Evaluation of rotavirus vaccines in a primate model

描述(申请人提供)：轮状病毒导致婴儿严重腹泻，导致全球约60万人死亡，每年给美国造成15亿美元的损失。FDA批准的唯一轮状病毒疫苗因与肠套叠有关而于1999年被撤回。我们正在开发的亚单位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的脱落作为量化疫苗效力的终点。已经发现，通过黏膜递送疫苗可以几乎完全预防随后的口服轮状病毒攻击。由于小鼠和人类在系统发育上相距遥远，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，将疾病减少作为衡量疫苗有效性的终点。在这项建议中，评估轮状病毒疫苗的灵长类动物模型的可行性是通过确定(1)“窗口”的大小，其中幼年恒河猴容易患上轮状病毒引起的疾病后的腹泻，以及(3)轮状病毒特异性抗体的滴度以及效应细胞中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应用中，我们将扩大规模并生产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 The only FDA-approved rotavirus vaccine was withdrawn in 1999 because of its association with intussusception.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.