Immunogenicity and Safety of Reduced-Dose Intradermal vs Intramuscular Influenza Vaccines: A Systematic Review and Meta-analysis

IMPORTANCE: Low-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages. OBJECTIVE: To compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020. STUDY SELECTION: All comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted. MAIN OUTCOMES AND MEASURES: Primary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events. RESULTS: A total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13 759 total participants, and 1 study was a cohort study of 164 021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses. CONCLUSIONS AND RELEVANCE: These findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.