Risk of Neonatal Vaccination for HIV/SIV Exposed Infants

疫苗接种是现代医学中最成功和最具成本效益的干预措施。艾滋病毒疫苗可以挽救数百万人的生命，并将成为根除艾滋病毒工作的核心。然而，在开发在人类中显示出实质性功效的疫苗方面仍然存在许多挑战。婴儿是一个可能受益于疫苗保护的群体，每年在全世界防止近40万例新的母婴传播艾滋病毒。在发达国家，获得抗逆转录病毒治疗已大大减少了母婴传播;然而，在资源贫乏的环境中，产后艾滋病毒传播仍然处于令人无法接受的高水平。其原因包括：配方奶喂养负担不起或不安全（水污染），不遵守抗逆转录病毒疗法，母乳喂养对婴儿健康的好处，以及所有感染艾滋病毒的孕妇及其婴儿获得抗逆转录病毒疗法。在南非（我们正在进行一项评估婴儿接种卡介苗影响的研究）和许多其他发展中国家，出生时接种的两种疫苗是卡介苗（BCG）和口服脊髓灰质炎疫苗（OPV）。虽然这些疫苗对结核病和脊髓灰质炎感染具有明显的保护作用，但也有潜在的不利因素。激发这些有益反应的免疫激活可能同时增加婴儿对HIV的易感性。STEP以及随后的猕猴SIV疫苗研究的子分析表明，特定的疫苗诱导的免疫应答促进了疫苗接受者的HIV感染。如果具有抗HIV/SIV活性的疫苗可以增强HIV/SIV的易感性， 目前的免疫策略可能会影响艾滋病毒暴露婴儿的艾滋病毒传播。本提案的目的是：1）评估BCG和OPV疫苗接种对婴儿恒河猴中HIV/SIV靶细胞募集和活化的免疫学影响，以及2）通过离体刺激猕猴和人细胞来确定BCG/OPV介导的免疫调节机制。本提案将检验以下假设，即早期接种（出生后数天内）经母体接种的卡介苗/口服脊髓灰质炎疫苗会增加婴儿口服SIV感染的风险。为了解决这一假设，Sodora实验室将利用我们在先天免疫学和SIV感染猕猴模型方面的丰富经验，同时与疫苗接种研究和适应性免疫专家Deborah Fuller博士合作，深入了解BCG/OPV诱导的免疫反应。该提案将确定新生儿接种疫苗对HIV/SIV靶细胞的募集和激活以及SIV传播的影响，以深入了解BCG/OPV新生儿接种对口服MTCT SIV/HIV传播的作用。目前对HIV暴露婴儿接种疫苗的调查使这些研究与当前的临床实践特别相关，同时也促进了对HIV暴露个体具有最佳安全性的有效HIV疫苗的开发。

DESCRIPTION (provided by applicant): Vaccinations are the most successful and cost-effective interventions in modern medicine. An HIV vaccine could save millions of lives and would be the centerpiece of HIV eradication efforts. However, numerous challenges remain in developing a vaccine that shows substantial efficacy in humans. Infants are one group likely to benefit from vaccine protection by preventing the nearly 400,000 new Mother-to-child transmissions (MTCT) of HIV worldwide each year. Access to anti-retroviral treatment (ART) has dramatically reduced MTCT in developed countries; however postpartum HIV transmission persists at unacceptably high levels in resource-poor settings. The reasons for this include: formula feeding not being affordable or safe (water contamination), lack of compliance to taking the ART, benefits of breastfeeding for the health of the infant and access of ART to all pregnant HIV-infected woman and their babies. In South Africa (where we have an ongoing study to assess impact of BCG vaccination in infants), and many other developing countries, the two vaccines given at birth are Bacillus Calmette-Guerin (BCG) and Oral Polio Vaccine (OPV). While these vaccines have clear protective benefits against disseminated tuberculosis and polio infection, there is also a potential downside. The very immune activation that elicits these beneficial responses may simultaneously increase an infant's susceptibility to HIV. Sub-analyses from the STEP as well as subsequent macaque SIV vaccine studies have implicated specific vaccine-induced immune responses in promoting HIV infection in vaccine recipients. If vaccines with anti-HIV/SIV activity can enhance HIV/SIV susceptibility, it is critical to assess if current immunization strategies can impact HIV transmission in HIV-exposed infants. The goals of this proposal are to: 1) Assess the immunologic impact of administration of BCG and OPV vaccines on HIV/SIV target cell recruitment and activation in infant rhesus macaques, and 2) Define the mechanism of BCG/OPV-mediated immune modulation through ex-vivo stimulation of macaque and human cells. This proposal will test the hypothesis that early administration (within days of birth) of the neonatally-administered vaccines BCG/OPV increases the risk of oral SIV acquisition in infants. To address this hypothesis, the Sodora laboratory will draw on our extensive experience in innate immunology and macaque models of SIV-infection while collaborating with Dr. Deborah Fuller, an expert in vaccination studies and adaptive immunity, to develop a thorough understanding of BCG/OPV-induced immune responses. This proposal will define the impact of neonatal vaccinations on recruitment and activation of HIV/SIV target cells as well as SIV transmission, to provide insights into the role of BCG/OPV neonatal vaccinations on oral MTCT SIV/HIV transmission. The investigation of vaccines currently administered to HIV-exposed infants makes these studies particularly relevant for current clinical practice while also facilitating the development of an effective HIV vaccine with optimal safety for HIV-exposed individuals.