This proposal is designed to explore the mechanisms of immunity to measles virus in rhesus macaques. Although the current live-attenuated measles virus vaccine is one of the safest and most efficacious vaccines of the twentieth century, several biological and practical issues limit its efficacy in the epidemic control of measles in developed countries and in the prevention of morbidity and mortality due to measles infection of infants in developing countries. In the presence of maternal immunity to measles virus, vaccination of infants in the first 6 to 9 months of life has a significant failure rate. In inner cities of the U.S. and in developing countries, exposure to measles puts infants in the first year of life at risk. Maternally-acquired neutralizing antibody can prevent take of the attenuated virus vaccine (which replicates poorly) but maternally-acquired antibody titers may not be sufficient to protect against infection with wild-type viruses. And maternally-acquired IgG cannot prevent initial replication of measles virus in the respiratory tract. In response to these issues, we aim to study the rhesus monkey infected with measles virus as an appropriate animal model. That measles virus strains of human origin replicate and produce disease in rhesus monkeys has been known for over 70 years. Rhesus monkeys were used to test vaccine strains of live-attenuated measles virus in the early 1960's, prior to human field trials. But probably because of the empirical success of the new vaccine, mechanisms of immunity and protection from measles virus - induced disease in rhesus monkeys have not been pursued. Research on the rhesus monkey's immune response to viral infection has progressed rapidly in a short time. The knowledge and methods that we have learned with simian AIDS will apply.directly to the study of measles virus immunity in rhesus monkeys. There will be 4 experimental procedures using rhesus monkeys. 1) A pathogenic stock of measles virus will be titrated for infectivity in juvenile monkeys by intranasal inoculation, and then protection from challenge infection will be attempted with the live- attenuated vaccine strain or a formalin-inactivated measles preparation. 2) Induction of a protective immune response to measles virus will be attempted by intranasal immunization with a genetically recombinant strain of attenuated adenovirus expressing measles virus antigens. 3) Measles- immunized dams will be boosted with measles hemagglutinin and fusion proteins during pregnancy to increase transfer of maternal neutralizing antibody to their infants. Alternatively, infants will be immunized mucosally (as determined in step 2 above) at birth. The infants will be challenged with pathogenic measles virus at 3 and 9 months of age. 4) To study the roles of helper and cytotoxic T lymphocytes in measles immunity, juvenile monkeys will receive anti-CD4 or anti-CD8 monoclonal antibodies I.V. to suppress the functions of these cells, and then be inoculated with measles virus.
| Zhu, Y D; Heath, J; Collins, J et al. (1997) Experimental measles. II. Infection and immunity in the rhesus macaque. Virology 233:85-92 |
| Zhu, Y D; Fennelly, G; Miller, C et al. (1997) Recombinant bacille Calmette-Guerin expressing the measles virus nucleoprotein protects infant rhesus macaques from measles virus pneumonia. J Infect Dis 176:1445-53 |
| McChesney, M B; Miller, C J; Rota, P A et al. (1997) Experimental measles. I. Pathogenesis in the normal and the immunized host. Virology 233:74-84 |
