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Rabies in the United States
Over the last 100 years, the epidemiology of rabies in animals in the United States has changed dramatically. More than 90% of all animal rabies cases reported annually to the Centers for Disease Control and Prevention (CDC) now occur in wildlife, whereas before 1960 the majority were in domestic animals. The principal rabies hosts today are wild carnivores and bats. Annual human deaths have fallen from more than a hundred at the turn of the century to one to two per year despite major outbreaks of animal rabies in several geographic areas. Within the United States, only Hawaii has remained rabies free. Although rabies among humans is rare in the United States, every year tens of thousands of people receive rabies vaccine for post-exposure prophylaxis.
Rabies is almost invariably fatal due to encephalomyelitis. Modern day prophylaxis has proven nearly 100% successful; most human fatalities now occur in people who fail to seek medical treatment, usually because they do not recognize a risk in the animal contact leading to the infection. Inappropriate post-exposure prophylaxis may also result in clinical rabies. Survival after clinical rabies is extremely rare, and is associated with severe brain damage and permanent disability.
RabAvert (rabies vaccine) (in combination with passive immunization with Human Rabies Immune Globulin (HRIG) and local wound treatment) in post-exposure immunization against rabies has been shown to protect, patients of all age groups from rabies, when the vaccine was administered according to the World Health Organization (WHO) guidelines and as soon as possible after rabid animal contact. Anti-rabies antibody titers after immunization have been shown to reach levels well above the minimal protective level of 0.5 IU/mL within 14 days after initiating the immunization series. The minimal antibody titer accepted as seroconversion is 0.5 IU, measured by the rapid fluorescent inhibition test (RFFIT) as specified by the WHO (1, 2) or a 1:5 titer (complete inhibition in RFFIT at 1:5 dilution) as specified by the CDC. Vaccine failure has only been reported when key elements of rabies post-exposure regimens were omitted or when the vaccine has been incorrectly administered.
The immunogenicity of RabAvert (rabies vaccine) has been demonstrated in clinical trials conducted in different countries such as the USA (3, 4), UK (5), Croatia (6), and Thailand (7, 8, 9). When administered according to the recommended immunization schedule (days 0, 7, 21), 100% of subjects attained a protective titer. Two studies carried out in the USA in 101 subjects antibody titers > 0.5 IU/mL were obtained by day 28 in all subjects. In studies carried out in Thailand in 22 subjects, and in Croatia in 25 subjects, antibody titers of > 0.5 IU/mL were obtained by day 14 (injections on days 0, 7, 21) in all subjects.
The ability of RabAvert (rabies vaccine) to boost previously immunized subjects was evaluated in three clinical trials. In the Thailand study, pre-exposure booster doses were administered to 10 individuals. Antibody titers of > 0.5 IU/mL were present at baseline on day 0 in all subjects (8). Titers after a booster dose were enhanced from geometric mean titers (GMT) of 1.91 IU/mL to 23.66 IU/mL on day 30. In an additional booster study, individuals known to have been immunized with Human Diploid Cell Vaccine (HDCV) were boosted with RabAvert (rabies vaccine) . In this study, a booster response was observed on day 14 for all (22/22) individuals (10). In a trial carried out in the USA (3), a RabAvert (rabies vaccine) IM booster dose resulted in a significant increase in titers in all (35/35) subjects, regardless of whether they had received RabAvert (rabies vaccine) or HDCV as the primary vaccine.
Persistence of antibody after immunization with RabAvert (rabies vaccine) has been evaluated. In a trial performed in the UK, neutralizing antibody titers > 0.5 IU/mL were present 2 years after immunization in all sera (6/6) tested.
RabAvert (rabies vaccine) , when used in the recommended post-exposure WHO program of 5 to 6 IM injections of 1 mL (days 0, 3, 7, 14, 30, and one optionally on day 90) provided protective titers of neutralizing antibody ( > 0.5 IU/mL) in 158/160 patients (7, 8, 11-14) within 14 days and in 215/216 patients by day 28 - 38. Of these, 203 were followed for at least 10 months. No case of rabies was observed (7, 8, 11-18). Some patients received HRIG, 20 - 30 IU per kg body weight, or Equine Rabies Immune Globulin (ERIG), 40 IU per kg body weight, at the time of the first dose. In most studies (7, 8, 11, 15), the addition of either HRIG or ERIG caused a slight decrease in GMTs which was neither clinically relevant nor statistically significant. In one study (14), patients receiving HRIG had significantly lower (p < 0.05) GMTs on day 14; however, again this was not clinically relevant. After day 14 there was no statistical significance.
