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Background Gonorrhea incidence is increasing rapidly in many countries, while antibiotic resistance is making treatment more difficult. Combined with evidence that two meningococcal vaccines are likely partially protective against gonorrhea, this has renewed interest in a gonococcal vaccine, and several candidates are in development. Key questions are how protective and long-lasting a vaccine needs to be, and how to target it. We assessed vaccination’s potential impact and the feasibility of achieving the World Health Organization’s (WHO) target of reducing gonorrhea incidence by 90% during 2018–2030, by comparing realistic vaccination strategies under a range of scenarios of vaccine efficacy and duration of protection, and emergence of extensively-resistant gonorrhea. Methods We developed a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behavior in men who have sex with men (MSM). We used data from England, which has a comprehensive, consistent nationwide surveillance system. Using particle Markov chain Monte Carlo methods, we fitted to gonorrhea incidence in 2008–2017, then used Bayesian forecasting to examine an extensive range of scenarios. Results Even in the worst-case scenario of untreatable infection emerging, the WHO target is achievable if all MSM attending sexual health clinics receive a vaccine offering ≥ 52% protection for ≥ 6 years. A vaccine conferring 31% protection (as estimated for MeNZB) for 2–4 years could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if > 70% of resistant gonorrhea remains treatable. Conclusions Even a partially-protective vaccine, delivered through a realistic targeting strategy, could substantially reduce gonorrhea incidence, despite antibiotic resistance., A gonorrhea vaccine offering partial protection for several years, pragmatically targeted to people testing for gonorrhea due to symptoms or screening due to sexual risk behavior, could substantially reduce gonorrhea incidence, combating increases in antibiotic resistance.

Outer Membrane Vesicles (OMV) have received increased attention in recent years as a vaccine platform against bacterial pathogens. OMV from Neisseria meningitidis serogroup B have been extensively explored. Following the success of the MeNZB OMV vaccine in controlling an outbreak of N. meningitidis B in New Zealand, additional research and development resulted in the licensure of the OMV-containing four-component 4CMenB vaccine, Bexsero. This provided broader protection against multiple meningococcal B strains. Advances in the field of genetic engineering have permitted further improvements in the platform resulting in increased yields, reduced endotoxicity and decoration with homologous and heterologous antigens to enhance immuno genicity and provide broader protection. The OMV vaccine platform has been extended to many other pathogens. In this review, we discuss progress in the development of the OMV vaccine delivery platform, highlighting successful applications, together with potential challenges and gaps.

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. 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.

Background Neisseria gonorrhoeae and Neisseria meningitidis are closely-related bacteria that cause a significant global burden of disease. Control of gonorrhoea is becoming increasingly difficult, due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recently, the outer membrane vesicle (OMV) meningococcal B vaccine, MeNZB, was reported to be associated with reduced rates of gonorrhoea following a mass vaccination campaign in New Zealand. To probe the basis for this protection, we assessed the cross-reactivity to N. gonorrhoeae of serum raised to the meningococcal vaccine Bexsero, which contains the MeNZB OMV component plus 3 recombinant antigens (Neisseria adhesin A, factor H binding protein [fHbp]-GNA2091, and Neisserial heparin binding antigen [NHBA]-GNA1030). Methods A bioinformatic analysis was performed to assess the similarity of MeNZB OMV and Bexsero antigens to gonococcal proteins. Rabbits were immunized with the OMV component or the 3 recombinant antigens of Bexsero, and Western blots and enzyme-linked immunosorbent assays were used to assess the generation of antibodies recognizing N. gonorrhoeae. Serum from humans immunized with Bexsero was investigated to assess the nature of the anti-gonococcal response. Results There is a high level of sequence identity between MeNZB OMV and Bexsero OMV antigens, and between the antigens and gonococcal proteins. NHBA is the only Bexsero recombinant antigen that is conserved and surfaced exposed in N. gonorrhoeae. Bexsero induces antibodies in humans that recognize gonococcal proteins. Conclusions The anti-gonococcal antibodies induced by MeNZB-like OMV proteins could explain the previously-seen decrease in gonorrhoea following MeNZB vaccination. The high level of human anti-gonococcal NHBA antibodies generated by Bexsero vaccination may provide additional cross-protection against gonorrhoea., This study demonstrates that Neisseria gonorrhoeae shares a high level of sequence identity with outer membrane vesicle antigens in 2 serogroup B meningococcal vaccines: MeNZB and Bexsero. The Bexsero neisserial heparin binding antigen (NHBA) recombinant antigen is also conserved in N. gonorrhoeae. Furthermore, serum from humans vaccinated with Bexsero is able to recognize several gonococcal proteins, including the gonococcal NHBA homologue.

Gonorrhoea is a major global public health problem that is exacerbated by drug resistance. Effective vaccine development has been unsuccessful, but surveillance data suggest that outer membrane vesicle meningococcal group B vaccines affect the incidence of gonorrhoea. We assessed vaccine effectiveness of the outer membrane vesicle meningococcal B vaccine (MeNZB) against gonorrhoea in young adults aged 15-30 years in New Zealand.We did a retrospective case-control study of patients at sexual health clinics aged 15-30 years who were born between Jan 1, 1984, and Dec 31, 1998, eligible to receive MeNZB, and diagnosed with gonorrhoea or chlamydia, or both. Demographic data, sexual health clinic data, and National Immunisation Register data were linked via patients' unique personal identifier. For primary analysis, cases were confirmed by laboratory isolation or detection of Neisseria gonorrhoeae only from a clinical specimen, and controls were individuals with a positive chlamydia test only. We estimated odds ratios (ORs) comparing disease outcomes in vaccinated versus unvaccinated participants via multivariable logistic regression. Vaccine effectiveness was calculated as 100×(1-OR).11 of 24 clinics nationally provided records. There were 14 730 cases and controls for analyses: 1241 incidences of gonorrhoea, 12 487 incidences of chlamydia, and 1002 incidences of co-infection. Vaccinated individuals were significantly less likely to be cases than controls (511 [41%] vs 6424 [51%]; adjusted OR 0·69 [95% CI 0·61-0·79]; p0·0001). Estimate vaccine effectiveness of MeNZB against gonorrhoea after adjustment for ethnicity, deprivation, geographical area, and sex was 31% (95% CI 21-39).Exposure to MeNZB was associated with reduced rates of gonorrhoea diagnosis, the first time a vaccine has shown any protection against gonorrhoea. These results provide a proof of principle that can inform prospective vaccine development not only for gonorrhoea but also for meningococcal vaccines.GSK Vaccines.

