Immunogenicity from reduced dose influenza vaccine, administered via intradermal injection, was not significantly different from the standard-dose intramuscular injection across all age groups, according to a meta-analysis published in JAMA Network Open. The findings suggested that low-dose intradermal influenza vaccine might be an effective alternative to standard intramuscular dose and could inform policy in case of shortages.

In this systematic review and meta-analysis of 30 studies published from 2010 until June 5, 2020, a team of investigators compared the immunogenicity and safety of influenza vaccine at different intradermal vaccine doses (3, 6, 7.5, 9, and 15 µg) with a standard intramuscular dose (15 µg) for each of the H1N1, H3N2, and B strains. Outcomes included seroconversion, seroprotection, geometric mean titer (GMT), and adverse events that were stratified by dose.

Of the studies included, 29 were randomized clinical trials that comprised of 13,759 total participants, and 1 was a cohort study comprised of 164,021 participants.

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Across all the viral strains, there was no statistical difference in seroconversion rates between the 3-μg, 6-μg, 7.5-μg, and 9-μg intradermal doses compared with standard intramuscular dose. However, seroconversion rate was significantly higher with the 15-μg intradermal dose compared with the intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01%-1.20%) and the B strain (RR, 1.40; 95% CI, 1.13%-1.73%).

Seroprotection rates for the 9-μg and 15-μg intradermal doses were not statistically significant compared with the standard intramuscular dose for all 3 strains, aside from the 15-μg intradermal dose being statistically higher for the H1N1 strain (RR, 1.05; 95% CI, 1.01%-1.09%).

GMTs were not statistically significant for the 3-μg and 6-μg intradermal dose vs intramuscular dose for the 3 strains, with the exception of a significant decrease for H1N1 with the 6-μg dose (RR, 0.88; 95% CI, 0.85%-0.90%). When comparing 9-μg intradermal dose with the intramuscular dose, GMT was only significant for the H3N2 strain (RR, 1.08; 95% CI, 1.05%-1.12%). When each of the 15-μg doses were compared, there was no difference in GMTs for the H1N1 and H3N2 strains, but GMT was higher for the B strain (RR, 1.21; 95%CI, 1.11%-1.32%).

Rates of erythema and swelling were higher across the different intradermal vaccine doses. Compared with the intramuscular dose, only the 9-μg intradermal dose was associated with greater risk of fever and chills.

A subgroup analysis that included adults aged 60 years and older showed no difference in seroconversion, seroprotection, and GMT between the 9-μg intradermal dose and the intramuscular dose for each of the 3 strains. When comparing each of the 15-μg doses, seroprotection was similar for the 3 strains, however, seroconversion and GMT was higher with the intradermal dose for the B strain.

Key limitation of this meta-analysis was the high heterogeneity among the included studies, which persisted even after stratification by age group.

“The 15-μg intradermal vaccine showed significantly better immunogenicity for some of the outcomes and strains, suggesting that the immunological response may be dose-related,” noted the investigators. “It will be important to determine if this dose-sparing finding holds true across age groups and for newer vaccines, particularly when recent high-dose formulations have demonstrated improved immunogenicity in older adults in whom immune responses have historically struggled,” they concluded.


Egunsola O, Clement F, Taplin J, et al. Immunogenicity and safety of reduced-dose intradermal vs intramuscular influenza vaccines: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(2):e2035693. doi:10.1001/jamanetworkopen.2020.35693