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FetA Antibodies Induced by an Outer Membrane Vesicle Vaccine Derived from a Serogroup B Meningococcal Isolate with Constitutive FetA Expression.

ABSTRACT: Invasive meningococcal disease causes over 3500 cases each year in Europe, with particularly high incidence among young children. Among serogroup B meningococci, which cause most of the cases, high diversity in the outer membrane proteins (OMPs) is observed in endemic situations; however, comprehensive molecular epidemiological data are available for the diversity and distribution of the OMPs PorA and FetA and these can be used to rationally design a vaccine with high coverage of the case isolates. The aim of this study was to determine whether outer membrane vesicles (OMVs) derived from an isolate with constitutive FetA expression (MenPF-1 vaccine) could be used to induce antibodies against both the PorA and FetA antigens. The immunogenicity of various dose levels and number of doses was evaluated in mice and rabbits, and IgG antibody responses tested against OMVs and recombinant PorA and FetA proteins. A panel of four isogenic mutants was generated and used to evaluate the relative ability of the vaccine to induce serum bactericidal activity (SBA) against FetA and PorA. Sera from mice were tested in SBA against the four target strains. Results demonstrated that the MenPF-1 OMVs were immunogenic against PorA and FetA in both animal models. Furthermore, the murine antibodies induced were bactericidal against isogenic mutant strains, suggesting that antibodies to both PorA and FetA were functional. The data presented indicate that the MenPF-1 vaccine is a suitable formulation for presenting PorA and FetA OMPs in order to induce bactericidal antibodies, and that proceeding to a Phase I clinical trial with this vaccine candidate is justified.

SUBMITTER: Sanders H

PROVIDER: S-EPMC4605655 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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FetA Antibodies Induced by an Outer Membrane Vesicle Vaccine Derived from a Serogroup B Meningococcal Isolate with Constitutive FetA Expression.

Sanders Holly H Norheim Gunnstein G Chan Hannah H Dold Christina C Vipond Caroline C Derrick Jeremy P JP Pollard Andrew J AJ Maiden Martin C J MC Feavers Ian M IM

PloS one 20151014 10

Invasive meningococcal disease causes over 3500 cases each year in Europe, with particularly high incidence among young children. Among serogroup B meningococci, which cause most of the cases, high diversity in the outer membrane proteins (OMPs) is observed in endemic situations; however, comprehensive molecular epidemiological data are available for the diversity and distribution of the OMPs PorA and FetA and these can be used to rationally design a vaccine with high coverage of the case isolat ...[more]

PMID: 26466091

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Project description:BackgroundDeclining antimicrobial susceptibility to current gonorrhoea antibiotic treatment and inadequate treatment options have raised the possibility of untreatable gonorrhoea. New prevention approaches, such as vaccination, are needed. Outer membrane vesicle meningococcal serogroup B vaccines might be protective against gonorrhoea. We evaluated the effectiveness of a serogroup B meningococcal outer membrane vesicle vaccine (MenB-4C) against gonorrhoea in individuals aged 16-23 years in two US cities.MethodsWe identified laboratory-confirmed gonorrhoea and chlamydia infections among individuals aged 16-23 years from sexually transmitted infection surveillance records in New York City and Philadelphia from 2016 to 2018. We linked gonorrhoea and chlamydia case records to immunisation registry records to determine MenB-4C vaccination status at infection, defined as complete vaccination (two MenB-4C doses administered 30-180 days apart), partial vaccination (single MenB-4C vaccine dose), or no vaccination (serogroup B meningococcal vaccine naive). Using log-binomial regression with generalised estimating equations to account for correlations between multiple infections per patient, we calculated adjusted prevalence ratios (APR) and 95% CIs to determine if vaccination was protective against gonorrhoea. We used individual-level data for descriptive analyses and infection-level data for regression analyses.FindingsBetween Jan 1, 2016, and Dec 31, 2018, we identified 167 706 infections (18 099 gonococcal infections, 124 876 chlamydial infections, and 24 731 gonococcal and chlamydial co-infections) among 109 737 individuals linked to the immunisation registries. 7692 individuals were vaccinated, of whom 4032 (52·4%) had received one dose, 3596 (46·7%) two doses, and 64 (<1·0%) at least three doses. Compared with no vaccination, complete vaccination series (APR 0·60, 95% CI 0·47-0·77; p<0·0001) and partial vaccination series (0·74, 0·63-0·88; p=0·0012) were protective against gonorrhoea. Complete MenB-4C vaccination series was 40% (95% CI 23-53) effective against gonorrhoea and partial MenB-4C vaccination series was 26% (12-37) effective.InterpretationMenB-4C vaccination was associated with a reduced gonorrhoea prevalence. MenB-4C could offer cross-protection against Neisseria gonorrhoeae. Development of an effective gonococcal vaccine might be feasible with implications for gonorrhoea prevention and control.FundingNone.

