Risk of Neonatal Vaccination for HIV/SIV Exposed Infants

描述（由申请人提供）：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努力的核心。然而，在开发一种对人类显示出实质性效力的疫苗方面，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，因为它可以预防全世界每年近40万例新的艾滋病毒母婴传播（MTCT）。在发达国家，获得抗逆转录病毒治疗大大减少了母婴传播；然而，在资源贫乏的环境中，产后艾滋病毒传播的水平仍然高得令人无法接受。造成这种情况的原因包括：配方奶喂养负担不起或不安全（水污染）、不遵守服用抗逆转录病毒药物、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都能获得抗逆转录病毒药物。在南非（我们正在进行一项研究，以评估婴儿接种卡介苗的影响）和许多其他发展中国家，出生时接种的两种疫苗是卡介苗和口服脊髓灰质炎疫苗。虽然这些疫苗对预防播散性结核病和脊髓灰质炎感染有明显的保护作用，但也有潜在的缺点。引起这些有益反应的免疫激活可能同时增加婴儿对艾滋病毒的易感性。STEP的亚分析以及随后的猕猴SIV疫苗研究表明，疫苗诱导的特异性免疫反应促进了疫苗接受者的艾滋病毒感染。如果具有抗艾滋病毒/SIV活性的疫苗可以增强艾滋病毒/SIV的易感性，那么对其进行评估至关重要

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.