Why the Rabies Vaccine Schedule Was Reduced from 5 to 4 Doses
The Advisory Committee on Immunization Practices (ACIP) reduced the rabies post-exposure prophylaxis schedule from 5 doses to 4 doses in 2010 because extensive evidence demonstrated that 4 doses combined with rabies immune globulin (RIG) elicit adequate protective antibody responses, and the fifth dose on day 28 does not contribute to more favorable clinical outcomes. 1
Evidence Supporting the 4-Dose Schedule
Real-World Safety Data
- Over 1,000 persons annually in the United States received only 3 or 4 doses of rabies vaccine (instead of the complete 5-dose regimen), with no resulting documented cases of human rabies, even though more than 30% of these individuals had confirmed exposure to rabid animals. 1
- No case of human rabies in the United States has ever been attributed to receiving fewer than the 5-dose vaccine course when modern cell-culture vaccines are used. 1
Immunologic Rationale
- Virus-neutralizing antibodies peak by approximately day 14-28 after starting vaccination, meaning the critical protective window occurs well before the fifth dose on day 28. 2
- All immunocompetent individuals completing the 4-dose schedule achieve neutralizing antibody titers ≥0.5 IU/mL by day 14, with seroprotection maintained through at least day 180. 2
- Human rabies immune globulin (HRIG) provides immediate passive immunity at the wound site during the first 7-10 days before vaccine-induced antibodies develop, making the early doses (days 0,3,7,14) most crucial. 2
Global PEP Failure Analysis
- A review of 21 documented rabies post-exposure prophylaxis failures in Burma, India, the Philippines, South Africa, Sri Lanka, and Thailand between 1984-2007 found that 20 patients developed symptoms and 15 died before day 28—none of these failures were attributed to missing the fifth dose. 1
- In 192 human rabies deaths analyzed in India, all were attributable to failure to seek any PEP, and none were attributed to missing the fifth dose. 2
The Current 4-Dose Regimen
Standard Schedule for Previously Unvaccinated Persons
- Administer 1.0 mL of human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) intramuscularly on days 0,3,7, and 14. 1, 3
- Combine with HRIG at 20 IU/kg body weight on day 0, infiltrated around and into the wound(s) when anatomically feasible. 1, 3
- Inject vaccine in the deltoid muscle for adults and older children, or the anterolateral thigh for young children—never use the gluteal area. 1, 2
Safety Profile
- Modern cell-culture rabies vaccines have uncommon adverse reactions compared to older nerve-tissue-based products. 1
- The ACIP Rabies Working Group identified no adverse events correlated to failure to receive the fifth vaccine dose. 1
- Omission of the day 28 dose may actually have some positive health benefits, as some adverse reactions are independent clinical events with each vaccine administration. 1
Economic Impact
- The reduction from 5 to 4 doses was estimated to save approximately $16.6 million annually in the U.S. healthcare system, assuming 100% compliance with the recommended regimen. 1, 3
- Patients benefit from both reduced vaccine costs and elimination of the additional medical visit required for the fifth dose. 1
Important Exception: Immunocompromised Patients
- Immunocompromised individuals (including those on corticosteroids, other immunosuppressive agents, or with HIV infection) still require the full 5-dose regimen on days 0,3,7,14, and 28, plus HRIG at 20 IU/kg on day 0. 2, 3, 4
- These patients require mandatory serologic testing 1-2 weeks after the final vaccine dose to confirm adequate antibody response (≥1:5 titer by RFFIT). 2, 4
Clinical Efficacy
- When the 4-dose regimen is administered promptly and appropriately with HRIG, it is nearly 100% effective in preventing human rabies. 2, 3, 4
- No failures of post-exposure prophylaxis have been documented in the United States since modern cell-culture vaccines and HRIG were licensed when the complete protocol is followed. 2