BACKGROUND: Observational studies made it possible to assess the impact of risk factors on the long-term effectiveness of mRNA and adenoviral vector (AdV) vaccines against COVID-19. METHODS: A computerized literature search was undertaken using the MEDLINE, EMBASE, and MedRxiv databases to identify eligible studies, with no language restrictions, published up to 28 February 2022. Eligible were observational studies assessing vaccine effectiveness (VE) by disease severity with reference groups of unvaccinated participants or participants immunized with one, two, or three vaccine doses. Our study was carried out in compliance with the PRISMA and MOOSE guidelines. The risk of study bias was identified using the Newcastle-Ottawa Quality Assessment Scale. The GRADE guidelines were applied to assess the strength of evidence for the primary outcome. The synthesis was conducted using a meta-analysis and meta-regression. RESULTS: Out of a total of 14,155 publications, 290 studies were included. Early VE of full vaccination against COVID-19 of any symptomatology and severity decreased from 96% (95% CI, 95-96%) for mRNA and from 86% (95% CI, 83-89%) for AdV vaccines to 67% for both vaccine types in the last 2 months of 2021. A similar 1-year decline from 98 to 86% was found for severe COVID-19 after full immunization with mRNA, but not with AdV vaccines providing persistent 82-87% effectiveness. Variant-reduced VE was only associated with Omicron regardless of disease severity, vaccine type, or vaccination completeness. The level of protection was reduced in participants aged >65 years, with a comorbidity or those in long-term care or residential homes independently of the number of doses received. The booster effect of the third mRNA dose was unclear because incompletely restored effectiveness, regardless of disease severity, declined within a short-term interval of 4 months. CONCLUSIONS: Full vaccination provided an early high, yet waning level of protection against COVID-19 of any severity with a strong impact on the high-risk population. Moreover, the potential risk of new antigenically distinct variants should not be underestimated, and any future immunization strategy should include variant-updated vaccines.

Centre for Public Health Promotion National Institute of Public Health 100 00 Prague Czech Republic

Department of Anesthesia and Intensive Medicine 1st Faculty of Medicine Charles University and University Military Hospital 100 00 Prague Czech Republic

Department of Epidemiology and Biostatistics 3rd Faculty of Medicine Charles University Ruská 87 100 00 Prague Czech Republic

Department of Health Care and Population Protection Faculty of Biomedical Engineering Czech Technical University Prague 272 01 Kladno Czech Republic

Department of Hygiene 3rd Faculty of Medicine Charles University 100 00 Prague Czech Republic

Department of Medical Biophysics and Informatics 3rd Faculty of Medicine Charles University 100 00 Prague Czech Republic

Laboratory for Atherosclerosis Research Centre for Experimental Medicine Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

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