Viral Vectored COVID-19 Vaccines in a Guinea Pig Perinatal Infection Model

豚鼠围产期感染模型中的病毒载体 COVID-19 疫苗

基本信息

批准号：
10515662
负责人：
YUYING LIANG
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515662
关键词：
2019-nCoV Address Adjuvant Adult Animal Model Animals Antibodies Antibody-Dependent Enhancement Antigens Area Arenavirus Attention Award Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes COVID-19 COVID-19 complications COVID-19 pandemic COVID-19 vaccination COVID-19 vaccine Cavia Cessation of life Child Clinical Clinical Trials Consensus Data Disease Enzyme-Linked Immunosorbent Assay Evaluation Family Fetus Future Generations Goals Health Histopathology Human Immune Immune response Immunity Immunization Immunoglobulin A Infant Infection Inflammatory Influenza Interferon Type II Intramuscular Knowledge Licensing Licensure Light Lymphocytic choriomeningitis virus Mediating Medical Methods Modeling Mucous Membrane Mus Neonatal Newborn Infant Patients Perinatal Perinatal Infection Perinatal transmission Pertussis Pichinde virus Placenta Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Protein Binding Domain Proteins Public Health RNA Viruses Reporting Reproductive Biology Reproductive Health Route SARS-CoV-2 infection SARS-CoV-2 spike protein SARS-CoV-2 transmission Safety Serum Syndrome System T cell response TNF gene Testing Uncertainty United States Vaccinated Vaccination Vaccines Variant Vasculitis Viral Viral Vector Virus Woman Work Writing antibody transfer clinical practice congenital infection coronavirus disease cytokine design disease transmission early pregnancy enzyme linked immunospot assay experimental study fetal guinea pig model immunogenicity improved maternal vaccination neonate neutralizing antibody novel pandemic response preclinical development preclinical study pregnant public health priorities public health relevance pup receptor binding response severe COVID-19 subcutaneous success transmission process vaccination strategy vaccine candidate vaccine development vaccine safety vaccine strategy vaccine trial vaccine-induced antibodies vector vector vaccine

项目摘要

Abstract The COVID-19 pandemic has had a profound, global impact on public health. Of the 120,000,000 cases documented world-wide, over 30 million cases have occurred in the Unites States, with >530,000 COVID deaths to date. Considerable progress in control of the pandemic has been realized in the USA by licensure of three effective vaccines, and many additional immunization strategies are now in preclinical study and clinical trials. An emerging consensus is that an effective vaccine will require responses to the viral-encoded spike (S) protein, in particular, its receptor-binding domain (RBD). However, uncertainties remain about the optimal expression platform(s), as well as concerns for untoward effects conferred by vaccination, including the concern of potential antibody-dependent enhancement of infection. Another major issue is the need for vaccine-mediated protection of the pregnant patient and the fetus/neonate. Although congenital and perinatal transmission of SARS-CoV-2 infection has been documented, and serious COVID-19 disease in children is increasingly described, no strategy for immunization during pregnancy has been forthcoming. To help inform and direct future vaccine strategies for COVID-19 disease, we will address these areas of knowledge deficiency using a guinea pig model of SARS-CoV-2 vaccination. Our plan is to test hypotheses about optimized COVID-19 vaccine strategies using a Pichinde virus (PICV) vector. PICV is an enveloped RNA virus within the Arenavirus family and is not known to cause disease in humans or most animals. We have developed a PICV-based viral vector rP18tri and demonstrated it as a safe, effective, and versatile vaccine vector that elicits a balanced antibody and T cell response. We have preliminary data showing that a novel rP18tri-based SARS-CoV-2 S RBD domain vaccine can induce specific antibodies, including neutralizing antibodies, in mice. In Aim 1, we will test the hypothesis that this PICV-vectored vaccine (and other vaccines with improved antigen design) will demonstrate immunogenicity in guinea pigs, with enhanced immune responses compared to an MPL-adjuvanted RBD protein vaccine. We will compare mucosal, subcutaneous and intramuscular routes of immunization, comparing ELISA and neutralization titers. We will also include mucosal read-outs, including IgA responses, and will test the hypothesis that the PICV vector is associated with enhanced IFN-γ ELISPOT responses (compared to adjuvanted RBD vaccine). In Aim 2, we will examine vaccine safety and transplacental antibody transfer in neonatal guinea pigs following immunization in early pregnancy, comparing PICV vectored and subunit RBD vaccines in a dam-to-newborn antibody transfer model. We will examine serum from newborn pups to test the hypothesis that virus-neutralizing antibodies cross the placenta. These experiments have high relevance to human health, and will lay the groundwork for future SARS-CoV-2 challenge studies in the guinea pig pregnancy model that, in turn, can help clarify the optimal vaccine strategies to control congenital and perinatally-acquired COVID-19 disease in women and infants.

