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Appendix D-11
The Prospects for Immunizing Against Rabies Virus

DISEASE DESCRIPTION

Rabies is a rapidly progressive and uniformly fatal viral meningoencephalitis in humans caused by the bullet-shaped viral particles of the rabies group of Rhabdoviridae, genus Lyssavirus (Shope, 1984). All mammals are susceptible to rabies, although canine rabies presents the greatest threat to humans. Exposure to rabid dogs is responsible for about 99 percent of the approximately 35,000 reported cases of human rabies in the world each year (World Health Organization, 1984). The disease is a major viral disease in humans living in the tropics, but it is enzootic worldwide.

Rabies virus usually enters the body through breaks in the skin caused by the bite of an infected animal, but it also may be transmitted across mucous membranes, via the conjunctiva, and perhaps in aerosolized form across respiratory membranes. The virus is neurotropic, entering local nerve endings directly or after primary replication in muscle cells near the site of entry into the body. It then moves through the axonal cytoplasm toward the central nervous system, where the infection becomes symptomatic. The period from inoculation of virus to overt clinical disease may be as short as 10 days or as long as a year or more depending on several factors. These include the severity of the bite, the size of the inoculating dose, unknown factors leading to sequestration at the site of inoculation (Shope, 1984), and distance between the site of inoculation and the central nervous system.

Clinical illness begins with prodromal symptoms including moderate fever, malaise, headaches, and nausea. Paresthesias at the original inoculation site may occur as well. The illness progresses in 2 to 4 days to a full-blown meningoencephalitis, with typical symptoms of hyperexcitability, photophobia, paralysis, stiff neck, and convulsions. There is often increased muscle tension, which can be quite painful.

The committee gratefully acknowledges the advice and assistance of W.H.Wunner. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-11 The Prospects for Immunizing Against Rabies Virus DISEASE DESCRIPTION Rabies is a rapidly progressive and uniformly fatal viral meningoencephalitis in humans caused by the bullet-shaped viral particles of the rabies group of Rhabdoviridae, genus Lyssavirus (Shope, 1984). All mammals are susceptible to rabies, although canine rabies presents the greatest threat to humans. Exposure to rabid dogs is responsible for about 99 percent of the approximately 35,000 reported cases of human rabies in the world each year (World Health Organization, 1984). The disease is a major viral disease in humans living in the tropics, but it is enzootic worldwide. Rabies virus usually enters the body through breaks in the skin caused by the bite of an infected animal, but it also may be transmitted across mucous membranes, via the conjunctiva, and perhaps in aerosolized form across respiratory membranes. The virus is neurotropic, entering local nerve endings directly or after primary replication in muscle cells near the site of entry into the body. It then moves through the axonal cytoplasm toward the central nervous system, where the infection becomes symptomatic. The period from inoculation of virus to overt clinical disease may be as short as 10 days or as long as a year or more depending on several factors. These include the severity of the bite, the size of the inoculating dose, unknown factors leading to sequestration at the site of inoculation (Shope, 1984), and distance between the site of inoculation and the central nervous system. Clinical illness begins with prodromal symptoms including moderate fever, malaise, headaches, and nausea. Paresthesias at the original inoculation site may occur as well. The illness progresses in 2 to 4 days to a full-blown meningoencephalitis, with typical symptoms of hyperexcitability, photophobia, paralysis, stiff neck, and convulsions. There is often increased muscle tension, which can be quite painful. The committee gratefully acknowledges the advice and assistance of W.H.Wunner. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Hyperactivity of the sympathetic nervous system causes increased sweating, salivation, and lacrimation. Periods of extreme anxiety and maniacal behavior alternate with periods of calm awareness of surroundings, tempered with an ever-present sense of foreboding. Painful spasm of the muscles of deglutition leads to active refusal to take liquids (hydrophobia). This spasm may be elicited even by fanning the patient’s face (aerophobia), a useful diagnostic sign. Periods of obtusion occur and progress into coma. Death ensues secondary to cardiac or respiratory failure, usually within a week of the onset of symptoms. Presumptive diagnosis may be made by consideration of the history, presenting signs and symptoms, and