By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: After bites by animals potentially infected with rabies, three-visit (over one week) intradermal rabies vaccination was compared to standard four-visit (over two weeks) intramuscular rabies vaccination. Both vaccine regimens prompted similarly protective neutralizing antibody and T-cell responses. While still off-label, the shorter, simpler regimen could protect patients at lower cost than the current standard regimen.
SOURCE: Auerswald H, Maestri A, Touch S, et al. Side-by-side comparative study of the immunogenicity of the intramuscular and intradermal rabies post-exposure prophylaxis regimens in a cohort of suspected RABV exposed individuals. Clin Infect Dis 2023; Jun 20:ciad304. doi: 10.1093/cid/ciad304. [Online ahead of print].
Rabies is transmitted in the saliva of infected animals. Vaccination is protective as long as it is given before symptoms begin, yet rabies kills approximately 60,000 people each year. Half the victims of rabies are children in Africa and Asia, and current vaccine regimens can be prohibitively costly. Intradermal dosing regimens are widely used for pre-exposure and post-exposure prophylaxis, but they have not been studied in actual victims of animal bites, and they have been studied only with complicated administration protocols.
Thus, researchers evaluated intradermal and intramuscular post-exposure rabies vaccination in 215 bite victims in Cambodia from July 2020 to February 2021; the mean age of subjects was 21 years. Study subjects had not previously been immunized against rabies and then were either bitten or scratched (65% by dogs, 34% by cats, 1% by monkeys) and sought rabies vaccination. They were randomly assigned to either intradermal or intramuscular treatment. The intradermal regimen included two different-site 0.1 mL Vero cell-based vaccine injections on the day of presentation (day 0) and then again after three and seven days. The intramuscular regimen was the currently standard series of 0.5 mL Vero cell-based vaccine injections intramuscularly on days 0, 3, 7, and 14. Rabies immune globulin was used according to standard protocols separate from the study design. Blood was collected on days 0, 14, and 28 for testing of neutralizing antibody titers. A subset of 57 patients were evaluated by an activation-induced markers assay for antigen-specific CD4 and CD8 T-cells. Five subjects dropped out of the study (mostly due to COVID-related travel restrictions, not related to rabies or the vaccine), leaving 210 patients for analysis.
All subjects had seroconverted by day 28 with protective neutralizing antibody titers. Those vaccinated intradermally had seroconverted by day 14 and did not have further increases in median antibody titers; antibody titers in those vaccinated intramuscularly continued to rise between days 14 and 28. Neither age nor concomitant use of rabies immune globulin affected antibody responses.
Compared to day 0, percentages of rabies virus-specific CD4 and CD8 cells were increased at day 28 in those who received intramuscular vaccination but not in those who received intradermal vaccination. CD4- and CD8-specific cytokine production rose similarly between day 0 and day 28 in both intradermally and intramuscularly vaccinated individuals.
Of note but likely not of clinical significance affecting the findings of this research, the study was funded by the company that manufactures the vaccine used in this investigation, and three of the 13 co-authors of the paper reporting the results are employees of the company that produces the vaccine that was used.
COMMENTARY
In 2021, there were five cases of human rabies in the United States, four from domestic bat exposures and one in a returned traveler who had been bitten by a dog in the Philippines. The United States has had no reported cases of human rabies in the past year and a half.1 In some parts of Southeast Asia, however, the rabies incidence has been reported to be as high as 1 per 1,000 people.2
With post-pandemic travel restrictions lifted and with the summer tourism season upon us, many of our patients likely are visiting areas where animals are contagious with rabies. Prior to the pandemic, 3.6% of returned travelers visiting travel clinics in Europe required post-exposure rabies prophylaxis.3 Emergency departments, travel clinics, and infectious disease experts can expect to deal increasingly with patients exposed to animals possibly infected with rabies virus as travel again becomes common. A recent review provides practical advice for emergency physicians.4 World Rabies Day will again highlight the problem of and potential solutions for rabies on Sept. 28.5
Rabies vaccines development has advanced significantly during the 138 years since Louis Pasteur’s first human rabies vaccine saved the life of a 9-year-old boy.6 Nonetheless, effective vaccines still are used in multiple-dose regimens over many days. The use of lower-volume intradermal doses reduces overall cost and, thus, improves access to care. Pre-exposure preventive dosing with intradermal vaccine administration over just one week (instead of three weeks) induces good initial antibody responses as well as effectively primes the subjects for subsequent boosted responses to simulated post-exposure prophylactic dosing.7 Intradermal pre-exposure vaccination produces lasting results (at least seven to 10 years), and there is even evidence that, if needed urgently, a single intramuscular pre-exposure dose has some, albeit limited, effectiveness.8,9 The current recommendation is for two-dose pre-exposure prophylaxis.10 Now, these new data from Cambodia give good evidence in support of shorter, simpler, less costly post-exposure regimens.
Of course, post-exposure prophylaxis must be given prior to the onset of symptoms of rabies. However, there are very rare reports of survival from symptomatic rabies.11,12
REFERENCES
- Centers for Disease Control and Prevention. Nationally Notifiable Infectious Diseases and Conditions, United States: Weekly Tables. https://wonder.cdc.gov/nndss/static/2022/52/2022-52-table1cc.html
- Jane Ling MY, Halim AFNA, Ahmad D, et al. Rabies in Southeast Asia: A systematic review of its incidence, risk factors and mortality. BMJ Open 2023;13:e066587.
- Gautret P. Decline in rabies cases in international travelers during the COVID-19 pandemic. Travel Med Infect Dis 2023;54:102592.
- Gibbons K, Dvoracek K. Rabies postexposure prophylaxis: What the U.S. emergency medicine provider needs to know. Acad Emerg Med 2023;May 27. doi: 10.1111/acem.14755. [Online ahead of print].
- Centers for Disease Control and Prevention. World Rabies Day. www.cdc.gov/worldrabiesday/index.html
- Natesan K, Isloor S, Vinayagamurthy B, et al. Developments in rabies vaccines: The path traversed from Pasteur to the modern era of immunization. Vaccines (Basel) 2023;11:756.
- Quiambao BP, Lim JG, Bosch Castells V, et al. One-week intramuscular or intradermal pre-exposure prophylaxis with human diploid cell vaccine or Vero cell rabies vaccine, followed by simulated post-exposure prophylaxis at one year: A phase III, open-label, randomized, controlled trial to assess immunogenicity and safety. Vaccine 2022;40:5347-5355.
- Mills DJ, Lau CL, Mills C, Furuya-Kanamori L. Long-term persistence of antibodies and boostability after rabies intradermal pre-exposure prophylaxis. J Travel Med 2022;29:taab188.
- Mills DJ, Lau CL, Mills C, Furuya-Kanamori L. Efficacy of one-dose intramuscular rabies vaccine as pre-exposure prophylaxis in travellers.J Travel Med 2021;28:taab059.
- Centers for Disease Control and Prevention. Rabies. Pre-Exposure Prophylaxis (PrEP). Page last reviewed May 4, 2022. https://www.cdc.gov/rabies/prevention/pre-exposure_vaccinations.html
- Hu WT, Willoughby RE Jr, Dhonau H, Mack KJ. Long-term follow-up after treatment of rabies by induction of coma. N Engl J Med 2007;357:945-946.
- de Souza A, Madhusudana SN. Survival from rabies encephalitis. J Neurol Sci 2014;339:8-14.
