Optimizing Oral Pediatric HIV Vaccines to Prevent Breast Milk Transmission

描述（由申请人提供）：在发展中国家，艾滋病毒母婴传播（MTCT）仍然很高，母乳喂养是向暴露于HIV-1的婴儿提供营养和保护性免疫力以对抗许多共感染病原体的必要手段。因此，迫切需要一种儿童艾滋病毒疫苗。 我们的目标是确定佐剂和疫苗输送策略，可以防止母乳传播艾滋病毒的新生儿。婴儿免疫系统的不成熟是儿科疫苗设计中的独特挑战。我们认为，旨在增加婴儿树突状细胞（DC）成熟的免疫介质将改善T细胞和促进T辅助细胞1的反应。此外，能够克服对CD 4帮助的需要的佐剂将导致更有效的B细胞刺激。具体来说，拟议的拨款申请将测试树突状细胞功能和抗体 通过将GM-CSF（Aim 1）和CD 40 L（Aim 2）与DNA引物共同施用，可以改善质量。GM-CSF佐剂将募集DC，增强DC功能，并且一直显示在SIV接种的成年猕猴中增加抗体应答。CD 40 L佐剂将提供所需的共刺激，以更有效地诱导婴儿的B细胞应答。我们进一步预测，当婴儿免疫系统最不成熟时，这种佐剂将是最有益的，因此，必须在疫苗方案的初免阶段提供。为了实现我们的长期目标，这里的研究将使用模型肌内DNA/MVA疫苗测试GM-CSF和CD 40 L作为佐剂，该疫苗已证明在预防成年猕猴直肠SIV或SHIV传播中的有效性。我们将首先证实这种含佐剂的DNA/ MVA疫苗可以增强对婴儿口服SIV获得的保护效力，然后证明口服疫苗递送将更有效。我们假设这些佐剂与DNA引物（目的3）的口服应用将促进局部免疫应答的诱导，包括伊加和HIV特异性T细胞，这些细胞将回到口腔粘膜。在病毒进入的部位产生的免疫反应应该是最能防止母乳经口感染艾滋病毒的。因此，主要的焦点在于确定免疫佐剂和交付策略，可以提高儿童艾滋病毒疫苗的保护效力。 研究将在口服SIV感染的幼年恒河猴模型中进行。这些结果有望确定（i）可以提高保护效力的佐剂，以及（ii）增强局部免疫反应以预防婴儿口服HIV感染的疫苗递送策略。 （1）Abel博士在婴儿SIV发病机制和疫苗研究方面的专业知识，（2）Kozlowski博士在粘膜免疫学方面的专业知识，以及（3）阿马拉博士在HIV疫苗设计方面的专业知识的结合将保证拟议研究的成功完成。

DESCRIPTION (provided by applicant): Mother-to-child-transmission (MTCT) of HIV continues to be high in developing countries where breast-feeding is a necessary means to provide nutrients and protective immunity against many co- infecting pathogens to HIV-1 exposed infants. Thus, a pediatric HIV vaccine is urgently needed. Our goal is to identify adjuvants and vaccine delivery strategies that can prevent breast milk transmission of HIV in newborns. The immaturity of the infant immune system is a unique challenge in pediatric vaccine design. We rationalized that immune mediators aimed at increasing infant dendritic cell (DC) maturation would improve T cell and promote T helper 1 responses. In addition, adjuvants that can overcome the need for CD4 help would result in more efficient B cell stimulation. Specifically, the proposed grant application will test whether dendritic cell function and antibody quality can be improved by co-administration of GM-CSF (Aim 1) and CD40L (Aim 2) with the DNA prime. The GM-CSF adjuvant will recruit DC, enhance DC function, and has consistently been shown to increase antibody response in SIV vaccinated adult macaques. The CD40L adjuvant will provide needed co-stimulation for more efficient induction of B cell responses in infants. We further predict that such adjuvants would be most beneficial when the infant immune system is most immature, and would, thus, have to be provided during the prime phase of the vaccine regimen. Towards our long-term goal, the studies here will test GM-CSF and CD40L as adjuvants using a model intramuscular DNA/MVA vaccine that has demonstrated efficacy in the prevention against rectal SIV or SHIV transmission in adult macaques. We will first confirm that this adjuvanted DNA/ MVA vaccine can enhance protective efficacy against oral SIV acquisition in infants, and then demonstrate that oral vaccine delivery would be even more effective. We hypothesize that the oral application of these adjuvants with the DNA prime (Aim 3) will promote the induction of local immune responses, including IgA and HIV-specific T cells that would home to the oral mucosa. Immune responses generated at the site of viral entry should be most protective against oral HIV acquisition by breast milk. Thus, the main focus lies in the identification of immune adjuvants and delivery strategies that can enhance the protective efficacy of pediatric HIV vaccines. The studies will be performed in the infant rhesus macaque model of oral SIV infection. The results are expected to identify (i) adjuvants that can increase protective efficacy, and (ii) vaccine delivery strategies that enhance local immune responses to prevent oral HIV acquisition in infants. The combined expertise of (1) Dr. Abel in infant SIV pathogenesis and vaccine studies, (2) Dr. Kozlowski in mucosal immunology, and (3) the expertise of Dr. Amara in HIV vaccine design will guarantee the successful completion of the proposed studies.