Exp. Pathol. 1991; 42: 1-9 Gustav Fischer Verlag Jena

Review

Institute of Veterinary Medicine (Robert von Ostertag Institute), Federal Health Office, Research Group Viral Zoonoses, Potsdam, F.R.G.

Immune reactions against rabies viruses infection and vaccination By J. Suss and H. SINNECKER t With 4 figures Received: April 26, 1989; Accepted: May 2, 1989 Address for correspondence: Dr. sc. nat. J. Suss, Institute of Veterinary Medicine (Robert von Ostertag Institute) Federal Health Office, Research Group Viral Zoonoses, TomowstraBe 21, D-O-1561 Potsdam, F.R.G. Key words: Rabies virus; infection; immune response; vaccination; pathogenesis; taxonomy; cell-mediated immune response; cell-mediated cytotoxicity; interferon Abbreviations: ADCC - antibody dependent cellular cytotoxicity; CNS - central nervous system; CTL cytotoxic T cells; DEV - duck embryo vaccine; DUV - Duvenhage strain (European rabies virus with antigenic relations to the Duvenhage strain); FAT - fluorescence antibody technique; G - glycoprotein; HDCV - human diploid cell vaccine; LGL - large granular leukocytes; LEP - low egg passage; M - matrix protein; mab - monoclonal antibody; N - nucleoprotein; NS - phosphoprotein; PCECV - purified chick embryo cell vaccine; PM - Pitman-Moore; PV - Pasteur virus; RNP - ribonucleoprotein; vRNA - virus

RNA

Rabies affecting humans as well as wild and domestic animals is a disease with a 100 % case fatality rate. This underscores the particular importance of this viral disease and, since LOUIS PASTEUR'S achievements at the end of the 19th century, has led to successful developments in the field of immune prophylaxis. Despite good results, a large part of deaths also refers to persons who underwent vaccination, which necessitates further intensive research in the field of rabies immunology and vaccination development as well as the pathogenesis of rabies. It must be emphasized that even the application of modem vaccines may not prevent severs complications. Immunology and pathogenesis of rabies are being increasingly investigated, yet thus far have been measurable only in single processes, and we are far from understanding these complex mechanisms (WUNNER 1987; WUNNER and DIETZSCHOLD 1987). As we know, since World War II rabies has spread as an epidemic from the east with 50 km per year westward in Central Europe and reached the Elbe in 1950. It is estimated that in Europe I million vaccinations are required per year. In the USA, 25,000 persons receive a post-exposure antirabies vaccination, 0-5 deaths per year have still occured since 1960 (PARKMAN and Hopps 1988). Overall, rabies is first a disease of wild animals, particularly of the fox, the second place is occupied by domestic animals and humans follow in the third place only. The World Health Exp. Pathol. 42 (1991) 1

Organization yearly registers some 15 ,000 deaths world wide, which certainly represents only a minimal portion of the actual cases, as alone in China 30,000 deaths occur per annum and, moreover, Vietnam reports several thousands of deaths. As to its outcome, a rabies virus infection is particularly determined by functions and reactions of the virus and host, therefore immunological considerations must imply remarks on pathogenesis/immunopathogenesis for the association of specific and non-specific defence processes for viral structure and the functions of the structural constituents and on the antigens and their variability. Futhermore, we would like to suggest that the immunological mechanisms in infection and immunization show essential differences .

