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Abstract This application is submitted in response to the notice of special interest identified as CA-21-033. The SARS- coronavirus-2 (SARS-CoV-2) has rapidly spread worldwide causing the global pandemic. There are a number of comorbidities and risk factors associated with COVID-19 and cancer patients could be at higher risk since they tend to be older, likely to have multiple comorbidities, and are often immunosuppressed. Cancer patients, especially those who are HIV+, in sub-Saharan Africa (SSA) where HIV is still epidemic are at particularly higher risk of disease since they may not be completely immune reconstituted. Our team has a long-term collaboration with our Zambia partners to study cancer pathogenesis in conjunction with HIV. With the increasing number of SARS-CoV-2 infection in Zambia, it is important to determine the effects of SARS-CoV-2 infection and COVID-19 in cancer patients with or without HIV. Our overall objective is to develop a better understanding of potential synergistic effects of HIV, and prior exposure to other infectious diseases in cancers patients on COVID-19 disease development in sub-Saharan Africa. This was suggested by our data showing that the sub-Saharan Africa populations have exposures to a number of human coronaviruses prior to the pandemic and may confer some cross-protective immune response against SARS-CoV-2 infection and subsequent COVID-19, if infected. In addition, we now have preliminary data showing that there are differential humoral immune responses against different infections between COVID-19 patients with and without cancers and HIV, which will provide an avenue for us to further investigate the role of other infectious diseases in COVID-19. Our secondary objective is to predict the efficacy of adenovirus-vector based SARS-CoV-2 vaccines through our high throughput analysis of the humoral immune responses against all potential infections. We hypothesize that COVID-19 patients with prior exposure to other infectious diseases including seasonal coronaviruses will have a more tempered COVID-19 disease course, but cancer and HIV infection in COVID-19 patients will lead to less effective immune responses in controlling SARS-CoV-2 and affect their disease courses. Our specific aims are: 1) To determine the relationships between COVID-19 with HIV and other infectious diseases and cancer. 2) Longitudinal follow up of COVID-19 cases and controls on their recovery to determine changes in their virological parameters, anti-SARS-CoV-2 humoral response, and inflammation status. The proposed study is significant and timely because it will synergize with our ongoing U54 project (ZAMDAPP) on HIV-associated malignancies. The results generated will help to determine whether prior exposure to other infectious disease can affect the COVID-19 course differently in the high risk HIV positive cancer patients in SSA, and may also predict the efficacy of adenovirus-vector based COVID-19 vaccines in the region. Our results will help predict the extent of COVID-19 course and prevent disease progression in the HIV infected cancer patients in Zambia and beyond.