International Notes Rabies Postexposure Immunization Regimens -- Thailand

In Thailand, greater than 100,000 persons receive rabies postexposure prophylaxis and greater than 200 persons die from rabies annually. For persons who have been bitten by rabid animals, immune globulin (IG) (passive immunization) and rabies vaccination (active immunization) are essential components of postexposure immunization. Although tissue culture (TC) rabies vaccines (e.g., human diploid cell rabies vaccine (HDCV)) are more immunogenic and less likely to cause adverse effects than neural tissue rabies vaccine (NTV), the routine use of TC vaccine is cost-prohibitive in many developing countries. To assess the efficacy of abbreviated, cost-reducing regimens of TC vaccines, in 1987-1989, investigators at the Queen Saovabha Memorial Institute, Bangkok, Thailand, conducted separate concurrent studies of modified postexposure TC vaccine regimens: one study used an abbreviated intramuscular (IM) schedule and the other substituted multisite intradermal (ID) injections for IM injections. This report summarizes results of the two studies.

In each study, 100 Thai patients severely exposed (1) to rabies were treated and followed for 1 year. Patients were selected based on seven criteria: 1) the patient had been bitten by an animal that had been proven rabid by fluorescent antibody testing; 2) the injury was transdermal and resulted in active bleeding; 3) postexposure treatment could be initiated within 5 days of the exposure; 4) the patient or a close family member lived and worked in metropolitan Bangkok; 5) the patient was not receiving corticosteroids or immunosuppressive drugs, using alcohol or drugs, or known to have chronic liver disease; 6) the patient had no prior history of rabies vaccination; and 7) the patient (or parent) agreed to participate.

For each study, patients received both IG and vaccine (purified Vero cell rabies vaccine* (PVRV; Pasteur-Merieux Serum and Vaccine, Lyon, France) (lot number AO254) with an antigen content of 3.17 IU per 0.5 mL ampule). In the first study, the 100 patients who were treated with the abbreviated IM regimen (2-1-1 IM) received 0.5 mL (a full dose of this vaccine) IM in the deltoid region of each arm on day 0, one dose on day 7, and one dose on day 21 (2). In the second study, the 100 patients treated with the Thai Red Cross ID (TRC-ID) regimen received two ID injections of 0.1 mL each at different deltoid area sites on days 0, 3, and 7 and one 0.1 mL ID injection on days 30 and 90 (3).

In each group, 96 patients received Equine Rabies Immune Globulin (ERIG) (Pasteur-Merieux, France). ERIG was given at 40 IU/kg of body weight as recommended by the World Health Organization (WHO) (1). The maximum volume possible of ERIG was injected around bite wounds; the remainder was administered IM into the gluteal region. Because four patients in each group had a positive skin test to ERIG, they each received human rabies immune globulin (20 IU/kg) by infiltration around the bite site. In each study group, blood samples were obtained from 10 randomly selected patients on days 14, 90, and 360; all serum was frozen and analyzed concurrently in 1989 for rabies neutralizing antibody by the rapid fluorescent focus inhibition test (4).

At the end of the study period, all members of each cohort were alive. On the basis of exposure severity and control data from published reports, 12% and 14% of the recipients of the 2-1-1 IM regimen and the TRC-ID regimen, respectively, would have been expected to die from rabies. The efficacy of each regimen was 100% (for the 2-1-1 IM regimen, 95% confidence interval (CI)=77%-100%, p less than 0.0001, exact binomial distribution, and for the TRC-ID regimen, 95% CI=81%-100%). Both of these regimens were well tolerated: in each group, 4% of patients experienced mild side effects (e.g., malaise, pain at injection sites, low-grade fever, or headache).

Of the 20 patients from whom serum samples were collected on day 14, neutralizing antibody titers were higher in patients who received the TRC-ID regimen than those who received the 2-1-1 IM regimen; however, in all patients in both groups, titers were greater than 0.5 IU/mL** (Table 1). On day 90, all patients in the TRC-ID group had titers greater than 0.5 IU/mL, compared with 80% of those who received the 2-1-1 IM regimen. On day 360, all patients who received the TRC-ID regimen had titers greater than 0.5 IU/mL; 50% of persons in the 2-1-1 IM group had titers less than 0.5 IU/mL. Reported by: S Chutivongse, H Wilde, C Supich, Queen Saovabha Memorial Institute, Thai Red Cross Society and Faculty of Medicine, Chulalongkorn Univ, Bangkok, Thailand. Program for Appropriate Technology in Health, Seattle, Washington. Div of Viral and Rickettsial Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Each year, an estimated 25,000 persons die from rabies and approximately 4 million persons worldwide receive rabies postexposure prophylaxis; greater than 90% of these persons live in developing countries in Asia, Africa, and South America. The least expensive TC vaccine generally is more than 10-fold the cost of locally produced NTV. Because NTVs are often provided free and a course of TC vaccine can cost several months' income, most patients receive NTVs, although NTVs are associated with a higher rate of serious adverse reactions and lower immunogenicity than TC vaccines. By using ID injections of either HDCV (5) or newer TC-derived rabies vaccines (3), investigators have attempted to lower the cost of rabies postexposure prophylaxis by reducing 1) the amount of TC vaccine used and 2) the number of clinic visits required. Although the 2-1-1 IM regimen can be accomplished in fewer visits, this regimen requires 4 ampules (2.0 mL) of vaccine: the TRC-ID schedule requires only 1.6 ampules (0.8 mL).