Rabies virus taxonomy, structure and antigen constituents The rhabdovirus group , which contains morphologically similar yet serologically different viruses , includes the following : Rhabdovirus group

Vesiculo-stomatitis virus Hart-Park virus Kern-Canyon virus Rabies virus (serotype 1) "street" virus "virus-fixe" strains with the strains to be differentiated, by mab, against surface glycoprotein (G) and nucleoprotein (NP) : Challenge Virus Standard ; Pitman Moore ; Street Alabama Dufferin; High egg passage/Low egg passage; Kelev , Flury. More closely related to the rabies virus (serotype l) are: Lagos-Bat virus (serotype 2) ; Mokola virus (serotype 3); Duvenhage virus (serotype 4); Kotonkan virus; Obodhiang virus. The rabies virus is composed of 5 structural proteins and one single-standard, nonsegmented vRNA which is of a length of about 12,000 nucleotides. The sequence of the genes is analogous to that of other rhabdoviruses, namely 3'-N-NS-M-G-L-5'. The structural proteins are the nucleoprotein (N), the virus transcriptase and a phosphoprotein (NS), which, together with the virus RNA, form the ribonucleoprotein. The envelope is formed by a lipid double layer which covers the RNP and with which a non-glycolized matrix protein is associated at the interior side of the lipid layer. Inserted into the lipid layer are surface projections, which are about 10 !-lm long, the surface glycoproteins, which cover the surface of the virus (fig. 1). This glycoprotein is mainly responsible for the virus-cell interactions, induces neutralizing antibodies and is the site of their binding, which leads to the neutralization of the virus.

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Exp. Pathol. 42 (1991) 1

Fig.l. Schematic design of a rabies virus (according to OXFORD and OBERG 1985; as well as WUNNER and DIETZSCHOLD 1987).

Pathogenesis of rabies In the pathogenesis of rabies, the late development of antibodies and the occurrence of death despite high antibody titers is characteristic. A reason for this seems to be the lacking cytopathogenicity of the virus in the early phase of the incubation period. At this point in time only very few viruses are found intercellularly, whereby an early immune response will hardly be initiated. Furthermore, in the neural phase of the incubation period, an induction of antibodies will hardly occur, but only in the end phase, whereby the infection then cannot be influenced (KOPROWSKI 1984). The extraneural early phase of the incubation period includes the phase of sequestration, i.e., the virus remains at the inoculation site for an indefinite time without viral replication and, thereafter, enters a replication phase at the inoculation site, especially in the striated musculature, then the virus reaches nerve endings also in the motor nerve end-plate and invades them via membrane fusion. From this early moment in the incubation period onward, protection by vaccination can apparently no longer be stained. At considerable speed, i.e. about 3 mm/h, the virus migrates within the exoplasm into the ganglion cells of the spinal marrow and then into the brain where it finally develops an extensive meningoencephalomyelitis. The propagation into the periphery takes place through the axoplasmatic pathway up to the endings of the motor, sensory and autonomous nervous system. The rabies virus appears in the salivery gland, in the epithelium of the nose and the papillae of the tongue which leads to transmission. A viraemia has not been described. With regard to the question which are the differences between pathogenic and non-pathogenic rabies viruses, WUNNER'S working group at the Wistar Institute in Philadelphia, PA, USA, has made essential contribution to clarification (for overview, see WUNNER and DIETZSCHOLD 1987). They used neutralization-resistant variants of the virus fixe strains, studied them regarding their behaviour of killing intracerebrally inoculated mice. Utilizing a variety of monoclonal antibodies against the glycoprotein, the binding of which leads to virus neutralization, they searched for functional epitopes for antibody binding. By comparative analyses of the glycoproteins of pathogenic and non-pathogenic strains (analysis of tryptic peptides, aminoacid sequence analysis) it became clear that the solution of the question of "pathogenic or non-pathogenic" depends on an amino-acid substitution in position 333 of the glycoprotein molecule. An arginine in position 333 is of importance for the integrity of an antigenic determinant at the glycoprotein and for the induction of a lethal infection in the mouse. The loss of pathogenicity of various rabies virus strains is generally associated with the arginine substitution in position 333. In vitro and in vivo the evidence was provided that pathogenic rabies viruses perform a much more intensive cell-to-cell spreading than the non-pathogenic ones do (DIETZSCHOLD et al. 1985).

