A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial

L Marsay, C Dold, C A Green, C S Rollier, G Norheim, M Sadarangani, M Shanyinde, C Brehony, A J Thompson, H Sanders, H Chan, K Haworth, J P Derrick, I M Feavers, M C Maiden, A J Pollard, L Marsay, C Dold, C A Green, C S Rollier, G Norheim, M Sadarangani, M Shanyinde, C Brehony, A J Thompson, H Sanders, H Chan, K Haworth, J P Derrick, I M Feavers, M C Maiden, A J Pollard

Abstract

Objectives: Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines.

Methods: The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults.

Results: MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA(on)PorA(off) compared to 51% in the strain 44/76 FetA(off)PorA(off), demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies.

Conclusion: This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

Keywords: FetA; Molecular epidemiology; Neisseria meningitidis; Outer membrane vesicles; Vaccine.

Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
A vaccine recipe (5PorA–FetA) based on that from Russell et al., 2008was used to estimate potential coverage and longevity of a PorA/FetA based recipe over a number of decades in England and Wales. (A) Potential coverage of PorA/FetA recipes in England and Wales 1975–1995, 2000–2002 and 2010–2013 dataset with increasing number of components (PorA variable regions – VRs). (B) Theoretical amount of disease incidence prevented/present if 5PorA/FetA recipe was implemented in England and Wales 1975–2012. Isolates with an exact match to at least one of the five PorA VR1, VR2 and FetA VRs were considered to be covered by the recipe.
Figure 2
Figure 2
Flow diagram for recruitment, enrolment and completion of trial. Withdrawals were not related to the study vaccine and all new and medically relevant information that was detected at screening were communicated to the candidate volunteers' General Practitioners with their permission.
Figure 3
Figure 3
Percentage of participants that had an SBA titre ≥1:4 at baseline and 4 weeks after 2 or 3 doses of MenPF-1. Percentage of participants with an SBA titre ≥1:4 as main bars (with 95% CI error bars) for participants receiving 25 μg of vaccine (lines) and 50 μg of vaccine (dark solid) at baseline and 4 weeks after 2 or 3 doses of MenPF-1. SBA titres were determined as the reciprocal dilution where bacterial survival was less than 50% of that of controls for the parental wild-type strain 44/76 (A), 44/76 FetAoffPorAoff(B), 44/76 FetAoffPorAon(C), 44/76 FetAonPorAoff(D) and 44/76 FetAonPorAon(E).

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