Within-host SARS-CoV-2 viral kinetics informed by complex life course exposures reveals different intrinsic properties of Omicron and Delta variants

The emergence of successive SARS-CoV-2 variants of concern (VOC) during 2020-22, each exhibiting increased epidemic growth relative to earlier circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics - such as varying levels of immunity - can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform COVID-19 planning and response, and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both inter-individual variation in Ct values and complex host characteristics - such as vaccination status, exposure history and age - we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least five prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04750356 ### Funding Statement TWR, LACC and AK were supported by funding from the Wellcome Trust (20650/Z/17/Z). AK was also supported by the National Institutes of Health (1R01AI141534-01A1). LACC was also supported by the National Institute for Health Research NIHR (200908). SA was funded by the Wellcome Trust (grant: 210758/Z/18/Z). RP acknowledges funding from the Singapore Ministry of Health. DH was supported by the National Institute for Health Research (NIHR; 1R01AI141534-01A1: DH). This research was partly funded by the National Institute for Health Research (NIHR) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care (16/136/46: BJQ; 16/137/109: BJQ). Bill & Melinda Gates Foundation (OPP1139859: BJQ). This research was funded in whole, or in part, by the Wellcome Trust [FC011104, FC011233, FC001030, FC001159, FC001827, FC001078, FC001099, FC001169]. This work was supported by the National Institute for Health Research University College London Hospitals Department of Health NIHR Biomedical Research Centre (BRC), as well as by the UK Research and Innovation and the UK Medical Research Council (MR/W005611/1), and by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC011104, FC011233, FC001030, FC001159, FC001827, FC001078, FC001099, FC001169, CC2230), the UK Medical Research Council (FC011104, FC011233, FC001030, FC001159, FC001827, FC001078, FC001099, FC001169), and the Wellcome Trust (FC011104, FC011233, FC001030, FC001159, FC001827, FC001078, FC001099, FC001169, CC2230). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469) and is sponsored by University College London Hospitals. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The dataset containing the Ct values at the three gene targets considered for the 140 infection episodes, symptom onset times and covariate data, along with the code to re-run the analysis can be found at this publicly available repository: https://github.com/thimotei/legacy\_ct\_modelling. [https://github.com/thimotei/legacy\_ct\_modelling][1] [1]: https://github.com/thimotei/legacy_ct_modelling