[Meningococcal B (4CMenB) vaccine : uptodate and recommendations]. / Vaccination contre le méningocoque (4CMenB) : actualités et recommandations.

Neisseria meningitidis is the cause of relatively rare invasive infections, but with very important morbi-mortality. Vaccines are already available for serogroups A, C, W, Y. A new vaccine against meningococcus B is on the Belgian market since March 2017. Serogroup B is the most prevalent in Western countries. The target populations are children and teenager, since it is at this age that peaks in the incidence of meningococcal disease are observed. The development of this vaccine has been made possible by a new process named " reverse vaccinology ", which uses the complete genome sequencing of the bacterium. Current studies focus on the immunogenicity of the vaccine, which is good for both children and teenager. However, there are still many unknowns with this vaccine such as the duration of protection and its impact on the pharyngeal carriage. Another difficulty lies in the extrapolation of the immunogenicity data among a population because this vaccine consists of protein antigens and we know that the expression and prevalence of these antigens may vary between different strains of meningococci. In England, where the vaccine has been included in the vaccination calendar, beneficial effects are demonstrated on the incidence of invasive meningococcal infections. The toxicity profile is also reassuring, only classic side effects have been observed, such as fever and local reactions. In 2017, the High Health Council issued a favorable opinion for individual protection, without recommending at this stage a collective vaccination in Belgium. After a review of the most recent data on this new vaccine, we will try to draw conclusions.

Neisseria meningitidis est à l'origine d'infections invasives relativement rares, mais greffées d'une morbi-mortalité très importante. Des vaccins sont déjà disponibles pour les sérogroupes A,C,W,Y et un nouveau vaccin contre le méningocoque B est sur le marché belge depuis mars 2017. Le sérogroupe B est le plus prévalent dans les pays occidentaux, avec pour populations cibles les nourrissons et les adolescents, puisque c'est à cet âge que l'on observe des pics d'incidence d'infection à méningocoque. Le développement de ce vaccin a été rendu possible grâce à un nouveau procédé appelé " vaccino-logie inverse ", qui utilise le séquençage complet du génome de la bactérie. Les études actuelles portent essentiellement sur l'immunogénicité du vaccin qui est bonne, tant chez les nourrissons que chez les adolescents. Cependant, il persiste encore beaucoup d'inconnues comme la durée de protection du vaccin et son impact sur le portage pharyngé. Une autre difficulté concerne l'extrapolation des données sur le plan clinique car ce vaccin est constitué d'antigènes protéiques, dont l'expression et la prévalence dans les méningocoques B peuvent varier entre les différentes souches. En Angleterre, où le vaccin a été intégré au calendrier vaccinal, des effets bénéfiques ont pu être démontrés sur l'incidence des infections invasives à méningocoques. Le profil de toxicité est également rassurant, seuls des effets secondaires classiques ont été observés, comme la fièvre et les réactions locales. En 2017, le Conseil supérieur de la Santé (CSS) a émis un avis favorable pour la protection individuelle, sans recommander à ce stade une vaccination collective en Belgique. Après une revue des connaissances actuelles sur ce nouveau vaccin, nous tenterons d'en dégager des conclusions.

Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease.

In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero® is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero® in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20-30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5-10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100-200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the index case.

Impact of meningococcal group B OMV vaccines, beyond their brief.

Meningococcal group B outer membrane vesicle vaccines have been used widely in Cuba, New Zealand, and Brazil. They are immunogenic and initially assessed largely by their ability to induce serum bactericidal activity. Measures of efficacy indicate good protection against homologous strains in older children and adults. Effectiveness appears broader than predicted by immunogenicity and efficacy studies. The recent discovery that meningococcal group B OMVs may protect against the related Neisseria species N.gonorrhoeae suggests more to these interesting antigen collections than meets the eye. Currently there are two OMV-containing group B vaccines available, the new recombinant protein-based Bexsero® developed by Novartis and VA-MENGOC-BC® developed by the Finlay institute in Cuba. Also, a third group B vaccine based on two recombinant factor H binding proteins (Trumenba®, Pfizer), has recently been licenced but it does not include OMV. This commentary explores the population impact that group B OMV vaccines have had on meningococcal and gonorrhoea diseases. Given the heterologous effect against diverse strains of the meningococcus observed in older children and adults, and recent evidence to suggest moderate protection against gonorrhoea, there may be a role for these vaccines in programmes targeting adolescents and groups high at risk for both meningococcal disease and gonorrhoea.

