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Public health perspective of a pentavalent meningococcal vaccine combining antigens of MenACWY-CRM and 4CMenB

Open AccessPublished:September 07, 2022DOI:https://doi.org/10.1016/j.jinf.2022.09.001

      Highlights

      • Multivalent vaccines have contributed to improved IMD vaccine coverage.
      • Multivalent vaccines have led to reduced IMD incidence of combined serogroups.
      • Pentavalent MenABCWY combines antigenic components of MenACWY-CRM and 4CMenB.
      • MenABCWY builds on clinical data and real-world evidence with MenACWY-CRM and 4CMenB.
      • MenABCWY may provide global health benefits via practical and broad IMD protection.

      Summary

      Objectives

      Invasive meningococcal disease (IMD) is a life-threatening disease that can rapidly progress to death or leave survivors with severe, life-long sequelae. Five meningococcal serogroups (A, B, C, W and Y) account for nearly all IMD. Meningococcal serogroup distribution fluctuates over time across the world and age groups. Here, we consider the potential public health impact of a pentavalent MenABCWY vaccine developed to help further control meningococcal disease and improve immunisation rates.

      Results

      The GSK MenABCWY vaccine combines the antigenic components of MenACWY-CRM (Menveo®) and 4CMenB (Bexsero®), building on a wide body of clinical experience and real-world evidence. Both approved vaccines have acceptable safety profiles, demonstrate immunogenicity, and are broadly used, including in national immunisation programmes in several countries. Since the advent of quadrivalent vaccines, public health in relation to IMD has improved, with a decline in the overall incidence of IMD and an increase in vaccine coverage.

      Conclusion

      A pentavalent MenABCWY has the potential to provide further public health benefits through practical, broad IMD protection programmes encompassing serogroups A, B, C, W and Y, and is currently in late-stage development.

      Keywords

      Introduction

      Systemic infection with gram-negative diplococcus Neisseria meningitidis (N. meningitidis) leads to serious, life-threatening conditions in humans, manifesting as meningitis, bacteraemia, bacteremic pneumonia and sepsis.
      • Cohn A.C.
      • MacNeil J.R.
      • Clark T.A.
      • et al.
      Prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (ACIP).
      ,
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      Invasive meningococcal disease (IMD) can be devastating: N. meningitidis infection develops rapidly, with early, non-specific symptoms that can rapidly progress to fulminant disease and lead to death within 24–48 h of onset;
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      overall case fatality rates range from 4 to 20% (overall rate 8%) depending on age, serogroup, and country,
      • Wang B.
      • Santoreneos R.
      • Giles L.
      • Haji Ali Afzali H.
      • Marshall H.
      Case fatality rates of invasive meningococcal disease by serogroup and age: a systematic review and meta-analysis.
      and long-term sequelae occurs in 11–19% of survivors.

      American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases.

      Individuals susceptible to N. meningitidis infection tend to be otherwise healthy infants, young children, adolescents and young adults.
      • Cohn A.C.
      • MacNeil J.R.
      • Clark T.A.
      • et al.
      Prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (ACIP).
      IMD is an uncommon disease but there are an estimated 1.2 million cases annually globally, with 135,000 IMD-related deaths.
      • Jafri R.Z.
      • Ali A.
      • Messonnier N.E.
      • et al.
      Global epidemiology of invasive meningococcal disease.
      A World Health Organization (WHO)-led initiative encompassing a multi-organisational partnership is currently underway, and aims to ‘defeat’ meningitis by the Year 2030.

      World Health Organisation Initiatives. Defeating meningitis by 2030. Available at: https://www.who.int/initiatives/defeating-meningitis-by-2030 (accessed 28 February, 2022).

      N. meningitidis is subdivided into serogroups based on distinct capsular polysaccharides,
      • Cohn A.C.
      • MacNeil J.R.
      • Clark T.A.
      • et al.
      Prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (ACIP).
      ,
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      six of which (A, B, C, W, X and Y) cause the majority of IMD cases worldwide.
      • Jafri R.Z.
      • Ali A.
      • Messonnier N.E.
      • et al.
      Global epidemiology of invasive meningococcal disease.
      However, the epidemiology of IMD is unpredictable and dynamic, varying over time and by age and geographical location.

      American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases.

      Vaccines have been developed that have demonstrated effectiveness in preventing IMD in susceptible populations. In particular, development of conjugate vaccines, which comprise carrier proteins covalently linked to bacterial capsular polysaccharides, has resulted in vaccines better able to induce immune responses in infants and children than vaccines composed of purified polysaccharides.
      • Terranella A.
      • Cohn A.
      • Clark T.
      Meningococcal conjugate vaccines: optimizing global impact.
      Initially, monovalent meningococcal vaccines were developed to prevent disease caused by a single serogroup, but the expansion and/or persistence of serogroups not covered by these vaccines and the resulting changes in epidemiology have led to the need for vaccines with broader serogroup coverage.
      • Booy R.
      • Gentile A.
      • Nissen M.
      • Whelan J.
      • Abitbol V.
      Recent changes in the epidemiology of Neisseria meningitidis serogroup W across the world, current vaccination policy choices and possible future strategies.
      • Mustapha M.M.
      • Marsh J.W.
      • Harrison L.H.
      Global epidemiology of capsular group W meningococcal disease (1970-2015): Multifocal emergence and persistence of hypervirulent sequence type (ST)-11 clonal complex.
      • Pelton S.I.
      The global evolution of meningococcal epidemiology following the introduction of meningococcal vaccines.
      Several MenACWY conjugate vaccines are available and used in national immunisation programmes (NIPs) in countries worldwide to control outbreaks.

      Dutch National Immunisation Programme: Meningococcal vaccine. Avaialble at: https://rijksvaccinatieprogramma.nl/english (accessed 28 February, 2022).

      • Borrow R.
      • Alarcón P.
      • Carlos J.
      • et al.
      The global meningococcal initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
      • Campbell H.
      • Saliba V.
      • Borrow R.
      • Ramsay M.
      • Ladhani S.
      Targeted vaccination of teenagers following continued rapid endemic expansion of a single meningococcal group W clone (sequence type 11 clonal complex), United Kingdom 2015.
      Development of a serogroup B (MenB) vaccine has been more challenging, but two MenB vaccines are now also available: outer membrane vesicle (OMV)-based 4CMenB (Bexsero®, GSK)

      GSK. Bexsero Summary of Product Characteristics. EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/bexsero (accessed 28 February, 2022).

      ,

      GSK. Bexsero Prescribing Information 2020. Available at: https://www.fda.gov/media/90996/download (accessed 28 February, 2022).

      and lipidated MenB-factor H binding protein (FHbp) (Trumenba®, Pfizer).

      Pfizer. Trumenba Summary of Product Characteristics. EMA, 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/trumenba-epar-product-information_en.pdf (accessed 28 June, 2022).

      ,

      Pfizer. Trumenba Prescribing Information, 2021. Available at: https://labeling.pfizer.com/showlabeling.aspx?id=1796 (accessed 28 June, 2022).

      In this article, we examine the current public health role of the available meningococcal vaccines against serogroups A, B, C, W and Y, and evaluate the potential advantages of using a pentavalent vaccine that combines components of two approved vaccines that have demonstrated both clinical trial and real-world safety, effectiveness and public health impact. The GSK candidate pentavalent meningococcal vaccine (MenABCWY) comprises the key components of the 4CMenB vaccine (Fig. 1) and the MenACWY-CRM vaccine (Menveo®, GSK; Fig. 2), and is currently in late-stage development. The MenABCWY vaccine will provide coverage for the five most common disease-causing serogroups (A, B, C, W and Y) and is currently being evaluated in a large, randomised, controlled, phase 3 immunogenicity study.

      Clinicaltrials.gov. NCT04502693. Study to assess effectiveness of GlaxoSmithKline's (GSK's) meningococcal Group B and combined ABCWY vaccines in healthy adolescents and young adults. Avaialble at: https://clinicaltrials.gov/ct2/show/NCT04502693 (accessed 28 February, 2022).

