Synthesis of a conjugate vaccine composed of pneumococcus type 14 capsular polysaccharide bound to pertussis toxin

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Abstract
Type 14 is one of the common types isolated from patients of all ages with infections caused by Streptococcus pneumoniae. Its capsular polysaccharide (Pn14) is composed of a neutrally charged tetrasaccharide repeat unit. Pn14 does not elicit protective levels of antibodies in infants and children and is a less than optimal immunogen of the 23-valent vaccine for adults. Pertussis toxin (PT) is both a virulence factor and protective antigen of Bordetella pertussis: it is not soluble at neutral pH and forms insoluble complexes with acidic polysaccharides. Both Pn14 and PT are potential components of vaccines for infants and children. Accordingly, a synthetic scheme was devised to prepare a conjugate of Pn14 and PT. An adipic acid hydrazide derivative of Pn14 was bound to PT at pH 3.9 by carbodiimide-mediated condensation. The conjugation procedure inactivated the PT as assayed by CHO cell and histamine-sensitizing activity. The Pn14-PT conjugate elicited antibodies in mice to Pn14 at levels estimated to be protective in humans and elicited neutralizing antibodies to PT. We plan to evaluate Pn14-PT clinically.