Meningococcal ACWYX Conjugate Vaccine in 2-to-29-Year-Olds in Mali and Gambia.

Background: An effective, affordable, multivalent meningococcal conjugate vaccine is needed to prevent epidemic meningitis in the African meningitis belt. Data on the safety and immunogenicity of NmCV-5, a pentavalent vaccine targeting the A, C, W, Y, and X serogroups, have been limited.

Methods: We conducted a phase 3, noninferiority trial involving healthy 2-to-29-year-olds in Mali and Gambia.

Vaccines to Prevent Meningitis: Historical Perspectives and Future Directions.

Despite advances in the development and introduction of vaccines against the major bacterial causes of meningitis, the disease and its long-term after-effects remain a problem globally. The Global Roadmap to Defeat Meningitis by 2030 aims to accelerate progress through visionary and strategic goals that place a major emphasis on preventing meningitis via vaccination. Global vaccination against type B (Hib) is the most advanced, such that successful and low-cost combination vaccines incorporating Hib are broadly available.

Evaluation of strain coverage of the multicomponent meningococcal serogroup B vaccine (4CMenB) administered in infants according to different immunisation schedules.

The 4-component vaccine 4CMenB, developed against invasive disease caused by meningococcal serogroup B, is approved for use in infants in several countries worldwide. 4CMenB is mostly used as 3 + 1 schedule, except for the UK, where a 2 + 1 schedule is used, and where the vaccine showed an effectiveness of 82.9%.

Breadth of coverage against a panel of 110 invasive disease isolates, immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents - Results from a randomized, controlled, observer-blind phase II study.

Background: Neisseria meningitidis serogroups A, B, C, W and Y cause most meningococcal disease worldwide. An investigational MenABCWY vaccine combining serogroup B antigens and a meningococcal ACWY CRM-glycoconjugate vaccine (MenACWY-CRM) could provide protection against all 5 serogroups. Complement mediated bactericidal activity induced by MenABCWY was tested against a panel of 110 randomly-selected serogroup B strains causing invasive disease in the US to evaluate the vaccine's breadth of coverage (BoC).

Immune Responses to Booster Vaccination With Meningococcal ABCWY Vaccine After Primary Vaccination With Either Investigational or Licensed Vaccines: A Phase 2 Randomized Study.

Background: Current meningococcal prime-boost vaccination schedules include separate vaccines for serogroups ACWY and B. An investigational combined serogroups ABCWY vaccine (MenABCWY) was developed to protect against clinically important Neisseria meningitidis serogroups.

Methods: In this phase 2, randomized, observer-blind, extension study (NCT01272180), participants 10-25 years of age received 1 booster dose of MenABCWY vaccine at 24 months (M) postprimary series of MenABCWY (2 doses), 4CMenB (2 doses) or MenACWY-CRM vaccine (1 dose).

Persistence of the immune response after MenACWY-CRM vaccination and response to a booster dose, in adolescents, children and infants.

Persistence of bactericidal antibodies following vaccination is extremely important for protection against invasive meningococcal disease, given the epidemiology and rapid progression of meningococcal infection. We present an analysis of antibody persistence and booster response to MenACWY-CRM, in adolescents, children and infants, from 7 clinical studies. Immunogenicity was assessed using the serum bactericidal assay with both human and rabbit complement.

Immunogenicity and safety of a novel quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) in healthy Korean adolescents and adults.

Objectives: This phase III placebo-controlled study evaluated the immunogenicity and safety of MenACWY-CRM vaccination in healthy Korean adolescents and adults.

Methods: Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination against all four meningococcal serogroups. The IgG concentration specific for serogroup W capsular polysaccharide was measured in a subset of subjects in a post-hoc analysis.

Factor H and neisserial pathogenesis.

Both Neisseria gonorrhoeae and N. meningitidis bind to factor H which enhances their ability to evade complement-dependent killing. While porin is the ligand for human fH on gonococci, meningococci use a lipoprotein called factor H binding protein (fHbp) to bind to factor H and enhance their ability to evade complement-dependent killing.

