Contribution of factor H-Binding protein sequence to the cross-reactivity of meningococcal native outer membrane vesicle vaccines with over-expressed fHbp variant group 1

PLoS One. 2017 Jul 25;12(7):e0181508. doi: 10.1371/journal.pone.0181508. eCollection 2017.

Abstract

Factor H-binding protein (fHbp) is an important meningococcal vaccine antigen. Native outer membrane vesicles with over-expressed fHbp (NOMV OE fHbp) have been shown to induce antibodies with broader functional activity than recombinant fHbp (rfHbp). Improved understanding of this broad coverage would facilitate rational vaccine design. We performed a pair-wise analysis of 48 surface-exposed amino acids involved in interacting with factor H, among 383 fHbp variant group 1 sequences. We generated isogenic NOMV-producing meningococcal strains from an African serogroup W isolate, each over-expressing one of four fHbp variant group 1 sequences (ID 1, 5, 9, or 74), including those most common among invasive African meningococcal isolates. Mice were immunised with each NOMV, and sera tested for IgG levels against each of the rfHbp ID and for ability to kill a panel of heterologous meningococcal isolates. At the fH-binding site, ID pairs differed by a maximum of 13 (27%) amino acids. ID 9 shared an amino acid sequence common to 83 ID types. The selected ID types differed by up to 6 amino acids, in the fH-binding site. All NOMV and rfHbp induced high IgG levels against each rfHbp. Serum killing from mice immunised with rfHbp was generally less efficient and more restricted compared to NOMV, which induced antibodies that killed most meningococci tested, with decreased stringency for ID type differences. Breadth of killing was mostly due to anti-fHbp antibodies, with some restriction according to ID type sequence differences. Nevertheless, under our experimental conditions, no relationship between antibody cross-reactivity and variation fH-binding site sequence was identified. NOMV over-expressing different fHbp IDs belonging to variant group 1 induce antibodies with fine specificities against fHbp, and ability to kill broadly meningococci expressing heterologous fHbp IDs. The work reinforces that meningococcal NOMV with OE fHbp is a promising vaccine strategy, and provides a basis for rational selection of antigen sequence types for over-expression on NOMV.

MeSH terms

  • Animals
  • Antibody Formation
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / immunology*
  • Antigens, Bacterial / therapeutic use
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • Bacterial Proteins / therapeutic use
  • Cloning, Molecular
  • Complement Factor H / immunology*
  • Female
  • Humans
  • Immunization
  • Meningococcal Infections / blood
  • Meningococcal Infections / immunology
  • Meningococcal Infections / prevention & control*
  • Meningococcal Vaccines / genetics
  • Meningococcal Vaccines / immunology*
  • Meningococcal Vaccines / therapeutic use
  • Mice
  • Mutation
  • Neisseria meningitidis / genetics
  • Neisseria meningitidis / immunology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / therapeutic use

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Meningococcal Vaccines
  • Recombinant Proteins
  • factor H-binding protein, Neisseria meningitidis
  • Complement Factor H

Grants and funding

The research leading to this publication has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007- 2013/ under REA grant agreement n° 316940, European Industrial Doctorate Programme VADER (Vaccine Design and Immune Responses), whose beneficiaries were GSK Vaccines Institute for Global Health (former Novartis Vaccine Institute for Global Health) and University of Birmingham. GSK Vaccines Institute for Global Health and University of Birmingham also contributed. ID, OK, CM, FM, SR, and AS were employees of Novartis Vaccines and Diagnostics Srl at the time of the study. Following the acquisition of Novartis Vaccines by the GSK group of companies in March, 2015, MA, ID, OK, FM, SR, AS are now employees of the GSK group of companies. The funder provided support in the form of salaries for authors [AM, MA, ID, OK, FM, CM, SR, AS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.