Unspecific and specific defence mechanisms in infection With respect to the induction of defence mechanisms, there are some differences compared to viruses that produce acute infectious disease: rabies viruses evade host immunity for a long time, which notably occurs in the early phase of infection by a marked neurotropism. In the nervous system itself, the virus is relatively isolated against antibodies and immune cells. Prior to the invasion into the nervous system a host response to the infection does not exist or it is not developed enough to achieve protection. The antiviral response is usually formed late in the course of the infection. As in other viral diseases, it is composed of a cascade in isolation or cooperating non-specific cellular and humoral mechanisms as well as of specific humoral and cell-mediated immune reactions. The significance of, e.g., interferons, macrophages, antibodies and various lymphocyte populations is being more and more investigated. Some of these components shall be explained in more detail: 1*

Exp. Pathol. 42 (1991) 1

3

Interferons Interferons are of great importance in the early phase of infection. The rabies virus is capable of interferon induction, in particular before its migration into the CNS. This is also the only time-point where interferons may playa significant part in modifying the infection. A later interferon induction is ineffective in preventing a viral replication. The action of the interferon itself is twofold; replication and spreading of the virus are reduced by direct inhibition of the replication and suppressed indirectly by induction or enhancement of the reaction of immune cells.

Macrophages Also in rabies are macrophages important cells of defence. By the phagocytic process they take up the virus and, thus, limit it in the wound, whereby the spreading to the muscle and nerve cell is decreased. According to in vitro findings, rabies viruses presumably cannot replicate in macrophages. For the induction of the immune reactions directed against the rabies virus, these cells exert an essential function by the virus antigen processing and the subsequent presentation of the antigen constituents.

Humoral immune response The concentration and the timing of the occurrence of virus-neutralizing antibodies in the serum during infection are of no great importance to the course of the infection. High antibody titers are often found in patients who died of rabies. The problem is that a stimulation of the antibody synthesis by the B-cells with involvement of rabies-virus-antigen-induced T-helper cells occurs in massive manner only when larger amounts of virus antigen have been synthetized. This intensive antibody synthesis frequently appears only when clinical symptoms occur. The antibody can be detected in the serum, often also in the liquor. Essentially, antibodies of the IgG class are formed and often few or no IgM, late in infection the latter being explained by the primarily slow progress of the disease. If, however, in an experimental infection of animals high virus doses are inoculated, the animal synthesizes larger quantities of IgM in 3-4 days. Virus-neutralizing antibodies are mainly immunoglobulins of the IgG class, which are directed against the glycoprotein; they are able, depending on the viral strain, to bind to 12-17 different epitopes, a fact that has been verified by employing monoclonal antibodies. Beyond viral neutralization, antibodies play a role after binding to viral antigens on the surface of infected cells in complement-dependent lysis or also in the antibody-dependent cellular cytotoxicity reactions (ADCC) by killer cells or large granular leukocytes (LGL). The meaning of the complement-dependent cytotoxicity reaction in the pathogenesis of rabies is unclear, perhaps this mechanism reduced the spreading of the virus from the lysed cell or it adds to the destruction of the virus-infected cells. The ADCC in vitro was described as a highly effective process (HARFAsT et al. 1977), the in vivo relevance is unknown, but it is a relatively early starting mechanisms, as only a relatively small amount of antibody molecules are required. Furthermore, through formation of complexes with the viruses and binding of these complexes to Fc-receptors of macrophages and subsequent phagocytosis, antibodies are able to better support processing and presentation of the viral antigens, whereby the effectivity of the immune response is elevated. It remains unclear whether IgM molecules can have also a virus-neutralizing effect and what is the role of IgA/slgA, in the latter case a viral neutralization on aerosol exposure of the mucous membrane at least being conceivable.