The results of several studies of normal volunteers who have been given the WHO regimen of vaccine for post-exposure use (10, 19-22), i.e., “simulated” post-exposure use, show that with sampling by day 28 - 30, 205/208 vaccinees had protective titers > 0.5 IU/mL.
Over a 10 year (7/85 - 6/95) period, 46 reports of suspected post-exposure vaccine failure have been evaluated (11.8 million doses distributed). In each case, post-exposure treatment had not been in compliance with WHO recommendations.
1. Smith JS, Yager, PA & Baer, GM. A rapid reproducible test for determining rabies neutralisation antibody. Bull WHO. 1973; 48: 535-541.
2. Eighth Report of the WHO Expert Committee on Rabies. WHO Technical Report Series, no. 824; 1992.
3. Dreesen DW, et al. Two-year comparative trial on the immunogenicity and adverse effects of purified chick embryo cell rabies vaccine for pre-exposure immunization. Vaccine. 1989; 7: 397-400.
4. Dreesen DW. Investigation of antibody response to purified chick embryo cell tissue culture vaccine (PCECV) or human diploid cell culture vaccine (HDCV) in healthy volunteers. Study synopsis 7USA401RA, September 1996 - December 1996 (unpublished).
5. Nicholson KG, et al. Pre-exposure studies with purified chick embryo cell culture rabies vaccine and human diploid cell vaccine: serological and clinical responses in man. Vaccine. 1987; 5: 208-210.
6. Vodopija I, 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: 245-248.
7. Wasi C, et al. Purified chick embryo cell rabies vaccine (letter). Lancet. 1986; 1: 40.
8. Wasi C. Rabies prophylaxis with purified chick embryo (PCEC) rabies vaccine. Protocol 8T--201RA, 1983 - 1984 (unpublished).
9. Wasi C. Personal communication to Behringwerke AG, 1990.
10. Bijok U, et al. Clinical trials in healthy volunteers with the new purified chick embryo cell rabies vaccine for man. J Commun Dis. 1984; 16: 61-69.
11. Vodopija I. Post-exposure rabies prophylaxis with purified chick embryo cell (PCEC) rabies vaccine. Protocol 7YU-201RA, 1983-1985 (unpublished).
12. John J. Evaluation of purified chick embryo cell culture (PCEC) rabies vaccine, 1987 (unpublished).
13. Tanphaichitra D, Siristonpun Y. Study of the efficacy of a purified chick embryo cell vaccine in patients bitten by rabid animals. Intern Med. 1987; 3: 158-160.
14. Thongcharoen P, et al. Effectiveness of new economical schedule of rabies postexposure prophylaxis using purified chick embryo cell tissue culture rabies vaccine. Protocol 7T--301IP, 1993 (unpublished).
15. Ljubicic M, et al. Efficacy of PCEC vaccines in post-exposure rabies prophylaxis. In: Vodopija, Nicholson, Smerdel & Bijok (eds.): Improvements in rabies post-exposure treatment (Proceedings of a meeting in Dubrovnik, Yogoslavia). Zagreb Institute of Public Health 1985.
16. Madhusudana SN, Tripathi KK. Post-exposure studies with human diploid cell rabies vaccine and purified chick embryo cell vaccine: Comparative Serological Responses in Man. Int . Med Microbiol. 1989; 271: 345-350.
17. Sehgal S, et al. Ten year longitudinal study of efficacy and safety of purified chick embryo cell vaccine for pre- and post-exposure prophylaxis of rabies in Indian population. J Commun Dis. 1995; 27: 36-43.
18. Sehgal S, et al. Clinical evaluation of purified chick embryo cell antirabies vaccine for post-exposure treatment. J Commun Dis. 1988; 20: 293-300.
19. Suntharasamai P,et al.: Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis. Epidemiol Infect. 1987; 99 (3): 755-765.
20. Meesomboon V, et al. Antibody response to PCEC-rabies vaccine. J Commun Dis. 1987; 13: 130-136.
21. Sehgal S. Report of the trials of PCEC (Purified Chick Embryo Cell) rabies vaccine in India. In: Vodopija, Nicholson, Smerdel & Bijok (eds.): Improvements in rabies post-exposure treatment (Proceedings of a meeting in Dubrovnik, Yugoslavia). Zagreb Institute of Public Health 1985 pp. 71-75.
22. Lesic L, Petrovic M. Study Report: Findings of Clinical Trials on Rabipur PCEC, Rabies Vaccine. National Reference Laboratory for Rabies, Novi Sad, Yugoslavia, 1988 (unpublished).
Last reviewed on RxList: 2/23/2009
This monograph has been modified to include the generic and brand name in many instances.
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