Evaluation of rotavirus vaccines in a primate model

描述（由申请人提供）：轮状病毒引起婴儿严重腹泻，导致全世界约60万人死亡，每年给美国造成15亿美元的损失。唯一一种经fda批准的轮状病毒疫苗于1999年因其与肠套叠相关而被撤回。我们正在开发的亚基轮状病毒疫苗已经在小鼠模型中进行了评估，该模型测量轮状病毒脱落作为量化疫苗效力的终点。经黏膜接种疫苗已发现可对随后的口服轮状病毒攻击产生几乎完全的保护作用。由于小鼠和人类在系统发育上距离较远，因此有必要建立一个非人类灵长类动物模型，该模型将用于验证我们的候选疫苗的有效性，并将减少疾病作为衡量疫苗有效性的终点。在这项提议中，通过确定(1)“窗口”的大小来评估灵长类动物模型评估轮状病毒疫苗的可行性，在这个“窗口”中，年轻的恒河猴在轮状病毒诱导的疾病后容易发生腹泻；(3)轮状病毒特异性抗体的滴度，以及效应CD4+和CD8+淋巴细胞中细胞因子的上调水平是否与保护相关。在后续的SBIR申请中，我们将扩大和生产gmp质量的疫苗，这些疫苗将用于安全性和免疫原性试验。

DESCRIPTION (provided by applicant): Rotavirus causes severe diarrhea in infants resulting in approximately 600,000 deaths worldwide and costing the United States 1.5 billion dollars annually. The only FDA-approved rotavirus vaccine was withdrawn in 1999 because of its association with intussusception. The subunit rotavirus vaccines that we are developing have been evaluated in a mouse model that measures rotavirus shedding as the endpoint for quantifying vaccine efficacies. Mucosal delivery of the vaccines has been found to elicit nearly complete protection against a subsequent oral rotavirus challenge. Because mice and humans are phylogenetically distant, it is necessary to establish a non-human primate model which will be used to validate the efficacy of our vaccine candidates using reduction of illness as the endpoint for measuring vaccine efficacies. In this proposal, the feasibility of a primate model for evaluating rotavirus vaccines is assessed by determining (1) the size of the "window", in which young rhesus macaques are susceptible to developing diarrhea following rotavirus-induced illness and (3) whether titers of rotavirus-specific antibodies, and upregulated levels of cytokines in effector CD4+ and CD8+ lymphocytes correlate with protection. In a follow-up SBIR application, we will scale up and produce GMP-quality vaccines which will be used in safety and immunogenicity trials.