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Exp. Pathol. 42 (1991) 1

Cell-mediated response The cell-mediated immune response is probably the most important partial mechanisms of the immune response to rabies viruses. In this context, the T-cells gain importance via the helper effect for B-cells, cytotoxic T-cells and macrophages, as effector cells of the cellmediated response in the form of cytotoxic T-cells, with a direct involvement in defence processes being supposed, via delayed-type hypersensitivity, as suppressor cells for T- and Bcells and via the immunological memory. Apart from evidence from experimental studies in vitro there is also evidence from animal experiments suggesting that cytotoxic T-cells (CTL) represent an effective component of defence: animals that survived rabies demonstrate a strong CTL reaction. Intracerebrally inoculated animals develop normal interferon and antibody titers but only weak CTL activity and die in this immunological situation from the disease.

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Compared to virus-neutralizing antibodies, specific CTL against rabies virus antigens have the advantage of a considerably greater cross-reactivity for various viral strains. This is related to the recognition of nucleoprotein and matrix protein on the surface of infected target cells. The exact role of T-helper cells in the elimination of rabies viruses is not known (CELIS et al. 1988), however, it is certain that a lack of T-helper cells will result in a lethal outcome for animals subjected to experimental infection. The host response to rabies viruses is shown in fig. 2. Exp. Pathol. 42 (1991) 1

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Induction of defence mechanisms after antirabies vaccination As mentioned above, the sequestration phase is followed by a fIrst replication phase at the site of inoculation of the rabies virus , particularly in the striated muscles, until the virus enters the nerve endings through membrane fusions. From this early time-point of the incubation period onward, vaccination obviously will hardly be able to protect from the disease . From this, the cogent conclusion must be drawn that the chances of a successful antirabies vaccination rapidly decline with time after exposure and that an early start of the active immunization - if possible, within hours - will provide optimal conditions. Of importance is also the reduction of the viral inoculum in the wound area by appropriate measures and the provision of an immediate protection by combined active and passive immunization in risk patients . Antirabies vaccines are particularly suitable if immediately, i.e. within hours, interferons are synthesized (fIg. 3), if within a few days virus-neutralizing IgG antibodies are induced (fig. 4) and , thus, within a few days also ADCC is developed , 3-4 days after vaccination also an elevated activity of CTL should be present. In order to achieve this, a few highly effective antigen applications during administration of vaccine are better suited than many antigen applications with low concentrations of viral antigens. 0'

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Fig. 3. Number of interferon-positive probands before and 7, 20, 24 and 30 h after the first vaccination with 1 ml (_) and 3 ml (0), respectively , of a purified chicken embryo cell vaccine. The threefold dose was given to 10 probands , the 1 ml dose was administered to 11 vaccinees (from BAER et al. 1986).

Fig. 4. Antibody profiles and kinetics of antibody formation in 11 probands after initial simultaneous vaccination with homologous , human rabies immunoglobulin (20 IU/kg b.wt.) and HDC vaccine and further vaccination on days 3, 7, 14, 30 and 90 ( .. .. ) as well as in 8 probands who received only vaccine on days 0, 3, 7, 14, 30 and 90 who served as controls (----). The curves of the mean values of the titers differ only in the first 10 days after the start of the trial (._.- IgM ; - DEV, IgM and IgG; - Hempt, IgM and IgG) (from BAER et al. 1986). Nevertheless, a correlation of the presently measurable immunologic parameters, such as neutralizing antibodies and interferons in the blood as well as the cell mediated immune response , with the outcome of an infection is difficult. Several historical and the currently utilized antirabies vaccines are compiled in table 1. Apart from the modem vaccines, certain modes of behaviour during an application of vaccine are required to attain the necessary optimal immune reaction within the shortest time possible. Such an optimal immune reaction is counteracted, e.g., by the following: abuse of 6

Exp. Pathol. 42 (1991) 1

Table 1.

Development of antirabies vaccines for application in humans.

