The live attenuated measles vaccine has an outstanding efficiency and safety record and induces enduring immunity. We hypothesize that a currently used measles virus (MV) vaccine strain is an ideal platform for the development of pediatric vaccines eliciting immunity against other pathogens. We will test two propositions of this hypothesis: first that vectored MVs can protect against infection with another pathogen. Second, that they can elicit a strong immune response against other human pathogens whilst maintaining vaccine function against measles. To test the first proposition we will complete the production of a panel of vectored MV with the potential of inducing strong humoral and/or cellular immune responses to a mouse pathogen. We will take advantage of the detailed knowledge of the determinants of the immune response against the Daniels strain of the picornavirus Theiler. Proteins or peptides of this virus will be expressed in MV vectors with different scopes: induction of high neutralizing antibody titers, of specific cytotoxic T lymphocytes, or of both. The quality and strength of the immune response and the efficiency of protection against challenge with Theiler virus will then be measured in genetically modified mice permissive for MV infection. The correlates of vaccine efficiency will be established. To test the second proposition we will produce recombinant MVs with the potential of eliciting strong and sustained immune responses against two human pathogens for which an inexpensive vaccine requiring a single immunization is highly desirable. Recombinant MV expressing the surface antigen of the hepatitis B virus at different levels will be used to define the expression strategy most effective in inducing a strong humoral immune response. Recombinant MV expressing different proteins and CTL-inducing peptides of the hepatitis C virus will also be produced, and the strength of the induced humoral and cellular immune responses measured. Those viruses inducing the strongest immune response against hepatitis B and hepatitis C virus components in genetically modified mice will be inoculated into juvenile macaques. Their efficacy in protecting these primates against wild type measles infection and in inducing an immune response against the additional pathogen will be measured. ? ?
