Project Summary/Abstract MWCCS participants are a high-risk group for severe COVID-19 disease in terms of being HIV-infected, predominately elderly, and having numerous underlying comorbidities. Therefore, it is imperative for their health that they be vaccinated with the new COVID-19 vaccines. To date, however, there are only anecdotal data on COVID-19 vaccine acceptance and efficacy in people with HIV (PWH). The MWCCS is ideal for analyzing (a) the acceptance and effects of COVID-19 vaccine(s) in male and female PWH and matched HIV- uninfected controls (HUC), (b) the impact of age and co-morbidities on vaccine immune response and protection against COVID-19, and (c) the social, economic, and behavioral changes after COVID-19 immunization as compared to the individuals who opted to not take the vaccine. To address this issue, we will have 2 groups of MWCCS participants in this study: Group A: Male and female PWH and HUC who choose to receive a COVID-19 vaccine, Group B: Male and female PWH and HUC who choose NOT to receive a COVID-19 vaccine. The aims of our proposed longitudinal observational study for this OAR Innovation application are: Aim 1: To conduct a MWCCS-wide, mixed-methods investigation of the prevalence, correlates, and nuances of COVID-19 vaccine hesitancy among MWCCS participants. The results will help us to better understand the concerns of PWH and HUC populations regarding COVID-19 vaccines based on age, sex, race/ethnicity, and underlying comorbidity burden. Aim 2: To determine the incidence of natural SARS- CoV-2 infections post-COVID-19 immunization in PWH as compared to HUC of the same age, sex, and ethnicity/race; and to compare the incidence of infections in vaccinated individuals with the incidence of infections in non-vaccinated individuals. As an adjustment for budgetary limitations, we will restrict Aim 2 to obtaining one specimen at baseline, just prior to vaccination in Group A, and within comparable time periods for Group B. Subsequent samples collected during the core MWCCS visits will be used in the serological analyses. These samples will allow us to test for S and N proteins to determine the serological COVID-19 status in pre-immunization and post-immunization seroconversions. The titration of anti-S responses post immunization will indicate vaccine immune response, while anti-N antibody titers will indicate natural SARS- CoV-2 infection. This information will allow the identification of asymptomatic and symptomatic individuals infected with SARS-CoV-2 post-vaccination and in the non-vaccinated group. The infections in the MWCCS will allow a targeted use of core samples for in depth investigations of the immune mechanisms of vaccine- mediated protection, the immunologic responses and virologic characteristics of breakthrough SARS-CoV-2 infections, and the impact of the vaccination on underlying HIV infection.