None of the persons vaccinated with either of the schedules in this study developed rabies, suggesting that the regimens are efficacious. Postexposure vaccine failures have been reported in 18 patients who received other postexposure regimens with TC vaccines in developing countries (6,7). However, in these cases, substantial departures occurred from standard postexposure practices, including failure to wash the bite wound, failure to administer passive immunization (i.e., to inject the wounds with IG), or administration of the rabies vaccine in the gluteal area rather than deltoid area.

In the United States, the only rabies postexposure prophylaxis regimen recommended by the Immunization Practices Advisory Committee (ACIP) is the combination of human rabies immune globulin (20 IU/kg, with up to one half infiltrated around the bite site and the rest administered IM in the gluteal area) and five 1-mL doses IM of HDCV or Rabies Vaccine Adsorbed (one dose each on days 0, 3, 7, 14, and 28 administered IM in the deltoid area). PVRV (the vaccine used in the studies) has not yet been licensed for use in the United States but is licensed and widely used in many European and Asian countries.

In Thailand, geometric mean titers (GMTs) for the study patients who received the 2-1-1 IM regimen appeared to be lower than those achieved by the ACIP-recommended regimen on days 14, 90, and 360. On day 90, GMTs were also low in patients receiving the TRC-ID regimen. Several factors could account for these lower neutralizing antibody titers. Unrecognized differences in the two study groups may have influenced their antibody responses. Only 10 patients in each group were followed serologically. On day 14, titers in the 2-1-1 IM group were lower even though this group received more than twice as much vaccine as the TRC-ID group during the first 7 days of treatment. Forty IU/kg of Human Rabies Immune Globulin (HRIG) (twice the recommended dose) can suppress the antibody response to a standard five-dose IM postexposure schedule of HDCV; the administration of 40 IU/kg of ERIG may suppress the early antibody response to vaccine administered IM more than vaccine administered ID. Suppression has been observed with the 2-1-1 IM schedule when PVRV or other TC-derived vaccines, including Purified Chick Embryo Cell and Purified Duck Embryo Cell, were administered with 20 IU/kg of HRIG (8).

Ideally, ID regimens should be administered by staff skilled in this technique; therefore, these regimens are probably most appropriate for clinics that treat many exposed patients. However, an acceptable titer of neutralizing antibody can be achieved following subcutaneous injection or inadvertent administration of less than a full ID dose (9,10). The serologic response of the 2-1-1 IM regimen in patients who are also treated with ERIG requires further evaluation. In 1991, the WHO Expert Committee on Rabies is expected to make official recommendations about these alternative regimens.

References

1. Anonymous. WHO expert committee on rabies. WHO Tech Rep Ser

1984;709:1-104.

2. Vodopija I, Sureau P, Lafon M, et al. An evaluation of second generation tissue culture rabies vaccines for use in man: a four-vaccine comparative immunogenicity study using a pre-exposure vaccination schedule and an abbreviated 2-1-1 postexposure schedule. Vaccine 1986;4:245-8.

3. Chutivongse S, Wilde H, Supich C, Baer GM, Fishbein DB. Postexposure prophylaxis for rabies with antiserum and intradermal vaccination. Lancet 1990;335:896-8.

4. Smith JS, Yager PA, Baer GM. A rapid reproducible test for determining rabies neutralizing antibody. Bull WHO 1973;48:535-41.

5. Warrell MJ, Nicholson KG, Warrell DA, et al. Economical multiple-site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet 1985;1:1059-62.

6. Bernard KW, Fishbein DB, Miller KD, et al. Pre-exposure rabies immunization with human diploid cell vaccine: decreased antibody responses in persons immunized in developing countries. Am J Trop Med Hyg 1985;34:633-47.

7. Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies postexposure treatment in Thailand. Vaccine 1989;7:49-52.

8. Vodopija I, Sureau P, Smerdel S, et al. Interaction of rabies vaccine with human rabies immunoglobulin and reliability of a 2-1-1 schedule application for postexposure treatment. Vaccine 1988;6:283-6.

9. Fishbein DB, Pacer RE, Holmes DF, Ley AB, Yager P, Tong TC. Rabies pre-exposure prophylaxis with human diploid cell rabies vaccine: a dose-response study. J Infect Dis 1987;156:50-5. 10. Phanuphak P, Khaoplod P, Benjavongkulchai M, Chutivongse S, Wilde H. What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously? Bull WHO 1990;68:83-5.

• Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

** This is the minimum titer recommended by the WHO Expert Committee on Rabies.

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