Ex vivo model of meningococcal bacteremia using human blood for measuring vaccine-induced serum passive protective activity.

The binding of complement factor H (fH) to meningococci was recently found to be specific for human fH. Therefore, passive protective antibody activity measured in animal models of meningococcal bacteremia may overestimate protection in humans, since in the absence of bound fH, complement activation is not downregulated. We developed an ex vivo model of meningococcal bacteremia using nonimmune human blood to measure the passive protective activity of stored sera from 36 adults who had been immunized with an investigational meningococcal multicomponent recombinant protein vaccine.

Binding of complement factor H (fH) to Neisseria meningitidis is specific for human fH and inhibits complement activation by rat and rabbit sera.

Complement factor H (fH), a molecule that downregulates complement activation, binds to Neisseria meningitidis and increases resistance to serum bactericidal activity. We investigated the species specificity of fH binding and the effect of human fH on downregulating rat (relevant for animal models) and rabbit (relevant for vaccine evaluation) complement activation. Binding to N.

Fine antigenic specificity and cooperative bactericidal activity of monoclonal antibodies directed at the meningococcal vaccine candidate factor h-binding protein.

No broadly protective vaccine is available for the prevention of group B meningococcal disease. One promising candidate is factor H-binding protein (fHbp), which is present in all strains but often sparsely expressed. We prepared seven murine immunoglobulin G monoclonal antibodies (MAbs) against fHbp from antigenic variant group 2 (v.

Complement-dependent synergistic bactericidal activity of antibodies against factor H-binding protein, a sparsely distributed meningococcal vaccine antigen.

Background: Antibodies to factor H (fH)-binding protein (fHBP), a meningococcal vaccine antigen, activate classical complement pathway serum bactericidal activity (SBA) and block binding of the complement inhibitor fH.

Methods: To understand these 2 functions in protection, we investigated the interactions of human complement and 2 anti-fHBP monoclonal antibodies (MAbs) with encapsulated Neisseria meningitidis.

Results: JAR 3 (IgG3) blocks fH binding and elicits SBA against 2 strains with naturally high fHBP expression and a low-expressing strain genetically engineered to express high fHBP levels.

Immunity to Neisseria meningitidis group B in adults despite lack of serum bactericidal antibody.

Serum-complement-mediated bactericidal antibody (SBA) remains the serologic hallmark of protection against meningococcal disease, despite experimental and epidemiologic data that SBA may underestimate immunity. We measured bactericidal activity against three strains of Neisseria meningitidis group B in sera from 48 healthy adults and in whole blood from 15 subjects. Blood was anticoagulated with lepirudin, a specific thrombin inhibitor not known to activate complement.

Prevalence of factor H-binding protein variants and NadA among meningococcal group B isolates from the United States: implications for the development of a multicomponent group B vaccine.

Background: Two promising recombinant meningococcal protein vaccines are in development. One contains factor H-binding protein (fHBP) variants (v.) 1 and 2, whereas the other contains v.

A universal vaccine for serogroup B meningococcus.

Meningitis and sepsis caused by serogroup B meningococcus are two severe diseases that still cause significant mortality. To date there is no universal vaccine that prevents these diseases. In this work, five antigens discovered by reverse vaccinology were expressed in a form suitable for large-scale manufacturing and formulated with adjuvants suitable for human use.

The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance.

Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs.

Improved immunogenicity of a H44/76 group B outer membrane vesicle vaccine with over-expressed genome-derived Neisserial antigen 1870.

A broadly protective vaccine against meningococcal group B disease is not available. We previously reported that an outer membrane vesicle (OMV) vaccine containing over-expressed genome-derived antigen (GNA) 1870 elicited broader protective antibody responses than recombinant GNA1870 or conventional OMV vaccines prepared from a strain that naturally expresses low amounts of GNA1870. Certain wildtype strains such as H44/76 naturally express larger amounts of GNA1870 and, potentially, could be used to prepare an improved OMV vaccine without genetic over-expression of the antigen.

