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的出现导致了全球大流行， 严重的呼吸道疾病。虽然老年人和患有合并症的成年人是高危人群， 冠状病毒病（COVID-19）可发生在所有年龄组的个体中，包括婴儿。因此 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重要的。 结束COVID 19大流行。虽然候选疫苗的初步安全性测试将在成年人群中进行， 将疫苗靶向于儿科疫苗时间表有许多潜在的优点， 儿童疫苗覆盖率和终身免疫潜力。事实上，婴儿对 以及蛋白抗原，包括乙肝B和候选HIV包膜疫苗，有证据表明， 感染艾滋病毒的婴儿能够更好地产生艾滋病毒中和抗体。此外，我们以前的 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 与成年人相当或更高幅度的反应，持续数月，并能够 提高。父母补助金P01 AI 117915 -06“预防青少年感染艾滋病毒的早期接种” 目的是评估候选HIV包膜mRNA和SOSIP三聚体疫苗在婴儿恒河猴非人中的应用 灵长类动物模型，并确定其对青春期艾滋病毒感染的有效性。作为相关补充 研究，我们建议评估候选SARS-CoV-2刺突蛋白的免疫原性和有效性， 在恒河猴幼猴中的mRNA疫苗候选物。我们假设婴儿可以有效地 对SARS-CoV-2疫苗接种的持续全身和粘膜抗体应答， 对抗病毒的挑战。这项工作将提供临床前安全性、免疫原性和有效性数据， 领先的SARS-CoV-2疫苗平台，可以降低儿童人群的人体试验风险， 绕过了耗时且昂贵的年龄递减研究。SARS-CoV-2大流行的结束 将需要全球高覆盖率的疫苗，以防止病毒传播，并产生持久的免疫力， 这可能最好通过儿科靶向疫苗来实现。

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.