      In this review, we highlight the scientific advances and potential public health value for this next-generation meningococcal vaccine, building on a wealth of clinical experience and real-world evidence.
      Fig 1
      Fig. 1Current evidence on the effect of 4CMenB on IMD caused by meningococcal serogroups and on gonorrhoea. Summary of properties,
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      • Masignani V.
      • Pizza M.
      • Moxon E.R.
      The development of a vaccine against meningococcus B using reverse vaccinology.
      licensure/recommendations for use,

      GSK. Bexsero Summary of Product Characteristics. EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/bexsero (accessed 28 February, 2022).

      GSK. Bexsero Prescribing Information 2020. Available at: https://www.fda.gov/media/90996/download (accessed 28 February, 2022).

      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.

      Public Health England. Routine vaccination schedule 2020. Available at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule (accessed 28 February, 2022).

      • Martinon-Torres F.
      • Banzhoff A.
      • Azzari C.
      • et al.
      Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.

      Government of South Australia. SA Health. Meningococcal B Immunisation Program. Available at: https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/conditions/immunisation/immunisation+programs/meningococcal+b+immunisation+program (accessed 28 February, 2022).

      • Alvarez Garcia F.J.
      • Cilleruelo Ortega M.J.
      • Alvarez Aldean J.
      • et al.
      [Immunisation schedule of the Spanish association of paediatrics: 2020 recommendations].

      Haute Autorite de Sante (HAS). Vaccination strategy for the prevention of invasive meningococcal infections: Serogroup B and the place of Bexsero. https://www.has-sante.fr/jcms/p_3066921/fr/strategie-de-vaccination-pour-la-prevention-des-infections-invasives-a-meningocoques-le-serogroupe-b-et-la-place-de-bexser (accessed 28 February, 2022).

      Ireland National Immunisation Office. Immunisation schedule. Available at: https://www.hse.ie/eng/health/immunisation/pubinfo/pcischedule/immschedule/ (accessed 28 February, 2022).

      Italy Ministry of Health. Piano Nazionale Prevenzione Vaccinale, PNPV 2017-2019. Available at: https://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf (accessed 28 February, 2022).

      Government of Malta. National immunisation schedule. Available at: https://deputyprimeminister.gov.mt/en/phc/pchyhi/Pages/National-Immunisation-Schedule.aspx (February 28, 2022).

      SAÚDE. Gabinete do Secretário de Estado da Saúde. Despacho n.° 12434/2019. Available at: https://dre.pt/application/conteudo/127608823 (accessed 28 February, 2022).

      • Deceuninck G.
      • Lefebvre B.
      • Tsang R.
      • Betala-Belinga J.F.
      • De Serres G.
      • De Wals P.
      Impact of a mass vaccination campaign against Serogroup B meningococcal disease in the Saguenay-Lac-Saint-Jean region of Quebec four years after its launch.
      evidence from clinical development,
      • Chiu N.C.
      • Huang L.M.
      • Willemsen A.
      • et al.
      Safety and immunogenicity of a meningococcal B recombinant vaccine when administered with routine vaccines to healthy infants in Taiwan: A phase 3, open-label, randomized study.
      • Gossger N.
      • Snape M.D.
      • Yu L.M.
      • et al.
      Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial.
      and real-world studies.
      • Martinon-Torres F.
      • Banzhoff A.
      • Azzari C.
      • et al.
      Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.
      • Ruiz Garcia Y.
      • Sohn W.Y.
      • Seib K.L.
      • et al.
      Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.
      • Longtin J.
      • Dion R.
      • Simard M.
      • et al.
      Possible impacts of wide-scale vaccination against serogroup B Neisseria meningitiditis on gonorrhoea incidence rates in one region of Quebec, Canada.
      • Abara W.E.
      • Bernstein K.T.
      • Lewis F.M.T.
      • et al.
      Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study.
      • Bryan P.
      • Seabroke S.
      • Wong J.
      • et al.
      Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study.
      • Ladhani S.N.
      • Campbell H.
      • Andrews N.
      • et al.
      First real world evidence of meningococcal group B vaccine, 4CMenB, protection against meningococcal group W disease; prospective enhanced national surveillance, England.
      • Hall G.C.
      • Douglas I.
      • Heath P.T.
      • et al.
      Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program.
      • Stowe J.
      • Andrews N.J.
      • Turner P.J.
      • Miller E.
      The risk of Kawasaki disease after pneumococcal conjugate & meningococcal B vaccine in England: a self-controlled case-series analysis.
      • Mentzer D.
      • Oberle D.
      • Keller-Stanislawski B.
      Adverse events following immunisation with a meningococcal serogroup B vaccine: report from post-marketing surveillance, Germany, 2013 to 2016.
      ACIP, US Advisory Committee on Immunization Practices; AE, adverse event; CDC, Centers for Disease Control and Prevention; fHbp, factor H binding protein; IMD, invasive meningococcal disease; NadA, Neisseria adhesin A; NHBA, Neisseria heparin binding antigen; OMV, outer membrane vesicle; RCT, randomised controlled trial; RWE, real-world evidence; y, year; SCDM, shared clinical decision-making; VE, vaccine effectiveness.
      Fig 2
      Fig. 2Current evidence on the effect of MenACWY-CRM on IMD caused by different meningococcal serogroups. Summary of properties,

      GSK. Menveo Prescribing Information 2020. Available at: https://gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Menveo/pdf/MENVEO.PDF (accessed 28 February, 2022).

      licensure/recommendations for use,
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      • Keshavan P.
      • Pellegrini M.
      • Vadivelu-Pechai K.
      • Nissen M.
      An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.

      GSK. Menveo Prescribing Information 2020. Available at: https://gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Menveo/pdf/MENVEO.PDF (accessed 28 February, 2022).

      GSK. Menveo Summary of Product Characteristics, EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/menveo (accessed 28 February, 2022).

      Public Health England. Routine vaccination schedule 2020. Available at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule (accessed 28 February, 2022).

      Switzerland: Federal Office of Public Health. Swiss Vaccination Schedule Synopsis. Available at: https://www.infovac.ch/docs/public/-main/synopsis-schweizerischer-impfplan-2020.pdf (accessed 28 February, 2022).

      ECDC Vaccine Scheduler. Meningococcal disease: Recommended vaccinations. Available at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=48&SelectedCountryIdByDisease=-1 (accessed 28 February, 2022).

      evidence from clinical development,
      • Keshavan P.
      • Pellegrini M.
      • Vadivelu-Pechai K.
      • Nissen M.
      An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
      • Read R.C.
      • Baxter D.
      • Chadwick D.R.
      • et al.
      Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.
      • Tipton M.
      • Daly W.
      • Senders S.
      • et al.
      MenACWY-CRM conjugate vaccine booster dose given 4–6 years after priming: Results from a phase IIIb, multicenter, open label study in adolescents and adults.
      and real-world studies.
      • Keshavan P.
      • Pellegrini M.
      • Vadivelu-Pechai K.
      • Nissen M.
      An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
      • Abdelnour A.
      • Silas P.E.
      • Lamas M.R.
      • et al.
      Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: results of an open-label, randomized, phase 3b controlled study in healthy infants.
      • Ruiz Garcia Y.
      • Abitbol V.
      • Pellegrini M.
      • Bekkat-Berkani R.
      • Soumahoro L.
      Clinical and real-world evidence after a decade of meningococcal ACWY-CRM vaccine for prevention of invasive meningococcal disease in the pediatric population.
      • Im J.H.
      • Woo H.
      • Ha B.M.
      • Lee J.S.
      • Chung M.H.
      • Jung J.
      Effectiveness of a single dose of the quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, in the Korean Armed Forces.
      • Yoo B.W.
      • Jung H.L.
      • Byeon Y.S.
      • et al.
      Results from a large post-marketing safety surveillance study in the Republic of Korea with a quadrivalent meningococcal CRM-conjugate vaccine in individuals aged 2 months-55 years.
      ACIP, US Advisory Committee on Immunization Practices; AE, adverse event; CRM, cross-reactive material; HIV, human immunodeficiency virus; IMD, invasive meningococcal disease; IRR, incidence ratio rate; NIP, national immunisation programme; OMV, outer membrane vesicle; PMSS, post-marketing safety surveillance; RCT, randomised controlled trial; RWE, real-world evidence.

