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Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate immunogenicity studies

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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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Data availability

All data has been disclosed.

Code availability

Not applicable.

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

Funding

This research was partially funded by the University of Cape Town (MSc scholarship for N.I.R).

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Authors and Affiliations

  1. Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Nicole I. Richardson & Neil Ravenscroft

  2. Department of Computer Science, University of Cape Town, Rondebosch, 7701, South Africa

    Michelle M. Kuttel

  3. Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, ON, K1A 0R6, Canada

    Frank St. Michael, Chantelle Cairns & Andrew D. Cox

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  1. Nicole I. Richardson
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  2. Michelle M. Kuttel
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  3. Frank St. Michael
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  4. Chantelle Cairns
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  5. Andrew D. Cox
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  6. Neil Ravenscroft
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Contributions

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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Correspondence to Neil Ravenscroft.

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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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