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% highest posterior density (HPD), 5.4–7.5 × 10−4) substitutions per site per year (s/s/y) for HCoV-229E spike (S) genes and 5.7 × 10−4 (95% HPD, 5–6.5 × 10−4) s/s/y for HCoV-OC43 S genes, which were about fourfold lower than the 2.5 × 10−3 (95% HPD, 2.3–2.7 × 10−3) s/s/y rate for IAV hemagglutinin (HA) genes. Coronavirus S genes accumulated about threefold 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 fivefold higher (P < 0.0001) than in other glycoprotein gene 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. 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.

中文翻译：

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人类地方性冠状病毒的进化动力学


社区保护性免疫可以通过在数年范围内选择新的抗原变体来影响 RNA 病毒的进化，例如需要每年评估流感疫苗。这种被称为抗原漂移的过程对冠状病毒的影响程度仍不清楚。与严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 一样，季节性人类冠状病毒 (HCoV) 过去很可能作为新的人类病原体从动物宿主中出现。因此，我们与人类甲型流感病毒 (IAV) 亚型 H3N2 相比，分析了普遍存在的 HCoV-229E 和 HCoV-OC43 的长期进化动态。我们专注于介导病毒进入细胞的病毒糖蛋白基因，并且是宿主中和抗体反应的主要目标。代表大约三十年 HCoV 和 IAV 进化的公开基因数据集的最大似然和贝叶斯系统发育表明，所有病毒都具有与抗原漂移兼容的相似梯状树形状，并得到不同树形状统计数据的支持。在贝叶斯框架中推断的进化速率为每年每个位点 (s/s/y) 6.5 × 10−4（95% 最高后验密度 (HPD)，5.4–7.5 × 10−4）替换 HCoV-229E 尖峰 (S ) 基因和 HCoV-OC43 S 基因的 5.7 × 10−4 (95% HPD, 5–6.5 × 10−4) s/s/y，大约比 2.5 × 10−3 (95% HPD, 5–6.5 × 10−4) s/s/y 低四倍。 IAV 血凝素 (HA) 基因的 2.3–2.7 × 10−3) s/s/y 速率。随着时间的推移，冠状病毒 S 基因累积的非同义突变 (dN) 比 IAV HA 基因少约三倍 (P < 0.001)。在 IAV 和 HCoV 中，受体结合域 (RBD) 内的平均 dN 率比其他糖蛋白基因区域高约五倍 (P < 0.0001)。 同样，大多数显示阳性选择证据的位点发生在 RBD 内（HCoV-229E，6/14 位点，P < 0.05；HCoV-OC43，23/38 位点，P < 0.01；IAV，13/15 位点，P = 0.08）。总之，HCoV 和 IAV 的进化动力学显示出一些相似之处，但与 IAV 相比，地方性 HCoV 中可能代表抗原漂移的氨基酸变化发生的规模较小。大流行性 SARS-CoV-2 的进化似乎与 IAV 的进化有相似之处，包括 RBD 中适应性变化的积累，需要定期更新疫苗，而 SARS-CoV-2 的进化稳定性与地方性 HCoV 类似，预计在后疫情阶段。