      Impact of the introduction of MenACWY quadrivalent vaccines on public health

      Monovalent MenC vaccines have been licensed for use in the European Union (EU) since 1999,
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      and countries implementing MenC conjugate vaccine programmes have seen a substantial decline in the incidence of MenC disease.
      • Trotter C.L.
      • Ramsay M.E.
      Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines.
      As with MenC conjugate vaccines, the incidence of MenA IMD in Africa decreased after implementation of a monovalent MenA mass vaccination programme.
      • Daugla D.M.
      • Gami J.P.
      • Gamougam K.
      • et al.
      Effect of a serogroup a meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study.
      ,
      • Kristiansen P.A.
      • Diomandé F.
      • Ba A.K.
      • et al.
      Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.
      Overall, conjugate vaccination programmes have had a dramatic impact on the incidence of MenA and Men C disease; however, this progress in controlling the global burden of IMD has coincided with shifts in serogroup epidemiology over time, including increased relative prevalence of IMD attributable to serogroup W in some regions.
      • Borrow R.
      • Alarcón P.
      • Carlos J.
      • et al.
      The global meningococcal initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
      ,
      • Keshavan P.
      • Pellegrini M.
      • Vadivelu-Pechai K.
      • Nissen M.
      An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
      In some countries, including the UK, there has been a rapid increase in IMD due to MenW sequence type 11 clonal complex associated with severe invasive disease, as a result of the rapid expansion of this hyper-virulent strain.
      • Campbell H.
      • Saliba V.
      • Borrow R.
      • Ramsay M.
      • Ladhani S.
      Targeted vaccination of teenagers following continued rapid endemic expansion of a single meningococcal group W clone (sequence type 11 clonal complex), United Kingdom 2015.
      In addition, serogroup X cases have emerged in sub-Saharan Africa, with sporadic cases also described in developed (EU) countries.
      • Boisier P.
      • Nicolas P.
      • Djibo S.
      • et al.
      Meningococcal meningitis: unprecedented incidence of serogroup X-related cases in 2006 in Niger.
      • Materu S.
      • Cox H.S.
      • Isaakidis P.
      • Baruani B.
      • Ogaro T.
      • Caugant DA.
      Serogroup X in meningococcal disease, Western Kenya.
      • Yazdankhah S.P.
      • Kriz P.
      • Tzanakaki G.
      • et al.
      Distribution of serogroups and genotypes among disease-associated and carried isolates of Neisseria meningitidis from the Czech Republic, Greece, and Norway.
      Although protein antigens in serogroup B vaccines are shared among serogroup B and non-B strains, and broad bactericidal antibody responses against African serogroup strains such as X have been reported with a native outer membrane vesicle FHbp vaccine,
      • Pajon R.
      • Lujan E.
      • Granoff D.M.
      A meningococcal NOMV-FHbp vaccine for Africa elicits broader serum bactericidal antibody responses against serogroup B and non-B strains than a licensed serogroup B vaccine.
      there remains a clear need for protective coverage across a wider range of serogroups, and in many countries, quadrivalent vaccines have replaced, or been added to, previous MenC (or MenA in African countries) NIPs to cover A, C, W and Y serogroups to better control IMD.
      • Borrow R.
      • Alarcón P.
      • Carlos J.
      • et al.
      The global meningococcal initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
      Currently available quadrivalent conjugate vaccines are MenACWY-D (Menactra®; approved in 2005 – the first licensed vaccine of this type), MenACWY-CRM (Menveo; approved in 2010), and two MenACWY-TT vaccines (Nimenrix®, approved in 2012 and MenQuadfi®, approved in 2020).
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      ,
      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.
      Since the implementation in the US of a recommendation of the Advisory Committee on Immunisation Practices (ACIP) to vaccinate adolescents aged 11–18 years with a MenACWY vaccine, the annual incidence of meningococcal disease decreased by 71% between 2006 and 2015.
      • MacNeil J.R.
      • Blain A.E.
      • Wang X.
      • Cohn AC.
      Current epidemiology and trends in meningococcal disease-United States, 1996-2015.
      A decline in the incidence of serogroups B, C and Y was observed between 1996 and 2015, while the incidence of serogroup W and other serogroups remained stable.
      • MacNeil J.R.
      • Blain A.E.
      • Wang X.
      • Cohn AC.
      Current epidemiology and trends in meningococcal disease-United States, 1996-2015.
      In the 11–15 years age group, the average annual incidence of IMD due to serogroups C, W and Y decreased by 67% after the introduction of a MenACWY-D primary dose over the period 2006‒2010, and decreased by 89% during the period 2011‒2017 after the introduction of MenACWY-CRM.
      • Mbaeyi S.
      • Pondo T.
      • Blain A.
      • et al.
      Incidence of meningococcal disease before and after implementation of quadrivalent meningococcal conjugate vaccine in the United States.
      In addition, following an ACIP recommendation in 2010 to administer a booster dose to individuals aged 16 years, a 77% reduction in incidence of serogroup CWY IMD was seen in the 16‒22 years age group between 2011 and 2017.
      • Mbaeyi S.
      • Pondo T.
      • Blain A.
      • et al.
      Incidence of meningococcal disease before and after implementation of quadrivalent meningococcal conjugate vaccine in the United States.
      The overall impact of the introduction of the various MenACWY vaccines over time, as demonstrated by a decrease in incidence rates (all ages) for all serogroups of IMD (2000–2018),

      Centers for Disease Control and Prevention. Meningococcal disease surveillance data tables. Avialable at: https://www.cdc.gov/meningococcal/surveillance/surveillance-data.html#figure01 (accessed 28 February, 2022).

      together with increased vaccination coverage for MenACWY in adolescents (13–17 years of age) in the US (2008–2019),

      Centers for Disease Control and Prevention. Teen vaccination coverage publications and resources. Available at: https://www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/pubs-presentations.html (accessed 28 February, 2022).

      is shown in Fig. 3.
      Fig 3
      Fig. 3Vaccination coverage for MenACWY in adolescents (13–17 years old) in the US (2008–2019) and incidence rates for all serogroups of IMD (2000–2018)

      Centers for Disease Control and Prevention. Meningococcal disease surveillance data tables. Avialable at: https://www.cdc.gov/meningococcal/surveillance/surveillance-data.html#figure01 (accessed 28 February, 2022).

      ,

      Centers for Disease Control and Prevention. Teen vaccination coverage publications and resources. Available at: https://www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/pubs-presentations.html (accessed 28 February, 2022).

      ,

      Centers for Disease Control and Prevention. Health, United States, 2018 - Data Finder. Available at: https://www.cdc.gov/nchs/hus/contents2018.htm#Table_032 (accessed 28 February, 2022).

      *National Interview Survey–Teen implemented a new definition of adequate provider data: data for 2013 and beyond are not directly comparable with data for earlier years. †CDC coverage data missing for 2009. CDC, Centers for Disease Control; FDA, US Food and Drug Administration; IMD, invasive meningococcal disease.
      The MenACWY-CRM vaccine is currently approved in the US and several other countries in persons aged 2 months to 55 years,
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      ,
      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.
      ,

      GSK. Menveo Prescribing Information 2020. Available at: https://gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Menveo/pdf/MENVEO.PDF (accessed 28 February, 2022).

      and in the EU in persons aged ≥2 years.
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      ,
      • Keshavan P.
      • Pellegrini M.
      • Vadivelu-Pechai K.
      • Nissen M.
      An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
      ,

      GSK. Menveo Summary of Product Characteristics, EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/menveo (accessed 28 February, 2022).

      A total of 72.9 million doses have been distributed since 2010 (GSK data on file). Several countries have integrated MenACWY-CRM into their NIPs for use in infants and children, including Argentina,

      Argentina National Immunisation Calendar. Available at: https://bancos.salud.gob.ar/sites/default/files/2021-12/calendario-nacional-vacunacion-2022.pdf (accessed 28 June, 2022).

      and the Netherlands

      Dutch National Immunisation Programme: Meningococcal vaccine. Avaialble at: https://rijksvaccinatieprogramma.nl/english (accessed 28 February, 2022).

      (Fig. 2), and for use in adolescents in some countries (e.g. the US,

      CDC. Recommended child and adolescent immunization schedule for ages 18 years or younger, United States 2020. Available at: https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fschedules%2Fhcp%2Fchild-adolescent.html (accessed 28 June, 2022).

      UK,

      Public Health England. Routine vaccination schedule 2020. Available at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule (accessed 28 February, 2022).

