An OMV Vaccine Derived from a Capsular Group B Meningococcus with Constitutive FetA Expression: Preclinical Evaluation of Immunogenicity and Toxicity

Abstract

Following the introduction of effective protein-polysaccharide conjugate vaccines against capsular group C meningococcal disease in Europe, meningococci of capsular group B remain a major cause of death and can result in debilitating sequelae. The outer membrane proteins PorA and FetA have previously been shown to induce bactericidal antibodies in humans. Despite considerable antigenic variation among PorA and FetA OMPs in meningococci, systematic molecular epidemiological studies revealed this variation is highly structured so that a limited repertoire of antigenic types is congruent with the hyperinvasive meningococcal lineages that have caused most of the meningococcal disease in Europe in recent decades. Here we describe the development of a prototype vaccine against capsular group B meningococcal infection based on a N. meningitidis isolate genetically engineered to have constitutive expression of the outer membrane protein FetA. Deoxycholate outer membrane vesicles (dOMVs) extracted from cells cultivated in modified Frantz medium contained 21.8% PorA protein, 7.7% FetA protein and 0.03 μg LPS per μg protein (3%). The antibody response to the vaccine was tested in three mouse strains and the toxicological profile of the vaccine was tested in New Zealand white rabbits. Administration of the vaccine, MenPF-1, when given by intramuscular injection on 4 occasions over a 9 week period, was well tolerated in rabbits up to 50 μg/dose, with no evidence of systemic toxicity. These data indicated that the MenPF-1 vaccine had a toxicological profile suitable for testing in a phase I clinical trial.

Bacterial outer membrane vesicles: New insights and applications

“…Immunogenicity of OMVs has been a subject of an experimental vaccine and has culminated in many promising results against a number of bacterial infections (Acevedo et al, 2014;Asensio et al, 2011;Gaillard et al, 2014;Leitner et al, 2015;Mitra et al, 2016;Norheim et al, 2015;Park et al, 2011;Price et al, 2016;Roberts et al, 2008;van der Pol et al, 2015). Small size, immunogenic properties, and nonreplicative behavior of OMVs make them a good choice for vaccination.…”

Immunogenicity profiling of protein antigens from capsular group B Neisseria meningitidis

“…However, the sequence hypervariability of several NmB OMPs has hampered the development of a universal vaccine using a single OMV. The protection induced by OMV vaccines is largely directed at the hypervariable PorA antigen, the most abundant protein in OMVs 8 . There is therefore a need to identify other vaccine candidates that are more conserved and can also provide protection against NmB infections.…”

“…Here we designed a panel of 91 OMPs, including iOMPs, which have been identified as potential vaccine candidates and are also OMV components 10,15 . The antisera used were derived from a Phase I study using an OMV preparation from a modified NmB strain H44/76, termed MenPF-1, in which the fetA promoter was modified to ensure constitutive expression of the iron transporter FetA 8,30,31 . This work represents the most comprehensive attempt yet to compare the immunogenicity of OMP components of an N. meningitidis OMV vaccine in humans and mice.…”

Emerging Technologies for Low‐Cost, Rapid Vaccine Manufacture

“…OMVs are spherical entities of endocytic origin with diameters normally ranging between 20–250 nm . These virus‐sized lipid bilayer vesicles with embedded proteins can be highly immunogenic . OMV‐based vaccines can be produced by: a) culturing wild‐type bacteria which naturally secrete OMVs; b) detergent extraction using sodium deoxycholate in the presence of EDTA; and c) culturing genetically altered bacteria for enhanced OMV production .…”