SUMMARYBackgroundGonorrhoea incidence is increasing rapidly: diagnoses in men who have sex with men (MSM) in England increased eight-fold 2008-2017. Concurrently, antibiotic resistance is making treatment more difficult, leading to renewed interest in a gonococcal vaccine. The MeNZB meningococcal B vaccine is partially protective, and several other candidates are in development. We modelled realistic vaccination strategies under various scenarios of antibiotic resistance and vaccine protection level and duration, to assess the impact of vaccination and examine the feasibility of the WHO’s target of reducing gonorrhoea incidence by 90% between 2016 and 2030.MethodsWe fitted a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behaviour, to gonorrhoea incidence in MSM in England, 2008-17, using particle Markov Chain Monte Carlo methods. Bayesian forecasting was used to examine future scenarios, including emergence of extensively antibiotic-resistant (ABR) gonorrhoea.FindingsEven in the worst-case scenario of untreatable infection emerging, the WHO target could be met by vaccinating all MSM attending sexual health clinics with a 53%-protective vaccine lasting for >6 years, or a 70%-protective vaccine lasting >3 years. A vaccine like MeNZB, conferring 30% protection for 2-4 years, could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if >70% of ABR gonorrhoea is treatable.InterpretationOur statistically-rigorous assessment shows that even a partially-protective vaccine, delivered through a practical targeting strategy, could have substantial benefit in reducing gonorrhoea incidence in the context of an epidemic with rising antibiotic resistance.

Introduction Gonorrhoea is becoming increasingly difficult to control due to antibiotic resistance and the absence of a vaccine. However, a vaccine to the closely related bacteria Neisseria meningitidis, the outer membrane vesicle (OMV) vaccine MeNZB, was reported to be associated with reduced rates of gonorrhoea. To investigate this possible cross-protection we assessed serum raised to the meningococcal vaccine Bexsero, which contains the MeNZB OMV component plus three recombinant antigens (NadA, fHbp-GNA2091, NHBA-GNA1030), in terms of its cross reactivity and functional activity against Neisseria gonorrhoeae. Methods The similarity of MeNZB and Bexsero antigens to gonococcal proteins was assessed bioinformatically. Sera from rabbits immunised with the OMV component or the three recombinant antigens of Bexsero, and sera from humans immunised with Bexsero were tested in Western blot, ELISA, serum bactericidal activity (SBA) and neutrophil opsonophagocytic (OPA) assays to assess the level and functional activity of antibodies recognising N. gonorrhoeae. Results There is a high level of sequence identity between MeNZB/Bexsero OMV antigens and gonococcal proteins. NHBA is the only Bexsero recombinant antigen that is conserved and surfaced exposed in N. gonorrhoeae. Rabbit antibodies to the OMV component or to the three recombinant antigens of Bexsero recognise gonococcal proteins and mediate SBA and OPA killing of N. gonorrhoeae. Furthermore, Bexsero induces antibodies in humans that recognise gonococcal proteins. Analysis of the functional activity of Bexsero-induced human antibodies against N. gonorrhoeae is ongoing. Conclusions The ability of antibodies induced by MeNZB OMV proteins to recognise and kill N. gonorrhoeae could explain the decrease in gonococcal cases associated with MeNZB vaccination. The presence of antibodies to OMV proteins plus NHBA following Bexsero vaccination may result in additional protection against gonorrhoea. Analysis of Bexsero-vaccinate human sera may also facilitate the identification of a correlate of protection to guide future development of a gonococcal vaccine. Disclosure No significant relationships.

Background Gonorrhoea infection is increasing and becoming harder to treat. In England, incidence among men who have sex with men (MSM) has increased eight-fold since 2008, reaching ≥21,000 cases in 2017. This epidemic, coupled with the growing threat of potentially untreatable antibiotic-resistant infection, has renewed interest in a gonococcal vaccine. Previous vaccine development attempts have failed; however, observational evidence suggesting the MeNZB meningococcal B vaccine is partially protective against gonorrhoea, with 31% effectiveness but uncertain duration, indicates it may be possible to develop a suitable vaccine. Methods We fitted a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behaviour, to gonorrhoea incidence in MSM in England over 2008–17 using particle Markov Chain Monte Carlo methods. Bayesian forecasting, considering realistic vaccination strategies under different scenarios of antibiotic resistance, determined how vaccine effectiveness and duration of protection affect population-level impact, and examined feasibility of achieving WHO’s target of reducing gonorrhoea incidence by 90% between 2016 and 2030. Results Even a partially-effective vaccine could have a substantial impact if protection lasts long enough. In a worst-case scenario of untreatable gonorrhoea, vaccinating all MSM attending sexual health clinics with a 58% effective vaccine protecting for ≥12 years (with boosters if required), or a 66% effective vaccine lasting ≥6 years, reduces expected incidence below the WHO target. A vaccine conferring 30% protection for 2–4 years reduces expected incidence in 2030 by 34% if gonorrhoea becomes untreatable, but if ≥80% of gonorrhoea cases are treatable then incidence is reduced by 95%. Conclusion Our statistically rigorous assessment shows that even a partially-effective vaccine, delivered through a practical targeting strategy, could have a substantial benefit in reducing gonorrhoea incidence in the context of an epidemic with rising antibiotic resistance. Our model can help design trials to measure vaccine effectiveness and duration of protection and assess cost-effectiveness of vaccination strategies. Disclosure No significant relationships.