      Argentina

      Argentina National Immunisation Calendar. Available at: https://bancos.salud.gob.ar/sites/default/files/2021-12/calendario-nacional-vacunacion-2022.pdf (accessed 28 June, 2022).

      and Switzerland

      Switzerland: Federal Office of Public Health. Swiss Vaccination Schedule Synopsis. Available at: https://www.infovac.ch/docs/public/-main/synopsis-schweizerischer-impfplan-2020.pdf (accessed 28 February, 2022).

      ). MenACWY-CRM has an acceptable safety profile in infants, children and adolescents/adults,
      • Keshavan P.
      • Pellegrini M.
      • Vadivelu-Pechai K.
      • Nissen M.
      An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
      ,
      • Abdelnour A.
      • Silas P.E.
      • Lamas M.R.
      • et al.
      Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: results of an open-label, randomized, phase 3b controlled study in healthy infants.
      ,
      • Ruiz Garcia Y.
      • Abitbol V.
      • Pellegrini M.
      • Bekkat-Berkani R.
      • Soumahoro L.
      Clinical and real-world evidence after a decade of meningococcal ACWY-CRM vaccine for prevention of invasive meningococcal disease in the pediatric population.
      which is similar to that of other MenACWY vaccines, including MenACWY-D.
      • Reisinger K.S.
      • Baxter R.
      • Block S.L.
      • Shah J.
      • Bedell L.
      • Dull P.M.
      Quadrivalent meningococcal vaccination of adults: phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra.
      Evidence from large post-marketing observational studies support a favourable benefit–risk profile that has been established after a decade of use, including carriage reduction and effectiveness in reducing IMD incidence (Fig. 2).
      • Ruiz Garcia Y.
      • Abitbol V.
      • Pellegrini M.
      • Bekkat-Berkani R.
      • Soumahoro L.
      Clinical and real-world evidence after a decade of meningococcal ACWY-CRM vaccine for prevention of invasive meningococcal disease in the pediatric population.
      A large study in a high-exposure group in the Republic of Korea (South Korea) Armed Forces, wherein meningococcal infections have consistently occurred, has provided robust evidence on the effectiveness of single-dose MenACWY-CRM in preventing meningococcal disease.
      • Im J.H.
      • Woo H.
      • Ha B.M.
      • Lee J.S.
      • Chung M.H.
      • Jung J.
      Effectiveness of a single dose of the quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, in the Korean Armed Forces.
      An analysis of data from more than 1.5 million soldiers observed for 19–23 months showed that routine vaccination was associated with an 88% reduction in the incidence of meningococcal disease in all serogroups after a single dose.
      • Pizza M.
      • Bekkat-Berkani R.
      • Rappuoli R.
      Vaccines against meningococcal diseases.
      ,
      • Im J.H.
      • Woo H.
      • Ha B.M.
      • Lee J.S.
      • Chung M.H.
      • Jung J.
      Effectiveness of a single dose of the quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, in the Korean Armed Forces.
      In this study, there were no cases of IMD resulting from serogroups A, C, W and Y, and no deaths during the study period, compared with four deaths in the 5 years before vaccination was implemented. Two cases of IMD were identified after implementation of the vaccination programme, and these were identified as serogroup B and X. As soldiers remained on duty for a maximum of 2 years, duration of protection could only be demonstrated for a 19–23-month follow-up period.
      • Im J.H.
      • Woo H.
      • Ha B.M.
      • Lee J.S.
      • Chung M.H.
      • Jung J.
      Effectiveness of a single dose of the quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, in the Korean Armed Forces.

      Impact of the introduction of MenB (Bexsero) vaccine on public health

      The first four-component MenB vaccine, 4CMenB, was licensed in the EU, Australia and Canada in 2013 in individuals ≥2 months of age (administered in a 2 + 1 or 3 + 1 [infants aged 2–5 months] schedule [EU]

      GSK. Bexsero Summary of Product Characteristics. EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/bexsero (accessed 28 February, 2022).

      or as a single dose [Australia and Canada]

      Australian Government, Department of Health. Clinical update: National Immunisation Program (NIP) schedule changes from 1 July 2020 – advice for vaccination providers. Available at: https://www.health.gov.au/news/clinical-update-national-immunisation-program-nip-schedule-changes-from-1-july-2020-advice-for-vaccination-providers (accessed 28 February, 2022).

      ,

      Government of Canada: Recommended immunization schedules: Canadian Immunization Guide. Available at: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html #p1c12a2 (accessed 28 June, 2022).

      ) and by the US Food and Drug Administration (FDA) in 2015 in individuals 10–25 years of age (in a two-dose schedule,

      GSK. Bexsero Prescribing Information 2020. Available at: https://www.fda.gov/media/90996/download (accessed 28 February, 2022).

      ) and it is now approved in more than 40 countries worldwide (Fig. 1).

      GSK Press Release, 23 January 2020. World's first meningitis B national infant vaccination programme shows 75% drop in cases over three years. Available at: https://www.gsk.com/en-gb/media/press-releases/world-s-first-meningitis-b-national-infant-vaccination-programme-shows-75-drop-in-cases-over-three-years/ (accessed 28 February, 2022).

      4CMenB is the only MenB vaccine used in infants in the EU and other countries.

      GSK. Bexsero Summary of Product Characteristics. EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/bexsero (accessed 28 February, 2022).

      ,

      GSK. Bexsero Prescribing Information 2020. Available at: https://www.fda.gov/media/90996/download (accessed 28 February, 2022).

      ,

      GSK Press Release, 23 January 2020. World's first meningitis B national infant vaccination programme shows 75% drop in cases over three years. Available at: https://www.gsk.com/en-gb/media/press-releases/world-s-first-meningitis-b-national-infant-vaccination-programme-shows-75-drop-in-cases-over-three-years/ (accessed 28 February, 2022).

      A total of 76.2 million doses have been distributed between 2015 and 2021 (GSK data on file). Since serogroup B meningococcal disease is uncommon, the efficacy of 4CMenB could not be assessed in clinical trials.
      • Borrow R.
      • Taha M.K.
      • Giuliani M.M.
      • Pizza M.
      • Banzhoff A.
      • Bekkat-Berkani R.
      Methods to evaluate serogroup B meningococcal vaccines: from predictions to real-world evidence.
      Instead, 4CMenB has been registered based on the protective immunogenicity and predicted coverage of circulating MenB strains, with the expectation that evidence of effectiveness would be gained after licensure. Common methods of predicting strain coverage (e.g. assays using human complement serum bactericidal antibody [hSBA] and meningococcal antigen typing system [MATS]) require cultured isolates, which are not always available.
      • Borrow R.
      • Taha M.K.
      • Giuliani M.M.
      • Pizza M.
      • Banzhoff A.
      • Bekkat-Berkani R.
      Methods to evaluate serogroup B meningococcal vaccines: from predictions to real-world evidence.
      Genomic approaches, such as the genetic MATS
      • Borrow R.
      • Taha M.K.
      • Giuliani M.M.
      • Pizza M.
      • Banzhoff A.
      • Bekkat-Berkani R.
      Methods to evaluate serogroup B meningococcal vaccines: from predictions to real-world evidence.
      and the Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) Index,
      • Rodrigues C.M.C.
      • Jolley K.A.
      • Smith A.
      • Cameron J.C.
      • Feavers I.M.
      • Maiden M.C.J.
      Meningococcal deduced vaccine antigen reactivity (MenDeVAR) index: a rapid and accessible tool that exploits genomic data in public health and clinical microbiology applications.
      provide alternative techniques for estimating MenB strain coverage. However, real-world effectiveness data are required to confirm the predictions generated. Routine immunisation with MenB vaccine has been implemented in NIPs in the UK, Ireland, Italy (including San Marino), Lithuania, Malta, Czech Republic, Portugal and Andorra.

      ECDC Vaccine Scheduler. Meningococcal disease: Recommended vaccinations. Available at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=48&SelectedCountryIdByDisease=-1 (accessed 28 February, 2022).

      ,
      • Martinon-Torres F.
      • Banzhoff A.
      • Azzari C.
      • et al.
      Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.
      In 2018 a MenB programme was implemented in South Australia for children aged 6 weeks to 12 months (3 dose series) and Year 10 students (aged 15 or 16; 2 doses).

      Government of South Australia. SA Health. Meningococcal B Immunisation Program. Available at: https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/conditions/immunisation/immunisation+programs/meningococcal+b+immunisation+program (accessed 28 February, 2022).

