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Current Trends Field Evaluations of Pre-Exposure Use of Human Diploid Cell Rabies Vaccine

Following a case of human rabies in a Peace Corps volunteer (PCV) in Kenya in August 1983, (1) CDC, in cooperation with the Office of Medical Services, U.S. Peace Corps, conducted serosurveys of 333 PCVs in eight countries to assess the adequacy of rabies pre-exposure prophylaxis. Initial results indicate a lower-than-expected antibody response at several time periods following primary immunization.

All PCVs had been immunized outside the United States between 1979 and 1983 using a three-dose regimen (days 0, 7, and 28) of 0.1 ml intradermal (ID) doses of human diploid cell rabies vaccine (HDCV) produced by the Merieux Institute (2). Serum specimens were collected by either CDC or the Peace Corps medical staff, and the rapid fluorescent focus inhibition test (RFFIT) for rabies-neutralizing antibody was performed at CDC on all specimens. Time from the initial immunization to sera collection ranged from 42 days to 2 years.

PCVs serving in Kenya were most extensively studied. From September 1983 to October 1983, complete immunization histories and serum samples for rabies antibody determination were obtained from 90 of the approximately 250 PCVs in Kenya. Three cohorts were identified based on the time between primary immunization and collection of sera: (1) those immunized 45 days before phlebotomy; (2) those immunized 10-16 months before phlebotomy; (3) those immunized 2 years before phlebotomy. Serologic results for these groups were compared with results from previously published data at similar time periods after primary immunization (Table 1). Of the 25 specimens obtained 45 days after the beginning of primary immunization, only 17 (68%) were 0.50 or more international units (IU)/ml, and five (20%) were lower than 1:16.* One of this group of 25 had no detectable antibody ( 1:5 or 0.05 IU/ml serum). An investigation in Kenya found no breaks in the vaccine cold chain; observations of vaccine administration revealed satisfactory ID technique.

In addition to the PCVs serving in Kenya, 83 PCVs from Malawi, Morocco, Nepal, Central African Republic, Senegal, and Sierra Leone were studied within 4 months of primary immunization; 36 (43%) had titers less than 0.5 IU/ml or lower than 1:50; one (1%) of these had no detectable antibody.

Initial surveys of groups immunized within the last 16 months with ID pre-exposure HDCV in the United States revealed different results. All 57 persons in a cohort from North Carolina had titers 1:50 or higher at 38 days after primary immunization. Forty-two days after primary immunization, all of 61 persons immunized ID and studied by the RFFIT in Wisconsin had antibody levels of 1:50 or higher. However, analysis of an adult cohort of 193 persons immunized in Maryland revealed 188 (97%) with titers of 1:50 or higher, four (2%) with titers 1:16-1:50, and one (1%) with no detectable antibody at 41-97 days after primary ID immunizations. Reported by K Pulley, PhD, R Gibbs, MD, K Miller, MD, Peace Corps, Washington, DC; S Waterman, M Mandara, Peace Corps, Nairobi, Kenya; B Ainsworth, Peace Corps, Lilongwe, Malawi; J Bond, MD, Washington County Health Dept, Hagerstown, Maryland; D Howard, DVM, North Carolina State University School of Veterinary Medicine, Raleigh; J Calkins, University Health Svc, University of Wisconsin--Madison, D Nelson, Wisconsin State Laboratory of Hygiene, Madison; Div of Viral Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The use of HDCV administered ID has become widespread throughout the world because of the cost savings when using small doses for rabies pre-exposure prophylaxis. However, the U.S. Food and Drug Administration's (FDA) National Center for Drugs and Biologics has not approved the ID use of rabies vaccine; and an application for licensure of ID rabies vaccine is presently being considered. In May 1982, the Immunization Practices Advisory Commitee (ACIP) reviewed the data from 11 carefully conducted clinical studies in the United States and Europe, and at that time, found the ID route an acceptable alternative to the intramuscular (IM) route (2). The rabies antibody titers following ID immunization were lower than those after IM immunization and persisted for a shorter period of time. The data presented here indicate that HDCV administered ID to PCVs in multiple countries has not resulted in antibody titers as high as those demonstrated in vaccine trials conducted in the United States and Europe between 1978 and 1982 (5,6). All the above studies are based on the use of Merieux Institute's HDCV; there are no available data on response to ID vaccination with Wyeth Laboratories' HDCV.

Several factors might hypothetically contribute to the less satisfactory antibody responses seen in PCVs, including immunosuppressive effects of multiple vaccinations, immune serum globulin, or malaria chemoprophylaxis administered concurrently with the vaccine; a greater likelihood of cold-chain infractions; and perhaps a greater likelihood of receiving vaccine subcutaneously rather than ID. However, none of these factors appears at this time sufficient to explain the magnitude of the discrepancies in antibody responses described in the published trials and those observed in these recent field experiences. CDC and FDA are investigating other factors, including variations in vaccine potency.

Because the nature and extent of the problem are not completely delineated, certain precautions appear to be indicated. If ID pre-exposure rabies prophylaxis is given, routine serologic testing should be done 2-3 weeks after immunization. Any individual with a postimmunization titer of lower than 1:16 (approximately 0.16 IU/ml) should receive an additional dose of vaccine and have serum retested 2-3 weeks later. Persons whose only experience with rabies vaccine has been ID pre-exposure prophylaxis and whose antibody response is unknown should, if immunized within the past 12 months, have serum tested for rabies antibody; if immunized more than 12 months previously, such persons should receive a single booster dose of vaccine and have serum retested 2-3 weeks later. Serologic testing does not appear to be necessary for persons receiving IM rabies pre-exposure prophylaxis.

For postexposure prophylaxis, persons (1) who have had three 1.0 ml IM doses of HDCV or (2) who have received ID vaccine and who have a documented rabies titer of 1:16 or higher should continue to receive two 1.0 ml IM doses of HDCV--one dose each on days 0 and 3, as currently recommended. Any person who has received ID vaccine and who has not had a documented rabies antibody titer of 1:16 or higher should be treated with a single, 20 IU/kg dose of human rabies immune globulin (HRIG) and five 1 ml IM doses of HDCV--one each on days 0, 3, 7, 14, and 28.

It should be reemphasized that all persons who have received adequate pre-exposure prophylaxis with HDCV should, following a rabies exposure, receive two 1.0 ml IM postexposure booster doses of vaccine to ensure protection.


  1. CDC. Human rabies--Kenya. MMWR 1983;32:494-5.

  2. ACIP. Supplementary statement on pre-exposure rabies prophylaxis by the intradermal route. MMWR 1982;31:279-80, 285.

  3. ACIP. Rabies prevention. MMWR 1980;29:265-80.

  4. Sinnecker H, Atanasiu P, Bahmanyar M, et al. Vaccine potency requirements for reduced immunization schedules and pre-exposure treatment. Joint WHO/IABS Symposium Standardization of Rabies Vaccines for Human Use Produced in Tissue Cultures (Rabies III), Marburg/Lahn. Develop Biol Standard 1977;40:267-71.

  5. Bernard KW, Roberts MA, Sumner J, et al. Human diploid cell rabies vaccine: effectiveness of immunization with small intradermal or subcutaneous doses. JAMA 1982;247:1138-42.

  6. Nicholson KG, Turner GS, Aoki FY. Immunization with a human diploid cell strain of rabies virus vaccine: two-year results. J Infect Dis 1978;137:783-8.

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