SUMMARY/ABSTRACT Although more than four years have passed since the initial virus appearance, nowadays, most of the population has been vaccinated with multiple doses of mRNA-based vaccines and has endured multiple infection events. Still, SARS-CoV-2 continues to cause disproportionately higher morbidity and mortality in older adults from these communities, especially in the Latino-origin population and other vulnerable populations like the hematopoietic stem cell transplants (HSCT) population. As newer versions of vaccines are adapted to recent SARS-CoV-2 variants (i.e., bivalent vaccines andXBB1.5), we must continue to determine how effective these vaccines are overtime against emerging variants and establish how those populations are still responding. We will characterizes the kinetics, magnitude, and durability of type-specific neutralizing antibody and T cells responses to different current SARS-CoV-2 variants after natural infection or vaccination, designed to reveal correlates associated with protective immunity or disease severity or progression to long COVID. We pursue to implement the following new tasks: AIM 1: Task 1.3. Implementation of a third Community Assessment for Public Health Emergency Response (CASPER) approach, we expect to collect about 2,000 new samples to expand the IDRB. During prior funding periods, we also supported CASPER I and II. AIM 2: Task 2.5: To evaluate the current anti-SARS-Cov-2 IgG levels in the population of Puerto Rico following the Community Assessment for Public Health Emergency Response (CASPER) approach. Task 2.6: characterizes the kinetics, magnitude, and durability of type-specific neutralizing antibody responses to different current SARS-CoV-2 variants designed to reveal correlates associated with protective immunity. Task 2.7: Supported in our prior findings, we propose determining whether such IgG4 levels induced by mRNA vaccination could be associated with persistent COVID-19 symptoms (Long-COVID) in our population. Task 2.8: Interrogation of the Antigen-Specific B Cell Response as described below in the approach section. Task 2.9: Breakthrough SARS-CoV-2 Infections: Investigate the relationship between breakthrough infections, vaccine immunogenicity, and long COVID symptomatology by actively monitoring HSCT patients. AIM3: Task 3.2: Expand the Innate and Adaptive Immune Response characterization in underrepresented populations: Investigate the phenotype and function of antigen-specific T cells, including TFH cells, which support antigen-specific B cell responses. Measure CD4 TFH cells' ability to support antigen-specific B cell antibody secretion using in vitro CD4-B cell cultures. Task 3.3: Define factors responsible for decreased T cell help leading to altered antigen-specific antibody responses in patients with HSCTs. AIM 4: Task 4.3: We will continue to focus on sequencing the circulating and emerging strains and variants and correlating them with the immunological profile characterized und...