The capsular group B meningococcal vaccine, 4CMenB : clinical experience and potential efficacy.

INTRODUCTION: Capsular group B meningococcal disease is a leading cause of childhood meningitis and septicaemia. Up to 10% of sufferers die, and sequelae remain in > 30% of survivors. A vaccine, four component meningococcal group B ( 4CMenB ), designed with the aim to induce broad coverage against this highly variable bacterium, has been licensed in countries including in the European Union, Canada and Australia. AREAS COVERED: Immunogenicity and safety data, published in peer-reviewed literature between 2004 and 2014, are presented in the context of the recent recommendation for the use of the vaccine in infants in the UK. EXPERT OPINION: 4CMenB induces significant reactogenicity when administered with routine infant vaccines, in particular with respect to fever rates. Fevers can be somewhat reduced using paracetamol. The efficacy of the vaccine is unknown but has been extrapolated from effectiveness data obtained from use of one of its components in New Zealand, immunogenicity data from clinical trials and estimation of coverage from in vitro studies. These data suggest that the vaccine will prevent a proportion of invasive meningococcal disease cases in infants and young children. Implementation and well-planned post-marketing surveillance will address uncertainties over field effectiveness.

Recombinant Lipoproteins as Novel Vaccines with Intrinsic Adjuvant.

A core platform technology for high production of recombinant lipoproteins with built-in immunostimulator for novel subunit vaccine development has been established. This platform technology has the following advantages: (1) easily convert antigen into lipidated recombinant protein using a fusion sequence containing lipobox and express high level (50-150mg/L) in Escherichia coli; (2) a robust high-yield up- and downstream bioprocess for lipoprotein production is successfully developed to devoid endotoxin contamination; (3) the lipid moiety of recombinant lipoproteins, which is identical to that of bacterial lipoproteins is recognized as danger signals by the immune system (Toll-like receptor 2 agonist), so both innate and adaptive immune responses can be induced by lipoproteins; and (4) successfully demonstrate the feasibility and safety of this core platform technology in meningococcal group B subunit vaccine, dengue subunit vaccine, novel subunit vaccine against Clostridium difficile-associated diseases, and HPV-based immunotherapeutic vaccines in animal model studies.

Vaccines for prevention of group B meningococcal disease: Not your father's vaccines.

For decades, there was no licensed vaccine for prevention of endemic capsular group B meningococcal disease, despite the availability of vaccines for prevention of the other most common meningococcal capsular groups. Recently, however, two new vaccines have been licensed for prevention of group B disease. Although immunogenic and considered to have an acceptable safety profile, there are many scientific unknowns about these vaccines, including effectiveness against antigenically diverse endemic meningococcal strains; duration of protection; whether they provide any herd protection; and whether there will be meningococcal antigenic changes that will diminish effectiveness over time. In addition, these vaccines present societal dilemmas that could influence how they are used in the U.S., including high vaccine cost in the face of a historically low incidence of meningococcal disease. These issues are discussed in this review.

Recombinant bacterial lipoproteins as vaccine candidates.

