Rabies is a viral zoonotic disease responsible for an estimated 59,000 human deaths and over 3.7 million disability-adjusted life years (DALYs) lost every year.
As a result of acute progressive encephalitis, rabies is almost invariably fatal once clinical signs appear..
Most cases occur in Africa and Asia, with approximately 40% of cases in children aged <15 years. All mammals are susceptible to infection by the rabies virus (RABV). Transmission of RABV by dogs is responsible for up to 99% of human rabies cases in rabies-endemic regions, with a small proportion due to transmission via wildlife (such as foxes, wolves, jackals, bats, racoons, skunks, and mongoose, among many others).
Prevention
Rabies is a vaccine-preventable disease in both humans and animals. Prevention relies heavily on the awareness of at-risk populations about the disease.
Human rabies vaccination is primarily used for postexposure prophylaxis (PEP), but also as preexposure prophylaxis (PrEP) in populations at high risk of infection.
Although there is no established correlate of protection for rabies, induction of a peak antibody response at or above the minimum acceptable antibody titer level (≥0.5 IU/mL) in response to the rabies vaccine serves as an indirect measure of protection (i.e. immunogenicity). Primary immunogenicity refers to immunogenicity that peaks 2–4 weeks after completing the recommended vaccination or vaccinations and elicits an anamnestic response to rabies virus exposures. Since publication of the 2008 ACIP recommendations, researchers have been evaluating data concerning the efficacy of shorter rabies PrEP dosing regimens.
Recent data indicate that PEP and PrEP regimens can be shortened in duration and number of doses required. Evidence of non-inferiority compared to current WHO recommended PEP regimens showed that intradermal (ID) PrEP regimens in adults can be shortened to 1 week with 2-visit (says 0 and 7).
Recent reviews show that more than 99% of the subjects tested within one week after having received a simulated PEP schedule had seroconverted (RVNA levels ≥0.5 IU/mL), regardless of the vaccination schedule used for the PEP, or the time delay between PrEP and PEP, which varied greatly between the different studies included (between 2 and 28 months). This suggests that single visit PrEP schedules would be sufficient to “prime” the immune system of most healthy, immunocompetent individuals. The fact that almost all patients which received a simulated PEP seroconverted within seven days regardless of the test used is very encouraging.
Single visit PrEP schedules seem promising in priming the immune system of most healthy, immunocompetent individuals to be able to elicit an adequate immune response against rabies after receiving booster PEP vaccination. Nonetheless, more studies are needed to confirm the efficacy of single visit PrEP schedules in real-life settings.
Rabies represents an unremitting and neglected global challenge. As such, new shortened ID schedules aim to be cost-dose and time-sparing, while maintaining safety and effectiveness. Safe and effective PrEP for travelers or people living in endemic rabies regions may be achieved with a double-dose 2-visit 0.1ID regimen, with 100% adequate antibody response following a booster injection of 0.1ID 1–3 years after primary vaccination.
Whether this schedule is safe and effective for children in low-income countries still needs urgent investigation.
The World Health Organization (WHO) 2018 guidelines revised and shortened PrEP, currently only recommending 2-visit schedules (double-dose ID or single-dose intramuscular vaccines administered on days 0 and 7) instead of the previous 3-visit schedules (adults only).
For a disease with virtually 100% case-fatality rate, PEP schedules with failure rate of 1% or higher are extremely concerning. The conclusions should be interpreted with caution, given the limited evidence (i.e. 4 studies and < 500 participants).
Recent studies demonstrated that PrEP using one-site IM and small vaccine doses (such as one- and two-site 0.1 ml ID) may be sufficient to prime the immune system; but a two-visit (on days 0 and 3) PEP is needed to rapidly boost antibodies to adequate levels in the event of potential rabies exposure. Studies investigating one-visit PrEP must include two-visit PEP to get an accurate assessment of the PrEP priming capacity.
Future studies should further investigate one-visit (one- and two-site) ID/IM PrEP which may be a cost-effective strategy, especially for people (children and adults) with risk of rabies exposure for short periods of time, such as travelers and others at high-risk.
References
- Hampson K et al. Estimating the Global Burden of Endemic Canine Rabies. Trop Dis. 2015; 9 (5):e0003786.
- Tarantola A. Four Thousand Years of Concepts Relating to Rabies in Animals and Humans, Its Prevention and Its Cure. Trop Med Infect Dis. 2017; 2, 5.
- Soentjens et al. CID 2019:68 (15 February)
- WHO Rabies Vaccines Position Paper. Weekly Epidemiological Record, No 16, 20 April 2018.
- B. Damanet et al. Travel Medicine and Infectious Disease 54 (2023) 102612
- MMWR (CDC) – May 6, 2022 / 71(18);619–627.
- Furuya-Kanamori L et.al. Journal of Travel Medicine, 2023, 1–3
