Children who are vaccinated against influenza vaccination were confirmed less likely to contract the illness than the unvaccinated, in a "natural," randomized trial1 that could rectify the lack of contemporaneous randomized data cited by the CDC2 as rationale for removing flu vaccine from annual childhood immunization recommendations.
Although large and costly randomized control trials (RCT) are unlikely to be conducted to further justify a vaccine found efficacious in earlier RCTs,3 investigators seized upon differences in vaccination rates in children by season of their birth, to conduct a multi-year, randomized "natural experiment."
Christopher Worsham, MD, MPH, Division of Pulmonary & Critical Care Medicine, Massachusetts General Hospital, Boston, and colleagues noted that more children born in the fall receive the flu vaccine at their 2nd through 5th birthday medical visits, which coincide with the onset of flu season, than those born in the summer, who require scheduling a second visit to coincide with the availability, and optimal timing of the vaccine.
"Under the assumption that children with fall vs summer birthdays should have otherwise similar baseline risk of influenza diagnosis, any differences on observed influenza diagnoses between the 2 groups can be attributed to differences in vaccination rates, permitting a quasi-experimental assessment of vaccine efficacy in each influenza season," Worsham and colleagues explain.
The investigators compared national insurance claims data for influenza vaccination and diagnosis among children aged 2 to 5 with fall vs summer births for 5 typical influenza seasons in the period from 2016 to 2023, excluding 2020-2021 and 2021-2022 due to COVID-19. In addition, as a falsification test, they compared differences in diagnoses of noninfluenza viral infections such as the common cold or gastrointestinal infections, as these would not be affected by influenza vaccination.
Worsham and colleagues affirmed that those with fall birthdays were more likely to receive influenza vaccination, and found that they were also less likely to be diagnosed with influenza than the children born in summer.Across the season years, 8.6 to 12.6 percent more fall birth children than summer birth children were vaccinated, and had 1.0 to 1.4 percent fewer diagnoses of influenza than summer birth children.
In the falsification test, there were no differences in diagnosis rates of non-influenza viral infection between the groups.This finding, the investigators suggest, would argue "against residual confounding from factors such as care-seeking behaviors."
Statistical analysis revealed that for every 100 children who were vaccinated because of their birthday season, there were 9 to 14 fewer diagnosed cases of influenza.
What You Need to Know
Influenza A RNA was detected in 60.8% of participants and influenza B RNA in 85.6%, suggesting that limited vaccine-virus replication in healthy adults occurs frequently following intranasal LAIV administration.
Influenza B was associated with longer viral persistence, showing higher proportions of moderate and slow clearance profiles, while influenza A was more likely to clear rapidly within four days.
Participants with detectable influenza A experienced a greater upper respiratory symptom burden, and the observed variation in viral replication and clearance highlights the need for further research into how post-vaccination shedding relates to mucosal immunity and protection against infection.
"In the United States, that's hundreds of thousands, if not a million cases of flu that we can avoid each year.That's a huge effect size," senior study author Anupam Jena, MD, PhD, Department of Health Care Policy, Harvard Medical School, Boston, MA, stated in a news release.4
As to their use of a "natural experiment" to provide randomized data to address the stated concern of the CDC, Jena was as enthusiastic about this research tool as their findings.
"It is impossible to do a randomized, controlled trial for every single thing that we want to know and understand," she said."But we have an incredible amount of data out there and there are randomized experiments like this sitting in that data, waiting to be uncovered."
References
1. Worsham CM, Bray CF, Jena AB. Pediatric vaccination effiacy. JAMAPediatr. 2026, published online June 1. doi:10.1001/jamapediatrics.2026.1546.
2. CDC News Release. CDC acts on presidential memorandum to update childhood immunization schedule. 2026, January 5. https://www.cdc.gov/media/releases/2026/2026-cdc-acts-on-presidential-memorandum-to-update-childhood-immunization-schedule.html. Accessed June 2, 2026.
3. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338:1405-1412. doi:10.1056/NEJM199805143382002.
4. Castañó L. New analysis confirms benefits of childhood flu vaccines. News Release, Harvard Medical School. 2026, May 26. https://hms.harvard.edu/news/new-analysis-confirms-benefits-childhood-flu-vaccines. Accessed June 2, 2026
