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

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.