议的第一个目标中，我们将 比较先前鉴定的母乳来源的HIV-1 Env特异性IgG和伊加的特异性和功能 通过母体MVA初免/Env T/F 1086.C加强免疫引发的抗体，以确定潜在的益处 母乳抗体反应诱导。在目标2中，我们将确定母体胎盘是否 转移的或母乳来源的疫苗引发的抗体提供对急性口服SHIV的保护 在婴儿中激发，模拟哺乳期间的急性母体感染。最后，在目标3中，我们将确定 这种母体Env免疫策略是否可以增强潜在的保护性母体抗体 在SHIV感染的，抗逆转录病毒治疗的怀孕猴子的反应，并确定他们的能力，以减少口服 SHIV暴露婴儿的自体SHIV获得。本项免疫原性和 孕产妇HIV-1 Env免疫接种对减少婴儿病毒感染的有效性将确定 母亲HIV-1免疫接种消除儿童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.