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Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate
Nicole I Richardson1, Michelle M Kuttel2, Frank St Michael3
1Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
Insights
Haemophilus influenzae serotype a is rising, especially in Indigenous North Americans. Molecular modeling reveals distinct structures for serotype a and b polysaccharides, explaining limited cross-protection and supporting a new serotype a vaccine.
Area of Science:
- Microbiology
- Immunology
- Computational Biology
Background:
- Haemophilus influenzae causes meningitis, particularly in children.
- Haemophilus influenzae serotype b (Hib) conjugate vaccines reduced disease, but serotype a is increasing, especially in Indigenous North American populations.
- Understanding polysaccharide structure is key to vaccine development.
Purpose of the Study:
- To investigate the molecular conformations of Haemophilus influenzae serotype a and b capsular polysaccharides using molecular modeling.
- To explore potential differences in polysaccharide structure that could affect antibody cross-reactivity.
- To provide insights supporting the development of a serotype a conjugate vaccine.
Main Methods:
- Utilized molecular modeling to simulate and analyze the preferred conformations of serotype a and b capsular polysaccharides.
- Compared the structural characteristics and surface properties of the polysaccharides.
- Correlated molecular modeling findings with existing immunological data on serotype cross-reactivity.
Main Results:
- Simulations revealed distinct conformational differences between Haemophilus influenzae serotype a and b polysaccharides.
- Identified potential variations in polysaccharide surfaces that may influence antibody binding and cross-reactivity.
- Findings align with immunological data showing limited cross-protection between heterologous serotypes.
Conclusions:
- The structural dissimilarity between serotype a and b capsular polysaccharides suggests a lack of cross-reactivity.
- Molecular modeling provides a basis for understanding observed immunological data.
- These findings strongly support the ongoing development of a conjugate vaccine targeting Haemophilus influenzae serotype a.
Abstract:
Haemophilus influenzae is a leading cause of meningitis disease and mortality, particularly in young children. Since the introduction of a licensed conjugate vaccine (targeting the outer capsular polysaccharide) against the most prevalent serotype, Haemophilus influenzae serotype b, the epidemiology of the disease has changed and Haemophilus influenzae serotype a is on the rise, especially in Indigenous North American populations. Here we apply molecular modeling to explore the preferred conformations of the serotype a and b capsular polysaccharides as well as a modified hydrolysis resistant serotype b polysaccharide. Although both serotype b and the modified serotype b have similar random coil behavior, our simulations reveal some differences in the polysaccharide conformations and surfaces which may impact antibody cross-reactivity between these two antigens. Importantly, we find significant conformational differences between the serotype a and b polysaccharides, indicating a potential lack of cross-reactivity that is corroborated by immunological data showing little recognition or killing between heterologous serotypes. These findings support the current development of a serotype a conjugate vaccine.
