Escalating combinations of enhanced infectivity and immune escape define SARS-CoV-2 Omicron lineage replacement

In 2022, consecutive sweeps of the highly transmissible SARS-CoV-2 Omicron-family maintained high viral transmission levels despite extensive antigen exposure on the population level resulting from both vaccinations and infections. To better understand variant fitness in the context of the highly dynamic immunity landscape of 2022, we aimed to dissect the interplay between immunity and fitness advantages of emerging SARS-CoV-2 Omicron lineages on the population-level. We evaluated the relative contribution of higher intrinsic transmissibility or immune escape on the fitness of emerging lineages by analyzing data collected through our local genomic surveillance program from Connecticut, USA. We compared growth rates, estimated infections, effective reproductive rates, average viral copy numbers, and likelihood for causing vaccine break-through infections. Using these population-level data, we find that newly emerging Omicron lineages reach dominance through a specific combination of enhanced intrinsic transmissibility and immune escape that varies over time depending on the state of the host-population. Using similar frameworks that integrate whole genome sequencing together with clinical, laboratory, and epidemiological data can advance our knowledge on host-pathogen dynamics in the post-emergence phase that can be applied to other communicable diseases beyond SARS-CoV-2. ### Competing Interest Statement NDG is a paid consultant for BioNTech, DMW has received consulting fees from Pfizer, Merck, and GSK, unrelated to this manuscript, and has been PI on research grants from Pfizer and Merck to Yale, unrelated to this manuscript. JLW has received consulting fees from Pfizer and Revelar Biotherapeutics Inc unrelated to this manuscript. ### Funding Statement This project is supported by the CDC Broad Agency Announcement Contracts 75D30122C14697 and 75D30121C10273, the Connecticut Department of Public Health (CDPH) contract 21PSX0049, and the Council of State and Territorial Epidemiologists contract NU38OT000297. This work does not necessarily represent the views of the CDC or CDPH. ### 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: The Institutional Review Board from the Yale University Human Research Protection Program determined that the RT-qPCR testing and sequencing of de-identified remnant COVID-19 clinical samples obtained from clinical partners conducted in this study is not research involving human subjects (IRB Protocol ID: 2000028599). 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 All data produced in the present study are available upon reasonable request to the authors.