Project description: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.

Project description: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.

Project description:Outer membrane vesicles (OMVs) are spontaneously released by many gram-negative bacteria during their growth and constitute an important virulence factor for bacteria, helping them to survive through harsh environmental conditions. Native OMVs, naturally-released from bacteria, are produced at a level too low for vaccine manufacturing, requiring chemical treatment (detergent-extracted) or genetic manipulation, resulting in generalized modules for membrane antigens (GMMAs). Over the years, the nature and properties of OMVs have made them a viable platform for vaccine development. There are a few licensed OMV vaccines mainly for the prevention of meningitis caused by Neisseria meningitidis serogroup B (MenB) and Haemophilus influenzae type b (Hib). There are several candidates in clinical development against other gram-negative organisms from which the OMVs are derived, but also against heterologous targets in which the OMVs are used as carriers (e.g. coronavirus disease 2019 [COVID-19]). The use of OMVs for targets other than those from which they are derived is a major advancement in OMV technology, improving its versatility by being able to deliver protein or polysaccharide antigens. Other advances include the range of genetic modifications that can be made to improve their safety, reduce reactogenicity, and increase immunogenicity and protective efficacy. However, significant challenges remain, such as identification of general tools for high-content surface expression of heterologous proteins on the OMV surface. Here, we outline the progress of OMV vaccines to date, particularly discussing licensed OMV-based vaccines and candidates in clinical development. Recent trends in preclinical research are described, mainly focused on genetic manipulation and chemical conjugation for the use of OMVs as carriers for heterologous protein and polysaccharide antigens. Remaining challenges with the use of OMVs and directions for future research are also discussed.

Project description:BackgroundThe meningococcal serogroup A (MenA) polysaccharide conjugate vaccine used in Sub-Saharan Africa does not prevent disease caused by MenW or MenX strains, which also cause epidemics in the region. We investigated the vaccine-potential of native outer membrane vesicles with over-expressed factor H-binding protein (NOMV-fHbp), which targeted antigens in African meningococcal strains, and was combined with a MenA polysaccharide conjugate vaccine.Methodology/principal findingsThe NOMV-fHbp vaccine was prepared from a mutant African MenW strain with PorA P1.5,2, attenuated endotoxin (?LpxL1), deleted capsular genes, and over-expressed fHbp in variant group 1. The NOMV-fHbp was adsorbed with Al(OH)3 and used to reconstitute a lyophilized MenA conjugate vaccine, which normally is reconstituted with liquid MenC, Y and W conjugates in a meningococcal quadrivalent conjugate vaccine (MCV4-CRM, Novartis). Mice immunized with the NOMV-fHbp vaccine alone developed serum bactericidal (human complement) activity against 13 of 15 African MenA strains tested; 10 of 10 African MenX strains, 7 of 7 African MenW strains, and 6 of 6 genetically diverse MenB strains with fHbp variant group 1 (including 1 strain from The Gambia). The combination NOMV-fHbp/MenA conjugate vaccine elicited high serum bactericidal titers against the two MenA strains tested that were resistant to bactericidal antibodies elicited by the NOMV-fHbp alone; the combination elicited higher titers against the MenA and MenW strains than those elicited by a control MCV4-CRM vaccine (P<0.05); and high titers against MenX and MenB strains. For most strains, the titers elicited by a control NOMV-fHbp knock out vaccine were <1?10 except when the strain PorA matched the vaccine (titers >1?000).Conclusion/significanceThe NOMV-fHbp/MenA conjugate vaccine provided similar or higher coverage against MenA and MenW strains than a quadrivalent meningococcal conjugate vaccine, and extended protection against MenX strains responsible for epidemics in Africa, and MenB strains with fHbp in variant group 1.

Dataset Information

FetA Antibodies Induced by an Outer Membrane Vesicle Vaccine Derived from a Serogroup B Meningococcal Isolate with Constitutive FetA Expression.

Publications

FetA Antibodies Induced by an Outer Membrane Vesicle Vaccine Derived from a Serogroup B Meningococcal Isolate with Constitutive FetA Expression.

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