Role of FNR and FNR-regulated, sugar fermentation genes in Neisseria meningitidis infection.

While it is generally accepted that anaerobic metabolism is required during infection, supporting experimental data have only been described in a limited number of studies. To provide additional evidence on the role of anaerobic metabolism in bacterial pathogens while invading mammalian hosts, we analysed the effect of the inactivation of FNR, the major regulatory protein involved in the adaptation to oxygen restrictive conditions, and of two of the FNR-regulated genes on the survival of Neisseria meningitidis serogroup B (MenB) in vivo. We found that fnr deletion resulted in more than 1 log reduction in the meningococcal capacity to proliferate both in infant rats and in mice.

Antibody persistence 3 years after immunization of adolescents with quadrivalent meningococcal conjugate vaccine.

Background: A quadrivalent meningococcal conjugate vaccine (MCV-4) is recommended for United States teenagers. The duration of protective immunity is unknown. We investigated serum antibody persistence 3 years after vaccination of adolescents.

Protective antibody responses elicited by a meningococcal outer membrane vesicle vaccine with overexpressed genome-derived neisserial antigen 1870.

Background. Meningococcal outer membrane vesicle (OMV) vaccines are efficacious in humans but have serosubtype-specific serum bactericidal antibody responses directed at the porin protein PorA and the potential for immune selection of PorA-escape mutants.Methods.

Immunogenicity of an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine in 2-year old children.

Background: One dose of a quadrivalent meningococcal conjugate (MC-4) vaccine elicits higher group C bactericidal responses in 2-year olds than a U.S.-licensed quadrivalent polysaccharide (MPS-4) vaccine [Granoff DM, Harris SL.

Persistence of group C anticapsular antibodies two to three years after immunization with an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine.

Background: An investigational quadrivalent (A, C, Y and W-135) meningococcal conjugate (MC-4) vaccine was reported to be more immunogenic in 2-year-olds than the currently licensed meningococcal polysaccharide vaccine, but persistence of serum antibody beyond 6 months after conjugate vaccination is unknown.

Objective: Determine persistence and the immunologic basis of protective activity of group C anticapsular antibodies in sera obtained 2-3 years after MC-4 vaccination.

Design: Group C antibody concentrations, bactericidal activity and passive protective activity were measured in sera from 48 children, ages 4-5 years, who had been immunized 2-3 years earlier with an MC-4 vaccine and from 47 children who had not been previously vaccinated.

Naturally acquired passive protective activity against Neisseria meningitidis Group C in the absence of serum bactericidal activity.

The hallmark of immunity to meningococcal disease is a bactericidal titer in serum of > or =1:4 measured with human complement, but this threshold titer may underestimate the extent of protection. We used the infant rat model of meningococcal bacteremia to measure group C passive protective activity in serum samples from 91 unimmunized adults living in California. A total of 35 sera (38.

Protective activity of monoclonal antibodies to genome-derived neisserial antigen 1870, a Neisseria meningitidis candidate vaccine.

Genome-derived neisserial Ag (GNA) 1870 is a meningococcal vaccine candidate that can be subdivided into three variants based on amino acid sequence variability. Variant group 1 accounts for approximately 60% of disease-producing group B isolates. The Ag went unrecognized until its discovery by genome mining because it is expressed in low copy number by most strains.

Antibody to genome-derived neisserial antigen 2132, a Neisseria meningitidis candidate vaccine, confers protection against bacteremia in the absence of complement-mediated bactericidal activity.

Genome-derived neisserial antigen 2132 (GNA2132) is a novel vaccine candidate that was identified during the Neisseria meningitidis group B strain MC58 genome-sequencing project. To assess the vaccine potential of GNA2132, we prepared antisera from mice immunized with recombinant GNA2132 (gene from strain NZ394/98). Anti-GNA2132 antibody bound to the surface of live bacteria from all 7 capsular group B or C strains tested and elicited deposition of human C3b on the bacterial surface.