clinical course. The diagnosis is confirmed by one of four methods: (1) observation of the typical inclusion bodies (Negri bodies) in nerve cells after appropriate staining of pathological specimens; (2) immunofluorescence staining of pathological specimens; (3) virus isolation through culturing in mice or other animals; and (4) direct and indirect immunoperoxidase staining of tissue (Shope, 1982, 1984). Existing Vaccines and Limitations A 1982 survey identified 74 manufacturers of rabies vaccine worldwide. Most produced vaccine on a small scale and used outdated and suspect technologies, such as adult animal brain cultures (World Health Organization, 1984). Vaccines produced in this way contain myelin, which can provoke a demyelinating immunological disease in the vaccinee. Vaccines consisting of inactivated viruses grown in the brains of suckling animals are used in South America (Shope, 1984). Seven to fourteen injections are required. The virus is purified by centrifugation to reduce the vaccine’s myelin content. Neurological reactions still occur with a frequency of about 5:100,000 vaccinees (Acha, 1981). These vaccines are effective and relatively inexpensive. Prior to 1980, the rabies vaccine most used in developed countries for pre- and post-exposure prophylaxis was the duck embryo vaccine (DEV). It is inexpensive and potent, but requires from 17 to 23 separate injections to provide adequate levels of protective antibody. It does not induce the anti-N antigen response (described below) as well as do newer nerve tissue or cell culture derived vaccines (Shope, 1982). Immunological and neurological complications occur at low frequencies; neurological complications, including postvaccinal encephalitis and transient neuroparalytic illness, occur in 1:25,000 vaccinees and lead to death in 1:225,000 (Rubin et al., 1969). The DEV remains the major rabies vaccine in many parts of the world. The newest available vaccine treatment for rabies is the human diploid cell vaccine (HDCV), which is an adapted, inactivated Pasteur strain of rabies virus. It is grown in human cell culture, inactivated, and purified by centrifugation. HDCV is very effective and produces protective post-exposure immunity with as few as six doses when used in conjunction with rabies hyperimmune globulin (RIG). It is less aller-

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries genic than the DEV, although nonfatal allergic reactions do occur with a frequency of 1:625 vaccinees (Shope, 1984). In addition, a type of serum sickness may occur after administration of a booster dose following a completed primary immunization series (American Public Health Association, 1985). Limitations on the use of the HDCV include the expensive production technology, difficulties with large-scale production, and the comparatively low yield of the method (Barth et al., 1984; World Health Organization, 1984). HDCV production may be too expensive for transfer to developing countries at this time. Modified live virus (MLV) vaccines for immunization of animals are in use worldwide. These vaccines give about 3 years of immunity per series of injections. Adverse reactions include both immunological and neurological disease. Rabies itself can be produced by these live virus vaccines in animals immunosuppressed by steroids or by hematologic malignancies, such as feline leukemia. MLV vaccines recently have been field tested successfully in Europe as oral (enteric) vaccines for wild animals (World Health Organization, 1984). Previous attempts to use inactivated vaccines in this way were not successful. There is a continuing need for a safe, easily produced, inexpensive vaccine for rabies in the developing world. PATHOGEN DESCRIPTION Rabies virus is a bullet-shaped particle 175 to 180 nm in length and 60 to 75 nm in width. Its capsid consists of five proteins designated G, N, M1, M2, and L. These include a glycoprotein (G), two matrix proteins, and a nucleoprotein (N). They are arranged helically and are enclosed in a lipid envelope through which the glycoprotein molecules extend 6 to 8 nm. In the center of the particle is a negative-sense RNA virion constituting the genetic material of the virus. A virion-associated RNA transcriptase is required to produce an active mRNA molecule from which protein translation can occur. Attenuation of rabies virus has been shown to be related to replacement of arginine in position 333 by either isoleucine or glutamine in the viral glycoprotein (World Health Organization, 1984). Virus adapted to laboratory conditions is characterized by a fixed and shortened incubation period and by a tendency for viral particles to bud from the plasma membranes rather than from intracytoplasmic membranes as is typical of wild virus (Shope, 1984). The nucleocapsid protein, N, is the antigen detected in immunofluorescence and complement fixation tests. The glycoprotein, G, induces neutralizing antibody (Shope, 1984). Four serotypes of the rabies group of Rhabdoviridae are recognized, and typing can be done using monoclonal antibodies. Differences among serotypes are apparently small enough that a vaccine made with a single type can protect against all types. Rabies virus is able to maintain itself in an enzootic condition in many mammalian species, including dogs, foxes, raccoons, and bats. In part, this broad susceptibility results from an adaptation of the virus