      From July 2020, 4CMenB was also implemented for Aboriginal and Torres Strait Islander infants less than 2 years of age due to the higher burden of disease in this group.

      Government of South Australia. SA Health. Meningococcal B Immunisation Program. Available at: https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/conditions/immunisation/immunisation+programs/meningococcal+b+immunisation+program (accessed 28 February, 2022).

      In addition, regional immunisation programmes were introduced in the Canary Islands and Castilla y León, Spain,
      • Alvarez Garcia F.J.
      • Cilleruelo Ortega M.J.
      • Alvarez Aldean J.
      • et al.
      [Immunisation schedule of the Spanish association of paediatrics: 2020 recommendations].
      and a Haute Autorité de Santé (HAS) initiative recommended a 4CMenB vaccination strategy for all infants (up to 4 years of age) in France.

      Haute Autorite de Sante (HAS). Vaccination strategy for the prevention of invasive meningococcal infections: Serogroup B and the place of Bexsero. https://www.has-sante.fr/jcms/p_3066921/fr/strategie-de-vaccination-pour-la-prevention-des-infections-invasives-a-meningocoques-le-serogroupe-b-et-la-place-de-bexser (accessed 28 February, 2022).

      Although 4CMenB strain coverage is not absolute, and MATS-predicted coverage of 66% was reported in a 2014‒2015 UK study,
      • Parikh S.R.
      • Newbold L.
      • Slater S.
      • et al.
      Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.
      large-scale observational studies have confirmed the impact and effectiveness of 4CMenB, with substantial reductions seen in MenB IMD in children during the first 3 years of the programme, including in the UK, which was the first country to provide 4CMenB through a publicly funded NIP for infants (Fig. 1).
      • Ladhani S.N.
      • Andrews N.
      • Parikh S.R.
      • et al.
      Vaccination of Infants with meningococcal group B vaccine (4CMenB) in England.
      ,
      • Parikh S.R.
      • Andrews N.J.
      • Beebeejaun K.
      • et al.
      Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study.
      Consistent results were seen in an Italian retrospective, observational analysis in which vaccine effectiveness was estimated to be 93.6% (95% CI: 55.4, 99.1) in Tuscany and 91.0% (95% CI: 59.9, 97.9) in Veneto,
      • Azzari C.
      • Moriondo M.
      • Nieddu F.
      • et al.
      Effectiveness and impact of the 4CMenB vaccine against group B meningococcal disease in two italian regions using different vaccination schedules: a five-year retrospective observational study (2014-2018).
      and in a case-control study in Portugal, vaccine effectiveness against MenB IMD was 79% (95% CI: 45, 92) in fully vaccinated children, and 82% (95% CI: 56, 92) in infants who received at least one dose.
      • Rodrigues F.M.P.
      • Marlow R.
      • Simoes M.J.
      • Danon L.
      • Ladhani S.
      • Finn A.
      Association of use of a meningococcus group B vaccine with group B invasive meningococcal disease among children in Portugal.
      In addition, real-world evidence from Quebec, Canada, showed that mass vaccination with 4CMenB, introduced due to a high rate of MenB IMD from 2006 to 2013, provided a high level of protection against MenB IMD in children and adolescents.
      • De Wals P.
      • Deceuninck G.
      • Lefebvre B.
      • et al.
      Impact of an immunization campaign to control an increased incidence of serogroup b meningococcal disease in one region of Quebec, Canada.
      Vaccine effectiveness estimates across different healthcare settings and study designs in these and other regions ranged from 59% to 100% in infants and from 50% to 100% in children and adolescents.
      • Martinon-Torres F.
      • Banzhoff A.
      • Azzari C.
      • et al.
      Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.
      In addition to the benefits associated with prevention of serogroup B IMD, a consistent body of evidence has now emerged suggesting that Neisseria meningitidis-derived OMV vaccines (e.g. 4CMenB and MeNZB) could have a cross-protective effect on gonorrhoea infections due to the genetic similarities between N. meningitidis and Neisseria gonorrhoeae (N. gonorrhoeae; 80–90% genetic homology in primary sequences).
      • Ruiz Garcia Y.
      • Sohn W.Y.
      • Seib K.L.
      • et al.
      Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.
      Of the four main antigenic components of 4CMenB (fHbp, Neisserial heparin-binding antigen [NHBA], Neisseria adhesin A and OMV), surface-expressed NHBA is believed to be the only recombinant antigen of 4CMenB that may be responsible for the observed N. gonorrhoeae cross-reactivity.
      • Ruiz Garcia Y.
      • Sohn W.Y.
      • Seib K.L.
      • et al.
      Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.
      Untreated gonorrhoea can lead to pelvic inflammatory disease, tubal scarring and infertility, and may be related to an increased risk of acquiring and transmitting HIV.
      • Vincent L.R.
      • Jerse A.E.
      Biological feasibility and importance of a gonorrhea vaccine for global public health.
      There are an estimated 78 million new cases of gonorrhoea annually worldwide, and an estimated 2300 deaths and 467,700–974,900 (depending on region) lost disability-adjusted life years resulting from morbidity due to the disease.
      • Vincent L.R.
      • Jerse A.E.
      Biological feasibility and importance of a gonorrhea vaccine for global public health.
      Thus, gonococcal vaccination is considered an important goal for global public health. Ecological data first suggested a potential cross-protective effect of meningococcal OMV-based vaccines on N. gonorrhoeae infection.
      • Ruiz Garcia Y.
      • Sohn W.Y.
      • Seib K.L.
      • et al.
      Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.
      ,
      • Longtin J.
      • Dion R.
      • Simard M.
      • et al.
      Possible impacts of wide-scale vaccination against serogroup B Neisseria meningitiditis on gonorrhoea incidence rates in one region of Quebec, Canada.
      ,
      • Petousis-Harris H.
      Impact of meningococcal group B OMV vaccines, beyond their brief.
      An observational impact study was performed in the Saguenay-Lac-Saint-Jean region of Canada to assess reduction in N. gonorrhoeae cases post-4CMenB introduction.
      • Longtin J.
      • Dion R.
      • Simard M.
      • et al.
      Possible impacts of wide-scale vaccination against serogroup B Neisseria meningitiditis on gonorrhoea incidence rates in one region of Quebec, Canada.
      During the 3 years post vaccination, the number of N. gonorrhoeae cases decreased in vaccinated individuals (14‒20 years of age) and increased in the unvaccinated cohorts (>21 years of age), leading to an estimated 59% (95% CI: ‒22, 84; p = 0.1) risk reduction in N. gonorrhoeae disease in those who had received 4CMenB.
      • Longtin J.
      • Dion R.
      • Simard M.
      • et al.
      Possible impacts of wide-scale vaccination against serogroup B Neisseria meningitiditis on gonorrhoea incidence rates in one region of Quebec, Canada.
      A retrospective case-control study was conducted in New York City and Philadelphia, examining 4CMenB vaccination history in individuals aged 16‒23 years across 18,099 cases (N. gonorrhoeae infections) and 124,876 controls (chlamydia trachomatis infections).
      • Abara W.E.
      • Bernstein K.T.
      • Lewis F.M.T.
      • et al.
      Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study.
      The results indicated that complete vaccination series was 40% (95% CI: 23, 53) effective against N. gonorrhoeae, after adjusting for gender, race and jurisdiction, while partial vaccination series was 26% (95% CI: 12, 37) effective.
      • Abara W.E.
      • Bernstein K.T.
      • Lewis F.M.T.
      • et al.
      Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study.
      An observational cohort and case-control study on the effectiveness and impact of 4CMenB was carried out 2 years after implementation of a vaccination programme in South Australia.
      • Wang B.
      • Giles L.
      • Andraweera P.
      • et al.
      Effectiveness and impact of the 4CMenB vaccine against invasive serogroup B meningococcal disease and gonorrhoea in an infant, child, and adolescent programme: an observational cohort and case-control study.
      In this study, moderate effectiveness was demonstrated against gonorrhoea among 53,356 adolescents and young adults who received at least one dose and 46,083 who received two doses of 4CMenB, with an estimated two-dose vaccine effectiveness of 32.7% (95% CI: 8.3, 50.6) based on a case-control method and age-matched control individuals with chlamydia infection.
      • Wang B.
      • Giles L.
      • Andraweera P.
      • et al.
      Effectiveness and impact of the 4CMenB vaccine against invasive serogroup B meningococcal disease and gonorrhoea in an infant, child, and adolescent programme: an observational cohort and case-control study.
      In a sensitivity analysis that excluded co-infection with chlamydia during the first or recurrent episodes, vaccine effectiveness was 34.7% (95% CI: 5.5, 54.9) for 2 doses compared with unvaccinated individuals.
      • Wang B.
      • Giles L.
      • Andraweera P.
      • et al.
      Effectiveness and impact of the 4CMenB vaccine against invasive serogroup B meningococcal disease and gonorrhoea in an infant, child, and adolescent programme: an observational cohort and case-control study.
      The potential public health impact of vaccination with MenB in men who have sex with men (MSM) has been demonstrated by integrated transmission-dynamic heath-economic modelling.
      • Whittles L.K.
      • Didelot X.
      • White PJ.
      Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis.
      This model of the public health impact and cost effectiveness of gonorrhoea vaccination in England indicated that inclusion of 4CMenB in a programme of vaccination according to risk could avert over 110,000 cases of gonorrhoea over 10 years in the MSM population, with substantial consequent savings in overall public health costs.
      • Whittles L.K.
      • Didelot X.
      • White PJ.
      Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis.
      The safety profile of 4CMenB has been consistent across clinical trials and is acceptable despite its association with a higher incidence of fever in infants under 6 months of age, which is increased if 4CMenB is co-administered with other routine vaccinations.
      • Chiu N.C.
      • Huang L.M.
      • Willemsen A.
      • et al.
      Safety and immunogenicity of a meningococcal B recombinant vaccine when administered with routine vaccines to healthy infants in Taiwan: A phase 3, open-label, randomized study.
      ,
      • Gossger N.
      • Snape M.D.
      • Yu L.M.
      • et al.
      Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial.
      After 4CMenB was introduced in the UK, a prospective surveillance study was conducted from September 2015 to May 2017 during which approximately 1.29 million infants and children received around 3 million doses of 4CMenB. In this study, no significant safety concerns were identified, and the vaccine was well accepted by parents and caregivers.
      • Bryan P.
      • Seabroke S.
      • Wong J.
      • et al.
      Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study.
      An increased awareness of potential reactogenicity and the use of prophylactic paracetamol are likely to have assisted in the clinical management and acceptance of transient reactogenicity. Overall, the safety profile of 4CMenB has been consistent with pre-licensure clinical trial data across real-world settings.

