Drivers of quasispecies development in SARS-CoV-2 and implications for emergent variants and COVID-19.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, significant research has focused on SARS-CoV-2 evolution and transmission. Most transmission studies rely on RT-qPCR and consensus sequencing for SARS-CoV-2 characterization, often overlooking the collection of viable genetically linked genomes characterized by one or more intra-host single nucleotide variants (iSNVs) within the same sample, defined as "quasispecies" (QS), which could influence disease outcomes. QS are highly variable in genomic position and frequency and have been proven to impact viral evolution substantially. Several de novo mutations were detected in QS before becoming lineage defining in variants of concern (VOCs). These mutations can also result from errors during replication and transcription leading to the development of defective viral genomes (DVGs) that are incapable of replicating, but important for propagating viral diversity during infection. In a continuously changing landscape of dominating VOCs and anti-SARS-CoV-2 therapy and vaccination strategies, this scoping review aims to summarize the current state-of-the-art and identify knowledge gaps in understanding QS development and their impact on intra-host SARS-CoV-2 evolution, virulence, and intra-host immunity. Finally, we explore the potential of studying inter-host transmission in households as a mirror for community transmission and evolution.