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries leading to the production of large numbers of viral particles in the salivary glands. This replication may occur before clinical symptoms appear, facilitating transmission through the saliva. In addition, some animals may become viral secretors, spreading disease over long periods of time without developing the disease. Humans are nontransmitting hosts for rabies virus. There are no documented cases of human-to-human spread of rabies, other than several cases resulting from corneal transplantation from unrecognized rabies victims. HOST IMMUNE RESPONSE Infection with rabies virus induces a humoral immune response, which in humans is not sufficient to prevent disease and death. Antirabies antibodies can prevent disease, however, if given passively before or shortly after infection. Possible explanations for this situation are that the humoral immune response is not rapid enough after infection, that a disrupted cell-mediated immune response (CMI) interferes with eradication of the virus, or that the intraneural infection is protected from the antibody response. Rabies virus does cause immunosuppression of the CMI response through enhancement of suppressor T-cell action. A state of anergy develops in which cytotoxic T-cells fail to act against rabies and other antigens. It also appears that low levels of protective antibody, resulting either from a suboptimal or decayed vaccination response, or from inadequate passive immunization, can lead to paradoxical immunosuppression and accelerated disease (Shope, 1984). The possibility of such an occurrence dictates that any new vaccine must be strongly immunogenic and that the duration of protective immunity be predictable. Rabies infection also induces interferon production, which may provide some protection by slowing the progress of disease. It is not yet known if the interferon response could be utilized therapeutically in early post-exposure prophylaxis or treatment. Finally, incomplete viral particles, called T particles (Shope, 1984), may be present in the infective inoculum or produced during the early course of disease. These particles cannot cause disease, but may interfere with the early course of infection by competing for cell membrane receptor sites, for example. The effect of T particles on the development of the immune response is not clear, although they may prolong the incubation period and allow more time for post-exposure prophylaxis. DISTRIBUTION OF DISEASE Geographic Distribution Canine rabies is enzootic in at least 87 countries and on every continent except Australia. Such islands as Hawaii, New Zealand, and

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Cyprus may never have experienced rabies. Such countries as Japan, Norway, Sweden, the United Kingdom, Taiwan, and Iceland have eliminated it and maintain this situation by strict quarantine (American Public Health Association, 1985). Ninety-nine percent of human rabies is related to exposure to canine rabies. Although the distribution of rabies is worldwide, human and animal cases occur more frequently in the tropical zones (Schneider and Bögel, 1983). Rabies has become a particular problem in the growing urban areas of developing countries. All age groups are susceptible, but a disproportionate number of cases occur in those under 15 years of age, perhaps because of increased contact with animals. The World Health Organization (WHO Expert Committee on Rabies, 1984; World Health Organization, 1984) collects information on the number of reported rabies cases worldwide. There are about 100 human cases in Europe each year; the primary reservoir of disease is sylvatic (in foxes) with spread to humans via dogs. South America has about 300 human deaths per year. Again, canines are the primary source, with an estimated 18,000 canine cases per year in the 1970s (World Health Organization, 1984). Rabies also is transmitted to cattle by vampire bats and is a major economic problem in South America. Africa and Asia are estimated to have 5,000 and 30,000 human cases per year, respectively. Wild dogs, through contact with domesticated dogs, are the primary source. These figures may be underestimates because of inadequacies in disease surveillance and death registration in many countries. Disease Burden Estimates The estimated human deaths from rabies in the developing world, by continent, are shown in Table D-11.1. The estimate for Oceania is based on an