      Current recommendations and prevalent practices for meningococcal vaccination in NIPs

      In the US, ACIP (a committee within the CDC) recommends routine MenACWY vaccination in all adolescents aged 11–12 years, with a booster dose administered at age 16 years (introduced in 2010).
      • Cohn A.C.
      • MacNeil J.R.
      • Clark T.A.
      • et al.
      Prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (ACIP).
      ACIP also recommends routine vaccination in persons aged ≥2 years who are at increased risk of meningococcal disease and in at-risk groups to control outbreaks.
      • Cohn A.C.
      • MacNeil J.R.
      • Clark T.A.
      • et al.
      Prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (ACIP).
      In Europe, recommendations for quadrivalent vaccination vary by country. Some countries (e.g. Greece, Malta, the Netherlands) recommend administering a quadrivalent vaccine in children <2 years of age, whereas adolescents aged 11 years onwards may be targeted in other countries (e.g. Austria, Ireland, Italy, Spain and the UK).

      Public Health England. Routine vaccination schedule 2020. Available at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule (accessed 28 February, 2022).

      ,

      ECDC Vaccine Scheduler. Meningococcal disease: Recommended vaccinations. Available at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=48&SelectedCountryIdByDisease=-1 (accessed 28 February, 2022).

      In the US, 4CMenB is approved for individuals aged 10–25 years as a two-dose series administered ≥1 month apart.

      GSK. Bexsero Prescribing Information 2020. Available at: https://www.fda.gov/media/90996/download (accessed 28 February, 2022).

      ,
      • Folaranmi T.
      • Rubin L.
      • Martin S.W.
      • Patel M.
      • MacNeil J.R.
      Use of serogroup B meningococcal vaccines in persons aged ≥10 years at increased risk for serogroup B meningococcal disease: recommendations of the advisory committee on immunization practices.
      The bivalent, recombinant, protein-based MenB-FHbp vaccine was approved in the US and EU in 2014 in the same age group (as a two- or three-dose series).

      Pfizer. Trumenba Summary of Product Characteristics. EMA, 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/trumenba-epar-product-information_en.pdf (accessed 28 June, 2022).

      ,

      Pfizer. Trumenba Prescribing Information, 2021. Available at: https://labeling.pfizer.com/showlabeling.aspx?id=1796 (accessed 28 June, 2022).

      ACIP recommends routine use of MenB vaccines in individuals aged ≥10 years who are at increased risk of serogroup B IMD.
      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.
      In addition a MenB series is recommended for adolescents and adults aged 16–23 years (preferably 16‒18 years) on the basis of shared clinical decision-making (referring to individually based vaccine recommendation informed by a decision-making process between the healthcare provider and the patient or parent/guardian).
      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.
      Despite widespread approvals and recommendations of quadrivalent and 4CMenB vaccines, as well as a positive impact on the incidence of MenB IMD, a number of factors may contribute to suboptimal vaccination levels, including diverse NIP immunisation schedules across regions.
      • Basta N.E.
      • Becker A.B.
      • Li Q.
      • Nederhoff D.
      Parental awareness of Meningococcal B vaccines and willingness to vaccinate their teens.
      • Kempe A.
      • Allison M.A.
      • MacNeil J.R.
      • et al.
      Adoption of serogroup B meningococcal vaccine recommendations.
      • Morrone T.
      • Napolitano F.
      • Albano L.
      • Di Giuseppe G.
      Meningococcal serogroup B vaccine: knowledge and acceptability among parents in Italy.
      • Ponticelli D.
      • D'Ambrosio A.
      • Cancellieri M.
      • Agozzino E.
      Do HCWs adequately know about meningitis and 4CMenB vaccine and recommend its use to parents? A cross sectional analysis in Campania Region, Italy.
      These differences are perpetuated by varied access to vaccination programmes; in addition, although healthcare professionals may proactively discuss MenB vaccination with patients when adequately informed, others will only reactively discuss vaccination if the parent or patient initiates discussion, leading to a lack of awareness on the benefits of vaccination in many cases.
      • Basta N.E.
      • Becker A.B.
      • Li Q.
      • Nederhoff D.
      Parental awareness of Meningococcal B vaccines and willingness to vaccinate their teens.
      • Kempe A.
      • Allison M.A.
      • MacNeil J.R.
      • et al.
      Adoption of serogroup B meningococcal vaccine recommendations.
      • Morrone T.
      • Napolitano F.
      • Albano L.
      • Di Giuseppe G.
      Meningococcal serogroup B vaccine: knowledge and acceptability among parents in Italy.
      • Ponticelli D.
      • D'Ambrosio A.
      • Cancellieri M.
      • Agozzino E.
      Do HCWs adequately know about meningitis and 4CMenB vaccine and recommend its use to parents? A cross sectional analysis in Campania Region, Italy.
      This potential lack of communication could contribute to suboptimal vaccination rates, despite evidence that parents are open to this discussion – one study surveying parents of teens reported that of the 445 parents, approximately 80% would like their healthcare provider to provide more information on MenB and MenACWY vaccines.
      • Basta N.E.
      • Becker A.B.
      • Li Q.
      • Nederhoff D.
      Parental awareness of Meningococcal B vaccines and willingness to vaccinate their teens.
      In addition, there are imbalances in MenACWY/MenB vaccination mandates for adolescents within the US. School or college entry requirements in the US usually include MenACWY; however, currently MenB is not a universal requirement, although this is also widely becoming mandatory.
      • Basta N.E.
      • Becker A.B.
      • Li Q.
      • Nederhoff D.
      Parental awareness of Meningococcal B vaccines and willingness to vaccinate their teens.
      ,

      Centers for Disease Control and Prevention. Group settings as a risk factor. https://www.cdc.gov/meningococcal/about/risk-community.html (accessed 28 February, 2022).

