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

SARS-CoV-2 稳定预灌注 Spike 蛋白疫苗在幼年恒河猴中的免疫原性和功效

• 批准号: 10223632
• 负责人: KOEN K VAN ROMPAY
• 金额: $ 88.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223632
• 关键词: 2019-nCoV; Adolescence; Adult; Antibodies; Antibody Response; Birth; COVID-19; Cessation of life; Childhood; Complement; Coronavirus; Development; Disease; Disease Outbreaks; Exhibits; HIV; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Infant; Infection; Life; Longevity; Lung; Macaca; Macaca mulatta; Mediating; Memory; Messenger RNA; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular; Mucous Membrane; Pathway interactions; Physiology; Plasma; Population; Positioning Attribute; Proteins; RNA vaccine; SARS coronavirus; Safety; Schedule; Severe Acute Respiratory Syndrome; Systems Biology; Testing; Vaccination; Vaccines; Viral; Virus; Virus Diseases; Virus Receptors; age group; base; combat; experimental study; fighting; human data; immunogenicity; lipid nanoparticle; neonatal infection; neutralizing antibody; novel vaccines; pandemic disease; parent grant; prevent; response; vaccine candidate; vaccine efficacy

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.

拟议的研究将补充我们在P01 AI117915-06中的研究“早期疫苗接种，以防止青少年的艾滋病毒获取”。在父授予中，我们将定义分子和免疫学，导致受保护的HIV ENV特异性抗体诱导，无论是广泛中和或FC介导的效应函数，响应于HIV ENV SOSIP SOSIP蛋白或HIV HIV蛋白或HIV HIV MRNA疫苗。正在采取类似的疫苗策略来对抗SARS-COV-2大流行。已经开始了第一个测试编码稳定的预灌注尖峰蛋白疫苗的mRNA的免疫原性的人类试验，以防止COVID-19。 与相关的冠状病毒，SARS和MERS的早期暴发相反，SARS-COV-2表现出增强的传播，并导致大流行。在全球范围内，已经确认了超过250万例案件，自爆发开始以来，近75万人死亡。与成年人相比，感染了SARS，MERS或SARS-COV-2的婴儿似乎患有米勒病，这意味着婴儿表现出更少的病毒受体，宿主限制因素不同，或者其免疫系统具有更好的能力来抗击这些冠状病毒菌株。疫苗被认为是遏制病毒并防止进一步爆发的最佳选择。出于安全原因，首先在成年人中评估疫苗免疫原性和安全性，但是由于1）有机会在儿童期生成受保护的免疫学，因此在儿童期间产生受保护的免疫学，这将在整个生命周期中预防疾病并限制病毒率，并且2）在儿童疫苗计划中最容易获得高疫苗的覆盖范围。我们处于独特的位置，可以在儿科环境中与成人试验并行测试已经可用的候选疫苗。在实验研究中，证明对SARS或MERS病毒峰值蛋白的中和抗体已证明可以预防病毒感染。但是，在从SARS或MERS感染中恢复的人类中，抗体反应似乎很短。我们假设婴儿可以对SARS-COV-2疫苗的有效和持续的抗体反应进行防止病毒挑战。我们的理由是基于人类和恒河猴研究的广泛数据，表明HIV ENV疫苗诱导与成年人的血浆IgG抗体（I）相当或更高的幅度，（ii）可以持续使用几个月，并且（III）可以提升，表明疫苗诱导的记忆力。我们使用HIV ENV SOSIP或mRNA疫苗的初步结果证实，如果在恒河猕猴出生时启动这两种新型的疫苗策略，可以像在成人猕猴中观察到的那样有效地诱导抗体。由于生理学和免疫发育与人类婴儿的相似性以及评估肺和肺部相关粘膜相关的粘膜组织中的系统性和局部免疫反应的机会，我们将在婴儿恒河猕猴模型中检验我们的假设。