VARIABLE GENE DEFECTS AND PNEUMOCOCCAL SUSCEPTIBILITY

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from Applicant's Abstract): The rationale for vaccination
with pneumococcal capsular polysaccharide (PPS) vaccines is to induce opsonic
antibodies to PPS, which are required for protection against Streptococcus
pneumoniae. However, available PPS-based vaccines are poorly immunogenic in
many patients at the highest risk for pneumococcal infection. Based on the
following evidence we hypothesize that reduced expression of immunoglobulin
genes from the VH3 subgroup translates into an impaired anti-PPS response: i)
antibodies to PPS are oligoclonal and use genes from the VH3 subgroup; ii)
reduced VH3 expression has been reported in patients at risk for pneumococcal
infection that generate poor responses to PPS vaccines. This application
proposes to determine structure-function relationships for human antibodies to
serotype 3 S. pneumoniae, a cause of invasive pneumococcal infection in adults
and children. The specific aims are: 1) To determine the molecular structure of
human mAbs to PPS 3 generated in transgenic mice reconstituted with human
immunoglobulin loci; 2) To characterize the infection in mice and as opsonic or
non-opsonic in vitro; 3) To use mAbs with molecular structure as defined in Aim
1 and functional efficacy as defined in Aim 2 to select peptide mimics of PPS 3
epitopes, and to use the peptides to determine if PPS-elicited antibodies in
patients recognize protective, non-protective or disease-enhancing epitopes.
Our studies will provide evidence to support or refute the hypothesis that
pneumococcal vaccine failure results from an inability to produce antibodies to
PPS epitopes with a certain molecular structure. This work will provide a new
scientific knowledge base regarding structure-function relationships for
antibodies to PPS 3 that can be used clinically to evaluate vaccine efficacy
and to develop more immunogenic vaccines for patients at risk for pneumococcal
infection.
StatusFinished
Effective start/end date4/1/013/31/02

Funding

  • National Institute of Allergy and Infectious Diseases: $376,875.00

ASJC

  • Microbiology (medical)
  • Infectious Diseases
  • Molecular Medicine
  • Virology
  • Immunology

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