Test negative studies have been used extensively for the estimation of COVID-19 vaccine effectiveness (VE). Such studies are able to estimate VE against medically-attended illness under certain assumptions. Selection bias may be present if the probability of participation is associated with vaccination or COVID-19, but this can be mitigated through use of a clinical case definition to screen patients for eligibility, which increases the likelihood that cases and non-cases come from the same source population. We examined the extent to which this type of bias could harm COVID-19 VE through systematic review and simulation. A systematic review of test-negative studies was re-analysed to identify studies ignoring the need for clinical criteria. Studies using a clinical case definition had a lower pooled VE estimate compared with studies that did not. Simulations varied the probability of selection by case and vaccination status. Positive bias away from the null (i.e., inflated VE consistent with the systematic review) was observed when there was a higher proportion of healthy, vaccinated non-cases, which may occur if a dataset contains many results from asymptomatic screening in settings where vaccination coverage is high. We provide an html tool for researchers to explore site-specific sources of selection bias in their own studies. We recommend all groups consider the potential for selection bias in their vaccine effectiveness studies, particularly when using administrative data.

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.