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Synthesis of a conjugate vaccine composed of pneumococcus type 14 capsular polysaccharide bound to pertussis toxin
R Schneerson1, L Levi, J B Robbins
1Laboratory of Developmental and Molecular Immunity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Insights
A new Streptococcus pneumoniae (Pn14) and Bordetella pertussis (PT) conjugate vaccine was developed. This Pn14-PT conjugate shows promise for protecting infants and children against both bacterial infections.
Area of Science:
- Immunology
- Vaccine Development
- Microbiology
Background:
- Streptococcus pneumoniae type 14 (Pn14) is a common pathogen but a poor immunogen in young children.
- Pertussis toxin (PT) is a key antigen for Bordetella pertussis vaccines but is poorly soluble and can be challenging to formulate.
- There is a need for improved vaccines targeting both S. pneumoniae and B. pertussis, especially for pediatric populations.
Purpose of the Study:
- To develop a conjugate vaccine combining Pn14 and PT.
- To assess the immunogenicity and efficacy of the Pn14-PT conjugate in a preclinical model.
Main Methods:
- A synthetic scheme was devised to conjugate Pn14 with PT using an adipic acid hydrazide linker and carbodiimide-mediated condensation.
- The biological activity of PT was assessed post-conjugation using CHO cell and histamine-sensitizing assays.
- Antibody responses to Pn14 and PT were measured in mice immunized with the conjugate.
Main Results:
- The conjugation process successfully inactivated PT, as demonstrated by reduced CHO cell and histamine-sensitizing activity.
- The Pn14-PT conjugate elicited antibodies against Pn14 at levels predicted to be protective in humans.
- The conjugate also induced neutralizing antibodies against PT in immunized mice.
Conclusions:
- The Pn14-PT conjugate is a promising candidate vaccine for simultaneously protecting against Streptococcus pneumoniae and Bordetella pertussis infections.
- The conjugate demonstrated effective immunogenicity in a preclinical model, warranting further clinical evaluation.
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.