Adaptive Immunity and Persistent SARS-CoV-2 Replication

Project Summary/Abstract: The pandemic caused by the novel coronavirus, SARS-CoV-2 (SARS2) has so far infected greater than3.5 million individuals and resulted in >138,000 deaths in the US. Although it has been suggested thatadaptive immunity plays an important role in improving clinical outcomes of patients infected withSARS2, protective immune responses have not been specifically defined. Also, the variability in clinicaldisease and outcome in patients with SARS2 infection has not been explained based on qualitative andquantitative antiviral immune responses. Interestingly, a significant proportion of children with presumeddeficits in immune competence secondary to cancer chemotherapy and hematologic disorders havebeen observed to shed virus from the upper respiratory tract for prolonged periods of time (>4 weeks),even after complete resolution of clinical symptoms. This finding raises the possibility that specificqualitative or quantitative deficits in adaptive immune responses in some individuals can result inincomplete control of virus replication and prolonged virus shedding. Therefore, an understanding of theimmune responses that lead to control of virus shedding could help define correlates of protectiveimmunity and perhaps more importantly, determine the potential value of vaccines to limit spread ofSARS2 to unvaccinated populations. The major goal of our studies is to quantify adaptive immuneresponses to SARS2 in a cohort of children with varying levels immune responsiveness and to relatethese responses to the control of virus shedding in the upper respiratory tract, thus allowing stratificationimmune reactivity and control of virus replication. Defining relationships between variations in immunecompetence and virus shedding could provide novel insight into the level and nature of adaptiveimmunity, more specifically antiviral antibodies, that can restrict or eliminate viral shedding in SARS2infected patients. Our studies will also identify SARS2 variants that arise during poorly controlled virusreplication in these patients as prolonged virus replication coupled with ineffective immunity offers anideal opportunity for the generation of viral variants. Analysis of these variants in terms of the quality andquantity of SARS2 antibody responses will help elucidate the role of SARS2 sequence variation andpersistent virus replication as a mechanism for prolonged virus replication. Together, these studies willtest our hypothesis that variations in immune responsiveness contribute to prolonged viral replicationand shedding.