Why Vaccination Strategy Matters: Evidence from COVID-19 Modeling

A modeling study published in JAMA Network Open in September 2025 evaluated projections for COVID-19 burden in the U.S. from April 2024 through April 2025 under varying vaccine policy and immune escape scenarios. This multi-team ensemble modeling effort estimated hospitalization and mortality outcomes and quantified the benefits of targeted versus universal vaccination strategies. These projections were designed to inform vaccination strategy and policy—not to forecast epidemiologic trends.

The US Modeling Hub convened nine teams to evaluate six scenarios that combined two levels of immune escape (low/20% or high/50% annual reduction in protection due to viral evolution) with three vaccine strategies: no recommendation, recommendation for high-risk groups only, or a universal recommendation for all individuals aged ≥6 months. High-risk individuals were defined as adults aged ≥65 years or those with underlying medical conditions associated with severe COVID-19. Vaccines were assumed to be reformulated to match circulating variants and available by September 1, 2024, with 75% effectiveness against hospitalization at the time of delivery.

Based on the scenario most closely aligned with observed U.S. trends from April 2023 to April 2024 (characterized by high immune escape and a universal vaccination recommendation), the projected COVID-19 burden for April 2024 to April 2025 included approximately 814,000 hospitalizations (95% projection interval [PI]: 400,000–1.2 million) and 54,000 deaths (95% PI: 17,000–98,000). Individuals aged ≥65 years represented more than half of hospitalizations and 84–87% of deaths across modeled scenarios.

In comparison to no vaccine recommendation, targeting only high-risk groups was estimated to prevent 76,000 hospitalizations (95% CI: 34,000–118,000) and 7,000 deaths (95% CI: 3,000–11,000) across immune escape conditions. A universal vaccination approach was projected to further reduce the burden by 28,000 additional hospitalizations (95% CI: 13,000–43,000) and 2,000 more deaths (95% CI: 800–3,000) under high immune escape assumptions. Overall, projections for vaccinating all eligible individuals resulted in a 10–20% reduction in total COVID-19 hospitalizations and deaths compared to no vaccination, with added indirect benefits to adults aged ≥65 years beyond those achieved by vaccinating high-risk groups only.

While the timing of hospitalizations during 2024–2025 deviated from the projections—particularly due to an unanticipated summer 2024 wave—the overall death estimates remained within projected uncertainty ranges. This divergence is attributed to the scenarios’ simplified immune escape assumptions, which did not account for irregular variant dynamics. In 2024, a high immune escape variant (KP.3.1.1) emerged in summer, followed by a low immune escape variant (XEC) in winter, reversing typical seasonal patterns. These findings highlight the complex interplay between viral evolution, immune waning, and transmission.

Taken together, these findings suggest that vaccination remains a key approach for reducing COVID-19 burden, with universal vaccine strategies offering the potential to save thousands of additional lives through both direct protection and indirect community-level benefits.

Reference
Loo SL, Jung SM, Contamin L, et al. Scenario Projections of COVID-19 Burden in the US, 2024-2025. JAMA Netw Open. 2025;8(9):e2532469. Published 2025 Sep 2. doi:10.1001/jamanetworkopen.2025.32469