1st Generation Brain tissue vaccines PASTEUR 1885, first application in humans FERMI 1908, Semple, high neurocomplication rate HEMPT 1925 Brain tissue vaccine from suckling mice with low neurocomplication rate (FUENZALIDA and PALACIOS 1955) 2nd Generation Chicken and duck embryo vaccines Duck embryo vaccine (DEV) 1955/56 (PECK et al.) 3rd Generation Cell culture vaccines Primary hamster kidney cells (FENJE 1960) Tissue culture vaccine with Vnukovo-32 strain (SELIMOV et al. 1967) Human diploid embryo lung fibroblasts since 1973 (highly effective, yet expensive) (WIKTOR et al. 1964/65), therefore development of further cell culture vaccines: PVR vaccine, purified Vero rabies virus (heteroploid vero cells) viral strain Pitman Moore 15033 M PCEC vaccine: purified chick embryo cell (primary chick embryo fibroblasts) 4th Generation (Experimental vaccines) genetic-engineering vaccines etc. • subunit vaccines in combination with "immunosomes" or liposomes or virosomes (PERRIN et al. 1988) • synthetic peptides (glycoprotein) anti-idiotypical antibodies since 1983 (REAGAN et al. 1983; REAGAN 1985; UYT DE HAAG et al. 1986) • cloning of the G-protein in bacteria, yeasts and viruses, vectors live or dead (adenovirus, vaccinia virus) (on a vaccinia-virus vector basis successfully employed for the sanitation of raccoons, RUPPRECHT et al. 1987)

alcohol, excessive antigenic stimulation, false or deficient nutrition, emotional stress (ROKOS et al. 1987) as well as smoking (KUNZE et al. 1987). An essential element in ensuring the effectivity of an antirabic vaccination is the conformity of the antigen epitopes of wild and vaccine viruses. These problems should be given more attention worldwide . Antigen differences between wild and vaccine virus strains are incriminated for deaths despite vaccination (CELIS et al. 1988). LAFON et al. (1988) performed investigations to protect mice with various inactivated rabies virus vaccines (Pitman-Moore, PM), Pasteur virus (PV4) , Flury LEP, LEP) and challenged the animals with the European bat virus with antigenic relations to the Duvenhage strain Hamburg (DUV3). PV vaccine protected the animals from DUV3, however, PM or LEP vaccine did not. As already has been pointed out, the antigenic structure ofthe rabies viruses and the rabies-like viruses is characterized in the genus lyssa by the nucleoprotein, a group-specific antigen which induced precipitating and complement-fixing antibodies, the detection of which in virus-infected cells with the aid of FAT enables to establish the diagnosis of lyssa, whereas the neutralizing antibodies are formed by the glycoproteins depending on the strain. These neutralizing antibodies react with essential epitopes of the virus glycoprotein, which can be differentiated by their function. The similarities or differences in these epitopes in different rabies virus strains are decisive for the formation of protection by vaccination (LAFON et al. 1988). Exp. Pathol. 42 (1991) 1

