Variable Gene Use and Pneumococcal Immunity in AIDS

Project: Research project

Project Details


This is a competitive renewal application to continue the study of mechanisms of vaccine efficacy against
Streptococcus pneumoniae. Pneumococcal disease remains a cause of significant mortality and morbidity in
patients with HIV infection, particularly in regions where HAART is not available, and could re-emerge as a
major problem in those receiving HAART as they reach senescence. The importance of understanding
mechanisms of vaccine efficacy against pneumococcus is heightened by the prevalence of drug-resistant
isolates and concerns about the efficacy of licensed vaccines in immunocompromised adults and serotype
replacement in vaccinated children. Available knowledge cannot predict whether vaccine-induced immune
responses will be protective or the individuals who will be protected by vaccination. In the prior funding
period my research program made the observation that although it did not promote opsonophagocytosis in
vitro, the efficacy of a protective serotype-specific IgM was associated with modulation of the
proinflammatory cytokine response to experimental pneumococcal challenge in mice. These findings
challenged the current paradigm that links vaccine efficacy to opsonic antibody. The focus of this competing
renewal application is on the antibody characteristics and host variables that govern vaccine efficacy against
pneumococcal bacteremia and pneumonia. Our central hypothesis is that certain serotype-specific
antibodies mediate protection by modulating the host inflammatory response to pneumococcal infection. We
propose to validate or refute this hypothesis in mouse strains with defined cellular immune defects, which will
allow us to precisely define the contributions of T and B cells to vaccine efficacy. Three Specific Aims are
proposed: 1) To identify components of innate and cellular immunity required for vaccine efficacy against
pneumococcal bacteremia and pneumonia;2) To assemble a mechanistic framework of vaccine efficacy
based on the nature of the Ab response and immune response of the host;and 3) To identify mechanisms of
Ab efficacy against bacteremia and pneumonia and determine their dependency on the nature of the Ab and
immune status of the host. We anticipate that the studies proposed herein will provide important new
knowledge about the protective immune response to S. pneumoniae that will translate into identification of
new correlates of vaccine efficacy and the generation of hypotheses for future testing in human studies.
Effective start/end date7/1/001/31/12


  • Infectious Diseases
  • Immunology


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