Publication date: Jun 22, 2026
Vaccination serves as an effective intervention for health promotion and disease prevention across the socioecological systems and has played an important role during the COVID-19 pandemic. However, global disparities in vaccine coverage have increased uncertainty about the trajectories of viral adaptation, and the potential interplay between SARS-CoV-2 adaptation and vaccine rollout warrants further quantification. Using over 13 million SARS-CoV-2 genomes across 86 countries from March 2020 to September 2022, we analyzed nonlinear associations between SARS-CoV-2 adaptation and vaccination coverage, considering public health and social measures, international travel, and infection dynamics, before and after the emergence of Omicron. Additionally, we examined the relationship between SARS-CoV-2 adaptation and COVID-19 mortality. During the pre-Omicron period, we found positive associations between nonsynonymous to synonymous divergence (dN/dS) ratios in the S1 subunit and medium levels of adjusted vaccine coverage (effect size: 0. 96 [95% CI 0. 47, 1. 45]), while the association became insignificant at high levels (effect size: -1. 89 [95% CI -4. 20, 0. 43]). However, no significant associations were found when Omicron dominated, possibly due to the immune escape ability of Omicron variants and the complex immune landscape shaped by mass hybrid immunity. Moreover, we observed evidence of dynamic interdependence and positive correlations between COVID-19 mortality and SARS-CoV-2 adaptation, with COVID-19 mortality interpreted as a proxy for uncontrolled viral spread. Our findings suggest a complex nonlinear relationship between vaccine-induced immunity and SARS-CoV-2 adaptation, with high vaccine coverage potentially linked to lower positive selection. We also observed directional coupling between COVID-19 mortality and SARS-CoV-2 adaptation. This may have implications for fair and fast vaccination in pandemic preparedness and response. Not applicable.
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| Concepts | Keywords |
|---|---|
| 13million | COVID-19 |
| Pandemic | Natural immunity |
| Vaccine | SARS-CoV-2 adaptation |
| Vaccine disparities | |
| Vaccines |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | COVID-19 pandemic |
| disease | MESH | infection |
| disease | MESH | Infectious Diseases |
| disease | MESH | Dis |
| pathway | REACTOME | Reproduction |
| disease | MESH | included |
| disease | MESH | Emerging Infectious Diseases |
| disease | MESH | Eco |
| drug | DRUGBANK | Coenzyme M |
| disease | MESH | strains |
| disease | MESH | Influenza |
| pathway | REACTOME | Translation |
| drug | DRUGBANK | Amino acids |
| disease | MESH | AIC |
| disease | MESH | CCM |
| disease | MESH | reinfection |
| pathway | KEGG | Viral replication |
| disease | MESH | death |
| drug | DRUGBANK | Spinosad |
| drug | DRUGBANK | Serine |
| disease | MESH | Severe Acute Respiratory Syndrome |
| drug | DRUGBANK | Stavudine |
| disease | MESH | Plague |
| drug | DRUGBANK | Aspartame |