Research Project
3148629
Streptococcus induced pneumonia is responsible for 40,000 deaths annually in the United States. This is true despite the presence of a multi-valent capsular polysaccharide vaccine and effective drug therapy. Infants, the immune compromised, and the elderly do not adequately respond to these T-independent antigens. Conjugations of polysaccharides to a carrier protein has overcome a similar problem with the Haemophilus influenzae b vaccine. This strategy would be difficult to apply directly to a pneumococcal vaccine which consists of 23 different polysaccharides. In the absence of an adjuvant, the shear mass of a pneumococcal conjugate vaccine would be to high and the cost of manufacturing prohibitive. Our proposed research program is designed to develop and characterize an improved 23 valent pneumococcal capsular polysaccharide vaccine. Improvements stem from the inclusion of OS-21 adjuvant, which is known to increase humoral immunity to polysaccharide antigens, and if necessary polysaccharides will be conjugated to diphtheria toxoid. Conjugate vaccines may gain an additional benefit from the addition of QS-21 since the adjuvant greatly enhances T-helper cell involvement in protein vaccines. Two chemically distinct polysaccharide types (14 and 19F) will be used for the initial evaluation of vaccine formulations. These types represent the 1st and 10th most frequently isolated pneumococcal types causing S. pneumonia bacteremia in the U.S. Experimental vaccine formulations, including the current vaccine, will be prepared and tested in mice and rats. The objective will be to 1) increase antibody titers, 2) broaden the isotype response, and 3) induce antibodies that mediate phagocyte directed bactericidal activity. Formulations which outperform the existing vaccine will be evaluated in a mouse bacteremia and rat pneumonia model. These models are designed as sublethal challenge to measure the ability of vaccines to limit the spread of L from the site of exposure. The overall goal of the program is to develop an improved pneumococcal vaccine that can provide increased protection to infants, the immune compromised, and the elderly.
