OVERALL ABSTRACT The overarching research theme for the Mount Sinai U54 Serological Center of Excellence “Vulnerability of SARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses,” is to fill the vital knowledge gap in factors contributing to the great vulnerability of lung cancer patients to morbidity and mortality from SARSCoV-2 infection through serological analysis of antibody responses and studies of inter-individual variation in patient-derived lung tumor and epithelial cells to SARS-CoV-2 infection. We will characterize and compare lung cancer patients’ antibody responses to SARS-CoV-2 infection or SARS-CoV-2 vaccines with a matched nonlung cancer control group; quantitate differences in SARS-CoV-2 viral replication in lung cancer and normal lung epithelial cells from different lung cancer patients; and quantitate differences in neutralizing antibody responses in lung cancer patients. This information is urgently needed to enact vaccine and other strategies for protecting lung cancer patients against development of COVID-19. While antibodies, induced by infection or vaccines, are protective against many viruses, it has not yet been established if antibodies to SARS-CoV-2 are protective, how much and what types of antibody are needed for protection, and how long protection will last are unknown. Likewise, we do not know if lung cancer patients can mount an effective immune response and if different aspects of lung cancer or its treatment influences this immune response. Our overall hypothesis is that lung cancer patients have a different (e. g. weaker) antibody response to SARS-CoV-2 infection compared to persons without lung cancer, and that their lung cancer or lung epithelial cells play a role in viral replication of host responses, which together could explain the aggressive course and high fatality rate demonstrated in lung cancer patients with COVID-19. Our U54 will determine whether natural infection or SARS-CoV-2 vaccines (forecast for deployment) will give comparable serological antibody responses longitudinally in 1,000 lung cancer patients and a matched non-lung cancer control group (1,000 individuals); and determine if there are differences in antibody responses related to age, gender, tobacco history, and race/ethnicity. The U54 proposal has two Projects and three Cores (Administrative, Clinical, and Data Sciences). Project 1: “Characterization of the Antibody Response to SARS-CoV-2 in Lung Cancer Patients” quantitatively characterizes anti-SARs-CoV-2 antibody responses and their functionality longitudinally in lung cancer patients compared to a control population after natural infection and vaccination, and relates the serological response characteristics to key clinical, demographic information. Project 2: “Susceptibility of Lung Cancer Cells to SARS-CoV-2 Infection and AntibodyMediated Neutralization,” determines the inter-individual variation in lung cancers and lung epithelial cells to support SARS-CoV-2 viral replication, the inter-individual variation of antibodies to neutralize viral infection, and how these host viral responses relate to host cell characteristics and important clinical demographic information.