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.

此处拟定的研究将补充我们在P01 AI 117915 -06“预防青少年HIV感染的早期生命疫苗接种”中的研究。在母基金中，我们将定义导致诱导保护性HIV Env特异性抗体的分子和免疫途径，这些抗体具有广泛中和或Fc介导的效应子功能，以响应HIV Env SOSIP蛋白或HIV Env mRNA疫苗接种。目前正在采取类似的疫苗战略来防治SARS-CoV-2大流行。第一个测试编码稳定的融合前刺突蛋白疫苗的mRNA的免疫原性以预防COVID-19的人体试验已经启动。 与早期爆发的相关冠状病毒SARS和MERS相比，SARS-CoV-2表现出更强的传播性，并导致了大流行。在全球范围内，自疫情开始以来，已确诊250多万例，死亡人数接近75万。与成人相比，感染SARS、MERS或SARS-CoV-2的婴儿似乎表现出较轻的疾病，这意味着婴儿表达的病毒受体较少，宿主限制因子不同，或者他们的免疫系统更有能力抵抗这些冠状病毒株。疫苗被认为是遏制病毒和防止进一步爆发的最佳选择。出于安全性原因，首先在成人中评价疫苗的免疫原性和安全性，但儿科疫苗是优选的，因为1）有机会在儿童期产生保护性免疫，从而在整个生命周期内预防疾病并限制病毒传播，以及2）在儿科疫苗计划中最容易获得高疫苗覆盖率。我们处于独特的地位，可以在儿科环境中测试已经可用的候选疫苗，同时进行成人试验。在实验研究中，针对SARS或MERS病毒刺突（S）蛋白的中和抗体已被证明可以防止病毒感染。然而，在从SARS或MERS感染中恢复的人类中，抗体应答似乎是短暂的。我们假设婴儿可以对SARS-CoV-2疫苗接种产生有效和持久的抗体应答，从而保护免受病毒攻击。我们的理由是基于我们来自人类和恒河猴研究的大量数据，这些数据表明HIV Env疫苗诱导的血浆IgG抗体（i）与成人相当或更高，（ii）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开始，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测试我们的假设，该模型已被证明具有高转化价值，因为其与人类婴儿的生理学和免疫发育相似，并且有机会评估肺和肺相关粘膜组织中的全身和局部免疫应答。