scholarly journals The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae

2020 ◽  
Vol 16 (12) ◽  
pp. e1008602
Author(s):  
Isabelle Leduc ◽  
Kristie L. Connolly ◽  
Afrin Begum ◽  
Knashka Underwood ◽  
Stephen Darnell ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Outer Membrane ◽  
Vaccine Development ◽  
Membrane Vesicle ◽  
Surface Proteins ◽  
Mouse Serum ◽  
Infection Model ◽  
Outer Membrane Vesicle ◽  
Species Protection ◽  
Significant Difference

There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.

scholarly journals The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae

2020 ◽  
Author(s):  
Isabelle Leduc ◽  
Kristie L. Connolly ◽  
Afrin Begum ◽  
Knashka Underwood ◽  
Nazia Rahman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neisseria Gonorrhoeae ◽  
Neisseria Meningitidis ◽  
Outer Membrane ◽  
Membrane Vesicle ◽  
Outer Membrane Proteins ◽  
Infection Model ◽  
Outer Membrane Vesicle ◽  
Epidemiological Evidence ◽  
Species Protection

AbstractThere is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero®) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. High titers of serum IgG1 and IgG2a and vaginal IgG1 that cross-reacted with Ng OMVs were induced by vaccination via either the subcutaneous or intraperitoneal routes, and a 4-fold increase in the serum bactericidal50 titers was detected against the challenge strain. Antibodies from vaccinated mice recognized several surface proteins in a diverse collection of Ng strains, including PilQ, BamA, MtrE, PorB, and Opa, and 4CMenB-induced antibodies bound PilQ and MtrE in native form on the surface of viable bacteria. In contrast, the antibodies were only cross-reactive against lipooligosaccharide species from a few Ng strains. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against Ng and implicate several Ng surface antigens as potentially protective targets. This work also validates the murine infection model as a relevant experimental system for investigating mechanisms of vaccine-mediated protection against gonorrhea.Author summaryOver 78 million Neisseria gonorrhoeae (Ng) infections occur globally each year and control of gonorrhea through vaccination is challenged by a lack of strong evidence that immunity to gonorrhea is possible. This contention was recently challenged by epidemiological evidence suggesting that an outer membrane vesicle (OMV) vaccine from the related species Neisseria meningitidis (Nm) protected humans against gonorrhea. Here we provide experimental evidence in support of this hypothesis by demonstrating that a licensed, modified version of this Nm OMV-based vaccine accelerates clearance of Ng in a mouse infection model. These results confirm the possibility cross-species protection and are important in that they support the biological feasibility of vaccine-induced immunity against gonorrhea. We also showed that several Ng outer membrane proteins are recognized by antisera from vaccinated mice that may be protective targets of the vaccine. Additionally, our demonstration that a vaccine that may reduce the risk of gonorrhea in humans protects mice against Ng, a highly host-restricted pathogen, validates the mouse model as a potentially useful tool for examining mechanisms of protection, which could be exploited in the development of other candidate gonorrhea vaccines.

scholarly journals Genetic Similarity of Gonococcal Homologs to Meningococcal Outer Membrane Proteins of Serogroup B Vaccine

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Henju Marjuki ◽  
Nadav Topaz ◽  
Sandeep J. Joseph ◽  
Kim M. Gernert ◽  
Ellen N. Kersh ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Vaccine Development ◽  
Membrane Vesicle ◽  
Outer Membrane Proteins ◽  
The United States ◽  
Cross Protection ◽  
Outer Membrane Vesicle ◽  
Content Type ◽  
Sequence Identity

ABSTRACT The human pathogens Neisseria gonorrhoeae and Neisseria meningitidis share high genome identity. Retrospective analysis of surveillance data from New Zealand indicates the potential cross-protective effect of outer membrane vesicle (OMV) meningococcal serogroup B vaccine (MeNZB) against N. gonorrhoeae. A licensed OMV-based MenB vaccine, MenB-4C, consists of a recombinant FHbp, NhbA, NadA, and the MeNZB OMV. Previous work has identified several abundantly expressed outer membrane proteins (OMPs) as major components of the MenB-4C OMV with high sequence similarity between N. gonorrhoeae and N. meningitidis, suggesting a mechanism for cross-protection. To build off these findings, we performed comparative genomic analysis on 970 recent N. gonorrhoeae isolates collected through a U.S surveillance system against N. meningitidis serogroup B (NmB) reference sequences. We identified 1,525 proteins that were common to both Neisseria species, of which 57 proteins were predicted to be OMPs using in silico methods. Among the MenB-4C antigens, NhbA showed moderate sequence identity (73%) to the respective gonococcal homolog, was highly conserved within N. gonorrhoeae, and was predicted to be surface expressed. In contrast, the gonococcal FHbp was predicted not to be surface expressed, while NadA was absent in all N. gonorrhoeae isolates. Our work confirmed recent observations (E. A. Semchenko, A. Tan, R. Borrow, and K. L. Seib, Clin Infect Dis, 2018, https://doi.org/10.1093/cid/ciy1061) and describes homologous OMPs from a large panel of epidemiologically relevant N. gonorrhoeae strains in the United States against NmB reference strains. Based on our results, we report a set of OMPs that may contribute to the previously observed cross-protection and provide potential antigen targets to guide the next steps in gonorrhea vaccine development. IMPORTANCE Gonorrhea, a sexually transmitted disease, causes substantial global morbidity and economic burden. New prevention and control measures for this disease are urgently needed, as strains resistant to almost all classes of antibiotics available for treatment have emerged. Previous reports demonstrate that cross-protection from gonococcal infections may be conferred by meningococcal serogroup B (MenB) outer membrane vesicle (OMV)-based vaccines. Among 1,525 common proteins shared across the genomes of both N. gonorrhoeae and N. meningitidis, 57 proteins were predicted to be surface expressed (outer membrane proteins [OMPs]) and thus preferred targets for vaccine development. The majority of these OMPs showed high sequence identity between the 2 bacterial species. Our results provide valuable insight into the meningococcal antigens present in the current OMV-containing MenB-4C vaccine that may contribute to cross-protection against gonorrhea and may inform next steps in gonorrhea vaccine development.