Have potential clues to an effective gonorrhea vaccine been lurking in international disease surveillance data for decades? While no clinically effective vaccines against gonorrhea have been developed we present direct and indirect evidence that a vaccine is not only possible, but may already exist. Experience from Cuba, New Zealand, and Canada suggest that vaccines containing Group B Neisseria meningitides outer membrane vesicles (OMV) developed to control type-specific meningococcal disease may also prevent a significant proportion of gonorrhea. The mechanisms for this phenomenon have not yet been elucidated but we present some strategies for unraveling potential cross protective antigens and effector immune responses by exploiting stored sera from clinical trials and individuals primed with a meningococcal group B OMV vaccine (MeNZB). Elucidating these will contribute to the ongoing development of high efficacy vaccine options for gonorrhea. While the vaccine used in New Zealand, where the strongest empirical evidence has been gathered, is no longer available, the OMV has been included in the multi component recombinant meningococcal vaccine 4CMenB (Bexsero) which is now licensed and used in numerous countries. Several lines of evidence suggest it has the potential to affect gonorrhea prevalence. A vaccine to control gonorrhea does not need to be perfect and modeling supports that even a moderately efficacious vaccine could make a significant impact in disease prevalence. How might we use an off the shelf vaccine to reduce the burden of gonorrhea? What are some of the potential societal barriers in a world where vaccine hesitancy is growing? We summarize the evidence and consider some of the remaining questions.

Have potential clues to an effective gonorrhea vaccine been lurking in international disease surveillance data for decades? While no clinically effective vaccines against gonorrhea have been developed we present direct and indirect evidence that a vaccine is not only possible, but may already exist. Experience from Cuba, New Zealand, and Canada suggest that vaccines containing Group B Neisseria meningitides outer membrane vesicles (OMV) developed to control type-specific meningococcal disease may also prevent a significant proportion of gonorrhea. The mechanisms for this phenomenon have not yet been elucidated but we present some strategies for unraveling potential cross protective antigens and effector immune responses by exploiting stored sera from clinical trials and individuals primed with a meningococcal group B OMV vaccine (MeNZB). Elucidating these will contribute to the ongoing development of high efficacy vaccine options for gonorrhea. While the vaccine used in New Zealand, where the strongest empirical evidence has been gathered, is no longer available, the OMV has been included in the multi component recombinant meningococcal vaccine 4CMenB (Bexsero) which is now licensed and used in numerous countries. Several lines of evidence suggest it has the potential to affect gonorrhea prevalence. A vaccine to control gonorrhea does not need to be perfect and modeling supports that even a moderately efficacious vaccine could make a significant impact in disease prevalence. How might we use an off the shelf vaccine to reduce the burden of gonorrhea? What are some of the potential societal barriers in a world where vaccine hesitancy is growing? We summarize the evidence and consider some of the remaining questions.

Antimicrobial resistance in Neisseria gonorrhoeae compromises gonorrhoea treatment globally and vaccines might be the only sustainable solution for gonorrhoea control. A new study for the first time provides a proof of principle for protection with ∼31% effectiveness against gonorrhoea, owing to cross-protection by the outer membrane vesicle Neisseria meningitidis serogroup B vaccine (MeNZB).

The utility of wild-type outer membrane vesicle (wtOMV) vaccines against serogroup B (MenB) meningococcal disease has been explored since the 1970s. Public health interventions in Cuba, Norway and New Zealand have demonstrated that these protein-based vaccines can prevent MenB disease. Data from large clinical studies and retrospective statistical analyses in New Zealand give effectiveness estimates of at least 70%. A consistent pattern of moderately reactogenic and safe vaccines has been seen with the use of approximately 60 million doses of three different wtOMV vaccine formulations. The key limitation of conventional wtOMV vaccines is their lack of broad protective activity against the large diversity of MenB strains circulating globally. The public health intervention in New Zealand (between 2004–2008) when MeNZB was used to control a clonal MenB epidemic, provided a number of new insights regarding international and public-private collaboration, vaccine safety surveillance, vaccine effectiveness esti...

Disadvantaged children of Māori and Pacific origin in New Zealand carry an inequitable burden of infectious diseases, many of which are preventable, some by vaccine. Immunisation is recognised in the developing world as a cheap, effective and efficient means of reducing inequalities. The MeNZB immunisation programme delivered in 2004–2006 towards the expected natural end of a projected 15-year epidemic appears to have had an effect (difficult to prove conclusively) on reducing the disproportionate burden of meningococcal disease carried by this group of children. It was delayed by the late engagement of the New Zealand Ministry of Health, fully briefed from 1996, leading to unnecessary and potentially avoidable deaths and sequelae, many lifelong. Further, failure to adequately assess vaccine effectiveness means that the contribution of MeNZB to the observed reduction in disease, particularly in those aged less than five years, will never be reliably known. However, the MeNZB campaign has at least left a legacy: the National Immunisation Register, which should enable New Zealand to minimise the ‘vaccine inverse care law’ and contribute to reducing ethnic inequity in the burden of vaccine preventable diseases.

