SARS-CoV-2 vaccine durability during SIV infection

SIV 感染期间 SARS-CoV-2 疫苗的耐久性

基本信息

批准号：
10618112
负责人：
Megan A O'Connor
金额：
$ 35.3万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618112
关键词：
2019-nCoV Alphavirus Anabolism Animals Antigens Automobile Driving B-Lymphocytes CAR T cell therapy CD4 Lymphocyte Count COVID-19 COVID-19 risk COVID-19 vaccination COVID-19 vaccine Cells Cessation of life Country Data Development Diabetes Mellitus Disease Dose Evaluation Exclusion Formulation Frequencies Generations Goals HIV HIV Infections HIV/AIDS Helper-Inducer T-Lymphocyte Hospitalization Human Immune System Diseases Immune response Immunity Immunization Immunocompromised Host Immunologic Factors Immunologic Memory Immunosuppression Impairment Individual Infection Influenza Hemagglutinin Lipids MS4A1 gene Macaca Macaca nemestrina Malignant Neoplasms Measures Memory Messenger RNA Methods Modeling Mus Persons Phase I Clinical Trials Population Prevalence Proteins Public Health RNA RNA replication RNA vaccine Regulatory T-Lymphocyte Replicon Resource-limited setting Role SARS-CoV-2 B.1.1.529 SARS-CoV-2 immunity SARS-CoV-2 infection SARS-CoV-2 spike protein SARS-CoV-2 variant SIV Secondary Immunization Structure of germinal center of lymph node T-Lymphocyte Testing Vaccines Viral Virus Replication Work antiretroviral therapy breakthrough infection cardiovascular disorder risk comorbidity cytokine exhaustion humoral immunity deficiency immune activation immunogenic immunogenicity immunosuppressed impaired driving performance improved lipid nanoparticle mortality nanoemulsion nanoparticle neutralizing antibody nonhuman primate novel pre-clinical receptor binding response severe COVID-19 treatment strategy vaccine access vaccine candidate vaccine delivery vaccine immunogenicity vaccine platform vaccine strategy vaccine trial variants of concern

项目摘要

PROJECT SUMMARY/ABSTRACT COVID-19 vaccination is safe, immunogenic, and durable in individuals with treated and virally suppressed HIV infection but is less immunogenic in immunosuppressed individuals and those with unsuppressed HIV infection. The rollout of COVID-19 vaccines is still limited in countries with high HIV prevalence and low access to antiretroviral therapy (ART), necessary to suppress HIV viral replication and reduce HIV-associated comorbidities. Thus, studying COVID-19 vaccination in immunosuppressed and untreated HIV populations is needed. We generated an Alphavirus-derived replicon RNA (repRNA) SARS-CoV-2 vaccine candidate, repRNA- CoV2S, encoding the SARS-CoV-2 spike protein and delivered by a novel Lipid InOrganic Nanoparticle (LION), a cationic nanoemulsion (CNE). This vaccine platform generates robust and durable protective immunity against SARS-CoV-2 infection in mice and nonhuman primates. Preliminary studies indicate this vaccine is immunogenic in non-human primates with HIV-induced immunosuppression and those with B-cell deficiencies, demonstrating that a repRNA-CoV2S vaccine could be employed to induce strong immunity against COVID-19 in immunosuppressed individuals living with HIV. Here, in a highly relevant pre-clinical SIV macaque model for HIV infection, we will test a 2nd generation COVID-19 vaccine, repRNA- Omicron, that 1) encodes the SARS-CoV-2 Omicron S protein and 2) is comprised of a novel chimeric immunogen (SHARP) which focuses immune responses to the receptor binding domain (RBD) and promotes neutralizing antibodies. We will evaluate the immunogenicity and durability of repRNA-Omicron during untreated SIV-associated immunosuppression and examine the role of SIV-induced immune activation and exhaustion on vaccine immune memory. Furthermore, our studies will aim to understand the mechanisms driving humoral memory by the novel repRNA/LION vaccine platform. If successful, this work will further contribute to understanding the mechanisms driving SARS-CoV-2 vaccine breakthrough infections and reinfections in people living with HIV and will inform improved treatment and vaccine strategies for people living with HIV and other immunocompromised individuals.

项目概要/摘要对于已接受治疗且病毒已被抑制的 HIV 个体来说，COVID-19 疫苗接种是安全的、具有免疫原性且持久的感染，但在免疫抑制个体和 HIV 感染未抑制的个体中免疫原性较低。在艾滋病毒感染率高且获得机会少的国家，COVID-19 疫苗的推广仍然有限抗逆转录病毒治疗 (ART)，对于抑制 HIV 病毒复制和减少 HIV 相关性是必要的合并症。因此，在免疫抑制和未经治疗的 HIV 人群中研究 COVID-19 疫苗接种是需要。我们生成了一种源自甲病毒的复制子 RNA (repRNA) SARS-CoV-2 候选疫苗，repRNA- CoV2S，编码 SARS-CoV-2 刺突蛋白，并由新型脂质无机纳米颗粒 (LION) 递送，阳离子纳米乳液（CNE）。该疫苗平台可产生强大而持久的保护性免疫力小鼠和非人灵长类动物中的 SARS-CoV-2 感染。初步研究表明该疫苗具有免疫原性在患有 HIV 诱导的免疫抑制的非人类灵长类动物和患有 B 细胞缺陷的非人类灵长类动物中，证明可以使用repRNA-CoV2S疫苗来诱导针对COVID-19的强大免疫力免疫抑制的艾滋病毒感染者。此处，在高度相关的 HIV 临床前 SIV 猕猴模型中感染，我们将测试第二代 COVID-19 疫苗，repRNA-Omicron，它 1) 编码 SARS-CoV-2 Omicron S 蛋白和 2) 由一种新型嵌合免疫原 (SHARP) 组成，该免疫原集中免疫对受体结合域 (RBD) 的反应并促进中和抗体。我们将评估在未经治疗的 SIV 相关免疫抑制期间，repRNA-Omicron 的免疫原性和持久性检查 SIV 诱导的免疫激活和耗竭对疫苗免疫记忆的作用。此外，我们的研究旨在了解新型repRNA/LION疫苗驱动体液记忆的机制平台。如果成功，这项工作将进一步有助于理解 SARS-CoV-2 的驱动机制疫苗突破了艾滋病毒感染者的感染和再感染，并将为改善治疗提供信息以及针对艾滋病毒感染者和其他免疫功能低下个体的疫苗策略。