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One of the most consequential unknowns of the COVID-19 pandemic is the frequency at which vaccine boosting provides sufficient protection from infection. We quantified the statistical likelihood of breakthrough infections over time following different boosting schedules with messenger RNA (mRNA)-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech). We integrated anti-Spike IgG antibody optical densities with profiles of the waning of antibodies and corresponding probabilities of infection associated with coronavirus endemic transmission. Projecting antibody levels over time given boosting every 6 months, 1, 1.5, 2, or 3 years yielded respective probabilities of fending off infection over a 6-year span of >93%, 75%, 55%, 40%, and 24% (mRNA-1273) and >89%, 69%, 49%, 36%, and 23% (BNT162b2). Delaying the administration of updated boosters has bleak repercussions. It increases the probability of individual infection by SARS-CoV-2, and correspondingly, ongoing disease spread, prevalence, morbidity, hospitalization, and mortality. Instituting regular, population-wide booster vaccination updated to predominant variants has the potential to substantially forestall-and with global, widespread uptake, eliminate-COVID-19. 

The durability of vaccine-mediated immunity to SARS-CoV-2, the durations to breakthrough infection, and the optimal timings of booster vaccination are crucial knowledge for pandemic response. Here, we applied comparative evolutionary analyses to estimate the durability of immunity and the likelihood of breakthrough infections over time following vaccination by BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford-AstraZeneca), and Ad26.COV2.S (Johnson & Johnson/Janssen). We evaluated anti-Spike (S) immunoglobulin G (IgG) antibody levels elicited by each vaccine relative to natural infection. We estimated typical trajectories of waning and corresponding infection probabilities, providing the distribution of times to breakthrough infection for each vaccine under endemic conditions. Peak antibody levels elicited by messenger RNA (mRNA) vaccines mRNA-1273 and BNT1262b2 exceeded that of natural infection and are expected to typically yield more durable protection against breakthrough infections (median 29.6 mo; 5 to 95% quantiles 10.9 mo to 7.9 y) than natural infection (median 21.5 mo; 5 to 95% quantiles 3.5 mo to 7.1 y). Relative to mRNA-1273 and BNT1262b2, viral vector vaccines ChAdOx1 and Ad26.COV2.S exhibit similar peak anti-S IgG antibody responses to that from natural infection and are projected to yield lower, shorter-term protection against breakthrough infection (median 22.4 mo and 5 to 95% quantiles 4.3 mo to 7.2 y; and median 20.5 mo and 5 to 95% quantiles 2.6 mo to 7.0 y; respectively). These results leverage the tools from evolutionary biology to provide a quantitative basis for otherwise unknown parameters that are fundamental to public health policy decision-making.