Recovery from measles is associated with life-long immunity that is reflected by the persistence of antibody. Protection after infection with wt virus or after live vaccine is closely associated with levels of neutralizing and hemagglutination-inhibiting antibody; experiences in immunosuppressed children also suggests that a virus-specific cellular immune response is essential for recovery. The currently licensed live attenuated measles virus vaccine is safe and effective when given at 9-15 months of age, but the vaccine is less effective in infants under the age of 9 months, and urban outbreaks have recently involved many young infants. Although immunization of infants as young as 4-6 months has been successful using a 10-100 fold higher dose of vaccine virus, such immunization has been associated with a poorly understood increase in susceptibility to subsequent infections and has been abandoned as a strategy for improving the vaccine and lowering the age of immunization. An inactivated vaccine was one of the earliest measles vaccines introduced. After 3 doses of alum-precipitated, formalin-inactivated vaccine, neutralizing antibody adequate to protect against wild-type viruses was present for a few months, but protection rapidly waned. In addition, approximately 15% of children immunized with this vaccine who subsequently contracted measles developed a severe form of the disease known as atypical measles. This complication has been ascribed to the low levels of antibody to the fusion protein that were induced by the inactivated vaccine, but this pathogenic mechanism has never been proven. Failure to understand the pathogenesis of atypical measles continues to impede the development of newer vaccines for all paramyxoviruses. The current proposal represents a competitive renewal of an original award granted in 1993 to investigate immune responses to measles and atypical measles in non-human primates. In this proposal the investigators propose follow-up studies and other work to determine the pathogenesis of atypical measles, characterize the immune responses to prototype live and inactivated vaccines, and to continue development of cDNA-based measles vaccines.
The specific aims of the proposal are: 1) to characterize the immune responses to formalin-inactivated vaccine and live attenuated vaccines by comparing the specificities and biological properties of anti-measles virus antibodies, T cell effector functions, and the cytokines induced by immunization; 2) to define the nature of the immune responses after challenge with wild-type measles virus in unimmunized monkeys and in monkeys previously immunized with live or formalin-inactivated vaccines; and 3) to determine the nature of the immune response to and the efficacy of H, F an d/or N cDNA vaccines delivered by different routes of inoculation in monkeys.
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|Pan, Chien-Hsiung; Valsamakis, Alexandra; Colella, Teresa et al. (2005) Inaugural Article: Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles. Proc Natl Acad Sci U S A 102:11581-8|
|Hoffman, Scott J; Polack, Fernando P; Hauer, Debra A et al. (2003) Measles virus infection of rhesus macaques affects neutrophil expression of IL-12 and IL-10. Viral Immunol 16:369-79|
|Hoffman, Scott J; Polack, Fernando P; Hauer, Debra A et al. (2003) Vaccination of rhesus macaques with a recombinant measles virus expressing interleukin-12 alters humoral and cellular immune responses. J Infect Dis 188:1553-61|
|Polack, Fernando P; Hoffman, Scott J; Moss, William J et al. (2003) Differential effects of priming with DNA vaccines encoding the hemagglutinin and/or fusion proteins on cytokine responses after measles virus challenge. J Infect Dis 187:1794-800|
|Polack, Fernando P; Hoffman, Scott J; Crujeiras, Gonzalo et al. (2003) A role for nonprotective complement-fixing antibodies with low avidity for measles virus in atypical measles. Nat Med 9:1209-13|
|Moss, W J; Polack, F P (2001) Immune responses to measles and measles vaccine: challenges for measles control. Viral Immunol 14:297-309|
|Robinson, H L; Pertmer, T M (2000) DNA vaccines for viral infections: basic studies and applications. Adv Virus Res 55:Jan-74|
|Polack, F P; Lee, S H; Permar, S et al. (2000) Successful DNA immunization against measles: neutralizing antibody against either the hemagglutinin or fusion glycoprotein protects rhesus macaques without evidence of atypical measles. Nat Med 6:776-81|
|Torres, C A; Yang, K; Mustafa, F et al. (1999) DNA immunization: effect of secretion of DNA-expressed hemagglutinins on antibody responses. Vaccine 18:805-14|
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