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The vaccination with the available vaccines induces neutralizing antibodies. This effect has so far been supposed to playa key role in protection from infection, but there is a variety of suggestions that antibodies alone cannot reduce mortality . BAER et al. (1986) compared the evolution of immunity after antirabies vaccination of humans with brain tissue vaccine (Hempt), duck embryo vaccine and human diploid cell vaccine (HDCV) (fig. 4). Using HDCV, neutralizing antibodies are formed very early after the commencement of vaccination (days 0, 3, 7,14,30,90), at 2-4 weeks they reach their peak values and can be identified for some 3 years. Here, the relatively early conversion of the IgM antibodies (after few days) is of special importance in attaining a solid protection. Despite a much lower number of administered doses and amounts of vaccine, the HDCV in this study is considered to be 10-30 times stronger in its antigenicity than the Hempt brain tissue vaccine. Furthermore, it also induces at least 3-4-fold higher antibody values than have been observed after protracted and stressful vaccination treatment with duck embryo vaccine. Interesting and important is also the finding that there is no interference between active and passive immunization. In case of appropriate vaccine, interferons are induced already after a few hours, but they persist only for a short time and often there is no restimulation by further administration of vaccine. Despite great differences in single vaccines and dosages, it becomes clear that these early induced interferons cause a protective effect, as could be documented in particular in studies on experimental animals. With respect to the cell-mediated immune response, a good antirabies vaccine can be expected to give a measurable CTL induction at 3 - 4 days, a maximal response at about 7 days, followed by a fall in the CTL activity at about the 10th or lith day after vaccination. In animal experiments, the CTL correlate with a protection from the disease. An effective attack of CTL on the virus-infected cell is not blocked by antibodies (e .g. , passive immunization) . It remains an open question whether the antgenic variability of the rabies viruses has also an influence upon the T-cell response. This problem is currently being studied with the aid of Thelper cell populations , e. g ., by means offragments ofthe glycoprotein. In general , T -helper cells are stimulated by these fragments equally well as by complete glycoprotein (WUNNER and DIETZSCHOLD 1987). The cross-reaction of the T -helper cells in antigen recognition seems to be greater than that of antibodies . T-cell clones were analyzed with high specificity for the virus used for immunization, other clones showed clear cross-reactivity with other rabies virus strains. The cross-reactivity of CTL is obviously also related to the recognition of internal viral antigens. The induction of CTL occurs by various vaccines to a very different extent, with high antigenicity always also leading to a strong reactivity of the CTL. Thus, an experimental vaccine, on the basis of a vaccinia virus vector with cloned gene for the glycoprotein , does indeed develop also specific CTL, however, the activity is clearly lower as compared to a whole virus vaccine (CELIS et al. 1985). In conclusion, a remark on the question of a possible potentiation of the immune response in case of combined application of antirabies virus antibodies with a rabies virus vaccine (when using mab against glycoprotein G). This results in a better phagocytosis of the immune complexes, leading to a better preparation and presentation of the antigens. The simultaneous vaccination not only results in an immediate availability of virus-neutralizing antibodies but also in a potentiation of the specific immune response (DEVANEY 1988). The hypothesis of the authors implies that the virus-mab-complex is phagocytized, all viral antigens, also nucleoprotein, are processed and transported to the surface of the antigen-presenting cell and are presented to the T-cells . These findings further contribute to warrant the application of combined active and passive immunization.

References BAER, J., SCHEIERMANN, N., MARCUS, I.: Tollwut : Epidemiologie und neue Impfstoffentwicklung. Die gelben Hefte 1986; 2: 67-78. CELIS, E., WIKTOR, T. J., DIETZSCHOLD, B., KOPROWSKI, H.: Amplification of rabies virus-induced stimulation of human T-cell lines and clones by antigen specific antibodies. J. Viro!. 1985; 56: 426-431.

