Implementation and Adherence to Regular Asymptomatic Testing in a COVID-19 Vaccine Trial

Abstract

AbstractBackgroundFor pathogens which cause infections that present asymptomatically, evaluating vaccine efficacy (VE) against asymptomatic infection is important for understanding a vaccine’s potential epidemiological impact. Regular testing for subclinical infections is a potentially valuable strategy but its success hinges on participant adherence and minimising false positives. This paper describes the implementation and adherence to weekly testing in a COVID-19 vaccine trial.MethodsCOV002 was a phase 2/3 trial assessing the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Asymptomatic infections were detected using weekly self-administered swabs for RT-PCR testing. We analysed adherence using mixed-effects regression models and estimated the probability of true and false positive asymptomatic infections using estimates of adherence and testing characteristics.Findings356,551 tests were self-administered by 10,811 participants during the 13-month follow-up. Median adherence was 75.0% (IQR 42·6-90·9), which translated to a 74·5% (IQR 50·9-78·8) probability of detecting a positive asymptomatic infection during the swabbing period, and between 21 and 96 false positives during VE evaluation. The odds of returning a swab declined by 8% per week and further after testing positive and unblinding. Adherence was higher in older age groups, females and non-healthcare workers.InterpretationThe COV002 trial demonstrated the feasibility of running a long-term regular asymptomatic testing strategy. This information could be valuable for designing future phase III vaccine trials in which infection is an outcome.FundingUK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland’s NIHR Clinical Research Network, AstraZeneca.Research in contextEvidence before this studyRegular testing for asymptomatic infections in clinical trials is useful for evaluating the role of candidate vaccines or drugs in preventing infection. While there is extensive research on loss to follow-up in clinical trials, there is minimal research on adherence to repeat clinical trial procedures. During the COVID-19 pandemic, regular asymptomatic testing was used for surveillance and contact tracing in isolated populations, and in two SARS-CoV-2 vaccine trials.We searched PubMed from database inception to Dec 17, 2023 using the following search terms (title or abstract) for articles published in English: (Adherence OR Compliance OR Uptake OR Implementation) AND (Repeat test* OR regular test* OR weekly test* OR monthly test* OR serial test*) AND (“covid*” OR “COVID-19*” OR “SARS-CoV-2*” OR “Severe Acute Respiratory Syndrome Coronavirus 2”), and reviewed the identified publications.Identified studies demonstrated the feasibility over short time periods of regular asymptomatic testing in hospital, care home, university, school and workplace settings. A small number evaluated differences in adherence by socio-demographic characteristics, mainly highlighting increased age as a predictor of adherence. No studies evaluated adherence in clinical trial settings or predictors of adherence over time.Added value of this studyWe evaluated the feasibility and adherence to regular asymptomatic testing in a phase III trial of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. We demonstrated high adherence across trial participants over a year of follow-up, but significant differences across socio-demographic characteristics. Adherence was highest in older age groups, females and non-healthcare workers, and declined most strongly over time in younger age groups. We show how the frequency of testing can be translated to an estimated probability of a false positive and negative infections.Implications of all the available evidenceThe overall evidence suggests that regular asymptomatic testing is a feasible strategy for tracking the risk of infection for diseases with a high proportion of subclinical infections. Strategies to support subpopulations to maintain adherence over prolonged periods of time may be necessary, and consideration needs to be given to the optimal time over which this type of intensive sampling provides valuable data. Further research into the effect of variation in adherence to regular testing on vaccine efficacy estimates would be valuable.