Background COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness. Methods This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status. Findings Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m 2 ) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older. Interpretation To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations. Funding ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, and the Alzheimer's Society.
