Fractional dose of intradermal compared to intramuscular and subcutaneous vaccination - A systematic review and meta-analysis

Abstract

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.

A guide to vaccinology: from basic principles to new developments

“…However, for some populations, such as older adults, a higher dose might be beneficial, as has been shown for the influenza vaccine 69 , 70 . Moreover, intradermal vaccination has been shown to be immunogenic at much lower (fractional) doses than intramuscular vaccination for influenza, rabies and HBV vaccines 71 .…”

Variants, vaccines and vaccination passports: Challenges and chances for travel medicine in 2021

“…A recent systematic review and meta-analysis demonstrated non-inferiority of ID administered vaccines at a statistically significant level for influenza, rabies and hepatitis B; with some other antigens administered via the ID route (e.g. Yellow Fever) yielding results trending towards non-inferiority but without reaching statistical significance due to a paucity of adequately powered clinical trials [ 10 ]. Another approach to antigen saving attracting research over the recent past years and ongoing are dose-sparing vaccination regimens, for example, against rabies (pre-exposure prophylaxis, PrEP [ 11 ] or post-exposure prophylaxis (PEP) [ 12 ] as well as the skipping of a booster immunisation dose (as with yellow fever [ 13 ]).…”

Intradermal Vaccination: A Potential Tool in the Battle Against the COVID-19 Pandemic?

“…The epidermis is the first and most formidable barrier against exposure to foreign substances and pathogens, and welcomes keratinocytes, fundamental cells of both structural and immune types, and cytokines. [2][3][4][5][6] The dermis comprises two layers: the more superficial papillary dermis and the deeper reticular dermis. The papillary dermis (100-300 μm) is the target layer for ID immunization and is rich in antigen presenting cells (APC), such as dermal dendritic cells (DDCs).…”