Impact of pre-existing SARS-CoV-2 immunity on vaccination against new variants

现有 SARS-CoV-2 免疫力对新变种疫苗接种的影响

• 批准号: 10399339
• 负责人: SEAN D SULLIVAN
• 金额: $ 50万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-10 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399339
• 关键词: 2019-nCoV; ACE2; Address; Alphavirus; Angiotensin Receptor; Antibody Repertoire; Antibody Response; Antigens; B-Lymphocytes; Binding; COVID-19; COVID-19 vaccine; Cells; Cessation of life; Data; Development; Dose; Evaluation; Evolution; Exhibits; Exposure to; Formulation; Funding; Generations; Genome; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunize; Individual; Infection; Influenza Hemagglutinin; Innate Immune Response; Knowledge; Lipids; Macaca; Macaca nemestrina; Measures; Mediating; Modeling; Mutation; Pathogenesis; Pilot Projects; Population; Proteins; RNA; RNA vaccine; Replicon; Resistance; Role; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 transmission; SARS-CoV-2 variant; Secondary Immunization; Ships; Specificity; Structure; Systems Biology; T cell response; Temperature; Update; Vaccinated; Vaccination; Vaccine Design; Vaccines; Variant; Venezuelan Equine Encephalitis Virus; Viral; Virus; adaptive immune response; base; design; immunogenicity; improved; memory recall; nanocarrier; neutralizing antibody; novel; novel vaccines; prevent; protective efficacy; receptor binding; response; scale up; transcriptomics

PROJECT SUMMARY The deployment of efficacious SARS-CoV-2 vaccines has prevented the death of millions of people. New SARS- CoV-2 variants that are more transmissible exhibit increased resistance to neutralizing antibodies elicited by either the current vaccine or by prior infection with the original strain. To address this, we have developed a 2nd generation COVID19 vaccine that employs a self-amplifying replicon RNA (repRNA) and is delivered using a novel nanolipid carrier formulation (LION) that can be rapidly scaled up and is more stable at warmer temperatures to support effective worldwide distribution. Our repRNA vaccine expresses a structurally intact receptor binding domain (RBD) immunogen (called SHARP) that matches variants exhibiting resistance to neutralization by current vaccines. Second generation vaccines like this one will be administered to people that are already pre-immune to earlier variants of SARS-CoV-2 due to prior immunization or infection but, to date, the impact of pre-immunity to the original variants on these new vaccines is not known. Pre-immunity may enable the new vaccines to induce even broader antibody responses against different variants. On the other hand, original antigenic sin (OAS), wherein the immune response to an infection preferentially recalls memory cells primed by the first antigenic exposure, could dampen efficacy of 2nd generation vaccines if upon exposure to the new variant, B cell responses primed by the original variant are preferentially recalled. To gain a better understanding of the impact of pre-existing immunity on 2nd generation COVID-19 vaccines, we propose a pilot study using a repRNA vaccine expressing SHARP to immunize macaques with pre-existing immunity to the original D614G variant due to prior immunization. Our goal is to determine if pre-immunity improves or, alternatively, dampens the immunogenicity and/or protective efficacy of 2nd generation vaccines designed to protect against new variants. These questions are best addressed in NHPs that closely model the repertoire of innate and adaptive immune responses in humans and can be challenged with SARS-CoV-2 to investigate the impact on protective efficacy and recall responses. Our Aims are: 1) Characterize the magnitude, specificity and type of immune responses induced in macaques pre-immune to the original D614G variant and boosted with a a repRNA vaccine expressing the B.1351 variant immunogen. 2) Investigate pathogenesis of B.1351 infection in pigtail macaques, protective efficacy of the repRNA B.1351 SHARP vaccine in pre-immune macaques, and immune correlates of protection. 3) Determine the impact of prior immunization with the original D614G variant on innate immune responses and their role in the immunogenicity and efficacy of the 2nd generation repRNA B.1351 SHARP vaccine. Knowledge gained on the impact of pre-immunity from this study will have broader implications for the development of this and other 2nd generation vaccines. If successful, this study will also support further development and evaluation of a trivalent repRNA SHARP vaccine that is more amenable for worldwide distribution than current mRNA vaccines and could provide broad protection against multiple variants.

项目摘要 有效的SARS-CoV-2疫苗的部署防止了数百万人的死亡。新SARS- 更具传播性的CoV-2变体表现出对由以下引起的中和抗体的抗性增加： 无论是当前的疫苗还是先前感染的原始菌株。为了解决这个问题，我们开发了第二个 第二代COVID 19疫苗，其采用自扩增复制子RNA（repRNA）并使用 一种新型纳米脂质载体制剂（LION），可快速放大，在较温暖的环境中更稳定 温度，以支持有效的全球分销。我们的repRNA疫苗表达了一种结构完整的 受体结合结构域（RBD）免疫原（称为SHARP），与表现出对 目前的疫苗。像这样的第二代疫苗将被给予那些 由于先前的免疫或感染，已经对SARS-CoV-2的早期变体预先免疫，但迄今为止， 对原始变体的预免疫对这些新疫苗的影响尚不清楚。预先豁免可能会使 新疫苗诱导针对不同变体的更广泛的抗体反应。另一方面，在一项研究中， 原始抗原罪恶（OAS），其中对感染的免疫反应优先召回记忆细胞 第一次抗原暴露引发，如果暴露于 新的变异体，由原始变异体引发的B细胞应答被优先召回。更好地 为了了解预先存在的免疫力对第二代COVID-19疫苗的影响，我们建议进行试点 使用表达SHARP的repRNA疫苗免疫具有预先存在的免疫力的猕猴的研究 D 614 G变异是由于先前的免疫接种。我们的目标是确定免疫力是否有所改善， 或者，减弱第二代疫苗的免疫原性和/或保护效力， 防止新的变种。这些问题最好在国家卫生方案中得到解决， 可以用SARS-CoV-2进行攻击，以研究 对保护效能和回忆反应的影响。我们的目标是：1）表征的大小，特异性和 在对原始D 614 G变体进行免疫前并用D 614 G增强的猕猴中诱导的免疫应答类型 一种表达B.1351变体免疫原的repRNA疫苗。2)研究B.1351感染的发病机制 在猪尾猕猴中，repRNA B.1351 SHARP疫苗在免疫前猕猴中的保护功效，以及 免疫相关的保护。3)确定先前使用原始D 614 G变体免疫的影响 先天免疫应答及其在第二代repRNA免疫原性和有效性中的作用 B.1351 SHARP疫苗。从本研究中获得的关于免疫前影响的知识将具有更广泛的 这对开发这种疫苗和其他第二代疫苗具有重要意义。如果成功，这项研究还将 支持进一步开发和评估更适合于 与目前的mRNA疫苗相比，它在全球范围内的分布范围更广，可以提供针对多种变体的广泛保护。