SARS-CoV-2 vaccine durability during SIV infection

项目摘要/摘要 对于经治疗和病毒抑制的艾滋病毒感染者，新冠肺炎疫苗是安全、免疫原性和持久性的 但在免疫抑制的个人和未被抑制的艾滋病毒感染者中，免疫原性较低。 在艾滋病毒高流行率和低获得性国家，新冠肺炎疫苗的推出仍然有限 抗逆转录病毒疗法(ART)，对抑制艾滋病毒复制和减少与艾滋病毒相关的 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新冠肺炎疫苗是 需要的。我们产生了一种甲型病毒衍生的复制子RNA(REPRNA)SARS-CoV-2候选疫苗，REPRNA- CoV2S，编码SARS-CoV-2刺突蛋白，由一种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感染SARS-CoV-2。初步研究表明这种疫苗具有免疫原性。 在HIV诱导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，证明 RepRNA-CoV2S疫苗可诱导小鼠对新冠肺炎产生较强的免疫应答 免疫抑制艾滋病毒携带者。在这里，在一个高度相关的艾滋病毒临床前SIV猕猴模型中 在感染方面，我们将测试编码SARS-CoV-2的第二代新冠肺炎疫苗 Omicron S蛋白和2)是由一种新的嵌合免疫原(SHARP)组成的，它专注于免疫 对受体结合域(RBD)作出反应，并促进中和抗体。我们将评估 未经治疗的SIV相关免疫抑制和免疫抑制期间的免疫原性和耐受性 研究SIV诱导的免疫激活和耗竭对疫苗免疫记忆的影响。此外， 我们的研究将致力于了解新型REPRNA/狮子疫苗驱动体液记忆的机制 站台。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 艾滋病毒携带者的疫苗突破性感染和再感染将有助于改进治疗 为艾滋病毒携带者和其他免疫功能受损的人提供疫苗战略。

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.