Immunogenicity of pre-exposure rabies vaccination comparing number of doses and routes of administration: A systematic review and meta-analyses

Introduction: Human rabies is rare, though almost universally fatal. Rabies pre-exposure prophylaxis (PrEP) simplifies the post-exposure prophylaxis regimen and may offer some protection from unrecognized rabies exposures. Several different PrEP schedules are recommended by different jurisdictions. The objective of this review was to systematically analyze the impact of schedule and route of administration on immune responses to rabies vaccine in the short-term, long-term, and post-booster, specifically comparing one-, two-, and three-dose schedules, and intramuscular (IM) and 2-site intradermal (ID) routes of administration. Methods: An existing systematic review was leveraged, and an updated search was conducted in three databases from inception to January 15, 2024. Meta-analyses of seroconversion (>= 0.5 IU/mL) and geometric mean titres (GMTs) from direct comparison studies, studies which allowed comparisons of schedules within the same participants/groups of participants, and pooled data across study arms were conducted. Results: Fifty-four studies met the eligibility criteria. Short-term, most participants who received two or three doses achieved titres >= 0.5 IU/mL regardless of route of administration; seroconversion and GMTs were significantly lower with one-dose schedules. Titres fell over time for all schedules with lower maintenance of seroconversion for two-dose IM schedules than three-dose IM schedules. Following the administration of booster doses, all schedules boosted to GMTs higher than after the primary series resulting in almost 100 % seroconversion, with the lowest seroconversion (98.7 %) for those who received a one 2-site ID dose for their primary vaccination. When comparing IM to 2-site ID administration of rabies vaccine, generally, no significant differences in seroconversion and limited differences in GMTs were observed. Conclusion: Two- and three-dose schedules had similar seroconversion regardless of route of administration in the short-term and after the booster, but two doses given IM resulted in lower maintenance of seroconversion in the long-term than three doses IM. Seroconversion was significantly reduced with a one-dose schedule in the shortand long-term. Immune responses to all schedules decreased over time, but almost all participants seroconverted following a booster dose. Responses between 2-site ID and IM administration were generally similar with only a few differences observed.