The evolutionary dynamics of endemic human coronaviruses

Abstract

Community protective immunity can affect RNA virus evolution by selecting for new antigenic variants on the scale of years, exemplified by the need of annual evaluation of influenza vaccines. The extent to which this process termed antigenic drift affects coronaviruses remains unknown. Alike the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), seasonal human coronaviruses (HCoV) likely emerged from animal reservoirs as new human pathogens in the past. We therefore analyzed the long-term evolutionary dynamics of the ubiquitous HCoV-229E and HCoV-OC43 in comparison with human influenza A virus (IAV) subtype H3N2. We focus on viral glycoprotein genes that mediate viral entry into cells and are major targets of host neutralizing antibody responses. Maximum likelihood and Bayesian phylogenies of publicly available gene datasets representing about three decades of HCoV and IAV evolution showed that all viruses had similar ladder-like tree shapes compatible with antigenic drift, supported by different tree shape statistics. Evolutionary rates inferred in a Bayesian framework were 6.5 × 10−4 (95% HPD, 5.4–7.5 × 10−4) substitutions per site per year (s/s/y) for HCoV-229E spike (S) genes and 5.7x10−4 (95% HPD, 5–6.5 × 10−4) s/s/y for HCoV-OC43 S genes, which were about 4-fold lower than the 2.5x10−3 (95% HPD, 2.3–2.7 × 10−3) s/s/y rate for IAV hemagglutinin (HA) genes. Coronavirus S genes accumulated about 3-fold less (p < 0.001) non-synonymous mutations (dN) over time than IAV HA genes. In both IAV and HCoV, the average rate of dN within the receptor binding domains (RBD) was about 5-fold higher (p < 0.0001) than in other glycoprotein regions. Similarly, most sites showing evidence for positive selection occurred within the RBD (HCoV-229E, 6/14 sites, p < 0.05; HCoV-OC43, 23/38 sites, p < 0.01; IAV, 13/15 sites, p = 0.08). In sum, the evolutionary dynamics of HCoV and IAV showed several similarities, yet amino acid changes potentially representing antigenic drift occurred on a lower scale in endemic HCoV compared to IAV H3N2. It seems likely that pandemic SARS-CoV-2 evolution will bear similarities with IAV evolution including accumulation of adaptive changes in the RBD, requiring vaccines to be updated regularly, whereas higher SARS-CoV-2 evolutionary stability resembling endemic HCoV can be expected in the post-pandemic stage.

Adaptation of the endemic coronaviruses HCoV-OC43 and HCoV-229E to the human host

“…Whereas most selected sites in the spike proteins and in HE are polymorphic in circulating viral populations (suggesting ongoing selection), those located in other regions are not ( Supplementary Table S3 ). In line with previous findings ( Jo, Drosten, and Drexler, 2021 ; Kistler and Bedford, 2021 ), the positively selected sites in the spike proteins of both HCoV-OC43 and HCoV-229E are clustered within regions that interact with the cellular receptors (9- O -acetylated sialoglycans, Sia-9-O and aminopeptidase N, ANPEP) and that were previously shown to modulate binding ( Figs. 1 and 2 ).…”

“…Notably, the heptad repeat region was previously described as a major target of selection in MERS-CoV and related camel viruses ( Cotten et al, 2014 ; Forni et al, 2015 ) and variants within this region and/or the fusion peptide were shown to modulate viral tropism and host range in several viruses, including animal coronaviruses ( de Haan et al, 2006 ; Yamada et al, 2009 ). It is also worth mentioning that, in line with our data, a previous analysis that focused on the spike proteins detected positive selection for both HCoV-OC43 and HCoV-229E, although the sites did not exactly correspond to the ones we describe herein ( Jo, Drosten, and Drexler, 2021 ). The reason for this is that different methodologies were applied to search for selection signatures.…”

“…Variations in the RBD loops, which progressively emerged over the last 50 years ( Fig. 3C ), were previously proposed to derive from immune selection ( Wong et al, 2017 ; Jo, Drosten, and Drexler, 2021 ; Kistler and Bedford, 2021 ). Inspection of the IEDB database revealed that no experimental epitope for the spike protein of HCoV-229E has been described.…”

“…As a consequence, the selected sites detected by gammaMap can be either fixed or polymorphic in circulating human strains. Conversely, Jo and coworkers did not include outgroup information and used methods that detected sites with dN/dS significantly higher than one in the sampled population of human viruses ( Jo, Drosten, and Drexler, 2021 ).…”

“…However, little is known about the past and ongoing selective events that accompanied the emergence and spread of these viruses in human populations. Recent works ( Jo, Drosten, and Drexler, 2021 ; Kistler and Bedford, 2021 ) focused on the spike proteins of the endemic coronaviruses and, by analyzing extant genetic diversity, detected evidence of positive selection in the receptor-binding domain (RBD). Here, we exploited the availability of animal viruses closely related to HCoV-229E and HCoV-OC43 to apply a method that jointly analyzes inter- and intra-specific diversity.…”