Community level variability in Bronx COVID-19 hospitalizations associated with differing viral variant adaptive strategies during the second year of the pandemic

The Bronx, New York, exhibited unique peaks in the number of COVID-19 cases and hospitalizations compared to national trends. To determine which features of the SARS-CoV-2 virus might underpin this local disease epidemiology, we conducted a comprehensive analysis of the genomic epidemiology of the four dominant strains of SARS-CoV-2 (Alpha, Iota, Delta and Omicron) responsible for COVID-19 cases in the Bronx between March 2020 and January 2023. Genomic analysis revealed similar viral fitness for Alpha and Iota variants in the Bronx compared to nationwide data. However, Delta and Omicron variants had increased fitness within the borough. While the transmission dynamics of most variants in the Bronx corresponded with mutational fitness-based predictions of transmissibility, the Delta variant presented as an exception. Epidemiological modeling confirms Delta’s advantages of higher transmissibility, and suggested pre-existing immunity within the community counteracted Delta virulence, contributing to unexpectedly low Bronx hospitalizations compared to preceding strains. There were few novel T-cell epitope mutations in Delta compared to Iota which suggests Delta had fewer immune escape mechanisms to subvert pre-existing immunity within the Bronx. The combination of epidemiological models and quantifying amino acid changes in T-cell and antibody epitopes also revealed an evolutionary trade-off between Alpha’s higher transmissibility and Iota’s immune evasion, potentially explaining why the Bronx Iota variant remained dominant despite the introduction of the nationwide dominant Alpha variant. Together, our study demonstrates that localized analyses and integration of orthogonal community-level datasets can provide key insights into the mechanisms of transmission and immunity patterns associated with regional COVID-19 incidence and disease severity that may be missed when analyzing broader datasets. One sentence summary A reduction in COVID-19 cases and hospitalizations during the Delta variant’s dominance are preceded with the prevalence of the immune-evading Iota variant over the globally dominant, more transmissible Alpha variant amongst the Bronx, indicating community-level variability associated with differing viral variant adaptive strategies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was in part funded by NIH R01 Grant (NS123445-01) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The source code used for analysis and figure generation, is hosted on Github at .