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A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program.

ABSTRACT: Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero®, Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical protection used was human complement-mediated serum bactericidal activity titers ?4 or 5 against indicator strains for individual antigens. Based on achievement of protective titers, a four-dose schedule (three primary doses and one booster dose) for infants and a two-dose schedule for adolescents provided the best results. Observed increases in injection site pain/tenderness and fever in infants, and injection site pain, malaise, and headache in adolescents compared with routine vaccines, were mostly mild to moderate; frequencies of rare events (Kawasaki disease, juvenile arthritis) were not significantly different from non-vaccinated individuals. 4CMenB is conservatively estimated to provide 66-91 % coverage against meningococcal serogroup B strains worldwide.

SUBMITTER: O'Ryan M

PROVIDER: S-EPMC3890039 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program.

O'Ryan Miguel M Stoddard Jeffrey J Toneatto Daniela D Wassil James J Dull Peter M PM

Drugs 20140101 1

Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero®, Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical pr ...[more]

PMID: 24338083

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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 four-component serogroup B meningococcal 4CMenB vaccine (Bexsero, GSK) has been routinely given to all infants in the United Kingdom at 2, 4 and 12 months of age since September 2015. After 3 years, Public Health England (PHE) reported a 75% [95% confidence interval 64%; 81%] reduction in the incidence of serogroup B invasive meningococcal disease (IMD) in age groups eligible to be fully vaccinated. In contrast, vaccine effectiveness (VE) evaluated in the same immunization program applying the screening method was not statistically significant. We re-analyzed the data using an incidence model. Aggregate data-stratified by age, year and doses received-were provided by PHE: serogroup B IMD case counts for the entire population of England (years 2011-2018) and 4CMenB vaccine uptake in infants. We combined uptake with national population estimates to obtain counts of vaccinated and unvaccinated person-time by age and time. We re-estimated VE comparing incidence rates in vaccinated and non-vaccinated subjects using a Bayesian Poisson model for case counts with person-time data as an offset. The model was adjusted for age, time and number of doses received. The incidence model showed that cases decreased until 2013-2014, followed by an increasing trend that continued in the non-vaccinated population during the immunization program. VE in fully vaccinated subjects (three doses) was 80.1% [95% Bayesian credible interval (BCI): 70.3%; 86.7%]. After a single dose, VE was 33.5% [12.4%; 49.7%]95%BCI and after two doses, 78.7% [71.5%; 84.5%]95%BCI. We estimated that vaccination averted 312 cases [252; 368]95%BCI between 2015 and 2018. VE was in line with the previously reported incidence reduction. Our estimates of VE had higher precision than previous estimates based on the screening method, which were statistically not significant, and in line with the 75% incidence reduction previously reported by PHE. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible for vaccination may not be precise enough and may produce misleading point-estimates. Precise and accurate VE estimates are fundamental to inform public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination.

Project description:OBJECTIVES:(1) To assess if co-administration of four-component meningococcal serogroup B vaccine (4CMenB) and other routine vaccines caused an interaction increasing the risk and/or severity of adverse events following immunisation (AEFI) compared with administration at separate visits and (2) to estimate the risk of AEFI recurrence. DESIGN:Risk-interval design SETTING: Three randomised controlled trials conducted in Europe. PARTICIPANTS:A total of 5026 healthy 2-month-old to 15-month-old infants. INTERVENTIONS:4CMenB and routine vaccines (hexavalent combined diphtheria-tetanus-acellular pertussis-inactivated polio-Haemophilus influenzae type b-hepatitis B vaccine+seven-valent pneumococcal conjugate vaccine or measles-mumps-rubella-varicella vaccine) administered concomitantly or separately 1 month apart, in regular (2, 4, 6 and 12 months), accelerated (2, 3, 4 and 12 months) or delayed (two doses of 4CMenB at ≥12 months of age) schedules. OUTCOME MEASURES:Primary: Fever (≥38°C) during the first 48 hours post immunisation. Secondary: crying, change in eating habits, diarrhoea, irritability and tenderness at the 4CMenB injection site. RESULTS:Compared with separate administration, concomitant administration decreased the overall incidence of fever (≥38°C), 86% versus 75%, and other systemic AEFIs but increased the incidence of 4CMenB injection site tenderness, 55% versus 66%, moderate/severe fevers (≥39°C), 13% versus 18%, and long-lasting (>1 day) fevers, 23% versus 33%. Co-administration reduced AEFI risk by 4%-49% with the greatest impact among infants with prior AEFI(s). Fever recurrence risk was proportional to the number of prior fever events: 79% at dose 2 with one prior episode; 44% and 74% at dose 3 with one and two prior episodes, respectively; and 29%, 45% and 60% at dose 4 with one, two and three prior episodes, respectively. Severity was not increased at recurrence and a similar pattern of recurrence risk proportional to the number of prior events was observed for other AEFIs. CONCLUSIONS:The cumulative risk of AEFI is reduced with concomitant versus separate administration of 4CMenB and routine infant vaccines. Infants with a prior AEFI are at higher risk of the same AEFI at subsequent immunisations, but severity with recurrence is usually not increased. TRIALS REGISTRATION NUMBER:NCT00657709, NCT00847145, NCT00721396 and NCT02712177; Pre-results.

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A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program.

Publications

A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program.

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