New Zealand has experienced a prolonged epidemic of meningococcal B disease since 1991. The epidemic has waned significantly since its most recent peak in 2001. A strain-specific vaccine, MeNZB, was introduced to control the epidemic in 2004, achieving 81% coverage of people under the age of 20. The vaccine was rolled out in a staged manner allowing the comparison of disease rates in vaccinated and unvaccinated individuals in each year. Vaccine effectiveness in people aged under 20 years is estimated using a Poisson regression model in the years 2001-2008, including adjustments for year, season, age, ethnicity, region and socioeconomic status. Further analyses investigate the dose response relationship, waning of the vaccine effect after one year, and cross-protection against other strains of meningococcal disease. The primary analysis estimates MeNZB vaccine effectiveness to be 77% (95% CI 62-85) after 3 doses and a mean follow-up time of 3.2 years. There is evidence for a protective effect after 2 doses 47% (95% CI 16-67), and no evidence for a waning of effectiveness after one year. Simultaneous modelling of invasive pneumococcal disease and epidemic strain meningococcal B suggests a degree of residual confounding that reduces the effectiveness estimate to 68%. There is evidence for some cross-protection of MeNZB against non-epidemic strains. The MeNZB vaccine was effective against the New Zealand epidemic strain of meningococcal B disease. Between July 2004 and December 2008 an estimated 210 epidemic strain cases (95% CI 100-380), six deaths and 15-30 cases of severe sequelae were avoided in New Zealand due to the introduction of the MeNZB vaccine.

Invasive disease caused by meningococcal capsular groups A, C, W-135, and Y is now preventable by means of glycoconjugate vaccines that target their respective polysaccharide capsules. The capsule of group B meningococci (MenB) is poorly immunogenic and may induce autoimmunity. Vaccines based on the major immunodominant surface porin, PorA, are effective against clonal epidemics but, thus far, have a limited scope of coverage against the wider MenB population at large. In an alternative approach, the first-generation, investigational, recombinant MenB (rMenB) plus outer membrane vesicle (OMV) (rMenB-OMV) vaccine contains a number of relatively conserved surface proteins, fHBP, NHBA (previously GNA2132), and NadA, alongside PorA P1.4-containing OMVs from the New Zealand MeNZB vaccine. MenB currently accounts for approximately 90% of cases of meningococcal disease in England and Wales. To assess potential rMenB-OMV vaccine coverage of pathogenic MenB isolates within this region, all English and Welsh MenB case isolates from January 2008 ( n = 87) were genetically characterized with respect to fHBP, NHBA, NadA, and PorA. Alleles for fHbp , nhba , and porA were identified in all of the isolates, of which 22% were also found to harbor nadA alleles. On the basis of genotypic data and predicted immunological cross-reactivity, the potential level of rMenB-OMV vaccine coverage in England and Wales ranges from 66% to 100%.

An emerging serogroup B clone can be prevented by vaccines., Emergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annual incidence rates (3.1 cases/100,000 population) of meningococcal disease in a defined German region, the city of Aachen and 3 neighboring countries (Greater Aachen) prompted us to investigate and determine the source and nature of this outbreak. Using molecular typing and geographic mapping, we analyzed 1,143 strains belonging to ST41/44 complex, isolated from persons with invasive meningococcal disease over 6 years (2001–2006) from 2 German federal states (total population 26 million) and the Netherlands. A spatially slowly moving clone with multiple-locus variable-number tandem repeat analysis type 19, ST42, and antigenic profile B:P1.7–2,4:F1–5 was responsible for the outbreak. Bactericidal activity in serum samples from the New Zealand MeNZB vaccination campaign confirmed vaccine preventability. Because this globally distributed epidemic strain spreads slowly, vaccination efforts could possibly eliminate meningococcal disease in this area.

Highly effective glycoconjugate vaccines exist against four of the five major pathogenic groups of meningococci: A, C, W-135, and Y. An equivalent vaccine against group B meningococci (menB) has remained elusive due to the poorly immunogenic capsular polysaccharide. A promising alternative, the investigational recombinant menB (rMenB)- outer membrane vesicle (OMV) vaccine, contains fHBP, NHBA (previously GNA2132), NadA, and outer membrane vesicles (OMVs) from the New Zealand MeNZB vaccine. MenB currently accounts for 90% of meningococcal disease in England and Wales, where the multilocus sequence type (ST) 269 (ST269) clonal complex (cc269) has recently expanded to account for a third of menB cases. To assess the potential cc269 coverage of the rMenB-OMV vaccine, English and Welsh cc269 isolates from the past decade were genetically characterized with respect to fHBP, NHBA, and NadA. All of the isolates harbored fHbp and nhba alleles, while 98% of the cc269 isolates were devoid of nadA . Subvariant profiling of fHbp , nhba , and porA against STs revealed the presence of two broadly distinct and well-defined clusters of isolates, centered around ST269 and ST275, respectively. An additional molecular marker, insertion sequence IS 1301 , was found to be present in 100% and 1301 within the ST269 cluster.

BACKGROUND: An outer membrane vesicle meningococcal vaccine (MeNZB), was developed for the New Zealand epidemic strain of Neisseria meningitidis B:4:P1.7-2,4. METHODS: A phase II, randomized, observer blind, controlled study evaluating the safety, reactogenicity, and immunogenicity of MeNZB administered with routine New Zealand immunizations at 6 weeks, 3 months, and 5 months of age (n = 375). Group 1 (n = 250) received 25 mug MeNZB and routine immunizations with a fourth MeNZB dose given at 10 months (n = 51). Group 2 (n = 125) received routine immunizations only. Sero-response was a > or =4-fold rise in vaccine strain serum bactericidal antibody titer compared with baseline or a titer of at least 1:8 for baselines

New Zealand (NZ) has experienced a Neisseria meningitidis serogroup B epidemic since 1991. MeNZB, a strain-specific outer membrane vesicle vaccine made using an NZ epidemic strain isolate, NZ98/254 (B:4:P1.7b,4), from two manufacturing sites, the Norwegian Institute of Public Health (NIPH) and Chiron Vaccines (CV; now Novartis), was evaluated for safety, immunogenicity, and reactogenicity in this observer-blind trial with 8- to 12-year-old children. In year 1, cohort A ( n = 302) was randomized 4:1 for receipt of NIPH-MeNZB or MenBvac (Norwegian parent vaccine strain 44/76; B:15:P1.7,16). In year 2, cohort B ( n = 313) was randomized 4:1 for receipt of CV-MeNZB or NIPH-MeNZB. Participants all received three vaccinations 6 weeks apart. Local and systemic reactions were monitored for 7 days. Seroresponse was defined as a fourfold or greater rise in the serum bactericidal antibody titer from the baseline titer as measured by a serum bactericidal assay. Those with baseline titers of

