The severe burden of COVID-19 has been much reduced because of vaccinations, allowing non-pharmaceutical therapies to be discontinued. However, vaccination techniques need to be reviewed due to declining immunity and the introduction of more transmissible strains of concern. Here, researchers employ a SARS-CoV-2 transmission model to determine optimal vaccination booster frequency, timing, and population subsets to lessen the public health burden and threat to healthcare systems. Annual or biannual boosters of those eligible (those who received doses 1 and 2) who are most vulnerable (60+ or living with comorbidities) or those 5+, at universal (98% of eligible) or lower coverage (85% of those 50+ or with comorbidities and 50% of 5-49-year-olds representing moderate vaccine fatigue and/or hesitancy), were estimated to prevent new infections and hospital admissions over 2 years. Investigators ran simulations under 3 scenarios where new variants never appear, 25% more infectious and immune-evading Omicron-level severity variants develop annually, become dominant, or emerge biannually. They also investigated how beliefs about vaccine efficacy, seasonality, immune evasion, infectiousness, severity, timeliness, and timing all play a role. Whether or not new variants of concern arise, boosters should be given to all eligible individuals, preferably 3-4 months ahead of peak winter, to prevent COVID-19-related hospitalizations during the next 2 years. Reducing the strain on healthcare systems by aiding only the most vulnerable is quite unlikely. Moreover, protecting the most vulnerable requires increasing everyone’s eligibility, not just the disadvantaged group. While this approach may not guarantee less strain on healthcare systems, it does show that the most vulnerable populations can benefit from boosting more than the rest of the population can per booster dose. This was because the most vulnerable populations were the most likely to seek hospital care once infected. When crucial model parameters were changed, the results held steady. Nonetheless, they discovered that boosters’ effect was reduced; whether taken annually or biannually, the more frequent variations occur. Infections and hospitalizations can be reduced by giving yearly COVID-19 vaccination boosters to all eligible people, with particular attention paid to the most vulnerable.