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

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

JOURNAL=Frontiers in Immunology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00562

DOI=10.3389/fimmu.2016.00562

ISSN=1664-3224

ABSTRACT=<sec id="ST1"><title>Background</title><p>Group B <italic>Neisseria meningitidis</italic>, 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 <italic>in vitro</italic> culture systems.</p></sec><sec id="ST2"><title>Methods</title><p>OMVs from wild type- and inactivated <italic>lpxL1</italic> gene mutant-<italic>N. meningitidis</italic> strains were characterized in human neonatal and adult <italic>in vitro</italic> 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.</p></sec><sec id="ST3"><title>Results</title><p>Δ<italic>lpxLI</italic> 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 <italic>in vitro</italic> than Bexsero, Δ<italic>lpxLI</italic> nOMVs still had moderate DC maturing ability and induced robust anti-<italic>N. meningitidis</italic> antibody responses after murine immunization.</p></sec><sec id="ST4"><title>Conclusion</title><p>A meningococcal vaccine comprised of attenuated LPS-based OMVs with a limited inflammatory profile <italic>in vitro</italic> induces robust antigen-specific immunogenicity <italic>in vivo</italic>.</p></sec>