Transmission of mutated SARS-CoV-2 variants is favored by relatively prolonged infections due to delayed immunity
- 1Fred Hutchinson Cancer Center
Abstract
SARS-CoV-2 evolution enhanced viral fitness and immune evasion, extending the COVID-19 pandemic and resulting in millions of excess deaths. Viral diversity is generated within infected individuals, yet the timing and interplay of viral and immunological forces that drive transmissible evolution are incompletely understood. We developed a multi-scale within host phylodynamic (WiPhy) model of SARS-CoV-2 infection which couples viral replication, innate and acquired immune responses, and viral mutation. We then validated the model against quantitative viral and phylodynamic metrics. Model output predicts that typical acute infections rapidly generate genetic diversity due to accumulation of minor variants which in most cases do not achieve sufficient concentrations for transmission. Delayed innate immune responses correlate with higher peak viral load and diversification, allowing higher transmission risk of the founder virus or with a novel variant that is equally or less fit. In contrast, the risk of transmitting a fitter variant is highest during the ~10% of infections in which viral loads remain sufficiently high for transmission after 10-14 days. In these cases, non-sustained innate and/or weak acquired immune responses allow sufficient time for selection of a variant with one or more fitness enhancing non-synonymous mutations. Across a simulated cohort of ~1500 individuals, 5% of transmission risk came from variants with enhanced fitness from nonsynonymous mutations, and 13% of simulated infections accounted for 90% of fitter variant transmission risk. Our results highlight how the timing and interplay of viral and immunological forces within a host create bottlenecks that severely limit between host evolution.
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BibTeX
@misc{owens2026transmission,
title = {{Transmission of mutated SARS-CoV-2 variants is favored by relatively prolonged infections due to delayed immunity}},
author = {K. Owens and P. Radecki and S. Tempia and A. von Gottberg and C. Cohen and E. Boritz and J. T. Schiffer and D. B. Reeves},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751875},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751875v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Transmission of mutated SARS-CoV-2 variants is favored by relatively prolonged infections due to delayed immunity
AU - K. Owens
AU - P. Radecki
AU - S. Tempia
AU - A. von Gottberg
AU - C. Cohen
AU - E. Boritz
AU - J. T. Schiffer
AU - D. B. Reeves
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751875
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751875v1
AB - SARS-CoV-2 evolution enhanced viral fitness and immune evasion, extending the COVID-19 pandemic and resulting in millions of excess deaths. Viral diversity is generated within infected individuals, yet the timing and interplay of viral and immunological forces that drive transmissible evolution are incompletely understood. We developed a multi-scale within host phylodynamic (WiPhy) model of SARS-CoV-2 infection which couples viral replication, innate and acquired immune responses, and viral mutation. We then validated the model against quantitative viral and phylodynamic metrics. Model output predicts that typical acute infections rapidly generate genetic diversity due to accumulation of minor variants which in most cases do not achieve sufficient concentrations for transmission. Delayed innate immune responses correlate with higher peak viral load and diversification, allowing higher transmission risk of the founder virus or with a novel variant that is equally or less fit. In contrast, the risk of transmitting a fitter variant is highest during the ~10% of infections in which viral loads remain sufficiently high for transmission after 10-14 days. In these cases, non-sustained innate and/or weak acquired immune responses allow sufficient time for selection of a variant with one or more fitness enhancing non-synonymous mutations. Across a simulated cohort of ~1500 individuals, 5% of transmission risk came from variants with enhanced fitness from nonsynonymous mutations, and 13% of simulated infections accounted for 90% of fitter variant transmission risk. Our results highlight how the timing and interplay of viral and immunological forces within a host create bottlenecks that severely limit between host evolution.
ER -