David B. Thaw

We study the experience with COVID-19 vaccination of an initially naïve population, which can inform planning for vaccination against the next novel, highly transmissible pathogen. We focus on the first two pandemic years (wild strain through Delta), because after the Omicron wave in early 2022, very few people were still SARS-CoV-2-naïve. Almost all were vaccinated, infected, or often both. We review the evidence on COVID-19 vaccine effectiveness (VE) and waning effectiveness over time and the relative effectiveness of the four principal vaccines used in developed Western countries: BNT162b2 (Pfizer-BioNTech), mRNA1273 (Moderna), Ad26.CoV2.S (Johnson&Johnson), and ChAdOx1-S (AstraZeneca). As a basis for our analysis, we conducted a PRISMA-compliant review of all studies on PubMed through 15 August 2022, reporting VE against four endpoints for these four vaccines: any infection, symptomatic infection, hospitalization, and death. The mRNA vaccines (BNT162b2, mRNA1273) had high initial VE against all endpoints but protection waned after approximately six months, with BNT162b2 declining faster than mRNA1273. Both mRNA vaccines outperformed the viral vector vaccines (Ad26.CoV2.S and ChAdOx1-S). A third “booster” dose, roughly six months after the initial doses, substantially reduced symptomatic infection, hospitalization, and death. In hindsight, a third dose should be seen as part of the normal vaccination schedule. Our analysis highlights the importance of the real-time population-level surveillance needed to assess evidence for waning, and the need for rapid regulatory response to this evidence.