In depth sequencing of a serially sampled household cohort reveals the within-host dynamics of Omicron SARS-CoV-2 and rare selection of novel spike variants

Bendall, E. E.; Dimcheff, D.; Papalambros, L.; Fitzsimmons, W. J.; Zhu, Y.; Schmitz, J. E.; Halasa, N.; Chappell, J. D.; Martin, E. T.; Biddle, J. E.; Smith-Jeffcoat, S. E.; Rolfes, M. A.; Mellis, A.; Talbot, H. K.; Grijalva, C. G.; Lauring, A. S.

doi:10.1101/2024.11.21.624722

bioRxiv · 10.1101/2024.11.21.624722

In depth sequencing of a serially sampled household cohort reveals the within-host dynamics of Omicron SARS-CoV-2 and rare selection of novel spike variants

Bendall, E. E.·Dimcheff, D.·Papalambros, L.·Fitzsimmons, W. J.·Zhu, Y.·Schmitz, J. E.·Halasa, N.·Chappell, J. D.·Martin, E. T.·Biddle, J. E.·Smith-Jeffcoat, S. E.·Rolfes, M. A.·Mellis, A.·Talbot, H. K.·Grijalva, C. G.·Lauring, A. S.

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Abstract

SARS-CoV-2 has undergone repeated and rapid evolution to circumvent host immunity. However, outside of prolonged infections in immunocompromised hosts, within-host positive selection has rarely been detected. The low diversity within-hosts and strong genetic linkage among genomic sites make accurately detecting positive selection difficult. Longitudinal sampling is a powerful method for detecting selection that has seldom been used for SARS-CoV-2. Here we combine longitudinal sampling with replicate sequencing to increase the accuracy of and lower the threshold for variant calling. We sequenced 577 specimens from 105 individuals from a household cohort primarily during the BA.1/BA.2 variant period. There was extremely low diversity and a low rate of divergence. Specimens had 0-12 intrahost single nucleotide variants (iSNV) at >0.5% frequency, and the majority of the iSNV were at frequencies <2%. Within-host dynamics were dominated by genetic drift and purifying selection. Positive selection was rare but highly concentrated in spike. Two individuals with BA.1 infections had S:371F, a lineage defining substitution for BA.2. A Wright Fisher Approximate Bayesian Computational model identified positive selection at 14 loci with 7 in spike, including S:448 and S:339. We also detected significant genetic hitchhiking between synonymous changes and nonsynonymous iSNV under selection. The detectable immune-mediated selection may be caused by the relatively narrow antibody repertoire in individuals during the early Omicron phase of the SARS-CoV-2 pandemic. As both the virus and population immunity evolve, understanding the corresponding shifts in SARS-CoV-2 within-host dynamics will be important.

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Bendall, E. E., Dimcheff, D., Papalambros, L., Fitzsimmons, W. J., Zhu, Y., Schmitz, J. E., Halasa, N., Chappell, J. D., Martin, E. T., Biddle, J. E., Smith-Jeffcoat, S. E., Rolfes, M. A., Mellis, A., Talbot, H. K., Grijalva, C. G., Lauring, A. S.. 2024-11-22. In depth sequencing of a serially sampled household cohort reveals the within-host dynamics of Omicron SARS-CoV-2 and rare selection of novel spike variants. https://doi.org/10.1101/2024.11.21.624722

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