Influenza Vaccination Reduces Disease Burden in Both Vaccinated and Unvaccinated, Modeling Study Finds

A new agent-based modeling study published in JAMA Network Open highlights the significant role of influenza vaccination in reducing infection rates across entire populations, including among those who remain unvaccinated. The study also underscores the limits of indirect protection in the context of highly transmissible viral strains, such as those seen in pandemic scenarios.

Researchers from the University of Pittsburgh used the Framework for Reconstructing Epidemiologic Dynamics (FRED) simulation platform to estimate both direct and indirect benefits of influenza vaccination in a synthetic population of 1 218 695 individuals statistically similar to the 2010 Allegheny County, Pennsylvania, census.

The study modeled a single influenza season under varying conditions of viral transmissibility (Rt), vaccine effectiveness, and population vaccine uptake. Vaccination rates were based on CDC-reported age-specific coverage, resulting in an overall uptake of approximately 51%.

With a vaccine effectiveness of 40%, the mean (SD) reduction in influenza cases ranged from 32.9% (0.9%) in high transmission scenarios (Rt = 1.88) to 41.5% (3.4%) in low transmission scenarios (Rt = 1.43). Greater vaccine effectiveness and increased uptake further enhanced the burden averted, with reductions up to 70.3% (4.0%) under optimal conditions.

Importantly, vaccination yielded benefits for both vaccinated and unvaccinated groups. However, in all modeled scenarios, vaccinated individuals experienced greater reductions in disease burden. For instance, in a high transmission scenario (Rt = 1.88) and 60% vaccine effectiveness, the attack rate (AR) was 21.0% for unvaccinated agents and 12.1% for vaccinated agents, yielding an AR ratio of 1.73. “An AR ratio of 1 would indicate that the unvaccinated portion of the population received the same benefit as the vaccinated portion,” researchers wrote, adding that greater than 1 signifies a higher benefit among the vaccinated.

Indirect protection diminished sharply in higher transmission scenarios. At approximate Rt values of 4.99 and 5.04—representative of pandemic spread—the unvaccinated population experienced negligible benefit from others’ vaccination, with ARs remaining high (93.6% and 96.6%, respectively). In contrast, vaccinated individuals still saw notable reductions in AR, between 52.6% and 61.0%, depending on vaccine effectiveness.

“Our results suggest that a strategy designed to protect the more vulnerable members of the public by allowing lower mortality groups to reach high enough levels of immunity to provide protection via herd immunity when vaccines are unavailable may not be successful for pathogens with high transmission rates,” investigators wrote.

The authors also cautioned that indirect protection can lead to underestimation of vaccine effectiveness in real-world assessments, as reduced disease burden among unvaccinated individuals may skew comparisons.

Overall, the study reinforces the importance of influenza vaccination as a critical public health measure capable of providing both direct protection and population-level benefits, particularly when viral transmissibility remains within seasonal norms. However, in high-transmission environments, vaccination alone may not be sufficient to protect unvaccinated individuals.

Source: Krauland MG, Mandell A, Roberts MS. Estimated Burden of Influenza and Direct and Indirect Benefits of Influenza Vaccination. JAMA Netw Open. 2025 Jul 1;8(7):e2521324. doi: 10.1001/jamanetworkopen.2025.21324