scholarly journals Cysteine Depletion Causes Oxidative Stress and Triggers Outer Membrane Vesicle Release by Neisseria meningitidis; Implications for Vaccine Development

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e54314 ◽  
Author(s):  
Bas van de Waterbeemd ◽  
Gijsbert Zomer ◽  
Jan van den IJssel ◽  
Lonneke van Keulen ◽  
Michel H. Eppink ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neisseria Meningitidis ◽  
Outer Membrane ◽  
Vaccine Development ◽  
Membrane Vesicle ◽  
Outer Membrane Vesicle ◽  
Vesicle Release

scholarly journals Enterotoxigenic Escherichia coli Elicits Immune Responses to Multiple Surface Proteins

2010 ◽  
Vol 78 (7) ◽  
pp. 3027-3035 ◽  
Author(s):  
Koushik Roy ◽  
Scott Bartels ◽  
Firdausi Qadri ◽  
James M. Fleckenstein
Keyword(s):  
Outer Membrane ◽  
Dna Sequences ◽  
Vaccine Development ◽  
Membrane Vesicle ◽  
Outer Membrane Proteins ◽  
Surface Proteins ◽  
Enterotoxigenic Escherichia Coli ◽  
Virulence Determinants ◽  
Human Sera ◽  
Considerable Morbidity

ABSTRACTEnterotoxigenicEscherichiacoli(ETEC) causes considerable morbidity and mortality due to diarrheal illness in developing countries, particularly in young children. Despite the global importance of these heterogeneous pathogens, a broadly protective vaccine is not yet available. While much is known regarding the immunology of well-characterized virulence proteins, in particular the heat-labile toxin (LT) and colonization factors (CFs), to date, evaluation of the immune response to other antigens has been limited. However, the availability of genomic DNA sequences for ETEC strains coupled with proteomics technology affords opportunities to examine novel uncharacterized antigens that might also serve as targets for vaccine development. Analysis of whole or fractionated bacterial proteomes with convalescent-phase sera can potentially accelerate identification of secreted or surface-expressed targets that are recognized during the course of infection. Here we report results of an immunoproteomics approach to antigen discovery with ETEC strain H10407. Immunoblotting of proteins separated by two-dimensional electrophoresis (2DE) with sera from mice infected with strain H10407 or with convalescent human sera obtained following natural ETEC infections demonstrated multiple immunoreactive molecules in culture supernatant, outer membrane, and outer membrane vesicle preparations, suggesting that many antigens are recognized during the course of infection. Proteins identified by this approach included established virulence determinants, more recently identified putative virulence factors, as well as novel secreted and outer membrane proteins. Together, these studies suggest that existing and emerging proteomics technologies can provide a useful complement to ongoing approaches to ETEC vaccine development.

scholarly journals Meningococcal Detoxified Outer Membrane Vesicle Vaccines Enhance Gonococcal Clearance in a Murine Infection Model

2021 ◽  
Author(s):  
Kathryn A Matthias ◽  
Kristie L Connolly ◽  
Afrin A Begum ◽  
Ann E Jerse ◽  
Andrew N Macintyre ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Membrane Vesicle ◽  
Outer Membrane Proteins ◽  
Epidemiological Studies ◽  
Cross Reactivity ◽  
Infection Model ◽  
Outer Membrane Vesicle ◽  
Igg Antibodies ◽  
Wild Type ◽  
Genital Tract Infection

Abstract Background Despite decades of research efforts, development of a gonorrhea vaccine has remained elusive. Epidemiological studies suggest that detoxified outer membrane vesicle (dOMV) vaccines from Neisseria meningitidis (Nm) may protect against infection with Neisseria gonorrhoeae (Ng). We recently reported that Nm dOMVs lacking the major outer membrane proteins (OMPs) PorA, PorB, and RmpM induced greater antibody cross-reactivity against heterologous Nm strains than wild-type (WT) dOMVs and may represent an improved vaccine against gonorrhea. Methods We prepared dOMV vaccines from meningococcal strains that were sufficient or deleted for PorA, PorB, and RmpM. Vaccines were tested in a murine genital tract infection model and antisera were used to identify vaccine targets. Results Immunization with Nm dOMVs significantly and reproducibly enhanced gonococcal clearance for mice immunized with OMP-deficient dOMVs; significant clearance for WT dOMV-immunized mice was observed in one of two experiments. Clearance was associated with serum and vaginal anti-Nm dOMV IgG antibodies that cross-reacted with Ng. Serum IgG was used to identify putative Ng vaccine targets, including PilQ, MtrE, NlpD, and GuaB. Conclusions Meningococcal dOMVs elicited a protective effect against experimental gonococcal infection. Recognition and identification of Ng vaccine targets by Nm dOMV-induced antibodies supports the development of a cross-protective Neisseria vaccine.

Preparation of Outer Membrane Vesicle from Escherichia coli

BIO-PROTOCOL ◽  
2013 ◽  
Vol 3 (23) ◽  
Author(s):  
Oh Kim ◽  
Bok Hong ◽  
Kyong-Su Park ◽  
Yae Yoon ◽  
Seng Choi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Outer Membrane ◽  
Membrane Vesicle ◽  
Outer Membrane Vesicle
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