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An Immune Stimulating Complex (ISCOM) Subunit Rabies Vaccine Protects Dogs and Mice Against Street Rabies Challenge

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An Immune Stimulating Complex (ISCOM) Subunit Rabies Vaccine Protects Dogs and Mice Against Street Rabies Challenge An immune stimulating complex (ISCOM) subunit rabies vaccine protects dogs and mice against street rabies challenge M. Fekadu*ll~ J.H. Shaddock*, J. Ekstr6m*, A. Osterhaus *, D.W. Sanderlin*, B. Sundquist ,~ and B. Morein* Dogs and mice were immunized with either a rabies glycoprotein subunit vaccine incorporated into an immune stimulating complex (ISCOM) or a commercial human diploid cell vaccine ( HDCV) prepared from a Pitman Moore ( PM) rabies vaccine strain. Pre-exposure vaccination of mice with two in traperitoneal ( i.p. ) doses of 360 ng ISCOM or 0.5 ml HDCV protected 95% (38/40) and 90% (36/40) of mice, respectively, against a lethal intracerebral (i.c.) dose with challenge virus strain (CVS). One 360 ng i.p. dose of ISCOM protected 87.5% (35/40) of mice against i.c. challenge with CVS. Three groups of five dogs were vaccinated intramuscularly ( i.m.) with 730 ng of rabies ISCOM prepared from either the PM or the CVS rabies strains, and they resisted lethal street rabies challenge. Postexposure treatment of mice with three or four 120 ng i.m. doses of ISCOM protected 90% (27/30) and 94% (45/48), respectively, of mice inoculated in the footpad with street rabies virus, but three doses of HDCV conferred no protection. When .four doses of HDCV were administered postexposure, 78% (32/41) of the mice died of anaphylactic shock; 21% (11/52) of mice had already died of rabies 4 days after the third vaccine dose was administered. Keywords : Rabies ; ISCOM ; human diploid cell vaccine ; postexposure ; treatment ; anaphylactic shock INTRODUCTION animals only pre-exposure vaccination is practised. Although the immunological basis of protection following Rabies is endemic in most of the world, and rabid dogs vaccination with inactivated or live attenuated rabies are responsible for >90% of human rabies deaths 1'2. virus vaccines is still not fully understood, it has been Various types of human and animal vaccines are used shown that both humoral and cellular immune responses worldwide for the prevention of rabies. These vaccines are induced by rabies virus vaccines 14~16. are prepared from brain tissue of adult or newborn Rabies virus particles contain five different proteins. animals 3-6, avian tissues v-9, or cell cultures 1°-11. The Closely associated with the nucleoprotein (N) are the virus strains used for vaccine production are usually non-structural (NS) protein and the virion transcriptase derived from the Pasteur fixed rabies virus strain, and (L). The N-protein represents the group-specific antigen the virus is usually inactivated by physical or chemical of the genus. The matrix (M) protein and the glycoprotein methods a 13. In humans, rabies vaccines are used for (G) are located in a lipoprotein envelope, through which both pre- and postexposure immunization, whereas in spikes of G protein project 17-19. Spike G-proteins are amphiphilic proteins with at least one subunit of the *Rabies Laboratory, Viral and Rickettsial Zoonoses Branch, oligomeric protein inserted into the lipid bilayer of the Division of Viral and Rickettsial Diseases, Center of Infectious viral envelope anchoring the spike to the membrane z°. Diseases, Centers for Disease Control, Public Health Service, US Department of Health and Human Services, Atlanta, GA For rabies virus and most other enveloped viruses, 30333, USA. "{'The National Veterinary Institute, Department the spike G-proteins are the antigens responsible for of Virology, Biomedical Center, Uppsala, Sweden. +National stimulating virus-neutralizing antibody 21-26. It has also Institute of Public Health and Environmental Hygiene, been shown that the N-protein (through another Bilthoven, The Netherlands. §The National Veterinary mechanism) can induce a protective immune response Institute, Division of Vaccine Research, Uppsala, Sweden. against rabies infection in animals zT'2s. lITo whom correspondence should be addressed. (Received One of the crucial points in eliciting immunity and 23 January 1991 ; revised 8 October 1991 ; accepted 8 October protection is the effective presentation of the desired 1991 ) antigens in a vaccine. To date, relatively little attention 0264~410X/92/030192~)6 ~: 1992 Butterworth-HeinemannLtd 192 Vaccine, Vol. 10, Issue 3, 1992 ISCOM subunit rabies vaccine: M. Fekadu et al. has been paid to the physical form in which antigens Triton X-100, and the unbound material was washed out should be presented to the immune system. Since it of the column with 10 volumes of TN-buffer. Mega-10 is now possible to isolate spike proteins as single was then introduced into the column at a concentration peplomers from virion or through recombinant-DNA of 0.05% in TN buffer. Material specifically bound to techniques, more immunogenic forms of presentation the lectin column was eluted with 0.2 r,! methyl have become available