Combined analyses of within-host SARS-CoV-2 viral kinetics and information on past exposures to the virus in a human cohort identifies intrinsic differences of Omicron and Delta variants.

The emergence of successive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) during 2020 to 2022, 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 Coronavirus Disease 2019 (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 interindividual 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 5 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. Trial Registration: The Legacy study is a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening for SARS-CoV-2 at University College London Hospitals or at the Francis Crick Institute (NCT04750356) (22,23). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469). 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. Written consent was given by all participants.
Competing Interests: C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc - collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, and Personalis. He is Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee Chair. He is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre – Shanghai, Metabomed (until July 2022), Relay Therapeutics SAB member, Saga Diagnostics SAB member and the Sarah Cannon Research Institute. C.S has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer, and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S declares a patent application (PCT/US2017/028013) for methods to lung cancer); targeting neoantigens (PCT/EP2016/059401); identifying patent response to immune checkpoint blockade (PCT/EP2016/071471); methods for lung cancer detection (US20190106751A1); identifying patients who respond to cancer treatment (PCT/GB2018/051912); determining HLA LOH (PCT/GB2018/052004); predicting survival rates of patients with cancer (PCT/GB2020/050221), methods for systems and tumour monitoring (PCT/EP2022/077987). C.S. is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity and under their terms of employment C.S is due a revenue share of any revenue generated from such license(s).
(Copyright: © 2024 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)