A Meningococcal Outer Membrane Vesicle Vaccine Incorporating Genetically Attenuated Endotoxin Dissociates Inflammation from Immunogenicity.

David J Dowling,Ilana Bergelson,Ofer Levy,Jeffrey Fernandez,Germie P J M Van Den Dobbelsteen,Carlo Pietrasanta,Spencer Brightman,Simon D Van Haren,Wing Ki Cheng,Sandra Van Amsterdam,Sweta Joshi,Holly Sanders

doi:10.3389/fimmu.2016.00562

Abstract

Group B Neisseria meningitidis, an endotoxin-producing Gram-negative bacterium, causes the highest incidence of group B meningococcus (MenB) disease in the first year of life. The Bexsero vaccine is indicated in Europe from 8 weeks of age. Endotoxin components of outer membrane vesicles (OMVs) or soluble lipopolysaccharide (LPS) represent a potential source of inflammation and residual reactogenicity. The purpose of this study was to compare novel candidate MenB vaccine formulations with licensed vaccines, including Bexsero, using age-specific human in vitro culture systems. OMVs from wild type- and inactivated lpxL1 gene mutant-N. meningitidis strains were characterized in human neonatal and adult in vitro whole blood assays and dendritic cell (DC) arrays. OMVs were benchmarked against licensed vaccines, including Bexsero and whole cell pertussis formulations, with respect to Th-polarizing cytokine and prostaglandin E2 production, as well as cell surface activation markers (HLA-DR, CD86, and CCR7). OMV immunogenicity was assessed in mice. ΔlpxLI native OMVs (nOMVs) demonstrated significantly less cytokine induction in human blood and DCs than Bexsero and most of the other pediatric vaccines (e.g., PedvaxHib, EasyFive, and bacillus Calmette-Guérin) tested. Despite a much lower inflammatory profile in vitro than Bexsero, ΔlpxLI nOMVs still had moderate DC maturing ability and induced robust anti-N. meningitidis antibody responses after murine immunization. A meningococcal vaccine comprised of attenuated LPS-based OMVs with a limited inflammatory profile in vitro induces robust antigen-specific immunogenicity in vivo.

Highlights

Human newborns and infants suffer a high frequency of infection compared to older children and adults [1], in part due to distinct early life immunity with impaired host defense [2]
A meningococcal vaccine comprised of attenuated LPS-based Outer membrane vesicle (OMV) with a limited inflammatory profile in vitro induces robust antigen-specific immunogenicity in vivo
Wild-type OMVs were produced from N. meningitidis H44/76 (B:P1.7,16;F3-3), while native OMVs (nOMVs) (Figure 1A), incorporating a genetically attenuated version of endotoxin, were produced from a H44/76 ΔRΔL mutant strain [16, 27]

Summary

Introduction

Human newborns and infants suffer a high frequency of infection compared to older children and adults [1], in part due to distinct early life immunity with impaired host defense [2]. Novartis’ 4-component aluminum hydroxide (Alum)-adjuvanted group B meningococcus (MenB) vaccine (4CMenB, Trade name: Bexsero) has been licensed by both the European Medicines Agency and the U.S Food and Drug Agency and comprised OMVs and three recombinant immunogenic N. meningitidis proteins identified by reverse vaccinology [8] Another meningococcal serogroup B vaccine, Trumenba, contains two recombinant proteins with no OMV component, is approved in the U.S for use in individuals 10 through 25 years of age, but lacks the potentially broader antigen repertoire inherent to OMVs. Group B Neisseria meningitidis, an endotoxin-producing Gram-negative bacterium, causes the highest incidence of group B meningococcus (MenB) disease in the first year of life. The purpose of this study was to compare novel candidate MenB vaccine formulations with licensed vaccines, including Bexsero, using age-specific human in vitro culture systems

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