Passive-Active Immunization Strategies Against Pediatric AIDS

除了安全和伦理问题外，开发新生儿艾滋病毒疫苗还有多种挑战。 由于相当大的传播率发生在前6个月，艾滋病毒疫苗必须迅速 即使在母体抗体存在的情况下，也能激发保护性免疫反应。另外，因为乳房- 哺乳婴儿在整个母乳喂养期间都有感染艾滋病毒的风险，这是一种早期接种的疫苗。 出生后需要给予长期免疫(几个月到几年)。可以理解的是，有 在疫苗有效，甚至免疫原性之前，不愿在婴儿身上进行艾滋病毒疫苗研究 候选人在成人身上进行了演示。然而，成人对疫苗的反应不能被认为是可靠的 预测疫苗在儿童和婴儿中的免疫原性或有效性。此外，艾滋病毒疫苗 目前正在评估的成人免疫方案似乎太慢，不能预防出生后的艾滋病毒 传播或儿童艾滋病。因此，对HIV疫苗免疫原性和效力的研究 快速免疫计划对于开发预防艾滋病毒母乳传播的疫苗至关重要； 然而，这样的研究在技术上要求极高，在伦理上也具有挑战性。我们提议的项目 将使用儿童艾滋病毒/艾滋病的SIV/新生儿恒河猴模型来评估免疫原性和 候选HIV疫苗策略在婴儿灵长类动物中的有效性。幼年恒河猴特别适合 提供研制艾滋病毒垂直传播疫苗和儿童艾滋病疫苗所需的信息， 因为人类和猕猴在生理学、免疫学和疾病发病机制上有许多相似之处。 像人类婴儿一样，新生恒河猴有能力产生病毒特异性的免疫反应。 接种后，包括接种减毒活疫苗。我们提议的项目的结果可以是 直接应用于设计疫苗，以预防人类新生儿和儿童感染艾滋病毒或疾病。 拟议项目的总体目标是评估两种复制的、减毒的SIV疫苗的能力。 策略[(1)水泡性口炎病毒和表达SIV抗原的改良安卡拉痘苗病毒，VSV-SIV+ MVA-SIV和(2)非致病性SIVmacIA11]to：(Aim1)诱导恒河猴新生儿产生SIV特异性免疫； (目的2)预防随后的口服SIV攻击；(Aim3)确定体内免疫相关性 这些活性疫苗方案的有效性。

Besides safety and ethical issues, there are multiple challenges to developing a neonatal HIV vaccine. Because a considerable rate of transmission occurs during the first 6 months, an HIV vaccine must rapidly elicit protective immune responses, even in the presence of maternal antibodies. In addition, because breast- feeding infants are at risk to acquire HIV infection throughout the breast-feeding period, a vaccine given early after birth needs to give long-term immunity (many months to several years). Understandably, there is reluctance to perform HIV vaccine studies in infants before efficacy, or even immunogenicity, of a vaccine candidate is demonstrated in adults. However, adult responses to vaccines cannot be assumed to reliably predict vaccine immunogenicity or effectiveness in children and infants. In additon, the HIV vaccine regimens currently being evaluated in adults appear to elicit immunity too slowly to prevent postnatal HIV transmission or pediatric AIDS. Thus, studies of the immunogenicity and efficacy of HIV vaccines with a rapid immunization schedule are essential to developing a vaccine to prevent HIV breast milk transmission; however, such studies are extremely technically demanding and ethically challenging. Our proposed project will use the SIV/neonatal rhesus macaque model of pediatric HIV/AIDS to evaluate immunogenicity and efficacy of candidate HIV vaccine strategies in infant primates. Infant rhesus macaques are uniquely suited to provide information needed to develop vaccines against vertical HIV transmission and pediatric AIDS, because of the many similarities in human and macaque physiology, immunology, and disease pathogenesis. Like human infants, newborn rhesus macaques are competent to develop virus-specific immune responses after vaccination, including vaccination with live-attenuated SIV. Results from our proposed project can be applied directly to design vaccines to prevent HIV infection or disease in human newborns and children. The overall goals of the proposed project are to evaluate the ability of two replicating, attenuated SIV vaccine strategies [(1) Vesicular Stomatitis Virus and Modified Vaccinia Ankara expressing SIV antigens, VSV-SIV + MVA-SIV, and (2) nonpathogenic SIVmacIA11] to : (Aim1) elicit SIV-specific immunity in rhesus neonates; (Aim 2) protect against subsequent oral SIV challenge and;(Aim3) determine in vivo immune correlates of the efficacy of these active vaccine regimens.