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.