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- KARR, R. W., DIETZSCHOLD, B., WUNNER, W. H., KOPROWSKI, H.: Genetic restriction and fine specificity of human T cell clones reactive with rabies. J. Immunol. 1988; 141: 2721-2728 . DEVANEY, M. A.: New approaches to animal vaccines utilizing genetic engineering. erit. Rev . Microbiol. 1988; 15: 269-295. DIETZSCHOLD, B., WIKTOR, T. J., TROJANOwSKI,J. Q.,MACFARLAN , R.I. , WUNNER, W. H., TORRES-ANJEL , M. J., KOPROWSKI, H. : Differences in cell-to-cell spread of pathogenic and apathogenic rabies virus in vivo and in vitro. J. Virol. 1985; 56: 12-18. FENJE, P. A.: A rabies vaccine from hamster kidney tissue cultures : preparation and evaluation in animals. Can. J. Microbiol. 1960; 6: 605-609. FUENZALIDA, E., PALACIOS, R.: Rabies vaccine prepared from brains of infected suckling mice. Boletino Instituto Bacteriologico Chile 1955; 8: 3-10. HARFAST, B., ANDERSSON, T., GRANDlEN, M.: Enhanced cytotoxicity of human lymphocytes against rabiesinfected cells by rabies-specific antibodies. Scand. J. Immunol. 1977; 6: 1107-1112. KOPROWSKI, H.: Rabies . In : Concepts in viral pathogenesis (eds. NOTKINS, A. L., OLDSTONE, M. B. A.), pp. 344-349. Springer-Verlag, New York-Berlin-Heidelberg-Tokyo 1984. KUNZE, R., HOSKENS, C. , ROKOS , K., HIELBIG , J., BOSKER , G., REICHART, P., KOCH , M. A.: EinfluB von Komponenten des Tabakkondensats auf die Reaktivitat humaner immunkompetenter Zellen in vitro. Bundesgesundheitsblatt 1987 ; 30 : 341- 348. LAFON , M., BOURHY, H., SUREAU, P.: Immunity against the European bat rabies (Duvenhage) virus induced by rabies vaccines: an experimental study in mice. Vaccine 1988; 6: 362-368. OXFORD, J. S., OBERG, B.: Conquest of viral diseases. Elsevier Amsterdam, New York, Oxford 1985, pp. 229-254. PARKMAN, P. D., HOPPE, H. E.: Viral vaccines and antivirals: Current use and future prospects. Ann. Rev. Public Health 1988; 9: 203-221. PECK, F. B., POWELL, H. M., CULBERTSON , C. G.: Duck embryo rabies vaccine. Study offixed virus vaccine grown from embryonated duck eggs and killed with beta-propiolactone (BPL). JAMA 1956; 162: 1373-1376. PERRIN, P. , JOFFRET, M. L. , OTH, D., LECLERC, C., SUREAU, P. , THIBODEAU, L. : Interleukin-2-production in vitro: a new approach to the study of rabies vaccine immunogenicity as appraised by testing different glycoprotein presentations. Vaccine 1988; 6: 331-338. RAEGAN , K. J. : Modulation of immunity to rabies virus induced by anti-idiotypic antibodies. Curro Top. Microbiol. Immunol. 1985; 119: 15-30. - WUNNER, W. H., WIKTOR, T. J., KOPROWSKI, H.: Antiidiotypic antibodies induce neutralizing antibodies to rabies virus glycoprotein. J. Virol. 1983; 48: 660-666. ROKOS , H., ROKOS, K., KUNZE, R. O. F.: Anderungen von Immunparametern bei physischer Belastung (Joggen). Bundesgesundheitsblatt 1987; 30: 239-243. RUPPRECHT, C. E., DIETZSCHOLD, B., KOPROWSKI, H., JOHNSTON, D. H.: Development of an oral wildlife rabies vaccine: Immunization of raccoons by a vaccinia-rabies glycoprotein recombinant virus and preliminary field baiting trials . In: Vaccines 87, Cold Spring Harbor Laboratory 1987, pp. 389-392. SELlMOV ,M. A., AKSENOVA, T. A., SEMENOVA, E. V.: Study of the antigenic activity and safety of the tissue culture rabies vaccine in human volunteers. Vopr. Virusol. 1967; U: 36-41. UYT DE HAAG, F. C. G. M., BUNSCHOTEN, H., WEllER, K., OSTERHAUS, A. D. M. E.: From Jenner to Jerne: towards idiotype vaccines. Immunol. Rev. 1986; 90: 93-113. WIKTOR, T. J., KOPROWSKI, H.: Successful immunization of primates with rabies vaccine prepared in human diploid cell strain, WI - 38. Proc. Soc. Exp. BioI. Med. 1965; 118: 1069- 1073 . WUNNER, W. H.: Rabies viruses - pathogenesis and immunity. In: Therhabdoviruses (ed. WAGNER, R. R.), pp. 361-426. Plenum, New York-London 1987. DIETZSCHOLD, B.: Rabies virus infection: Genetic mutations and the impact on viral pathogenicity and immunity. Contribution Microbiol. Immunol. 1987; 8: 103-124.

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Immune reactions against rabies viruses--infection and vaccination.

Exp. Pathol. 1991; 42: 1-9 Gustav Fischer Verlag Jena Review Institute of Veterinary Medicine (Robert von Ostertag Institute), Federal Health Office...
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