This study presents detailed analyses of total and specific serum antibody levels among 26 and 24 adult volunteers before vaccination and after the third dose of the meningococcal serogroup B outer membrane vesicle (OMV) vaccines MeNZB and MenBvac, respectively, in a clinical trial in New Zealand (V. Thornton, D. Lennon, K. Rasanathan, J. O’Hallahan, P. Oster, J. Stewart, S. Tilman, I. Aaberge, B. Feiring, H. Nokleby, E. Rosenqvist, K. White, S. Reid, K. Mulholland, M. J. Wakefield, and D. Martin, Vaccine 24:1395‐1400, 2006). With the homologous vaccine strains as targets, both vaccines induced significant increases in serum bactericidal and opsonophagocytic activities and in the levels of immunoglobulin G (IgG) to OMV antigens in an enzyme-linked immunosorbent assay (ELISA) and to live meningococci by flow cytometry. They also induced high levels of activity against the heterologous strains, particularly in terms of opsonophagocytic activity and IgG binding to live bacteria. The antibody levels with the homologous and heterologous strains in the four assays showed high and significant positive correlations. Specific IgG binding to 10 major OMV antigens in each vaccine was measured by scanning of immunoblots; ELISAs for two antigens, lipopolysaccharide and Neisseria surface protein A (NspA), were also performed. Both vaccines elicited significant increases in IgG binding to all homologous and heterologous OMV antigens except NspA. The total IgG band intensity on the blots correlated significantly with the IgG levels determined by the OMV ELISA and flow cytometry. In conclusion, the results of the various immunological assays showed that both OMV vaccines gave rise to high levels of specific and cross-reacting antibodies. Since 1991, an epidemic of meningococcal disease in New Zealand has caused over 200 deaths and nearly 6,000 cases of disease in a population of 4 million people (www.moh.govt.nz). Most of the cases are caused by serogroup B strains, and from 1991 through 2004, 86% of these expressed the P1.7-2,4 (P1.7b,4) PorA and belonged to the sequence type 41/44 complex (lineage III) (13, 15). The majority of these strains also expressed the serotype 4 PorB protein (14). In contrast to the other capsular meningococcal polysaccharides, group B polysaccharide is poorly immunogenic in humans (65); and vaccines based on subcapsular antigens, such as outer membrane proteins or outer membrane vesicles (OMVs) from various group B strains, have been developed and used in clinical trials (6, 9, 12, 18, 48). The experience of the Norwegian Institute of Public Health (NIPH) with the development and production of the OMV vaccine (MenBvac) for the protection trial in Norway (6, 19) led to a partnership with Chiron Vaccines (now Novartis Vaccines & Diagnostics) and the New Zealand Ministry of Health, in which NIPH developed and produced a tailor-made OMV vaccine (MeNZB) from a representative strain of the New Zealand epidemic (NZ98/254)

MenBvac and MeNZB are safe and efficacious outer membrane vesicle (OMV) vaccines against serogroup B meningococcal disease. Antibody responses have previously been investigated in a clinical trial with these two OMV vaccines given separately (25 μg/dose) or in combination (12.5 and 12.5 μg/dose) in three doses administered at 6-week intervals. Here, we report the results from analyzing cellular immune responses against MenBvac and MeNZB OMVs in terms of antigen-specific CD4 + T cell proliferation and secretion of cytokines. The proliferative CD4 + T cell responses to the combined vaccine were of the same magnitude as the homologous responses observed for each individual vaccine. The results also showed cross-reactivity in the sense that both vaccine groups receiving separate vaccines responded to both homologous and heterologous OMV antigen when assayed for antigen-specific cellular proliferation. In addition, a multiplex bead array assay was used to analyze the presence of Th1 and Th2 cytokines in cell culture supernatants. The results showed that gamma interferon, interleukin-4 (IL-4), and IL-10 responses could be detected as a result of vaccination with both the MenBvac and the MeNZB vaccines given separately, as well as when given in combination. With respect to cross-reactivity, the cytokine results paralleled the observations made for proliferation. In conclusion, the results demonstrate that cross-reactive cellular immune responses involving both Th1 and Th2 cytokines can be induced to the same extent by different tailor-made OMV vaccines given either separately or in combination with half the dose of each vaccine.

A protracted epidemic of group B meningococcal disease in New Zealand led to the testing of a strain-specific tailor-made vaccine, MeNZB. Immunogenicity levels achieved during age group trials enabled New Zealand's regulatory authority to grant licensure to deliver MeNZB to all individuals under age 20. During the trials target strains for serum bactericidal antibody measurements included the vaccine target strain NZ98/254 and two comparator epidemic-type strains (NZ94/167 and NZ02/09). In this study, 12 other strains differing variously from the vaccine strain by their capsular group, PorB type, and PorA variable region specificities, or PorA expression, were used as target strains. The PorA specificity of the serum bactericidal antibody responses to the vaccine was determined for 40 vaccinees. Sets of 10 pre- and postvaccination sera were chosen randomly from the young infant, older infant, toddler, and school-age group trials. Antibody recognition of linearized PorA proteins was also determined using immunoblotting. Across all age groups vaccine-induced serum bactericidal antibodies specifically targeted the VR2 P1.4 epitope of the PorA P1.7-2,4 protein irrespective of the PorB type and/or capsular type of the target strain. Deletion of amino acids within the VR2 epitope or replacement of the epitope through genetic exchange allowed strains variously to resist antibody-directed complement-mediated lysis and negated PorA-specific antibody recognition in immunoblots. The demonstration that the immunodominant antibody response was specifically for the VR2 P1.4 epitope of the PorA protein supports the public health decision to use a strain-specific vaccine for the control of New Zealand's epidemic of meningococcal disease.

