Early SARS-CoV-2 dynamics and immune responses in unvaccinated participants of an intensely sampled longitudinal surveillance study

Abstract

Background A comprehensive understanding of the SARS-CoV-2 infection dynamics and the ensuing host immune responses is needed to explain the pathogenesis as it relates to viral transmission. Knowledge gaps exist surrounding SARS-CoV-2 in vivo kinetics, particularly in the earliest stages after exposure. Methods An ongoing, workplace clinical surveillance study was used to intensely sample a small cohort longitudinally. Nine study participants who developed COVID-19 between November, 2020 and March, 2021 were monitored at high temporal resolution for three months in terms of viral loads as well as associated inflammatory biomarker and antibody responses. CD8 + T cells targeting SARS-CoV-2 in blood samples from study participants were evaluated. Results Here we show that the resulting datasets, supported by Bayesian modeling, allowed the underlying kinetic processes to be described, yielding a number of unexpected findings. Early viral replication is rapid (median doubling time, 3.1 h), providing a narrow window between exposure and viral shedding, while the clearance phase is slow and heterogeneous. Host immune responses different widely across participants. Conclusions Results from our small study give a rare insight into the life-cycle of COVID-19 infection and hold a number of important biological, clinical, and public health implications.

Clinical SARS-CoV-2 Kinetic Profiles Are Dependent on the Viral Strain and Host Vaccination Status

“…It has been suggested that amplification and detection of the short sequences targeted by primers used in the clinical RT-qPCR tests may measure SARS-CoV-2 RNA fragments rather than infectious virus, thereby biasing the length of the observed clearance phase. Our results contradict this rationale, because we previously measured SARS-CoV-2 RNA in COVID-19 patients for up to 90 days ( 2 ), while the time from C max to undetectable was less than 1 week in the current study using the same methods.…”

“…The t d and C max values were comparable to those observed in our previous study ( 2 ) ( Fig. 1G ), but the clearance phase was much shorter, with both participants being SARS-CoV-2 RNA positive for less than 2 weeks ( Fig.…”

“…(F) The log-transformed viral loads plotted against time for subject 56 were used to calculate the proliferation phase doubling time ( t d , 3.5 h; R 2 , 0.934). (G) Comparison of the viral proliferation doubling times from the current study with those in our previous study ( 2 ) involving unvaccinated participants infected with an earlier SARS-CoV-2 strain. Participant SARS-CoV-2 vaccination histories were as follows: subject 35, Pfizer-BioNTech (19 March 2021 and 9 April 2021) and Moderna (13 November 2021); subject 56, J&J-Janssen (1 April 2021) and Pfizer-BioNTech (27 October 2021).…”

“…Since 23 March 2020, we have been conducting a continuous, ongoing workplace clinical study involving the longitudinal and intensive characterization of coronavirus disease 2019 (COVID-19) prevalence and incidence ( 1 ). This intensely sampled observational study has enabled participants who developed COVID-19 to be identified in the early stages of exponential viral growth (i.e., proliferation phase) and has allowed them to be observed longitudinally via serial measurements with high temporal resolution ( 2 ). In our previous study, we followed unvaccinated participants who developed COVID-19 in late 2020 or early 2021, including measurement of viral RNA copy numbers by reverse transcription-quantitative PCR (RT-qPCR) analysis of nasal swab samples.…”

“…Black arrows identify viral load maxima ( C max ), while gray arrows identify viral load minima. (C) Overlaid nasal swab sample viral load trajectories for 8 unvaccinated study participants who became infected with an earlier SARS-CoV-2 strain in our previous study ( 2 ). Only positive test results are shown.…”