A randomized clinical trial to assess the immunogenicity of a single-visit four-dose intradermal booster rabies regimen with topical imiquimod

Abstract

Background: Two-visit intradermal pre-exposure rabies vaccination schedules (PrEP) are now advised by the WHO. Moreover, a double-dose single-visit intradermal 12ID PrEP schedule showed robust immune responses following four-dose or double-dose single-visit intradermal post-exposure prophylaxis (14ID or 12ID PEP) (Soentjens P et al. Clin Infect Dis Aug 2019). Such accelerated 1-visit schedules for PrEP and PEP at very low cost are very practical. Methods and materials: Aim. To investigate the additional effect of the topical pre-administration of imiquimod (IMIQ) (during 1-visit intradermal PrEP) on the neutralizing antibody responses after a four-dose 1-visit intradermal booster schedule. Methods. Belgian soldiers (N = 268) were vaccinated with a 12ID PrEP schedule and boosted with a 14ID PEP schedule, using the Purified Chicken Embryo Cell Vaccine (PCECV). In this study (EudraCT 2017-002953-12), subjects were randomized (during PrEP) for the topical treatment with IMIQ versus placebo cream, as well as for the use of an intradermal device (VAX-ID™) versus routine intradermal syringe. We investigated the serological responses, by rabies fluorescent focus inhibition test (RFFIT) on day 7, after 14ID PrEP in the four treatment groups for 162 of the 268 subjects. A titer ≥3.0 IU/ml is considered to be a strong and adequate antibody response. Results: Median age was 23.5 (IQR 22.7–24.7). 83% were male. Timing between PrEP and PEP was 1.13 years (IQR 1.13–1.13). The GMT of RFFIT on day 7 after 14ID PEP was 19.42 IU/mL (CI 12.43–30.35). 92.3% of the 52 subjects had a RFFIT ≥0.5 IU/mL at day 7 of which 88,5% a level >3.0 IU/mL and 83% >10.0 IU/mL, following 12ID PrEP. The GMT (2 groups comparison) of RFFIT on day 7 after 14ID by intervention groups was 20.20 (10.58–38.57) and 18.66 (9.63–36.15) for the IMIQ versus placebo group respectively, and 18.09 (8.39–39.00) and 20.84 (12.47–34.85) for the VAX-ID versus needle group respectively. Conclusion: Good anamnestic booster responses following 14ID PEP, one year after 12ID PrEP, were recorded. This powered clinical data, in addition with the data of 12ID PrEP by Soentjens et al., proofs that the concept of single-visit priming and single-visit boosting (PrEP and PEP) is very promising and deserves more promotion.