抽象的在 1.2 亿病例中，COVID-19 大流行对全球公共卫生产生了深远的影响。据全球记录，美国已发生超过 3000 万例病例，其中超过 530,000 例新冠肺炎病例迄今为止，美国在控制大流行方面已取得了显着进展。三种有效的疫苗和许多其他免疫策略目前正处于临床前研究和临床阶段一项新兴的共识是，有效的疫苗需要对病毒编码的刺突（S）做出反应。蛋白质，特别是其受体结合域（RBD）然而，最佳方案仍然存在不确定性。表达平台，以及对疫苗接种带来的不良影响的担忧，包括另一个主要问题是对潜在抗体依赖性感染增强的担忧。疫苗介导的对怀孕患者和胎儿/新生儿的保护，尽管是先天性的。 SARS-CoV-2 感染的围产期传播已有记录，严重的 COVID-19 疾病在儿童越来越多地被描述，但尚未制定怀孕期间的免疫策略。为了帮助告知和指导未来针对 COVID-19 疾病的疫苗策略，我们将解决以下领域的问题：我们的计划是使用 SARS-CoV-2 疫苗接种的豚鼠模型来检验假设。关于使用 Pichinde 病毒 (PICV) 载体优化的 COVID-19 疫苗策略 PICV 是一种包膜 RNA。沙粒病毒属于沙粒病毒家族，目前尚不清楚它是否会导致人类或大多数动物患病。开发了基于 PICV 的病毒载体 rP18tri 并证明其是一种安全、有效和多功能的疫苗我们有初步数据表明，一种新的载体能够引起平衡的抗体和 T 细胞反应。基于 rP18tri 的 SARS-CoV-2 S RBD 结构域疫苗可以诱导特异性抗体，包括中和抗体在目标 1 中，我们将测试这种 PICV 载体疫苗（以及其他疫苗）的假设。改进的抗原设计）将在豚鼠中展示免疫原性，增强免疫与 MPL 佐剂的 RBD 蛋白疫苗相比，我们将比较粘膜、皮下疫苗的反应。以及肌内免疫途径，比较 ELISA 和中和滴度。粘膜读数，包括 IgA 反应，并将检验 PICV 载体相关的假设 IFN-γ ELISPOT 反应增强（与佐剂 RBD 疫苗相比）。在目标 2 中，我们将检查。早期免疫后新生豚鼠的疫苗安全性和经胎盘抗体转移妊娠，在母鼠至新生儿抗体转移模型中比较 PICV 载体疫苗和亚单位 RBD 疫苗。我们将检查新生幼犬的血清，以检验病毒中和抗体可以跨越病毒的假设。这些实验与人类健康具有高度相关性，并将为未来奠定基础。豚鼠妊娠模型中的 SARS-CoV-2 挑战研究反过来可以帮助阐明最佳的控制妇女和婴儿先天性和围产期获得性 COVID-19 疾病的疫苗策略。