Decomposing the sources of SARS-CoV-2 fitness variation in the United States

Abstract

The fitness of a pathogen is composite phenotype determined by many different factors influencing growth rates both within and between hosts. Determining what factors shape fitness at the host population-level is especially challenging because both intrinsic factors like pathogen genetics and extrinsic factors such as host behaviour influence between-host transmission potential. These challenges have been highlighted by controversy surrounding the population-level fitness effects of mutations in the SARS-CoV-2 genome and their relative importance when compared against non-genetic factors shaping transmission dynamics. Building upon phylodynamic birth-death models, we develop a new framework to learn how hundreds of genetic and non-genetic factors have shaped the fitness of SARS-CoV-2. We estimate the fitness effects of all amino acid variants and several structural variants that have circulated in the United States between February and September 2020 from viral phylogenies. We also estimate how much fitness variation among pathogen lineages is attributable to genetic versus non-genetic factors such as spatial heterogeneity in transmission rates. Up to September 2020, most fitness variation between lineages can be explained by background spatial heterogeneity in transmission rates across geographic regions. Furthermore, no genetic variant including the Spike D614G mutation has had a significant effect on population-level fitness. Instead, the rapid increase in the frequency of the Spike D614G can be explained by the variant having a spatial transmission advantage due to first establishing in regions with higher transmission rates during the earliest stages of the pandemic.

Neutralising antibody escape of SARS‐CoV‐2 spike protein: Risk assessment for antibody‐based Covid‐19 therapeutics and vaccines

“…Interestingly, that particular mutation is not worrying for antibody‐based therapeutics and vaccines since it actually increases the susceptibility to neutralisation 60,61 . D614G first established in countries where transmission rates at the beginning of the pandemic were higher, 23,62 leading to huge expansions. The P323L mutation in the RNA‐dependent RNA polymerase (often referred as NSP12b:P314L) accompanies the D614G Spike mutation in most of the analysed sequences (MR = 0.994) 19…”

Studies on the enzymatic specificity of diguanylate cyclases domains and the production of new second messengers

“…Why mutations R203K and G204R have such frequencies in most of the continents, why in North America, those mutations were not so successful and why currently Europe is dominated by OTU_2 are open questions. Some studies showed that at the moment, there are not mutations that significative increase the fitness of the SARS-CoV-2 (Kepler et al, 2020;van Dorp et al, 2020).…”