assumed incidence of 1 per 100,000 population. Other figures are based on information from the World Health Organization (1984). Population figures for calculating rates are from the 1984 World Population Data Sheet (Population Reference Bureau, 1984). The breakdown of cases by age group is based on the assumption that the incidence rates in the two younger age groups are twice those in the two older age groups. Disease burden estimates for rabies in the developing world are shown in Table D-11.2. These estimates are based on reported cases and may therefore underestimate the total disease burden. PROBABLE VACCINE TARGET POPULATION A few identifiable groups are at high risk for rabies and warrant pre-exposure immunization. They include veterinarians, wildlife conservation personnel in endemic areas, animal quarantine facility personnel, and laboratory and field personnel working with rabies (American Public Health Association, 1985). Unfortunately, it is difficult to identify other well-defined risk groups in the general

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-11.1 Estimated Number of Deaths from Rabies in Various Regions of the Developing World       Age Group (years)       Under 5 5–14 15–59 60 and Over Continent Total Number of Reported Deaths Death Rate (per 100,000) Number of Deaths Death Rate (per 100,000) Number of Deaths Death Rate (per 100,000) Number of Deaths Death Rate (per 100,000) Number of Deaths Death Rate (per 100,000) South America 300 0.076 62 0.11 108 0.11 116 0.05 14 0.05 Africa 5,000 0.942 1,258 1.3 1,839 1.3 1,725 0.65 177 0.65 Asia 30,000 1.130 5,616 1.63 10,889 1.63 12,028 0.817 1,468 0.817 Oceania 50 1 12 1.4 18 1.4 18 0.7 2 0.7 Total 35,350   6,948   12,854   13,887   1,661  

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-11.2 Disease Burden: Rabies Virus       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity                   B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work                   C Severe pain, severe short-term impairment, or hospitalization Meningoencephalitis, paralysis, convulsions 6,948 7 12,854 7 13,887 7 1,661 7 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)     n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)     n.a.   n.a.   n.a.   n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   6,948 n.a. 12,854 n.a. 13,887 n.a. 1,661 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries population. Rabies transmission to humans depends primarily on the rabies situation in the local canine population, which fluctuates from place to place and from time to time. A rabies vaccination program would have to target most of the developing world’s population to eliminate the incidence of human rabies. However, universal human pre-exposure immunization for the entire developing world is probably not a cost-effective strategy for rabies control. The main role of a rabies vaccine for humans is to provide post-exposure prophylaxis for dog and other animal bites. Post-exposure prophylactic regimens have been published widely (American Public Health Association, 1985) and are effective, especially when used in conjunction with local wound care and rabies immunoglobulin (RIG). An estimated 5.6 million people worldwide need post-exposure treatment for rabies annually, but only 3.5 million actually receive it (WHO Expert Committee on Rabies, 1984). Efforts should continue to make rabies vaccine available to this high-risk group of exposed individuals through improved production and distribution networks. Educational efforts to increase awareness of this treatment also would be helpful. Such efforts are under way (World Health Organization, 1984). The target population for two of the envisaged vaccines—the vero cell derived vaccine and the glycoprotein vaccine produced by rDNA technology—would be the group requiring post-exposure prophylaxis, estimated by the World Health Organization (1984) to be 5.6 million people each year. The third envisaged vaccine—a live vector virus carrying the gene for the immunogenic glycoprotein—would, it is hoped, be economical for delivery as pre-exposure prophylaxis to high risk populations. These populations include all of India, Thailand, Pakistan, Bangladesh, Sri Lanka, Nepal, Indonesia, the Philippines, and Turkey, and the urban populations of Africa and Latin America (excluding Chile, Guyana, Jamaica, and Uruguay, where rabies is reportedly not a severe problem). In the steady state of vaccine usage, a vaccination program would be directed at the birth cohort in these regions, which is estimated from Population Reference Bureau (1984) data to be 53 million. Such a vaccine could probably be delivered through the World Health Organization Expanded Program on Immunization (WHO-EPI) to infants or young children. Vaccine Preventable Illness* Nearly two-thirds of individuals who require post-exposure prophylaxis currently receive it (World Health Organization, 