Recombinant bacterial lipoproteins (RLP) with built-in immuno-stimulating properties for novel subunit vaccine development are reviewed. This platform technology offers the following advantages: easily converts antigens into highly immunogenic RLP using a fusion sequence containing lipobox; the lipid moiety of RLP is recognized as the danger signals in the immune system through the Toll-like receptor 2, so both innate and adaptive immune responses can be induced by RLP; serves as an efficient and cost-effective bioprocess for producing RLP in Escherichia coli and the feasibility and safety of this core platform technology has been successfully demonstrated in animal model studies including meningococcal group B subunit vaccine, dengue subunit vaccine, novel subunit vaccine against Clostridium difficile-associated diseases and HPV-based immunotherapeutic vaccines.

Label-free quantitative mass spectrometry for analysis of protein antigens in a meningococcal group B outer membrane vesicle vaccine.

The development of a multivalent outer membrane vesicle (OMV) vaccine where each strain contributes multiple key protein antigens presents numerous analytical challenges. One major difficulty is the ability to accurately and specifically quantitate each antigen, especially during early development and process optimization when immunoreagents are limited or unavailable. To overcome this problem, quantitative mass spectrometry methods can be used. In place of traditional mass assays such as enzyme-linked immunosorbent assays (ELISAs), quantitative LC-MS/MS using multiple reaction monitoring (MRM) can be used during early-phase process development to measure key protein components in complex vaccines in the absence of specific immunoreagents. Multiplexed, label-free quantitative mass spectrometry methods using protein extraction by either detergent or 2-phase solvent were developed to quantitate levels of several meningococcal serogroup B protein antigens in an OMV vaccine candidate. Precision was demonstrated to be less than 15% RSD for the 2-phase extraction and less than 10% RSD for the detergent extraction method. Accuracy was 70 to 130% for the method using a 2-phase extraction and 90-110% for detergent extraction. The viability of MS-based protein quantification as a vaccine characterization method was demonstrated and advantages over traditional quantitative methods were evaluated. Implementation of these MS-based quantification methods can help to decrease the development time for complex vaccines and can provide orthogonal confirmation of results from existing antigen quantification techniques.

Meningococcal group B vaccines.

Meningococcal disease remains a devastating and feared infection with a significant morbidity and mortality profile. The successful impact of meningococcal capsular group C glyconconjugate vaccines introduced into the UK infant immunization schedule in 1999, has resulted in >80% of disease now being attributable to meningococcal capsular group B (MenB). MenB glyconconjugate vaccines are not immunogenic and hence, vaccine design has focused on sub-capsular antigens. Recently, a four component vaccine to combat MenB disease (4CMenB) has progressed through clinical development and was approved by the European Medicines Agency at the end of 2012. This vaccine has proven safe and immunogenic and has been predicted to provide protection against ~73% of the MenB disease from England and Wales. Recommendation/implementation of the vaccine into the UK infant schedule is currently being evaluated. 4CMenB has the potential to provide protection against a significant proportion of MenB disease in the UK which is currently unpreventable.

Advance and challenge in research on meningococcal group B vaccines / 药物评价研究

It is generally accepted that vaccinations are one of the most effective tool for control of infectious diseases.In recent years,the research on meningococcal group B vaccines has made progress extensively.A new meningococcal group B vaccine,developed by the reverse vaccinology technology,has been approved by the European Medicines Agency and the Food and Drag Administration.Although no related products has been approve till now in China,some meningococcal group B vaccines are also developing in domestic companies and research institutes.Therefore,to further understand these vaccines and facilitate the development of meningococcal group B vaccines,this paper reviews advance and challenge in research on meningococcal group B vaccines.

Advance and challenge in research on meningococcal group B vaccines / 药物评价研究

It is generally accepted that vaccinations are one of the most effective tool for control of infectious diseases.In recent years,the research on meningococcal group B vaccines has made progress extensively.A new meningococcal group B vaccine,developed by the reverse vaccinology technology,has been approved by the European Medicines Agency and the Food and Drag Administration.Although no related products has been approve till now in China,some meningococcal group B vaccines are also developing in domestic companies and research institutes.Therefore,to further understand these vaccines and facilitate the development of meningococcal group B vaccines,this paper reviews advance and challenge in research on meningococcal group B vaccines.