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

这里建议的研究将补充我们在P01 AI117915-06“预防青少年感染艾滋病毒的早期疫苗接种”中的研究。在家长拨款中，我们将定义在HIV Env SOSIP蛋白或HIV Env mRNA疫苗接种时，导致诱导保护性HIV Env特异性抗体的分子和免疫途径，包括广泛中和或Fc介导的效应功能。正在采取类似的疫苗战略来抗击SARS-CoV-2大流行。第一个测试编码稳定的预融合Spike蛋白疫苗的mRNAs的免疫原性以预防新冠肺炎的人体试验已经启动。 与早先爆发的相关冠状病毒SARS和MERS不同，SARS-CoV-2表现出更强的传播性，并导致了大流行。自疫情爆发以来，全球已确诊250多万例病例，近75万人死亡。与成人相比，感染SARS、MERS或SARS-CoV-2的婴儿出现的疾病似乎较轻，这意味着婴儿表达的病毒受体较少，宿主限制因素不同，或者他们的免疫系统更好地准备好抵御这些冠状病毒株。疫苗被认为是遏制病毒和防止进一步爆发的最佳选择。出于安全原因，首先在成人中评估疫苗的免疫原性和安全性，但儿科疫苗更可取，因为1)在儿童时期有机会产生保护性免疫，在整个生命周期内预防疾病并限制病毒传播，2)在儿科疫苗计划内最容易获得高疫苗覆盖率。我们处于独特的地位，可以在儿科环境中与成人试验同时测试已经可用的候选疫苗。在实验研究中，针对SARS或MERS病毒尖峰蛋白(S)的中和抗体已被证明可以预防病毒感染。然而，在从SARS或MERS感染中恢复的人类中，抗体反应似乎是短暂的。我们假设婴儿可以对SARS-CoV-2疫苗产生有效和持久的抗体反应，以保护其免受病毒攻击。我们的理由是基于我们从人类和恒河猴研究中获得的大量数据，这些数据表明，HIV Env疫苗可以诱导出与成人相当或更高的血浆免疫球蛋白抗体(I)，(Ii)可持续数月，(Iii)可以增强，表明疫苗诱导的记忆。我们对HIV Env SOSIP或mRNA疫苗的初步结果证实，这两种新的疫苗策略，如果在恒河猴出生时启动，可以像在成年猕猴中观察到的那样有效地诱导抗体。我们将在婴儿恒河猴模型中验证我们的假设，该模型已被证明具有很高的翻译价值，因为该模型在生理和免疫发育方面与人类婴儿相似，并有机会评估肺和肺相关粘膜组织中的全身和局部免疫反应。

The proposed studies here will complement our studies in the P01 AI117915-06 “Early Life Vaccination to Prevent HIV Acquisition in Adolescence”. In the parent grant, we will define the molecular and immune pathways resulting in the induction of protective HIV Env-specific antibodies, both broadly neutralizing or Fc-mediated effector functions, in response to HIV Env SOSIP protein or HIV Env mRNA vaccination. Similar vaccine strategies are being pursued to combat the SARS-CoV-2 pandemic. The first human trial to test the immunogenicity of the mRNA encoding the stabilized prefusion Spike protein vaccine to prevent COVID-19 has been initiated. In contrast to the earlier outbreaks with the related coronaviruses, SARS and MERS, the SARS-CoV-2 exhibits enhanced transmissibility and has resulted in a pandemic. Globally, more than 2.5 million cases have been confirmed, with close to 750,000 deaths since the beginning of the outbreak. Infants infected with SARS, MERS, or SARS-CoV-2 appear to present with milder disease compared to adults, implying that that infants express fewer virus receptors, differ in host restriction factors, or that their immune system is better equipped to fight off these coronavirus strains. A vaccine is considered the best option to contain the virus and to prevent further outbreaks. For safety reasons, vaccine immunogenicity and safety are first evaluated in adults, yet a pediatric vaccine is preferable due to 1) the opportunity to generate protective immunity in childhood that will prevent disease throughout the lifespan and limit viral spread, and 2) high vaccine coverage is most easily obtained within the pediatric vaccine schedule. We are in the unique position to test already available candidate vaccines in parallel to adult trials in the pediatric setting. In experimental studies, neutralizing antibodies to the SARS or MERS virus spike (S) protein have proven to protect against virus infection. However, in humans recovering from SARS or MERS infections, antibody responses appear to be short lived. We hypothesize that infants can mount effective and persistent antibody responses to SARS-CoV-2 vaccination that will protect against virus challenge. Our rationale is based on our extensive data from human and rhesus macaque studies demonstrating that HIV Env vaccines induce plasma IgG antibodies (i) of comparable or higher magnitude to that of adults, (ii) that persist for months, and (iii) can be boosted, indicative of vaccine-induced memory. Our preliminary results with HIV Env SOSIP or mRNA vaccines confirm that these two novel vaccine strategies, if initiated at birth in rhesus macaques, can induce antibodies as efficiently as observed in adult macaques. We will test our hypothesis in the infant rhesus macaque model that has been proven to be of high translational value due to the similarities in physiology and immune development to that of human infants and the opportunity to assess systemic and local immune responses in the lung and lung-associated mucosal tissues.