1984). Extending this protection will need educational efforts to ensure that *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries exposed individuals seek and receive immunization, as well as a supply of potent vaccine that is more readily available in developing countries at an affordable price. Assuming that coverage can be extended to those who need it, the burden of illness represented in Table D-11.2 is fully preventable by post-exposure prophylaxis; that is, the proportion of the disease burden that is theoretically vaccine preventable is 1.0. Such an estimate is recognized to be optimistic for the near future, but as primary health care services are extended in the coming decades, it will become more realistic. The number of cases that occur because of modes of transmission that are difficult to recognize (i.e., other than animal bites) is considered to be negligible. The vaccine that would be delivered to the birth cohort in high-risk areas (see above) would need to provide long-lasting, probably lifetime, protection. Based on this assumption, the entire disease burden in the populations of those regions is potentially vaccine preventable. After review of information presented by Schneider and Bögel (1983), a value of 0.75 was chosen to represent that portion of the total disease burden that falls in the high-risk populations and that is theoretically preventable by the envisaged “vector” rabies vaccine. SUITABILITY FOR VACCINE CONTROL As stated above, rabies is potentially controllable through the use of rabies vaccine. However, suitable target populations are difficult to define at this time. Universal immunization may be too difficult technically and too costly to be a viable control strategy. Efforts in the near future should be directed toward providing post-exposure treatment for those in need. Alternative Control Measures and Treatments Post-exposure prophylaxis can be an effective prevention strategy. It requires production and distribution of a suitable vaccine, including an adequate cold chain. Optimal treatment also includes vigorous local wound cleansing and debridement and the use of RIG both systemically (parenterally) and infiltrated locally around the area of the wound. Education of the population to seek medical care after a possible exposure also is important. Animal control, and specifically dog control, is the foundation of any rabies control program. According to the World Health Organization (1984), a national program for control of rabies in dogs should include (1) epidemiological surveillance to monitor canine rabies at the local level; (2) community education and participation to teach the importance of rabies, to elicit cooperation in dog control efforts, and to reduce exposure, especially among children; (3) immunization of family dogs and cats; (4) dog control through immunization and registration of family pets, and destruction of stray populations (control efforts could include animal contraception and mass immunization of dogs in endemic areas); and (5) centralized organization and implementation.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Finally, control measures can be taken with respect to wild animal reservoirs of rabies. Enteric immunization, using vaccine in bait food, may be a viable strategy. It is unlikely, however, that the disease can be eradicated from wild animal populations; thus rabies is likely to be a public health problem for the foreseeable future. PROSPECTS FOR VACCINE DEVELOPMENT New vaccine development is aimed at producing safe, effective, and inexpensive vaccines that can be given with a short immunization schedule. Several prospective vaccines are in various stages of development. A purified chick embryo cell vaccine (Barth et al., 1984) has been shown to induce antibodies in monkeys and to protect guinea pigs from disease after parenteral rabies virus challenge. The vaccine is inactivated using betapropiolactone, and is purified and concentrated by continuous zonal centrifugation. This is becoming a standard technique for removing allergenic materials from vaccine preparations. Highly purified and concentrated forms of the standard duck embryo vaccine (DEV) also are being developed (Keller et al., 1984). These appear to be more immunogenic and less allergenic than their predecessors, allowing a reduced vaccination schedule. DEV has the advantage of being relatively inexpensive. An alternative cell culture medium is a continuous, aneuploid cell line derived from the vervet monkey kidney, called Vero (WHO Expert Committee on Rabies, 1984). This process allows higher yields of vaccine antigens than the HDCV approach and may be cheaper and more appropriate for use in the developing world. Wunner et al. (1983) have isolated rabies virus G protein fragments using an isoelectric focusing column. The G proteins form the glycoprotein knobs projecting through the viral lipid envelope and are responsible for