      The availability of a combined vaccine would potentially remove the need for discussions on individual serogroup protection by focussing on the benefit of combined protection from the outset.
      A retrospective health insurance claims analysis of vaccine series completion and adherence to dosing schedule in 16‒23 year olds in the US from 2017 to 2018 (N=213,162) showed that, although MenB vaccine series completion was suboptimal regardless of vaccine type, series completion was significantly higher for the 4CMenB than the MenB-FHbp vaccine (48‒61% vs 34‒50%, respectively; p < 0.001).
      • Packnett E.R.
      • Zimmerman N.M.
      • Kim G.
      • et al.
      A real-world claims data analysis of meningococcal serogroup B vaccine series completion and potential missed opportunities in the United States.
      An earlier analysis also showed that there was an improved adherence to dosing schedule for 4CMenB vs MenB-FHbp (48‒62% vs 8‒18%, respectively; p < 0.0001) and shorter completion time.
      • Packnett E.
      • Irwin D.E.
      • Novy P.
      • et al.
      Meningococcal-group B (MenB) vaccine series completion and adherence to dosing schedule in the United States: a retrospective analysis by vaccine and payer type.
      This study reported that the more flexible dosing schedule of 4CMenB, versus MenB-FHbp, may be a factor in the observed differences in time to completion, and underlines the importance of a simplified vaccination schedule.
      • Packnett E.
      • Irwin D.E.
      • Novy P.
      • et al.
      Meningococcal-group B (MenB) vaccine series completion and adherence to dosing schedule in the United States: a retrospective analysis by vaccine and payer type.
      In addition, this study highlighted the need to optimise protection by ensuring vaccine completion (multi-dose vaccination completion rates range from 27% to >90%
      • Gallagher K.E.
      • Kadokura E.
      • Eckert L.O.
      • et al.
      Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.
      ), and rates of completion were similar to those seen with other vaccines in older (up to 19 years) adolescents. Further evidence in favour of combined vaccines and associated simplified schedules/visits is provided by additional studies that show accelerated HBV vaccination schedules and shorter time between visits can be significant predictors of improved completion rates in high-risk attendees (although rates were still below 50%).
      • Macdonald V.
      • Dore G.J.
      • Amin J.
      • van Beek I.
      Predictors of completion of a hepatitis B vaccination schedule in attendees at a primary health care centre.
      Thus, combination meningococcal vaccine strategies may contribute to improved meningococcal vaccination rates. Modelling the impact of combined 4CMenB and MenACWY vaccination strategies on IMD in England allowed for evaluation of several scenarios to identify the best combination vaccine strategy.
      • Beck E.
      • Klint J.
      • Garcia S.
      • et al.
      Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: an application to England.
      The model showed that a 4CMenB programme in infants is an essential building block in IMD vaccination to achieve comprehensive coverage. Inclusion of an adolescent 4CMenB vaccination to the current English strategy (the infant 4CMenB and adolescent MenACWY programme) resulted in the greatest level of protection.
      • Beck E.
      • Klint J.
      • Garcia S.
      • et al.
      Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: an application to England.
      However, although this schedule clearly provides an overall reduction in IMD worldwide by targeting the five most prevalent serogroups, it requires additional injections.

      Potential benefits of combined vaccine products in clinical practice

      A single combined vaccine including five of the most common serogroups would provide broader coverage and potentially a simplified and clearer strategy for meningococcal immunisation across NIPs. This could contribute to higher vaccination series completion rates and improved overall IMD protection. Experience with numerous other combination vaccines shows that combining antigens in one vaccine has advantages over continuing to deliver them as separate injections. Most importantly, combination vaccines reduce the overall number of injections required to deliver routine immunisations, and this has been shown to improve convenience, compliance and timeliness of vaccination, which ultimately leads to better protection against disease.
      • Obando-Pacheco P.
      • Rivero-Calle I.
      • Gomez-Rial J.
      • Rodriguez-Tenreiro Sanchez C.
      • Martinon-Torres F.
      New perspectives for hexavalent vaccines.
      ,
      • Maman K.
      • Zollner Y.
      • Greco D.
      • Duru G.
      • Sendyona S.
      • Remy V.
      The value of childhood combination vaccines: from beliefs to evidence.
      Furthermore, a reduction in the number of injections reduces the potential for local adverse reactions and the overall burden of pain and discomfort for children.
      • Obando-Pacheco P.
      • Rivero-Calle I.
      • Gomez-Rial J.
      • Rodriguez-Tenreiro Sanchez C.
      • Martinon-Torres F.
      New perspectives for hexavalent vaccines.
      ,
      • Maman K.
      • Zollner Y.
      • Greco D.
      • Duru G.
      • Sendyona S.
      • Remy V.
      The value of childhood combination vaccines: from beliefs to evidence.
      A combination vaccine strategy also has the potential to facilitate the introduction of new antigens into a schedule without increasing the number of injections, which are already numerous in order to comply with current recommendations – such a strategy could provide enhanced coverage of the population from vaccine-preventable diseases.
      In the case of meningococcal vaccines, recommendations have shifted in many countries from monovalent vaccines to those with a broader spectrum of coverage. In 1999, the UK became the first country to include a monovalent MenC vaccine in routine infant vaccination schedules.
      • Miller E.
      • Salisbury D.
      • Ramsay M.
      Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story.
      In vaccinated and unvaccinated persons, reductions in serogroup-specific IMD were observed after the introduction of serogroup-specific vaccines such as MenC; however, a shift in serogroup relative proportion was noted after the introduction of this and other monovalent meningococcal vaccines.
      • Pelton S.I.
      The global evolution of meningococcal epidemiology following the introduction of meningococcal vaccines.
      This led to the development and introduction of quadrivalent vaccines to provide broader protection, and these vaccines are currently widely recommended and used in NIPs. Adoption of quadrivalent meningococcal vaccines increases the spectrum of coverage for IMD due caused by serogroups A, C, W and Y, while helping to simplify immunisation schedules. In the US, introduction of combined MenACWY vaccines has coincided with a steady increase in meningococcal coverage among adolescents (aged 13–17 years) from 2008 onwards, which further increased and was maintained after the introduction of MenACWY-CRM in 2010 (Fig. 3).

      Centers for Disease Control and Prevention. Teen vaccination coverage publications and resources. Available at: https://www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/pubs-presentations.html (accessed 28 February, 2022).

      ,

      Centers for Disease Control and Prevention. Health, United States, 2018 - Data Finder. Available at: https://www.cdc.gov/nchs/hus/contents2018.htm#Table_032 (accessed 28 February, 2022).

      During this period, coverage of other routine vaccines in this age group was either stable or also increased,

      Centers for Disease Control and Prevention. Teen vaccination coverage publications and resources. Available at: https://www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/pubs-presentations.html (accessed 28 February, 2022).

      ,

      Centers for Disease Control and Prevention. Health, United States, 2018 - Data Finder. Available at: https://www.cdc.gov/nchs/hus/contents2018.htm#Table_032 (accessed 28 February, 2022).

