Functional profile to HIV vaccine elicited antibodies in infants

要消除母乳中艾滋病毒-1的传播可能需要多种方法的结合，包括免疫- 以儿童HIV-1疫苗等干预措施为基础。只有少数几个疫苗试验包括儿科 而且没有一个人测试了疗效。由于成人和婴儿的免疫力不同 目前尚不清楚成人和婴儿接种HIV疫苗后产生的抗体是否能够介导类似的 效应器功能。这项研究将通过比较猪瘟病毒引起的抗体的功能图谱来解决这一差距 在成人和婴儿中使用相同的佐剂艾滋病毒疫苗。关于疫苗保护的见解可以从 中度有效的成人RV144试验，其中HIV-1感染风险降低与高风险相关 抗HIV-1包膜(Env)V1V2环的免疫球蛋白水平。我们已经证明了给婴儿接种疫苗 Rgp120/MF59疫苗诱导的血浆潜在保护性抗V1V2抗体水平是对照组的22倍 比成人RV144疫苗接种者的水平更高。重要的是，最近有报道称，MF59不会导致 成人的高强度潜在保护性抗体反应。然而，我们的初步数据显示，婴儿 用rgp120/MF59疫苗免疫比成人产生更强的HIV Env特异性应答 用同样的疫苗进行免疫。这表明不同的佐剂可能会以不同的方式调节疫苗- 在成人和婴儿中引起了反应。这些差异可能会影响效应器的功能并决定 疫苗的效力。本应用的目的是评价婴儿疫苗诱导的环境蛋白的功能。 并确定不同佐剂对婴儿功能性抗体反应的影响。我们的 中心假设是，婴儿接种HIV-1疫苗产生的抗体能够介导不同的抗- 病毒效应器功能与成人抗体相比，婴儿抗体功能谱受到影响 通过疫苗佐剂。我们的中心假设将在以下具体目标中得到验证：1)定义 婴儿与成人HIV疫苗免疫后抗体功能的比较 相同的HIV Env疫苗；2)定义从Env特异性分离的mAbs的进化、特异性和功能 3)评估疫苗佐剂对艾滋病毒的影响 疫苗抗体Fc在婴儿恒河猴(RMS)中的功能及其与免疫功能的关系 特异的B细胞基因通路上调及其效应功能。我们预计这项研究将确定 成人和婴儿之间效应器功能的差异，突显了测试有希望的疫苗的必要性 儿科人群中的候选人。此外，与最佳基因途径相关的基因通路的鉴定 通过我们建议的组学方法进行疫苗反应，将允许合理设计和筛选 婴儿疫苗和佐剂候选，因为他们有能力靶向这些B细胞基因特征。

Eliminating breast milk HIV-1 transmission will likely require a combination of approaches, including immune- based interventions such as a pediatric HIV-1 vaccine. Only a few vaccine trials have included pediatric populations and none of them tested efficacy. Because of differences between the adult and infant immune system, it is unclear if antibodies elicited by HIV vaccination in adults and infants are able to mediate similar effector functions. This study will address this gap by comparing the functional profile of antibodies elicited by the same adjuvanted HIV vaccines in adults and infants. Insights on vaccine protection can be drawn from the moderately effective adult RV144 trial in which a reduced risk of HIV-1 acquisition was associated with high levels of IgG against the HIV-1 Envelope (Env) V1V2 loops. We have demonstrated that infant vaccination with a rgp120/MF59 vaccine induces plasma levels of potentially-protective anti-V1V2 IgG that are 22 times higher than levels found in adult RV144 vaccinees. Importantly, it was recently reported that MF59 does not induce high magnitude potentially-protective antibody responses in adults. Yet, our preliminary data show that infants immunized with the rgp120/MF59 vaccine developed higher magnitude HIV Env-specific responses than adults immunized with the same vaccine. This suggests that distinct adjuvants may differently modulate vaccine- elicited responses in adults and infants. These differences are likely to influence effector functions and dictate vaccine efficacy. The objective of this application is to evaluate the function of infant vaccine-elicited Env- specific antibodies and define the impact of different adjuvants on infant functional antibody responses. Our central hypothesis is that antibodies elicited by infant HIV-1 vaccination are capable of mediating distinct anti- viral effector functions when compared to adult antibodies, and infant antibody functional profile is influenced by the vaccine adjuvant. Our central hypothesis will be tested in the following specific aims: 1) Define the functional profile of HIV vaccine-elicited antibodies in infants in comparison with that of adults immunized with the same HIV Env vaccine; 2) Define the evolution, specificity, and function of mAbs isolated from Env-specific memory B cells of HIV-exposed HIV-vaccinated infants; and 3) Assess the impact of vaccine adjuvants on HIV vaccine antibody Fc-mediated functions in infant rhesus macaques (RMs) and the relationship between specific B cell gene pathways upregulation and effector function. We expect that this study will identify differences in effector functions between adults and infants, highlighting the need to test promising vaccine candidates in pediatric populations. In addition, the identification of gene pathways associated with optimal vaccine responses through our proposed ‘omics approach, will allow for the rational design and screening of infant vaccine and adjuvant candidates for their ability to target these B cell gene signatures.