ABSTRACT MWCCS participants are a high-risk group for severe COVID-19 disease in terms of being HIV- infected, predominately of elderly age, 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 acceptancy 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 an MWCCS-wide, mixed- methods investigation of the prevalence, correlates, and nuances of COVID-19 vaccine hesitancy among MWCCS participants. Results will help better understand the concerns of PWH and HUC populations regarding COVID-19 vaccines based on age, sex, race/ethnicity, and underlying comormidity 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 also compare with the incidence of infections in non-vaccinated individuals. Because of budgetary limitations in the OAR Innovation Fund supplement, we will restrict Aim 2 to obtaining one specimen at baseline, just prior 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 analyzes. These samples will allow us to determine the serological COVID-19 status pre-immunization, and post-immunization seroconversions for S and N proteins. 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 non-vaccinated group. The if these infections in the MWCCS will allow a targeted use of core samples in depth investigation 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. Importantly, timely funding from this OAR Innovation opportunity is critical to our addressing these aims prior to the broad rollout of the COVID-19 vaccines to our PWH participants. We are in a race to obtain this critical information and specimens prior to the wide availability of current FDA EUA vaccines to our MWCCS participants. The MWCCS clinical research sites across the United States and the data center are ready to launch this new study as soon as funding is available and we receive sIRB approval.

COVID Vaccine Study Supplement to MWCCS Principal Investigators: C. Rinaldo and J. Martinson Narrative A safe, highly immunogenic vaccine to prevent primary SARS-CoV-2 infection is needed to control the COVID-19 pandemic. As of January, 2021, the United States is racing to vaccinate a significant percentage of our 330 million population to control the COVID-19 pandemic. This extraordinary rapid development resulted from FDA emergency use authorization (EUA) of two COVID-19 vaccines in December, 2020, i.e., the Moderna mRNA-1273 vaccine that codes for the stabilized pre-fusion SARS- CoV-2 spike protein 1, and the Pfizer/BioNTech vaccine BNT162b1 that is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain of the spike glycoprotein of SARS-CoV-2 2. Despite this enormous public health issue of stopping the COVID-19 pandemic, there are essentially no data on COVID-9 vaccine acceptance or efficacy in people with HIV (PWH). This is critically important for public health, in that an estimated 1.2 million people aged 13 and older have HIV in the United States, including an estimated 161,800 (14%) people whose infections had not been diagnosed 3. Although several COVID-19 vaccine clinical efficacy trials enrolled PWH without specific selectivity, there are insufficient data exist to determine the efficacy of COVID-19 vaccines in PWH. Indeed, prior to the COVID-19 pandemic, the CDC recommended that PWH with CD4 T cell counts of ≥200 or percentages ≥15% receive all licensed vaccines. Further, the CDC stated in a release December 12, 2020 (https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-12/slides-12-12/COVID- 03- Mbaeyi.pdf): “The recently FDA-authorized Pfizer-BioNTech COVID-19 vaccine is not contraindicated for people living with HIV or others with immunocompromised conditions, though vaccine efficacy data does not currently exist for potentially immunocompromised individuals”. According to the CDC Advisory Committee on Immunization Practices (ACIP), “people living with HIV may still receive the vaccine, but should be counseled on unknown vaccine safety and efficacy profiles in immunocompromised persons.” The ACIP also recently recommended that health care personnel and residents of long-term care facilities (LTCFs) be offered vaccination in the initial phase of the COVID-19 vaccination program (Phase 1a) 4. In sum, PWH are looking to us for advice as their scientific and clinical HIV experts, with our response being that the COVID-19 vaccines “should be” safe and effective in them based on no specific data. Our proposed study aims to supply such data through a well-designed protocol nested in the most well-established and trusted MACS-WIHS Combined Cohort Study (MWCCS). In 2019, the WHO listed vaccine hesitancy, or the delay in acceptance or refusal of vaccination despite availability of vaccination services, as one of the top 10 threats to global health 5. As vaccine hesitancy rises, misinformation and anti-vaccine attacks on social media continue to circulate and dominate the vaccine conversation and present barriers to widespread vaccine uptake 6. Public acceptability of the MMR vaccine, HPV vaccine and pandemic vaccines (H1N1) has been contentious due to a combination of safety and efficacy concerns. Distrust in vaccines has led to low vaccination rates for measles and the flu. A 2018 survey from National Opinion Research Center (NORC) at the University of Chicago found that 43% of Americans forgo getting vaccinated against influenza. Vaccine hesitancy towards the COVID-19 vaccine is likely, while at the same time, research shows that enthusiasm for a vaccine is highest during a pandemic and immediately following vaccine release 7. In a recent study of determinants of COVID-19 vaccine acceptance in the US, 67% of participants said they would accept a COVID-19 vaccine if it is recommended for them 8. COVID Vaccine Study Supplement to MWCCS Principal Investigators: C. Rinaldo and J. Martinson Other surveys found that 3 out of 4 people will get vaccinated at some time after a COVID-19 vaccine was available, with only 30% wanting to receive the vaccine as soon as it became available 7,9,10 Hence, as of the current public roll-out of COVID-19 vaccines, there is only anecdotal evidence about COVID-19 vaccine hesitancy in PWH, and the immune responses and protective effects to SARS-CoV-2 vaccines. There also are no data on sex-based differences in PWH in the acquisition, progression, severity, and response to treatment of SARS-CoV-2 infection. PWH have low risk for AIDS due to extraordinary control of the infection by antiretroviral therapy (ART). Nevertheless, PWH are at increased risk of severe comorbidities 11. The MWCCS cohort (n=4016) currently has 1,169 active HIV- infected men and 1,569 active HIV infected women. The cohort is racially and ethnically diverse: 49% of participants identify as Black; 13% as Hispanic; 35% as White; and 3% as Asian, Middle Eastern, and other ethnoracial backgrounds. The current average age is 64/58yo HIVpos/HIVneg male and 52/54yo HIVpos/HIVneg female. Many have documented evidence of significant cardiovascular, pulmonary and other comorbidities. At last study visit (2018/2019), substantial proportions of active participants had prevalent underlying morbidities consistent with risk for severe COVID-19 disease sequelae: 42% had body-mass index≥30, consistent with obesity; 56% had prevalent hypertension; 22% had prevalent diabetes; 64% had dyslipidemia; 7% had history of cancer; and 12% had kidney disease 12. Thus, our MWCCS cohort represents a high-risk group for severe SARS-CoV-2 infection in terms of both elderly age and underlying comorbidities. Studies to date suggest that PWH are at similar risk of acquiring SARS-CoV-2 infection and undergoing severe symptoms and death as are HIV-uninfected persons of similar age, sex, and race/ethnicity 13-19. An analysis of SARS-CoV-2 infection in 122 PWH in England found that mortality was higher in PWH than HIV uninfected controls (HUC) after adjusting for age 20. HIV infection was associated with an increased risk of mortality among persons hospitalized for COVID-19. A recent surveillance study in the MWCCS indicates that PWH are twice likely to have a positive test for COVID-19 than HIV seronegative men and women 21 . Although age, race, current smoking, and BMI were not risk factors for positivity, the odds of SARS-CoV-2 positivity were higher among PWH than HIV seronegatives and among those living with another person versus living alone. In sum, we believe that it is critically important for the OAR to support this initiative and capitalize on the MWCCS platform and participants to address the acceptancy and demonstrate the benefits of the COVID-19 vaccines in PWH. This is similar to their capitalizing on existing NIH research platforms such as the HVTN and ACTG to study COVID-19 vaccines and treatments.