As the first step towards control of a strain specific epidemic of meningococcal disease in New Zealand (NZ), this study, an observer-blind, randomised controlled trial in 75 healthy adults, evaluated safety and immunogenicity of two different dosages of a meningococcal group B vaccine administered in a three dose regime. The "tailor-made" outer membrane vesicle (OMV) vaccine (candidate vaccine) developed using a New Zealand meningococcal group B strain (B:4:P1.7b,4) was well tolerated with no vaccine related serious adverse events. Similar local and systemic reactions were observed in those receiving the New Zealand candidate vaccine and the control parent Norwegian vaccine (MenBvac). A four-fold rise in serum bactericidal antibodies (SBAb) against the vaccine strain 4-6 weeks after the third vaccination was achieved in 100% of New Zealand candidate vaccine 2,519 microg participants and in 87% of 50 microg participants. The safety and immunogenicity profile observed in this study of healthy adults enabled studies in children to be initiated using 25 microg dosage.

Clinical studies have been conducted in New Zealand evaluating the safety and immunogenicity of an outer membrane vesicle (OMV) vaccine, MeNZB, developed to control epidemic disease caused by group B meningococci, subtype P1.7b,4. MeNZB, administered in a three-dose regimen, was well tolerated and induced a seroresponse, defined as a four-fold rise (> or =titre 8) in serum bactericidal antibodies against the vaccine strain 4-6 weeks after the third vaccination, in 96% (95% confidence interval (CI): 79-100%) of adults, 76% (95% CI: 72-80%) of children, 75% (95% CI: 69-80%) of toddlers and 74% (95% CI: 67-80%) of infants receiving MeNZB. In conclusion, these findings suggest that MeNZB is safe and is likely to confer protection against systemic group B meningococcal disease caused by the epidemic strain.

Provisional licensure of the trial vaccine, MeNZB, required demonstration of immune responses in vaccines, as measured by a validated Serum Bactericidal Assay (SBA). Reported are the investigations undertaken to define test parameters, lower limits of quantitation and measurement of SBA reproducibility. Results helped to formulate the operating procedure for the measurement of serum bactericidal antibodies during six age-group MeNZB vaccine trials. The lower limit of quantitation was determined as a titre of 4. A four-fold rise in antibody (sero-conversion) from a pre-vaccination titre of 2 (

New Zealand is experiencing an epidemic of serogroup B meningococcal disease, which has taken the rate of disease from an average of 1.5/100,000 population in the preepidemic years of 1989 and 1990 to 14.0/100,000 in 1996. Sterile-site isolates of Neisseria meningitidis from cases of invasive disease have been phenotypically characterized by serogrouping, serotyping, and serosubtyping, revealing the involvement of a strain with phenotype B:4:P1.4. Macrorestriction analysis using pulsed-field gel electrophoresis on 667 meningococci isolated from cases during the epidemic has identified the clonal relationship of meningococci expressing the PorA P1.4 antigen. Multilocus enzyme electrophoresis has shown the epidemic strain B:4:P1.4 to belong to lineage III. The recorded characteristics of New Zealand's epidemic are consistent with previous serogroup B epidemics in other parts of the world.

A meningococcal group B (15:P1.3) outer membrane protein vaccine was tested for efficacy in a randomized, double-blind controlled study in Iquique, Chile. A total of 40 811 volunteers, ages 1-21 years, enrolled in the study. Volunteers received two doses of vaccine six weeks apart by jet injector. Both the experimental vaccine and the control vaccine (Menomune, A, C, Y and W135 meningococcal polysaccharide vaccine) were well tolerated with minor side-effects. Active surveillance for suspected cases of meningococcal disease was conducted for 20 months in Iquique. Eighteen cases of group B meningococcal disease were confirmed during the 20 months. Efficacy was estimated to be 51% (p = 0.11) for all ages combined. In children aged 1-4 no protection was evident, but in volunteers aged 5-21 vaccine efficacy was 70% (p = 0.045). The IgG antibody response by ELISA was characterized by a large booster effect after the second dose, followed by a substantial drop in antibody levels by 6 months. The youngest children had the highest responses. The bactericidal antibody response, on the other hand, was characterized by the lack of a significant booster response, higher responses in the older children, and an increase in the geometric mean titer in the later months of the study in the older children.

Background A New Zealand serogroup B meningococcal epidemic prompted trials of a strain-specific (B:4:P1.7-2,4) outer membrane vesicle vaccine (MeNZB). Methods Adults, school children, and infants provided serum after three MeNZB doses to evaluate antibody persistence via serum bactericidal assay. Toddler (16–24 months) non-responders and responders received a fourth MeNZB dose 11 and 17 months after dose three respectively. Response was a ≥4-fold rise in bactericidal titre to a titre of ≥8. Results Geometric mean bactericidal titres (GMTs), with 95% CI, after dose 3: adults: 27 (14–52), 5 (3–11), and 7 (3–15) at 1, 10, and 22 months; school children: 18 (13–25) and 4 (3–6) at 1 and 4 months; infants: 27 (19–39) and 2 (2–3) at 1 and 7 months. The titre achieved after priming significantly influenced persistence.Toddler non-responder GMTs were 4 (3–5) and 1 (1–1) at 1 and 11 months after dose 3 and 69 (46–106) 1 month after dose 4. Responder GMTs were 24 (19–30) and 3 (2–4) at 1 and 17 months after dose 3 and 259 (184–363) 1 month after dose 4. Dose 4 had no safety concerns. Conclusions Immune response to MeNZB was most sustained in adults. In infants, bactericidal titres decayed almost to baseline by 7 months after dose 3. Toddlers showed marked immune response following a fourth dose suggesting memory. Persisting antibody is likely to be necessary for ongoing protection, as seen with serogroup C meningococci.

