TESTING MUCOSAL VACCINES IN AN ANIMAL MEASLES MODEL

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Measles, given the appropriate vaccine, is an eradicable disease. Problems with both fixed and live-virus vaccines have created interest in new approaches to measles vaccination. New vaccines should be effective when administered in the presence of maternal antibody because early immunization is essential in endemic settings. An impediment (perhaps more illusory than real) to testing new vaccine strategies has been that non- primate, laboratory animals do not develop a measles-like illness when inoculated with measles virus. However, canine distemper virus (CDV), a morbillivirus and thus a close relative of measles virus, does produce a measles-like infection in ferrets, a natural host of CDV: CDV is spread by the same route, infects the same target cells, causes a similar disseminated disease, and protection against reinfection is conferred by immunization with the same virus structural proteins (the fusion [F] and hemagglutinin [HA] proteins) as with measles. In addition, young ferrets are naturally protected against CDV infection by maternal antibody. In short, CDV is an ideal model for testing new morbillivirus vaccine strategies. Our long-term goal is to develop an effective measles vaccine that can be safely administered to all age groups. We will develop candidate vaccines for CDV suitable for mucosal and parenteral administration using the HA, F and N proteins. The mucosal route will be explored as a means to avoid the inhibitory effects of maternal antibody. We will develop recombinant vaccinia viruses for this purpose. We will also purify F and HA by affinity chromatography for parenteral and mucosal administration with the cholera-toxin binding-subunit (CTB) as an adjuvant, and for preparation of ISCOMs. We will then determine the protective efficacy of these candidate vaccines in immunologically naive ferrets and in infant ferrets protected by maternal antibody. The contribution of mucosal and serum antibody to protection will be assessed by measuring total, HA- and F-specific serum and secretory antibody, virus-neutralization and fusion inhibition. We will also determine if F-, HA- and N-specific ferret antibodies will enhance infection of ferret macrophages in vitro, a principal target cell of CDV in vivo, because such enhancement could affect vaccination strategy and may have been a factor in the development of atypical measles after administration of formalin- fixed measles vaccines.