Shortening intradermal rabies post-exposure prophylaxis regimens to 1 week: Results from a phase III clinical trial in children, adolescents and adults

Background: This phase III clinical trial compared the immunogenicity and safety of a purified chick-embryo cell rabies vaccine (PCECV) administered according to a shortened post-exposure prophylaxis (PEP) 4-site/1-week intradermal regimen, compared with the currently recommended 2-site/Thai Red Cross (TRC) regimen. Methodology/Principal findings: This controlled, open-label, multi-center study (NCT02177032) enrolled healthy individuals ≥1 year of age, randomized into 4 groups to receive intradermal PCECV according to one of the 2 regimens, with or without human rabies immunoglobulin (HRIG) administration at first visit (in adults only). Rabies virus neutralizing antibody (RVNA) concentrations and percentages of participants with RVNA concentrations ≥0.5 IU/mL (considered as adequate concentrations following PEP) were assessed up to day (D) 365 post-first vaccination. Non-inferiority of the 4-site/1-week regimen to the 2-site/TRC regimen was demonstrated if at D49, the lower limit of the 95% confidence interval (CI) for the difference between groups in the percentage of participants with adequate RVNA concentrations was >-5%. Of the 443 participants receiving the 4-site/1-week regimen, 88 adults received HRIG; 442 participants received the 2-site/TRC regimen (88 with HRIG). All participants achieved adequate RVNA concentrations by D14. At D49, the difference in percentage of participants with adequate RVNA concentrations between the 4-site/1-week and the 2-site/TRC groups was -1 (95%CI: -2.4–0.0); thus, non-inferiority was concluded. RVNA geometric mean concentrations were 18 IU/mL in 4-site/1-week groups and 12 IU/mL in 2-site/TRC groups at D14, and subsequently declined in all groups. RVNA concentrations were consistently lower in adults with HRIG administration than in those without. The 2 regimens had similar safety profiles. Of the 15 serious adverse events reported in 4-site/1-week groups and 19 in 2-site/TRC groups, none were vaccination-related. Significance: The data suggest that the 4-site/1-week regimen might be an alternative to current recommendations, with potential benefits in terms of improved cost-efficiency and compliance to vaccination. Author summary: Rabies is a deadly, but vaccine-preventable disease which still causes tens of thousands of deaths yearly, mostly in Asia and Africa. Rabies virus is spread via the saliva of infected mammals to humans, usually through bites or contamination of open wounds. Access to measures like wound cleansing with soap and rabies vaccination immediately after contact with a suspected rabid animal (exposure) can be life-saving. The post-exposure vaccination schedule currently recommended by the World Health Organization for intradermal injection is the Thai Red Cross regimen, requiring 4 clinic visits in one month, with 2 injections given at each visit on days (D) 0 (day of the contact), 3, 7, and 28. In this study, we evaluated the antibody responses and the safety profile of a new shortened schedule, requiring 3 clinic visits and only 1 week to complete, consisting of 4 intradermal injections given at each visit on D0, 3, and 7 (the 4-site/1-week regimen). The study was conducted in the Philippines and Thailand which enrolled 885 healthy volunteers, at least 1 year of age, with no real exposure to rabies. The two schedules induced adequate antibody responses in similar proportion of volunteers at day 49. The vaccine administration according to both schedules was well tolerated.