Background Vaccine supply shortages are of global concern. We hypothesise that intradermal (ID) immunisation as an alternative to standard routes might augment vaccine supply utilisation without loss of vaccine immunogenicity and efficacy. Methods We conducted a systematic review and meta-analysis searching Medline, Embase and Web of Science databases. Studies were included if: licensed, currently available vaccines were used; fractional dose of ID was compared to IM or SC immunisation; primary immunisation schedules were evaluated; immunogenicity, safety data and/or cost were reported. We calculated risk differences (RD). Studies were included in meta-analysis if: a pre-defined immune correlate of protection was assessed; WHO-recommend schedules and antigen doses were used in the control group; the same schedule was applied to both ID and control groups (PROSPERO registration no. CRD42020151725). Results The primary search yielded 5,873 articles, of which 156 articles were included; covering 12 vaccines. Non-inferiority of immunogenicity with 20–60% of antigen used with ID vaccines was demonstrated for influenza (H1N1: RD -0·01; 95% CI -0·02, 0·01; I 2 = 55%, H2N3: RD 0·00; 95% CI -0·01, 0·01; I 2 = 0%, B: RD -0·00; 95% CI -0·02, 0·01; I 2 = 72%), rabies (RD 0·00; 95% CI -0·02, 0·02; I 2 = 0%), and hepatitis B vaccines (RD -0·01; 95% CI -0·04, 0·02; I 2 = 20%). Clinical trials on the remaining vaccines yielded promising results, but are scarce. Conclusions There is potential for inoculum/antigen dose-reduction by using ID immunisation as compared to standard routes of administration for some vaccines (e.g. influenza, rabies). When suitable, vaccine trials should include an ID arm.

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Although fatal once symptomatic, rabies is preventable by administration of pre- and post-exposure vaccines. International guidelines suggest lifelong protection by a pre-exposure vaccination scheme followed by timely post-exposure vaccines. Rapidity and magnitude of the antibody recall response after booster inoculation are essential, as many people have been previously immunized a long time ago. The objective of this study was therefore to systematically review the evidence on the boostability of rabies immunization to date. We included 36 studies, of which 19 studies were suitable for meta-analysis. Reduced antibody levels were found after intradermal primary schedules as compared to intramuscular schedules. However, responses after booster immunization were adequate for both routes. Although studies showed that antibody levels decline over time, adequate booster responses were still retained over long time intervals indicating that post-exposure treatment is effective without extra measures after long periods of time.