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

• 批准号: 10369372
• 负责人: YUYING LIANG
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369372
• 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; 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; base; 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 disease; preclinical development; preclinical study; pregnant; public health priorities; public health relevance; pup; receptor binding; response; severe COVID-19; subcutaneous; success; vaccination strategy; vaccine candidate; vaccine development; vaccine safety; vaccine strategy; vaccine trial; vaccine-induced antibodies; vector; vector vaccine

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 COVID-19大流行对公共卫生产生了深远的全球影响。在120,000,000案件中 在世界范围内有记录的世界各州发生了超过3000万个案件，> 530,000 covid 迄今为止的死亡。在美国，通过 临床前研究和临床上，三种有效的疫苗和许多其他免疫刺激策略现在 试验。新兴共识是有效的疫苗需要对病毒编码的尖峰的反应 蛋白质，特别是其受体结合结构域（RBD）。但是，不确定性仍然是最佳的 表达平台以及对疫苗接种赋予不良影响的关注，包括 对潜在抗体依赖性感染增强的关注。另一个主要问题是需要 疫苗介导的怀孕患者和胎儿/新生儿的保护。虽然先天和 已记录了SARS-COV-2感染的围产期传播，并严重的Covid-19中的疾病 越来越多地描述儿童，怀孕期间没有免疫策略。 为了帮助并指导未来的疫苗策略，以解决Covid-19疾病，我们将解决这些领域 使用SARS-COV-2疫苗接种的豚鼠模型的知识缺乏。我们的计划是检验假设 关于使用Pichinde病毒（PICV）载体进行优化的COVID-19疫苗策略。 PICV是一个包裹的RNA 竞技病毒家族中的病毒，不知道会引起人类或大多数动物的疾病。我们有 开发了基于PICV的病毒矢量RP18Tri，并将其证明是一种安全，有效且多才多艺的疫苗 引起平衡抗体和T细胞反应的载体。我们有初步数据，表明一本小说 基于RP18TRI的SARS-COV-2 S RBD结构域疫苗可以诱导特定抗体，包括中和 抗体，在小鼠中。在AIM 1中，我们将检验以下假设：该PICV量的疫苗（和其他疫苗 随着抗原设计的改进）将证明豚鼠的免疫原性，并具有增强的免疫。 与MPL-Adjuvant的RBD蛋白疫苗相比。我们将比较粘膜皮下 并比较ELISA和神经仿真滴定器的肌肉内途径。我们还将包括 粘膜读出，包括IGA响应，并将测试与PICV矢量相关的假设 具有增强的IFN-γELISPOT响应（与调整RBD疫苗相比）。在AIM 2中，我们将检查 早期免疫后，新生儿豚鼠的疫苗安全和移植抗体转移 怀孕，比较了大坝 - 纽伯恩抗体转移模型中的PICV载体和亚基RBD疫苗。 我们将检查新生幼崽的血清，以测试病毒中和化抗体穿越的假设 胎盘。这些实验与人类健康具有很高的相关性，并将为未来奠定基础 豚鼠妊娠模型中的SARS-COV-2挑战研究又可以帮助阐明最佳 控制妇女和婴儿中先天性和周围可获得的Covid-19疾病的疫苗策略。