Passive-Active Immunization Strategies Against Pediatric AIDS

描述(由申请人提供)：迫切需要一种疫苗，以防止艾滋病毒传播和艾滋病在整个发展中世界迅速增加的艾滋病毒感染妇女所生的孩子中发生。任何预防儿童艾滋病的疫苗在出生时必须是安全的，并且必须在母亲有抗病毒抗体的情况下迅速诱导病毒特异性免疫，以防止出生后通过母乳喂养多次接触艾滋病毒。目前正在对成人进行评估的艾滋病毒疫苗似乎激发免疫力的速度太慢，无法预防艾滋病毒的出生后传播或儿童艾滋病。因此，对艾滋病毒免疫原在人类婴儿中的免疫原性和有效性的研究对于开发预防儿童艾滋病的艾滋病毒疫苗至关重要；然而，这种研究在技术上极其苛刻，在伦理上也具有挑战性。我们建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候选灵长类慢病毒疫苗在新生儿和婴儿灵长类动物中的免疫原性和有效性；该模型唯一适合于提供开发抗艾滋病毒垂直传播和儿童艾滋病疫苗所需的信息。为了确定两种基于重组痘病毒的减毒疫苗(MVA-SIVgpe和ALVAC-SIVgpe)诱导的宿主防御反应，这两种疫苗对于保护婴儿恒河猴免受多次、低剂量口服SIV攻击(4周龄)是必要的，我们将： 1)评价以痘病毒为基础的SIV疫苗免疫的成年猕猴被动转移高免疫血清能否保护幼猴免受口服SIV感染或疾病的影响。 2)确定在猕猴出生时接种SIV-痘病毒疫苗方案是否可以在具有或缺乏被动获得的SIV和痘病毒特异性抗体的婴儿中快速诱导对口腔SIV感染或疾病的保护性免疫。 3)在口服SIV攻击前，通过选择性地消耗接种动物的细胞(用单抗)，确定特定的免疫细胞群(即CD8+细胞、NK细胞)对于疫苗介导的婴儿猕猴口服SIV保护是必要的还是足够的。

DESCRIPTION (provided by applicant): A vaccine is urgently needed to prevent HIV transmission and AIDS in children born to the rapidly increasing number of HIV-infected women throughout the developing world. Any vaccine to prevent AIDS in children must be safe to give at birth and must rapidly elicit virus-specific immunity in the presence of maternal antiviral antibodies to protect against the multiple postnatal exposures to HIV through breast feeding. HIV vaccines 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 immunogens in human infants are essential to developing an HIV vaccine to prevent pediatric AIDS; however, such studies are extremely technically demanding and ethically challenging. Our proposed project will use the SIV/neonatal rhesus model of pediatric HIV/AIDS to evaluate immunogenicity and efficacy of candidate primate lentiviral vaccines in newborn and infant primates; this model is uniquely suited to provide information needed to develop vaccines against vertical HIV transmission and pediatric AIDS. To determine the host defense responses elicited by two attenuated, recombinant poxvirus-based SIV vaccines (MVA-SIVgpe and ALVAC-SIVgpe) that are necessary to protect infant rhesus macaques against multiple, low dose oral SIV challenge (at 4 weeks of age) we will: 1) Evaluate whether passive transfer of hyper-immune serum from adult macaques immunized with poxvirus-based SIV vaccines can protect infant macaques against infection or disease after oral SIV exposure. 2) Determine whether an SIV-poxvirus vaccine regimen administered to macaques at birth can elicit protective immunity against oral SIV infection or disease rapidly in infants who have, or who lack, passively-acquired SIV- and poxvirus-specific antibodies. 3) Determine if specific immune cell populations (i.e. CD8+ cells, NK cells) are necessary or sufficient for vaccine-mediated protection of infant macaques against oral SIV by selectively depleting cells (with monoclonal antibodies) in vaccinated animals before oral SIV challenge.