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.
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Abbreviations
- BSA:
-
Bovine serum albumin
- CPS:
-
Capsular polysaccharide
- ELISA:
-
Enzyme-linked immunosorbent assay
- Glc:
-
Glucose
- Hia:
-
H. influenzae Type a
- Hib:
-
H. influenzae Type b
- HibMe:
-
H. influenzae Type b methylated at O2 of ribose
- PRP:
-
Polyribosylribitolphosphate; Ribf: ribose/ribofuranose
- Rib-ol:
-
Ribitol phosphate
- RU:
-
Repeating unit
- SBA:
-
Serum bactericidal assay
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Acknowledgements
Computations were performed using facilities provided by the University of Cape Town’s ICTS High Performance Computing team: http://hpc.uct.ac.za. The authors wish to thank the staff of the NRC-Ottawa animal facility who carry out all animal work following NRC’s Human Health Therapeutics Research Centre’s animal care committee approved procedures that fall under the Canadian Council of Animal Care jurisdiction
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This research was partially funded by the University of Cape Town (MSc scholarship for N.I.R).
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Conceptualization, M.M.K and N.R; methodology, M.M.K; software, M.M.K and N.I.R; validation, M.M.K and N.I.R; investigation, N.I.R., F.S.M and C.C; resources, M.M.K. and N.R; data curation, M.M.K; writing—original draft preparation, A.C. and N.I.R.; writing—review and editing, M.M.K and N.R; supervision, A.C, M.M.K and N.R; visualization, M.M.K and N.I.R.; funding acquisition, M.M.K and N.R.
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Richardson, N.I., Kuttel, M.M., Michael, F.S. et al. Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate immunogenicity studies. Glycoconj J 38, 735–746 (2021). https://doi.org/10.1007/s10719-021-10020-0
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DOI: https://doi.org/10.1007/s10719-021-10020-0