Immunogenicity and Efficacy of SARS-CoV-2 stabilized prefusion Spike protein vaccines in infant rhesus macaques

摘要 高度传播的新型冠状病毒SARS-CoV-2的出现导致了一场全球范围的疫情 严重的呼吸道疾病。虽然老年人和患有共病的成年人是高危人群， 冠状病毒病(新冠肺炎)可发生在所有年龄段的个人中，包括婴儿。因此，它 开发一种可以在生命早期接种并产生长期免疫力的疫苗将是非常重要的 结束柯萨奇病毒19大流行。虽然候选疫苗的初步安全性测试将在成人人群中进行， 将疫苗定向到儿科疫苗计划中有许多潜在的优势，包括高 儿科疫苗覆盖率和终身免疫潜力。事实上，婴儿可以做出显著的反应 对蛋白质抗原很好，包括乙肝和候选艾滋病毒包膜疫苗，而且有证据表明 感染艾滋病毒的婴儿更有能力产生艾滋病毒中和抗体。而且，我们之前的 在人类和恒河猴身上的研究已经证实，婴儿能够产生HIV Env疫苗 与持续数月的成人反应相当或更高的反应 增强了。家长授予P01 AI117915-06“预防青少年感染艾滋病毒的早期疫苗接种” 目的是评估婴儿恒河猴非人类HIV包膜基因和SOSIP三聚体候选疫苗 灵长类动物模型，并确定其在青春期抗艾滋病毒感染的有效性。作为相关的补充 研究中，我们建议评估候选SARS-CoV-2刺突蛋白(S)和 幼年恒河猴的候选mrna疫苗。我们假设婴儿可以有效地和 对SARS-CoV-2疫苗的持续系统和粘膜抗体反应将保护 抵御病毒挑战。这项工作将提供临床前的安全性、免疫原性和疗效数据 领先的SARS-CoV-2疫苗平台，可以降低儿科人群人体试验的风险，并证明 绕过耗时且昂贵的年龄降级研究。SARS-CoV-2大流行的结束 将需要高全球覆盖率的疫苗，以防止病毒传播并产生持久的免疫力， 这可能是通过儿科靶向疫苗最好的实现。

ABSTRACT The emergence of the highly-transmissible novel coronavirus SARS-CoV-2 has led to a global pandemic of severe respiratory disease. While elderly individuals and adults with co-morbidities are high risk populations, coronavirus disease (COVID-19) can occur in individuals across all age groups, including infants. Therefore, it will be important to develop a vaccine that can be administered in early life and generate long term immunity to end the COVID19 pandemic. While initial safety testing of vaccine candidates will occur in adult populations, there are many potential advantages of targeting the vaccine to the pediatric vaccine schedule including high rates of pediatric vaccine coverage and potential for lifelong immunity. In fact, infants can respond remarkably well to protein antigens, including the hepatitis B and candidate HIV envelope vaccines, and there is evidence that HIV-infected infants are better equipped to generate HIV-neutralizing antibodies. Moreover, our previous work in human and rhesus monkeys has established that infants are able to generate HIV Env vaccine responses of comparable or higher magnitude to that of adults that persist for months and are able to be boosted. The parent grant P01 AI117915-06 “Early Life Vaccination to Prevent HIV Acquisition in Adolescence” aims to assess candidate HIV envelope mRNA and SOSIP trimer vaccines in infant rhesus monkey nonhuman primate model and determine their efficacy against HIV acquisition in adolescence. As related complementary studies, we propose to assess the immunogenicity and efficacy of candidate SARS-CoV-2 spike (S) protein and mRNA vaccine candidates in infant rhesus monkeys. We hypothesize that infants can mount effective and persistent systemic and mucosal antibody responses to SARS-CoV-2 vaccination that will protect against virus challenge. This work will provide preclinical safety, immunogenicity, and efficacy data on leading SARS-CoV-2 vaccine platforms that can de-risk human trials in pediatric populations and justify bypassing time consuming and expensive age de-escalation studies. The end of the SARS-CoV-2 pandemic will require high global coverage with a vaccine that prevents viral spread and generates long lasting immunity, which may best be achieved with a pediatric targeted vaccine.