New Zealand developed a strain-specific group B meningococcal vaccine to control an epidemic. Following a mass vaccination campaign of three doses to the population under 20 years of age, commencing in July 2004, the vaccine continued to be offered routinely as a four-dose schedule from 6 weeks of age. There is little international data on when to cease epidemic vaccination campaigns. The decision to stop using this vaccine needed to take into account a range of factors. These included epidemiology, vaccine effectiveness and duration of immunity, vaccine coverage, concomitant use with other vaccinations being added to the infant schedule, vaccine supply and cost–benefit criteria. This paper discusses these issues, along with the potential challenges for communication to both health professionals and the public.

New Zealand introduced a tailor-made vaccine (MeNZB) for epidemic control of Group B meningococcal disease. The Intensives Vaccine Monitoring Programme (IVMP), which prospectively collected data electronically on a cohort of children receiving vaccinations in sentinel practices across NZ, was developed as part of a national multi-faceted safety strategy. The main aim of the IVMP was to identify the presence of unexpected adverse events occurring with MeNZB vaccination. We describe the methodology and success factors plus consider the limitations encountered in this system which shows potential as a means for post-marketing vaccine and medicine surveillance in the future.

SUMMARYThis study evaluated the first use of a combination of the lyophilized components of the conjugated group C vaccine Menjugate™ reconstituted with the liquid group B outer membrane vesicle (OMV) vaccine MeNZB™. At 6-week intervals, healthy residential students received three doses of MeNZB alone or concomitantly with one dose of Menjugate (MeNZB+MenC). Short-lasting injection-site reactions of mild or moderate intensity were frequent in both groups. There were no vaccine-related serious adverse events. After three doses, the percentage of subjects with serum bactericidal assay (SBA) titres ⩾1:8 against the serogroup B strain NZ98/254 was 82% for MeNZB+MenC and 78% for MeNZB. All subjects in the MeNZB+MenC group achieved SBA titres ⩾1:8 against serogroup strain C11 and 67% in the MeNZB group. All SBA and ELISA responses of the combined vaccine were at least as good as for MeNZB alone. After vaccination, the pharyngeal carriage rate of any meningococcus in the vaccinated group had declined from 40% to 21%.

MenBvac and MeNZB are safe and efficacious vaccines against serogroup B meningococcal disease. MenBvac is prepared from a B:15:P1.7,16 meningococcal strain (strain 44/76), and MeNZB is prepared from a B:4:P1.7-2,4 strain (strain NZ98/254). At 6-week intervals, healthy adults received three doses of MenBvac (25 μg), MeNZB (25 μg), or the MenBvac and MeNZB (doses of 12.5 μg of each vaccine) vaccines combined, followed by a booster 1 year later. Two-thirds of the subjects who received a monovalent vaccine in the primary schedule received the other monovalent vaccine as a booster dose. The immune responses to the combined vaccine were of the same magnitude as the homologous responses to each individual vaccine observed. At 6 weeks after the third dose, 77% and 87% of the subjects in the combined vaccine group achieved serum bactericidal titers of ≥4 against strains 44/76 and NZ98/254, respectively, and 97% and 93% of the subjects achieved a fourfold or greater increase in opsonophagocytic activity against strains 44/76 and NZ98/254, respectively. For both strains, a trend of higher responses after the booster dose was observed in all groups receiving at least one dose of the respective strain-specific vaccine. Local and systemic reactions were common in all vaccine groups. Most reactions were mild or moderate in intensity, and there were no vaccine-related serious adverse events. The safety profile of the combined vaccine was not different from those of the separate monovalent vaccines. In conclusion, use of either of the single vaccines or the combination of MenBvac and MeNZB may have a considerable impact on the serogroup B meningococcal disease situation in many countries.

The effectiveness of a new group B strain-specific meningococcal vaccine referred to as "MeNZB," developed by Chiron Vaccines (Siena, Italy) in collaboration with the Norwegian Institute of Public Health, was assessed in a prospective observational study following a nationwide vaccination program in New Zealand. The vaccination program began in July 2004, and the study uses data from January 2001 to June 2006. A generalized estimating equation model was used to estimate vaccine effectiveness that included potential confounding variables, such as disease progression over time, age, ethnicity, socioeconomic status, seasonality, and geographic region. The model provides strong statistical evidence for a vaccine effect (p < 0.0001), with estimated disease rates 3.7 times higher in the unvaccinated group than in the vaccinated group (95% confidence interval: 2.1, 6.8) and a vaccine effectiveness of 73% (95% confidence interval: 52, 85). An estimated 54 epidemic strain meningococcal cases were prevented in the 2 years since the vaccination program began (95% confidence interval assuming a fixed population size: 22, 115). In a sensitivity analysis, these estimates proved to be robust to modeling assumptions, including population estimates, estimates of the numbers vaccinated, effects of partial vaccination, and temporal autocorrelation.

To control the devastating group B meningococcal epidemic in New Zealand a strain-specific OMV vaccine (MeNZB) was extensively tested before vaccination of >1,000,000 people under 20 years. After the three-dose course 75% of 6-8-month-old infants and 16-24-month-old toddlers showed four-fold increases in bactericidal antibodies. In 6-10-week-old infants a fourth dose was needed to obtain similar results. After primary vaccination, the antibody titre decline was most pronounced among the youngest but both young infants and toddlers showed a clear booster response to a fourth dose. MeNZB was safe and well tolerated. The comprehensive post-licensure safety surveillance revealed no safety concerns.

MenBvac is an OMV vaccine against systemic serogroup B Neisseria meningitidis disease. MenBvac was developed for control of a B:15:P1.7,16 subtype epidemic in Norway and administered to 180,000 subjects in 28 clinical studies. MeNZB, a daughter vaccine of MenBvac, was developed for a clonal B:4:P1.7b,4 epidemic in New Zealand and administered to 1 million people20 years. The vaccines were similar regarding reactogenicity profile. Serious adverse events (SAEs) in general and particularly neurologic SAEs were very rare. Despite frequently reported local reactions and fever in those under 5 years, these OMV-based vaccines containing 25 microg antigen can be considered safe for use in all age groups.