such as protein micelles, virosomes, glycopyranoside dissolved in TN-buffer, containing 0.5% or the recently described immune stimulating complexes Mega-10. After elution peak, fractions were pooled and (ISCOMs). In addition, antigenically and physically concentrated by a 30 K cut-off ultrafiltration device defined subunit vaccines can now be formulated15,~ 6,29-33. (Filtron) to a final volume of 25 ml. To this concentration Although protein micelles or liposomes containing 4 mg lipid was added from a stock solution containing multiple copies of virus G-protein have been shown to 10mg cholesterol and 10mg phosphatidyl choline have considerable immunogenicity 34'35, this immuno- dissolved in water with 20% Mega-10. Quil-A was added genicity largely depends on the addition of suitable to a final concentration of 0.1%, and the mixture was adjuvant 36. dialysed for 3 days against three changes of TN-buffer, The ISCOM structure was developed to create a well pH 7.4, at room temperature. The formation of ISCOM defined submicroscopic particle, one that presents several was confirmed by determination of the S-value 46 in copies of antigen exposed on a built-in saponin adjuvant sucrose gradient centrifugation by negative contrast (Quil-A)35'37-39. ISCOMs containing one or more viral electron microscopy of the gradient fractions. envelope proteins of more than 20 different membrane viruses belonging to eight different virus families have Animals been prepared ; all were shown to be highly immunogenic in various animal species, and they induced high All animals used in this experiment were raised in protective immunity and good T-cell response 3v'4°-44. closed colonies at the Centers for Disease Control animal This report presents data on the serological response and breeding facility. None of the dogs had been previously protection from challenge in animals immunized with vaccinated against rabies, and none had rabies virus- either an ISCOM containing the rabies G-protein or with neutralizing antibodies (VNA) at the time of inoculation a commercial human diploid cell rabies vaccine. (vaccination). MATERIALS AND METHODS Determination of antigenic values ISCOM preparation The National Institutes of Health (NIH) potency test 4v was used to determine and standardize the ISCOMS 35'45 were prepared from either the Pitman antigenic values of the ISCOMs, HDCV and reference Moore (PM) or the challenge virus standard (CVS) vaccine 48. In brief, mice were vaccinated twice intra- rabies strains. Briefly, to ~ 200 mg purified virus in 8 ml peritoneally (i.p.) at a one-week interval with fivefold TN-buffer (0.05 M Tris-hydrochloride, pH 7.4, 0.1 M dilutions of each antigen. The vaccinated mice, along NaCI), 0.9 ml of a stock solution of detergent Mega-10 with groups of unvaccinated control mice, were then (decanoyl-N-methylglucamide) (Sigma)* was added to challenged intracerebrally (i.e.) with 30-100 mouse a final concentration of 2% and left for 2 h at room intracerebral lethal dose 50% (MICLDs0) ofCVS 1 week temperature. The solubilized virus was layered on top of after the last vaccination. All test antigens were then 10% sucrose in TN buffer containing 0.2% Mega-10 diluted to obtain similar antigenic values for use in the (w/v), which was layered on 30% sucrose in TN buffer. protection experiments. The solubilized virus was concentrated at 30000 rev min -1 for 2h at 20°C in a TST 41.14 rotor. The top fraction consisting of the sample volume plus the 10% Determination of VNA titres sucrose layer was collected and Quil-A was added to a VNA titres in sera collected from experimental animals final concentration of 0.1%. The mixture was extensively were determined by the rapid fluorescent focus inhibition dialysed for 72 h against three changes of TN buffer at test (REFIT)49. Results were expressed in international room temperature. units (IU) using an international standard reference For comparative purposes a commercial human serum 49. diploid cell vaccine (HDCV) (Imovax, lot no. Z-1355) prepared from the PM strain, and a reference rabies Immunofluorescence vaccine prepared from CVS (kindly supplied by National Veterinary Laboratory, Iowa, USA) served as controls. All dog sera were also tested for anti-nucleocapsid antibody titre by the indirect fluorescent antibody (IFA) Purification of ISCOM by lectin affinity chromatography technique using fluorescein-conjugated rabbit anti-dog globulin. Approximately 40 mg purified rabies virus was solubilized in 175 ml of 1% Triton X-100 solution and the viral G-protein was purified by affinity chromato- Pre-exposure vaccination of mice graphy on a lentil lectin-conjugated Sepharose CL-4B Groups of 4-week-old female CDs-ICR mice were column (Pharmacia Fine Chemicals, Uppsala, Sweden). vaccinated i.p. on days 0 and 7 with 0.5 ml containing The solubilized virus material was applied to the lectin 360 ng Gp of the respective ISCOM preparations, 0.5 ml column and equilibrated with TN-buffer containing 1% (containing 2.5 IU) HDCV, or the reference vaccine prior * Use of trade name or commercial sources is for identification only to i.e.
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