SARS-CoV-2 vaccine durability during SIV infection

SIV 感染期间 SARS-CoV-2 疫苗的耐久性

• 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
• 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

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.

项目总结/摘要 COVID-19疫苗接种在接受治疗和病毒抑制的HIV患者中是安全的，免疫原性和持久的 但在免疫抑制个体和未抑制HIV感染者中免疫原性较低。 COVID-19疫苗的推广在艾滋病毒感染率高和获得性低的国家仍然有限。 抗逆转录病毒治疗（ART），抑制HIV病毒复制和减少HIV相关的 合并症。因此，在免疫抑制和未经治疗的艾滋病毒人群中研究COVID-19疫苗接种， needed.我们产生了一种甲病毒衍生的复制子RNA（repRNA）SARS-CoV-2疫苗候选物，repRNA- CoV 2S，编码SARS-CoV-2刺突蛋白，由新型脂质无机纳米颗粒（LION）递送， 阳离子纳米乳液（CNE）。这种疫苗平台产生强大和持久的保护性免疫力， SARS-CoV-2在小鼠和非人灵长类动物中的感染。初步研究表明这种疫苗具有免疫原性 在患有艾滋病毒诱导的免疫抑制的非人灵长类动物和B细胞缺陷的灵长类动物中，表明 repRNA-CoV 2S疫苗可用于诱导针对COVID-19的强免疫力， 免疫抑制的HIV感染者。这里，在一个高度相关的临床前SIV猕猴模型中， 感染，我们将测试第二代COVID-19疫苗，repRNA-Omicron，1）编码SARS-CoV-2 Omicron S蛋白和2）由一种新的嵌合免疫原（SHARP）组成， 受体结合结构域（RBD）的反应，并促进中和抗体。我们将评估 repRNA-Omicron在未经治疗SIV相关免疫抑制期间的免疫原性和持久性， 研究SIV诱导的免疫激活和耗竭对疫苗免疫记忆的作用。此外，委员会认为， 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了解驱动SARS-CoV-2的机制 艾滋病毒感染者的疫苗突破性感染和再感染，并将为改善治疗提供信息 艾滋病毒感染者和其他免疫功能低下者的疫苗策略。