Translation of immunologic technologies from basic research into pre-clinical non

疫苗有保护作用吗？士兵接种炭疽疫苗是因为恶意感染的可能性很高 炭疽杆菌的孢子。但疫苗真的能保护他们免受疾病发病率和死亡率的影响吗？没有 直接在人体上测试FDA批准的AVA疫苗或任何其他候选疫苗的手段。抗体滴定， 在接种疫苗的个体中，表位特异性和毒素中和活性显示出令人不安的变异性。在……里面 与我们的U19免疫学家合作，这项建议将使用非人类灵长类炭疽热模型来解决这些问题 模仿人类的反应。在之前的资助期间，我们开发了一种狒狒，并对其进行了表征和验证 炭疽菌血症模型，模拟人类孢子萌发后的晚期疾病，展示了关键的 败血症对致命性的作用。目前的提议建立在这一基础上，并基于这样的假设：如果 已知的特异性和中和活性的抗体可以预防感染或降低疾病的严重性，原因是 在经过验证的狒狒模型中接种炭疽杆菌，那么接种了类似抗体的个体也将同样受到保护。 由于不是每个人对疫苗的反应方式都相同，这一信息可能有助于风险分层 接种疫苗的人。我们的目标是：1)鉴定已知表位特异性的多克隆和单抗 功能；2)开发和表征狒狒的肺孢子模型；并使用这些模型来测试是否 在非人类灵长类疾病模型中，特征性抗体具有保护性。这种方法是强有力的，因为 猴和人类对AVA的体液反应将是特征的，许多抗原特异性抗体将是 经过筛选，最有希望的将在狒狒疾病模型中进行全面测试。在最低限度上，我们将 能够识别几种可能立即有用的候选抗体，作为被动免疫的辅助手段 治疗学。我们有一个独特的机会来回答关键问题，通过结合遗传多样性的非人类 灵长类动物模型，有用新技术模拟人类对炭疽热挑战的反应的成熟历史 由免疫学家在这笔U19拨款中提供。

Does the vaccine protect? Soldiers are vaccinated against anthrax due to the high probability of malicious infection with the spores of B. anthracis. But will the vaccine actually protect them from disease morbidity and mortality? There is no means to test the FDA-approved AVA vaccine or any other vaccine candidate directly in humans. Antibody tilers, epitope specificity, and toxin neutralizing activity in vaccinated individuals show a disturbing degree of variability. In concert with our U19 immunologists, this proposal will address these issues using nonhuman primate models of anthrax that mimic human responses. In the previous funding period, we developed, characterized and validated a baboon anthrax bacteremia model that mimics late stage disease in humans after spore germination, demonstrating the critical role of sepsis toward lethality. The current proposal builds on this foundation and is based on the hypothesis that if antibodies of known specificity and neutralizing activity can prevent infection or reduce disease severity due to B.anthracis in validated baboon models, then vaccinated individuals with similar antibodies will likewise be protected. Since not everyone responds in the same way to the vaccine, this information may contribute to risk stratification of vaccinated individuals. We aim to 1) identify polyclonal and monoclonal antibodies of known epitope specificity and functionality; 2) develop and characterize pulmonary spore models in baboons; and use these to 3) test whether the characterized antibodies are protective in the nonhuman primate disease models. The approach is strong because both baboon and human humoral responses to AVA will be characterized, many antigen-specific antibodies will be screened, and the most promising will be comprehensively tested in the baboon disease models. Minimally, we will be able to identify several candidate antibodies that may be useful immediately as passive immunity adjunctive therapeutics. We have a unique opportunity to answer critical questions by combining a genetically diverse nonhuman primate model which has a proven history of mimicking human responses to anthrax challenge with novel technologies provided by the immunologists on this U19 grant.