Rabies Vaccines a Review of Progress Towards Improved Efficacy and Safety
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BioDrugs 1998 Oct; 10 (4): 317-328 IMMUNOLOGY-BASED AGENTS 1173-8804/98/0010-0317/$06.00/0 © Adis International Limited. All rights reserved. Rabies Vaccines A Review of Progress Towards Improved Efficacy and Safety Henri Tsiang Rabies Unit, Institut Pasteur, Paris, France Contents Abstract . 317 1. World Rabies Situation . 318 1.1 North and South America . 319 1.2 Europe . 319 1.3 Asia . 319 1.4 Africa . 319 2. History of Rabies Virus Vaccine . 320 2.1 The Original Pasteur Vaccine . 320 2.2 The Improved Brain Tissue Vaccines . 320 2.3 The Avian Embryo Vaccine . 320 3. Tissue Culture Vaccines . 320 3.1 Primary Hamster Kidney Cell Vaccine . 321 3.2 Human Diploid Cell Vaccine . 321 3.3 VERO Cell Vaccine . 322 3.4 Purified Chick Embryo Cell Vaccine . 322 3.5 Adsorbed Rabies Vaccine . 322 4. Rabies Vaccination . 322 4.1 History . 322 4.2 World Situation of Rabies Vaccination . 323 4.3 Recommended Vaccination Regimens . 323 4.3.1 Brain Tissue Vaccines . 323 4.3.2 The Essen Vaccination Regimen . 323 5. Reduced Vaccination Regimens . 323 5.1 The 2-1-1 Regimen . 323 5.2 Intradermal Inoculation of Vaccines . 324 5.3 The Pre-Exposure Vaccination . 324 5.4 Postexposure Treatment with Antirabies Serum . 324 6. Research and Development in Rabies Vaccines . 325 6.1 Subunit Vaccines . 325 6.2 Polypeptides . 325 6.3 Immunosomes, ISCOMS and Microspheres . 325 6.4 Genetic Engineering . 325 7. Conclusions . 326 Abstract Over the years, the technology for producing human rabies vaccines has un- dergone many improvements. These improvements consist in the use of tissue cultures for the production of viral antigens, replacing the former nervous tissue substrate vaccines. The low virus yields in tissue cultures led to the development 318 Ts i a n g of the concentration and purification of virus supernatants. Another technical improvement was obtained by using microcarriers for virus production in VERO cell suspension cultures. This technique permits commercial-scale production of rabies vaccine, lowering production costs and thus extending the availability of the vaccine to a broader population in developing countries. Besides improvements in rabies vaccine production technology, the use of various vaccination regimens and routes of administration in field trials has re- sulted in considerable gains in our experience of postexposure treatment (PET) of this disease. The standard WHO recommended regimen for PET using con- centrated and purified tissue culture vaccines consists of a 5-dose course of in- tramuscular injections at days 0, 3, 7, 14 and 28. Reduced vaccination regimens such as the 2-1-1 have been proven to be efficient in raising protective antibody responses. Reduction in the total volume of rabies vaccine is also possible by using the intradermal route of injection, provided the vaccine is administered at several sites. The overall consequence is a progressive shift in the worldwide use of rabies vaccines from those of nervous tissue origin to the contemporary tissue culture vaccines. Unlike most other infectious viral diseases, ra- procedure that involves a series of inoculations. Al- bies is the only one for which postexposure treat- though the number of injections has been signifi- ment (PET) based on vaccination can be per- cantly reduced by using tissue culture instead of formed. For all the other viral infections, only nervous tissue vaccines, clinical trials have estab- preventive vaccinations can be applied. The unique lished the limits of the reduction possible without situation with rabies occurs because the contami- impairment of the protective antibody response. nation occurs mainly through a well identified event: a bite from a potentially rabid animal. This 1. World Rabies Situation is not the case for most other viral diseases (such as influenza, polio or measles). PET for rabies is World wide, the rabies situation is continually thus a race between the spread of the virus from the evolving. In some areas, difficulties in collecting site of the virus entry (a wound) to the final target information are a major drawback to the attainment of comprehensive data from different continents. cells (neurons in the CNS), and the elicitation of an Human rabies has a low incidence in industrialised immune response able to eliminate the virus from countries (North America, Europe) and is not found the organism, preventing the disease from occur- in island countries such as Australia, Great Britain, ring. Japan, New Zealand, etc. The incidence is also rel- During the past century, since the discovery of atively low in Latin America, but the data for Africa a rabies vaccine by Louis Pasteur, continuous ef- are incomplete. Cases of human rabies are mostly forts have been made to produce more potent vac- concentrated in Asia, and mainly on the