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

doi:10.1016/j.jinf.2015.05.006

Abstract

SummaryObjectivesOuter 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.MethodsThe 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.ResultsMenPF-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 FetAonPorAoff compared to 51% in the strain 44/76 FetAoffPorAoff, demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies.ConclusionThis 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.

Highlights

Capsular group B Neisseria meningitidis (MenB) is the predominant cause of invasive meningococcal disease (IMD) in most European countries.[1]
As Ferric enterobactin receptor (FetA) immunogenicity is less certain than PorA, which is immunodominant, we aimed to demonstrate that constitutive expression of FetA in an Outer membrane vesicle (OMV) vaccine simultaneously induces FetA and PorA bactericidal responses, to provide a proof-of-concept for a PorAeFetA vaccine
A vaccine recipe based on that from Russell et al.[35] was used to estimate potential coverage of a PorA/FetA vaccine based on meningococcal disease isolates collected over a number of decades in England and Wales, which had been characterised by PorA and FetA variable region (VR) sequence typing

Summary

Introduction

Capsular group B Neisseria meningitidis (MenB) is the predominant cause of invasive meningococcal disease (IMD) in most European countries.[1]. Successes with meningococcal A, C,Y and W polysaccharideeprotein conjugate vaccines have not been reproduced with MenB, perhaps due to antigenic similarity of group B capsule sialic acid and human foetal neuronal cells, which is a safety concern.[5,6] This has led to the development of formulations based on outer membrane vesicles (OMVs) containing PorA and other outer membrane proteins.[7] OMV vaccines have been shown to be safe, to induce protective serosubtype (PorA)-specific immune responses, and have been used to successfully control clonal outbreaks of MenB disease.8e14 these vaccines offer limited protection against different serosubtypes (PorA types) of MenB. The vaccine 4CMenB, recently licensed in Australia, Europe, Canada and the US, includes an OMV component in addition to recombinant proteins[15] to induce protection against one PorA type.[16]

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