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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 terrestrial 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 epizootics 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 postexposure prophylaxis.
Rabies is a viral infection transmitted via the saliva of infected mammals. The virus enters the central nervous system of the host, causing an encephalomyelitis that is almost invariably fatal. The incubation period varies between 5 days and several years, but is usually between 20 and 60 days. Clinical rabies presents either in a furious or in a paralytic form. Clinical illness most often starts with prodromal complaints of malaise, anorexia, fatigue, headache, and fever followed by pain or paresthesia at the site of exposure. Anxiety, agitation, irritability may be prominent during this period, followed by hyperactivity, disorientation, seizures, aero- and hydrophobia, hypersalivation, and eventually paralysis, coma and death.
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 postexposure 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 (in combination with passive immunization with Human Rabies Immune Globulin [HRIG] and local wound treatment) in postexposure treatment against rabies has been shown to protect patients of all age groups from rabies, when the vaccine was administered according to the CDC's Advisory Committee on Immunization Practices (ACIP) or 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 minimum antibody titer accepted as seroconversion (protective titer) within 14 days after initiating the postexposure treatment series. The minimum antibody titer accepted as seroconversion is a 1:5 titer (complete inhibition in the rapid fluorescent focus inhibition test [RFFIT] at 1:5 dilution) as specified by the CDC1, or ≥ 0.5 IU per milliliter (mL) as specified by the WHO2,3.
The immunogenicity of RabAvert has been demonstrated in clinical trials conducted in different countries such as the USA4,5, UK6, Croatia7, and Thailand8-10. When administered according to the recommended immunization schedule (days 0, 7, 21 or 0, 7, 28), 100% of subjects attained a protective titer. In 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 to boost previously immunized subjects was evaluated in three clinical trials. In the Thailand study, preexposure booster doses were administered to 10 individuals. Antibody titers of > 0.5 IU/mL were present at baseline on day 0 in all subjects9. 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. In this study, a booster response was observed on day 14 for all (22/22) individuals11. In a trial carried out in the USA4, a RabAvert IM booster dose resulted in a significant increase in titers in all (35/35) subjects, regardless of whether they had received RabAvert or HDCV as the primary vaccine.
Persistence of antibody after immunization with RabAvert 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.
Preexposure Vaccination in Children
Preexposure administration of RabAvert in 11 Thai children from the age of 2 years and older resulted in antibody levels higher than 0.5 IU/mL on day 14 in all children12.
RabAvert, when used in the recommended postexposure 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 patients8,9,13-16 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 observed8,9,13-20. Some patients received Human Rabies Immune Globulin (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 studies8,9,13,17, the addition of either HRIG or ERIG caused a slight decrease in GMTs which was neither clinically relevant nor statistically significant. In one study16, 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 receiving the postexposure WHO regimen, i.e., “simulated” postexposure, show that with sampling by day 28 - 30, 205/208 vaccinees had protective titers > 0.5 IU/mL.
No postexposure vaccine failures have occurred in the United States since cell culture vaccines have been routinely used1. Failures have occurred abroad, almost always after deviation from the recommended postexposure treatment protocol21-24. In two cases with bites to the face, treatment failed although no deviation from the recommended postexposure treatment protocol appeared to have occurred25.
Postexposure Treatment in Children
In a 10-year serosurveillance study, RabAvert has been administered to 91 children aged 1 to 5 years and 436 children and adolescents aged 6 to 20 years19. The vaccine was effective in both age groups. None of these patients developed rabies.
One newborn has received RabAvert on an immunization schedule of days 0, 3, 7, 14 and 30; the antibody concentration on day 37 was 2.34 IU/mL. There were no clinically significant adverse events26.
1. CDC. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Human Rabies Prevention - United States, 1999. Morbidity and Mortality Weekly Report Recommendations and Report, January 8, 1999, Vol.48, RR-1, pg 1.1-21.
2. Smith JS, Yager, PA & Baer, GM. A rapid reproducible test for determining rabies neutralizing antibody. Bull WHO. 1973; 48: 535-541.
3. Eighth Report of the WHO Expert Committee on Rabies. WHO Technical Report Series, no. 824; 1992.
4. Dreesen DW, et al. Two-year comparative trial on the immunogenicity and adverse effects of purified chick embryo cell rabies vaccine for preexposure immunization. Vaccine. 1989; 7: 397-400.
5. Dreesen, DW. Investigation of antibody response to puified 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).
6. Nicholson KG, et al. Preexposure 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.
7. 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 preexposure vaccination schedule and an abbreviated 2-1-1 postexposure schedule. Vaccine. 1986; 4: 245-248.
8. Wasi C, et al. Purified chick embryo cell rabies vaccine (letter). Lancet. 1986; 1: 40.
9. Wasi C. Rabies prophylaxis with purified chick embryo (PCEC) rabies vaccine. Protocol 8T--201RA, 1983 - 1984 (unpublished).
10. Wasi C. Personal communication to Behringwerke AG, 1990.
11. 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.
12. Lumbiganon P, et al. Preexposure vaccination with purified chick embryo cell rabies vaccines in children. Asian Pacific J Allergy Immunol 1989; 7: 99-101.
13 Vodopija I. Post-exposure rabies prophylaxis with purified chick embryo cell (PCEC) rabies vaccine. Protocol 7YU-201RA, 1983-1985 (unpublished).
14. John J. Evaluation of purified chick embryo cell culture (PCEC) rabies vaccine, 1987 (unpublished).
15. 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.
16. 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).
17. 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 1985.17.
18. Madhusudana SN, Tripathi KK. Post exposure studies with human diploid cell rabies vaccine and purified chick embryo cell vaccine: Comparative Serological Responses in Man. Zbl Bakt 1989; 271: 345-350.
19. Sehgal S, et al. Ten year longitudinal study of efficacy and safety of purified chick embryo cell vaccine for pre- and postexposure prophylaxis of rabies in Indian population. J Commun Dis. 1995; 27: 36-43.
20. Sehgal S, et al. Clinical evaluation of purified chick embryo cell antirabies vaccine for postexposure treatment. J Commun Dis. 1988; 20: 293-300.
21. Fishbein DB, et al. Administration of human diploid-cell rabies vaccine in the gluteal area. N Engl J Med 1988; 318: 124-125.
22. Shill M, et al. Fatal rabies encephalitis despite appropriate postexposure prophylaxis. A case report. N Engl J Med 1987; 316: 1257-1258.
23. Wilde H, et al. Failure of rabies postexposure treatment in Thailand. Vaccine 1989; 7: 4952.
24. Kuwert EK, et al. postexposure use of human diploid cell culture rabies vaccine. Dev Biol Stand 1977; 37: 273-286.
25. Hemachudha T, et al. Additional reports of failure to respond to treatment after rabies exposure in Thailand. Clin Infect Dis 1999; 28: 143-144.
26. Lumbiganon P, Wasi C. Survival after rabies immunisation in newborn infant of affected mother. Lancet 1990; 336: 319-320.
Last reviewed on RxList: 9/22/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Rabavert Information
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