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.