Streptococcus pneumonia is the most common cause of bacterial pneumonia in HIV+ individuals. Despite routine pneumococcal polysaccharide vaccination (PPV23) and the widespread use of HAART, antibody levels and the functional activity of antibodies are lower than in HIV-negative persons and disease incidence therefore remains 35-50 fold higher than in HIV negative individuals. Similarly, PPV23 is less effective in the elderly. The introduction of HAART has led to a significant increase in life-expectancy of HIV+ persons and soon more than 50% of HIV positive individuals will be older than 50. This population will likely be at very high risk for IPD based on their immune deficiencies secondary to HIV AND immunosenescence as suggested using multivariate analysis. Although there is considerable overlap in B cell alterations caused by HIV and by aging we have recently found that aging and HIV result in distinct B cell deficiencies. The recommendations for pneumococcal vaccination in HIV+ persons have recently changed to include the 13-valent conjugate vaccine (PCV13). Although several studies show short-term efficacy or increased antibody response in HIV+ persons with PCV13, others do not, in either HIV+ population or in elderly. Large efficacy trials necessary to establish clinical superiority of PCV13 compared to PPV23 will likely not be conducted, particularly in the aging HIV+ population. It is therefore essential that we define immune responses to conjugated and free- polysaccharide preparations by examining traditional antibody and functional levels and at B and T cell levels, critically affected by aging and HIV, both characterized by chronic inflammation. The fundamental question posed in this proposal is: will PCV followed by PPV23 elicit an immune response compatible with improved protection or is it identical to the immune response following PPV23, known to be associated with suboptimal protection? Aim 1 test the hypothesis that vaccination with either PPV23 alone or a PCV13 containing regimen results in comparable antibody levels/functional activity, determined by levels of chronic inflammation.
In aim 2, we test the hypothesis that the levels and phenotype of PPS-specific B cells will be comparable between the PPV23 and PCV13/PPV23 recipients. Phenotype analysis using a variety of B cell markers will be used to characterize PPS-labeled B cells. Specific phenotypes will be correlated with antibody levels, OPA and inflammatory markers and compared to historic populations immunized with PPV23.
In aim 3 we will test the hypothesis that functional T cell helper responses to the conjugate vaccine will predict levels of switched B cells and IgG produced after vaccination. This work is important and novel because it examines antigen-specific responses post immunization to the number one cause of pneumonia in HIV and elderly patients. It is high impact as it will determine if either of the present vaccines is acceptable methods of inducing protective immunity or new methods with different adjuvants are required.

Public Health Relevance

The goal of the research proposed in the current application is to define potential differences in how aging HIV-positive individuals respond to the T-independent form of the pneumococcal polysaccharide vaccine (PPV) compared to the presently recommended T-cell dependent form of the vaccine, the pneumococcal conjugate vaccine. The knowledge gained from these studies will determine if either of the present vaccines are acceptable methods of inducing protective immunity in this vulnerable population or new methods with different adjuvants are required.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG045973-02
Application #
8716638
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fuldner, Rebecca A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Toledo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Toledo
State
OH
Country
United States
Zip Code
43614