For children who have never been vaccinated against the flu, getting two doses of the inactivated flu vaccine was associated with improved protection compared with getting one dose, but only in those younger than three years, according to a systematic review and meta-analysis published in JAMA Network Open.
According to the University of Melbourne’s Jessie Goldsmith, PhD student in the Sullivan research group at the Doherty Institute, first author of the study, across 51 studies with over 400,000 participants, the pooled absolute increase in vaccine effectiveness of a second inactivated flu vaccine dose in the first year of vaccination was 15 percentage points for those younger than nine years and 28 percentage points for those younger than three years.
In 12 studies on the real-world vaccine effectiveness of inactivated flu vaccines, starting vaccine-naive children younger than 9 years on one dose delivered a pooled vaccine effectiveness against any flu strain of 35 per cent compared with a 43 per cent vaccine effectiveness after two doses. Five studies that compared one- and two-dose estimates showed pooled vaccine effectiveness rates of 31 per cent and 43 per cent, respectively, with a pooled difference of change in vaccine effectiveness of 15 percentage points.
Among children younger than three years, the combined vaccine effectiveness for one dose fell to 14 per cent, while the two-dose vaccine effectiveness was a significantly greater 41 per cent, and the pooled difference of change in vaccine effectiveness increased to 28 percentage points.
In five studies looking at vaccine efficacy, the pooled two-dose vaccine efficacy was 52 per cent in children younger than nine years and 51 per cent in those younger than three years.
“For [inactivated] vaccine effectiveness studies, the benefit of the second dose in the first year of vaccination against influenza is more definitive when the studies were limited to children under three compared with the broader age group of children younger than nine years,” said Goldsmith in an interview with MedPage Today.
The WHO recommends that children younger than nine years who haven't had a flu vaccine receive two doses to start, at least four weeks apart, and then one dose each year after that. The American Academy of Pediatrics also recommends two doses to start in vaccine-naive children younger than nine years, given four weeks apart.
Immunogenicity studies have shown that two doses in vaccine-naive young children help them reach a seropositivity threshold at which adults see a 50 per cent reduction in their risk of flu. However, research supporting that threshold's value in children is limited.
What's driving the differences in vaccine effectiveness between those younger than 3 years and older children?
“There are two factors that are likely to contribute to the reduction in benefit of the second dose in the first year of influenza vaccination as children age,” Goldsmith said.
“Their immune system has had the opportunity to develop further, and they are more likely to have been exposed to the influenza virus.”
A lack of sufficient data prevented real-world vaccine effectiveness estimates comparing one-dose and two-dose approaches with the live attenuated influenza vaccine, which is recommended for children ages two years and up. Seven trials showed that pooled vaccine efficacy against any flu strain was 51per cent for one dose and 82 per cent for two doses.
For this systematic review and meta-analysis, Goldsmith and colleagues used the Medline, Embase and CINAHL (trusted databases that store scientific and medical research) from inception to March 24, 2025, to search for peer-reviewed studies that reported vaccine efficacy or vaccine effectiveness against influenza by dose number for flu vaccine-naive children ages six months to younger than nine years. They included 51 studies with 415,050 participants.
The authors conducted separate analyses for inactivated and live attenuated flu vaccines, given the two vaccines' differing starting ages.
Study limitations included the small number of available estimates and those estimates' high levels of uncertainty. Insufficient estimates also prevented a separate analysis of how two doses impacted children between the ages of three and nine years.
This article is adapted from an article originally published by MedPage Today, reproduced with permission.
Peer-review: Goldsmith J, et al. Comparison of 2 Doses vs 1 Dose in the First Season Children Are Vaccinated Against Influenza. JAMA Network Open (2025).
DOI: http://www.doi.org/10.1001/jamanetworkopen.2025.35250
Collaboration: This work is a result of a collaboration between the Doherty Institute, Monash University, University of California and University of San Francisco.
Funding: This research was supported by the National Institutes of Allergy and Infectious Diseases (US NIAID), the Australian Government Medical Research Future Fund (MRFF), the VESKI Victorian Near-miss Award and the University of Melbourne.
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