Indian sub- cines containing fewer exogenous biological pro- continent (India, Pakistan, Bangladesh, Nepal); in teins, specifically by reducing and ultimately other Asian countries, the incidence is lower. Esti- eliminating nervous tissues present in the vaccines mates of the number of cases of human rabies in- produced in brain tissues. Another aim is also of fection during the last decades range from 35 000 importance: the production of more economical to 45 000 annually (table I). It is interesting to note vaccines for use in tropical regions and in develop- that after elimination of the risk of transmission of ing countries. dog rabies in industrialised countries (North Amer- Rabies vaccination is also the only vaccination ica and Europe), the disease reservoir and vectors © Adis International Limited. All rights reserved. BioDrugs 1998 Oct; 10 (4) Improving Rabies Vaccines 319 Table I. Estimated incidence of human rabies cases soning did not prevent the spread of the disease, Total 35 000-45 000 and it was only after the use of oral vaccines in Europe 10-20 animal baits that a continuous reduction in the North America 4-8 global incidence of rabies could be seen (table III). Latin America 200-400 Human rabies is rare in Europe. Most reported Africa 500-5000 Asia 35 000-45 000 cases are from dog bites in the former Soviet Union (India 30 000-40 000) (an average of 10 or fewer cases annually), or im- ported cases of patients who were bitten by dogs in countries where the disease is still endemic have shifted to wildlife, whereas in Africa and Asia (Asia, Africa).[3] the dog remains the major vector for transmission of the disease. 1.3 Asia 1.1 North and South America The main vector in Asia is the dog. The Asian continent accounts for the majority of human ra- From the 1996 report on rabies surveillance in bies cases.[4] There is a general consensus that the [1] the US, it appears that the situation is extremely approximate number of deaths is 40 000 annually; complex. A total of 7877 nonhuman cases were India accounts for the great majority. Several coun- reported in 1995, from which a majority (92%) tries have established national programmes for ra- were wild animals (raccoons, 3964; skunks, 1774; bies prevention and prophylaxis, significantly re- foxes, coyotes, etc., are also involved). Several ducing the number of human cases (China, species of bats were among the animals found to Indonesia, Malaysia, Thailand), while the situation be rabid (787 cases), with an increase of 24.7% remains serious in others (India, Bangladesh, over the 1994 figures. It must be noted that bats Nepal, Sri Lanka, Myanmar, Laos). have been involved in half of the cases of rabies which have occurred during the past decade, most 1.4 Africa of the patients presenting without a history of ex- posure. The dog remains the major cause of human ra- From the 1995 report of the rabies situation in bies in Africa (average of 90% of cases). Over 4000 the Americas,[2] the annual number of cases in hu- animal rabies cases have been reported per year, of mans in Latin America has been reported to be which 2600 have been confirmed by laboratory about 200 (table II), although unreported infec- diagnosis.[5] It is also likely that a high proportion tions might occur. of rabies cases are not reported, especially in re- mote areas. Human rabies (141 cases in 1994)[5] is 1.2 Europe mainly reported as having been clinically diag- nosed as fewer than 10% of cases are diagnosed by The history of rabies in Europe has been one of continual change during the past century. After the elimination of dog rabies by the vaccination of do- Table II. Annual number of cases of rabies in North and South America mestic animals and massive elimination of stray dogs, several Western European countries were ra- 1995 154 1994 150 bies-free for various periods of time. Following the 1993 216 Second World War, adaptation of the rabies virus 1992 225 to the red fox allowed the disease to spread to most 1991 215 European countries, with the exception of those 1990 252 bordering the Mediterranean countries. The at- 1980-1989 293 (mean value) tempt to eliminate fox rabies by hunting and poi- 1970-1979 255 (mean value) © Adis International Limited. All rights reserved. BioDrugs 1998 Oct; 10 (4) 320 Ts i a n g Table III. Annual number of reported cases of rabies in Europe L. Pasteur: difficulty in maintenance of spinal Wildlife Domestic Human cords at different times of dessication, occurrence 1996 5 385 2673 8 of cases of vaccine recipients developing rabies 1995 5 816 2750 10 and accidental paralysis because of the presence of 1994 6 698 2284 9 high concentration of myelin. 1993 6 914 2088 3 [8] 1992 8 330 2685 6 Major modifications were introduced by Fermi, [9] 1991 12 585 2894 0 and Semple who used sheep brain homogenates, 1990 14 765 4791 10 increasing the reproducibility of vaccine prepara- 1989 16 975 3762 4 tions.