Measles is the major childhood cause of death in the world attributable to a single cause. The overall objective of this proposal is to develop a novel strategy to provide protection against measles infection at the earliest time after birth with measles proteins expressed in recombinant BCG (rBCG), which is not neutralized by maternal antibody. There is a limit to the effectiveness of existing live attenuated measles vaccines in infants less than 9 months of age because they are neutralized by maternal IgG and, when given in a high-titer to overcome neutralization, are associated with increased mortality. While it is quite clear that antibodies against the measles conformational protective H and F proteins are effective at neutralization, they may not be appropriately presented in rBCG. The candidate's principal aim, then, is to attempt to prime for memory T cells with the nucleocapsid protein or other proteins of measles virus in the absence of production of neutralizing antibodies There are precedents involving T and B cell recognition of influenza that support these immunization principles. The general questions to be tested are whether upon subsequent challenge with a vaccine booster or natural virus infection, sufficient memory for T cell help is developed such that: 1) an accelerated secondary type neutralizing antibody response is developed, which if not able to prevent infection, can eliminate its serious consequences such as neurological damage and death; and 2) whether development of cytotoxic and lymphokine-producing T cells is sufficient to protect against viral disease. To test whether T cell priming with the internal N protein of measles leads to an accelerated secondary type antibody response to the protective conformational H and F epitopes after challenge with measles virus, rBCG::measles N primed mice will be challenged with intact virions and the kinetics of appearance of serum measles HAI and neutralizing antibody titers will be measured. In a similar manner, H and F antibody responses I.n mice primed with rBCG::measles H and F constructs will be studied. To determine whether rBCG measles constructs engage T cells in a manner that will elicit a protective immune response, measles-susceptible strains of mice (in which measles protection is largely cell-mediated) will be challenged with the rodent-adapted/CAM measles virus. In vitro measles purified N and whole virion-specific T cell proliferation, cytotoxic activity, and cytokine and lymphokine production will be determined along with viral titers and histopathology. Finally, the ability of beagles and cynomolgus monkeys vaccinated with rBCG::measles protein strains at a time when they have circulating maternally-acquired measles neutralizing antibody to later mount a protective immune response to either canine distemper virus (CDV), (a closely related Morbillivirus) or to virulent measles virus will be studied.
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| 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 |
| Fennelly, G J; Flynn, J L; ter Meulen, V et al. (1995) Recombinant bacille Calmette-Guerin priming against measles. J Infect Dis 172:698-705 |