Vaccine trials with infants enrolled between 6 and 10 weeks of age (young infants) and 6 and 8 months of age (older infants) provided an opportunity to evaluate immunoglobulin G (IgG) isotype distribution and avidity maturation as indicators of antibody function and immunologic memory. Following vaccination with a strain-specific outer membrane vaccine, MeNZB, pre- and postvaccination sera were used to determine IgG isotype responses and avidity indices (AI) in subsets of vaccinated subjects. Measurements of IgG isotypes involved 100 infants from each trial. AI were measured in 50 infants from the young infant trial who received a fourth vaccine dose and in 40 older infants from whom serum was collected 7 months after the primary vaccination course. IgG1 and IgG3 dominated the responses to the vaccine. A modest linear correlation ( P < 0.001) occurred between serum bactericidal antibody (SBAb) titers and the total IgG or the IgG1 antibody units in older infants. The young infants showed a modest linear correlation between SBAb and total IgG ( P = 0.005) and a weak linear correlation between SBAb and IgG1 ( P = 0.003). Increased avidity with age was demonstrated in both groups. The AI in the young infants increased from 51.5% (95% confidence interval [CI], 47.7 to 54.7) postvaccination to 68.7% (95% CI, 65.5 to 71.9%) following the fourth dose of vaccine ( P < 0.001). The mean avidity of the older infants increased significantly ( P = 0.00012) from 42.4% (95% CI, 39.1 to 45.3%) postvaccination to 50.4% (95% CI, 47.2 to 53.6%) 4 months later. A fourth dose of MeNZB is now being given to young infants at 10 months of age.

A nationwide strategy to control a group B meningococcal disease epidemic in New Zealand using an epidemic strain-specific vaccine (MeNZB ) commenced in 2004. In the absence of randomised controlled trials investigating the efficacy of this particular vaccine, a complement of observational methods are planned to evaluate the post-licensure effectiveness of this vaccine strategy. The two main approaches involve a Poisson regression model investigating the overall impact of the MeNZB programme on disease rates over time capitalising on detailed population-based disease surveillance data and the staged roll-out of the vaccine campaign, and a case-control study that aims to estimate vaccine effectiveness in pre-school children. The studies are designed to minimise the potential biases inherent in all observational methods and provide critical data on the effectiveness of a major public health intervention.

New Zealand's epidemic of meningococcal disease began in mid 1991. Surveillance of meningococcal disease in New Zealand is based on a combination of disease notification and organism characterisation. Case numbers and population rates rose from 53 (1.5 per 100,000 population) in 1990 to a high of 650 (17.4 per 100,000 population) in 2001. The highest rates of disease occur in Pacific peoples under 20 years but the highest percentages of cases occur in Maori and European New Zealanders. The epidemic has been driven by a strain identified as B:4:P1.7b,4, ST-41/44 complex/Lineage III. The stability of the P1.7b,4 Por A protein has been demonstrated suggesting that the epidemic may be controlled by a strain-specific OMV vaccine.

ContextMeningococcal disease occurs worldwide, and serogroup B disease accounts for a large proportion of cases. Although persons younger than 4 years are at greatest risk for serogroup B meningococcal disease, vaccine efficacy has not been demonstrated in this age group.ObjectiveTo evaluate serum bactericidal activity (SBA) against homologous vaccine type strains and a heterologous Chilean epidemic strain of Neisseria meningitidis as a potential correlate for vaccine efficacy.DesignDouble-blind, randomized controlled trial conducted between March 14 and July 20, 1994. All blood samples were taken by December 1994.SettingSantiago, Chile, where a clonal serogroup B meningococcal disease epidemic began in 1993.ParticipantsInfants younger than 1 year (n=187), children aged 2 to 4 years (n=183), and adults aged 17 to 30 years (n=173).InterventionParticipants received 3 doses of outer-membrane protein (OMP) meningococcal vaccine developed in either Cuba or Norway or a control vaccine, with each dose given 2 months apart. Blood samples were obtained at baseline, prior to dose 3, and at 4 to 6 weeks after dose 3.Main Outcome MeasureImmune response, defined as a 4-fold or greater rise in SBA titer 4 to 6 weeks after dose 3 compared with prevaccination titer.ResultsChildren and adult recipients of either meningococcal vaccine were more likely than controls to develop an immune response to the heterologous epidemic strain. After 3 doses of vaccine, 31% to 35% of children responded to the vaccine vs 5% to placebo; 37% to 60% of adults responded to vaccine vs 4% to placebo (P

For more than 15 years, Norway has had the highest incidence of meningococcal disease in northern Europe, with 80% of cases being due to serogroup B meningococci. The case-fatality has remained high, at about 10%. In this study, an outer membrane vaccine, which had previously been shown to induce an increase in bactericidal antibodies to the parent strain, was assessed in a large-scale, randomised, double-blind trial. From October, 1988, 171,800 students in secondary schools volunteered to take part in a double-blind, placebo-controlled, efficacy trial with school as the randomisation unit. Hospitals and clinics that routinely receive patients with infectious disease were asked to report urgently all cases of suspected meningitis and/or septicaemia in 13-21-year-old students in Norway. These cases were registered and further investigated according to a detailed protocol. 89 out of the 221 cases investigated by June 3, 1991, were shown to be severe systemic disease due to group B meningococci. 36 cases in 35 schools took part in the trial (11 schools with vaccinated students and 24 with students given placebo). The calculated rate of protection was thus 57.2% (p = 0.012, one-sided test). The findings suggest that, although the vaccine conferred protection against group B meningococcal disease, the effect was insufficient to justify a public vaccination programme.