eliciting virus neutralizing antibodies. The amino acid sequence of the G protein has been determined, and it has been produced using recombinant DNA technology (Malek et al., 1984). However, the product was not immunologically active, possibly due to a discrepancy in amino acid sequences. Correction of this discrepancy by site-directed mutagenesis appears to be possible (Koprowski et al., 1985; Lathe et al., 1985), which suggests that it may be possible to develop a totally synthetic rabies vaccine. Such a vaccine would contain neither whole virus particles nor the reactogenic components of cell culture vaccines. Thus, inactivation procedures would be unnecessary, and less complex purification techniques might be possible. A recombinant vaccinia virus expressing the rabies G protein has also been developed (Koprowski et al., 1985; Wiktor et al., 1984). Inoculation of mice with the altered vaccinia vector virus induced immunity that was protective even against severe intracerebral challenge with live rabies virus (Lathe et al., 1985). Finally, synthetic peptide and anti-idiotypic approaches to vaccines against rabies are under investigation (Koprowski et al., 1985).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries From among these various vaccine strategies the committee chose to evaluate three candidates that it felt were technically feasible within a decade and were representative of fundamentally different strategies. The three candidates selected were a vero cell derived vaccine, a glycoprotein based vaccine, and a vector vaccine approach. REFERENCES Acha, P.N. 1981. A review of rabies prevention and control in the Americas, 1970–1980. Overall status of rabies. Bull. Off. Int. Epiz. 93(1–2):9–52. American Public Health Association. 1985. Rabies. Pp. 310–318 in Control of Communicable Diseases in Man, A.S.Benenson, ed. Washington, D.C.: American Public Health Association. Barth, R., H.Gruschkau, U.Bijok, J.Hilfenhaus, J.Hinz, L.Mikke, H.Moser, O.Jaeger, H.Ronneberger, and E.Weinmann. 1984. A new inactivated tissue culture rabies vaccine for use in man. Evaluation of PECE-vaccine by laboratory tests. J. Biol. Stand. 12:29–46. Keller, H., A.Gluck, A.Wegmann, and A.I.Wandeler. 1984. Immunogenicity of a new, highly purified and concentrated duck embryo rabies vaccine. Schweiz. Med. Wschr. 114:648–653. Koprowski, H., K.J.Reagan, R.I.McFarlan, B.Dietzschold, and T.J. Wiktor. 1985. New generation of rabies vaccines: Rabies glycoprotein gene recombinants, anti-idiotypic antibodies and synthetic peptides. Pp. 151–156 in Vaccines 85. Molecular and Chemical Basis of Resistance to Parasitic, Bacterial, and Viral Diseases, R.A.Lerner, R.M.Chanock, and F.Brown, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Lathe, R., M.-P.Kieny, J.-P.Lecocq, P.Drillien, T.J.Wiktor, and H. Koprowski. 1985. Immunization against rabies using a vaccinia-rabies recombinant virus expressing surface glycoprotein. Pp. 157–162 in Vaccines 85. Molecular and Chemical Basis of Resistance to Parasitic, Bacterial, and Viral Diseases, R.A. Lerner, R.M.Chanock, and F.Brown, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Malek, L.T., G.Soostmeyer, R.T.Garvin, and E.James. 1984. The rabies glycoprotein gene is expressed in Escherichia coli as a denatured polypeptide. Pp. 203–208 in Modern Approaches to Vaccines, R.M.Chanock and R.A.Lerner, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Population Reference Bureau. 1984. 1984 World Population Data Sheet. Washington, D.C.: Population Reference Bureau. Rubin, R.H., J.Black, and G.R.Sharpless. 1969. Rabies in citizens of the United States. 1963–1968: Epidemiology, treatment, and complications of treatment. J. Infect. Dis. 120:268–273. Schneider, L.G., and K.Bögel. 1983. The current global situation of human and canine rabies and its control. Paper presented at the Third Inter-American Meeting, at the Ministerial Level, on Animal Health, Washington, D.C., April 11–14, 1983.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Shope, R.E. 1982. Rabies. Pp. 455–470 in Viral Infections of Humans, 2d ed., A.S.Evans, ed. New York: Plenum. Shope, R.E. 1984. Rabies. Pp. 612–619 in Tropical and Geographic Medicine, K.S.Warren and A.A.F.Mahmoud, eds. New York: McGraw-Hill. WHO Expert Committee on Rabies. 1984. Seventh Report. Technical Report Series, No. 709. Geneva: World Health Organization. World Health Organization. 1984. Transfer of Technology for Production of Rabies Vaccine: Report of a WHO Consultation. Geneva, Switzerland, October 23–26, 1984. Wiktor, J.T., R.I.MacFarlan, K.J.Reagan, B.Dietzschold, P.J. Curtis, W.H.Wunner, M.-P.Kieny, R.Lathe, J.-P.Lecocq, M. Mackett, B.Moss, and H.Koprowski. 1984. Protection from rabies by a vaccinia virus recombinant containing the rabies virus glycoprotein gene. Proc. Natl. Acad. Sci. USA 81:7194–7198. Wunner, W.H., B.Dietzschold, P.J.Curtis, and T.J.Wiktor. 1983. Rabies subunit vaccines. J. Gen. Virol. 64:1699–1656.