      including vaccines requiring multiple doses, such as human papillomavirus and measles, mumps and rubella (MMR) vaccines; this was in line with published data showing an association between completion of these vaccinations and meningococcal vaccination completion and compliance.
      • Cheng W.Y.
      • Chang R.
      • Novy P.
      • O'Connor C.
      • Duh M.S.
      • Hogea C.S.
      Determinants of meningococcal ACWY vaccination in adolescents in the US: completion and compliance with the CDC recommendations.
      Importantly, by 2018 MenACWY coverage in the US had reached 86.6% for ≥1 dose and 50.8% for ≥2 doses in adolescents aged 13–17 years across most ethnicities and all levels of socioeconomic status,
      • Walker T.Y.
      • Elam-Evans L.D.
      • Yankey D.
      • et al.
      National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years - United States, 2018.
      both of which may be factors associated with vaccination education/awareness, access, utilisation and completion rates.
      • Gallagher K.E.
      • Kadokura E.
      • Eckert L.O.
      • et al.
      Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.
      ,
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      Thus, coverage may be improved through simplified combination vaccination schedules that improve access and reduce existing confusion over serogroup variation.
      • Kempe A.
      • Allison M.A.
      • MacNeil J.R.
      • et al.
      Adoption of serogroup B meningococcal vaccine recommendations.
      ,
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      ,
      • Huang L.
      • Goren A.
      • Lee L.K.
      • Li V.W.
      • Dempsey A.
      • Srivastava A.
      Disparities in healthcare providers' interpretations and implementations of ACIP's meningococcal vaccine recommendations.
      Despite coverage afforded by quadrivalent vaccines, serogroups A, B, C, W and Y remain prevalent and are responsible for most cases of meningococcal disease, with predominant serogroups varying across countries and regions.
      • Jafri R.Z.
      • Ali A.
      • Messonnier N.E.
      • et al.
      Global epidemiology of invasive meningococcal disease.
      However, in the US, in contrast to MenACWY, only 17.2% of persons aged 17 years received ≥1 dose of MenB, and less than half completed the two-dose vaccination series.
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      Data from the National Immunization Survey-Teen showed that, in 2019, 88.9% of adolescents received at least one dose of MenACWY vaccine, 53.7% of those aged 17 years received the booster dose, while only 21.8% of adolescents received at least one dose of MenB vaccine.
      • Elam-Evans L.D.
      • Yankey D.
      • Singleton J.A.
      • et al.
      National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 Years - United States, 2019.
      Although these data represent increases from 2018, a significant proportion of the population remain unprotected from serogroup B IMD.
      • Haimowitz R.
      • Torres R.
      • Caleb S.
      • et al.
      Serogroup B meningococcal vaccination practice patterns on college campuses.
      A survey of Student Health Centre (SHC) administrators showed that a greater emphasis was placed on MenACWY vaccine coverage than MenB vaccine coverage among college students.
      • Haimowitz R.
      • Torres R.
      • Caleb S.
      • et al.
      Serogroup B meningococcal vaccination practice patterns on college campuses.
      Of note, significantly more colleges required all students to receive the MenACWY vaccine than the MenB vaccine (53.5% vs 10.5%; p < 0.001).
      • Haimowitz R.
      • Torres R.
      • Caleb S.
      • et al.
      Serogroup B meningococcal vaccination practice patterns on college campuses.
      Financial issues in the form of upfront costs incurred by SHCs with regard to stocking and administering MenB was a commonly cited issue contributing to sub-optimal MenB vaccine coverage among students. This was exacerbated by the fact that many SHC centres operate payment models that do not include private insurance.
      • Haimowitz R.
      • Torres R.
      • Caleb S.
      • et al.
      Serogroup B meningococcal vaccination practice patterns on college campuses.
      Furthermore, among adolescents who had received a first dose of 4CMenB, 61% of those with commercial insurance coverage and 48% of those covered by Medicaid received a second dose.
      • Packnett E.R.
      • Zimmerman N.M.
      • Kim G.
      • et al.
      A real-world claims data analysis of meningococcal serogroup B vaccine series completion and potential missed opportunities in the United States.
      Among non-completers, 35‒40% had ≥1 missed opportunity for series completion.
      • Packnett E.R.
      • Zimmerman N.M.
      • Kim G.
      • et al.
      A real-world claims data analysis of meningococcal serogroup B vaccine series completion and potential missed opportunities in the United States.
      Disparities between MenACWY and MenB vaccine uptake, including that of first and second doses, indicate that many individuals may not be fully vaccinated against IMD, and further highlight the importance of completing the vaccination series to reduce incidence of IMD and improve overall public health. Of note, a study of correlates and disparities in MenB vaccination coverage among US adolescents found that coverage was higher in those who were up-to-date with MenACWY vaccination than in those who were not (25.8% vs 7.2%, respectively), and MenACWY vaccination coverage was almost 50% lower in those who had not received MenB vaccination (48.0% vs 86.4% in those who had received MenB).
      • La E.M.
      • Garbinsky D.
      • Hunter S.
      • Poston S.
      • Novy P.
      • Ghaswalla P.K.
      Meningococcal B vaccination coverage among older adolescents in the United States.
      These data underscore the importance of regular healthcare visits and completion of vaccination schedules, and again point toward potential improvements that could be achieved through simplified visit schedules that incorporate combination vaccines. The success of this strategy has been observed with other vaccines; in a US analysis, replacement of MMR and a separate varicella vaccine with a quadrivalent measles, mumps, rubella, varicella (MMRV) vaccine was associated with a decrease in the number of injections and a modest increase in the concomitant and on-time administration of other ACIP-recommended vaccines.
      • Ackerson B.K.
      • Sy L.S.
      • Yao J.F.
      • Cheetham C.T.
      • Jacobsen S.J.
      Impact of MMRV combination vaccine on childhood vaccination compliance.
      Similarly, vaccine coverage for varicella increased after the introduction of a quadrivalent MMRV vaccine in Alberta, Canada.
      • MacDonald S.E.
      • Tough S.
      • Guo X.
      • Kellner JD.
      Impact of combination MMRV vaccine on first-dose coverage for measles and varicella: a population-based study.
      These combined data support a wide acceptance of combination vaccines and an ensuing increase in coverage.
      In regions outside the US, further evidence supports the simplification of vaccination schedules as a clear strategy for increasing vaccination uptake. Three hexavalent vaccines are in widespread use for the delivery of routine childhood vaccinations.
      • Obando-Pacheco P.
      • Rivero-Calle I.
      • Gomez-Rial J.
      • Rodriguez-Tenreiro Sanchez C.
      • Martinon-Torres F.
      New perspectives for hexavalent vaccines.
      These vaccines have been effective for more than 15 years in protecting against WHO-recommended immune-preventable diseases without impacting other immunisation schedules or disease occurrence.
      • Obando-Pacheco P.
      • Rivero-Calle I.
      • Gomez-Rial J.
      • Rodriguez-Tenreiro Sanchez C.
      • Martinon-Torres F.
      New perspectives for hexavalent vaccines.
      A cross-sectional study in France showed that hepatitis B vaccination coverage increased considerably over a 3-year period after a hexavalent vaccine was approved for reimbursement.
      • Vie le Sage F.
      • Gaudelus J.
      • Lert F.
      • et al.
      Public health impact of Infanrix hexa (DTPa-HBV-IPV/Hib) reimbursement: a study programme in France. Part 2: evolution of the acceptability of infants' vaccination against hepatitis B in general and pediatric practices - the PRALINE study.
      Prior to introduction of the hexavalent vaccine, physicians and paediatricians had to obtain separate consent for a hepatitis B vaccine and the vaccine had to be administered as an additional series of injections.
      The concept of adding serogroup antigens to a vaccine is not unique to meningococcal vaccines, and vaccines containing multiple pneumococcal antigens have been available for over a decade. For example, pneumococcal conjugate vaccine (PCV13), which contains capsular polysaccharide antigens for a broad range of serotypes, was introduced in 2011 for infants and young children, and provided a decrease in the incidence of invasive pneumococcal disease in the US.
      • Lee G.M.
      • Kleinman K.
      • Pelton S.
      • et al.
      Immunization, antibiotic use, and pneumococcal colonization over a 15-year period.
      Nonetheless, the emergence of serotypes not covered by PCV1393 highlights the need for ongoing surveillance of populations and continued innovation in vaccine development programmes.

      Pentavalent MenABCWY vaccine development

      Since the global distribution of meningococcal serotypes is dynamic and diverse, a pentavalent MenABCWY vaccine is expected to provide broad IMD protection and represent a further advance in reducing the global burden of this disease and move us one step closer towards a meningococcal-free world. A recent population-based dynamic model estimated the potential impact of a pentavalent MenABCWY vaccine on public health in the US.
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      It was estimated that, over 10 years, a pentavalent vaccine could prevent up to approximately 100 additional cases compared with separate MenB and MenACWY vaccination (165 cases prevented with the use of existing vaccines versus 189‒256 cases with the use of MenABCWY, depending on schedule).
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      These values were based on similar coverage rates to those currently seen for MenACWY.
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      The potential impact on public health could thus be a reduction in IMD caused by the five major serogroups while also reducing injection numbers, leading to a potential improvement in vaccination coverage.
      • Huang L.
      • Snedecor S.J.
      • Balmer P.
      • Srivastava A.
      Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
      A GSK clinical development programme dedicated to the development of a meningococcal pentavalent MenABCWY vaccine has led to phase 2 evaluation of a pentavalent vaccine incorporating MenACWY combined with recombinant proteins from serogroup B and outer membrane vesicles from New Zealand strain NZ98/254.
      • Block S.L.
      • Szenborn L.
      • Daly W.
      • et al.
      A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: results of a phase 2 randomized, controlled trial.
      • Saez-Llorens X.
      • Aguilera Vaca D.C.
      • Abarca K.
      • et al.
      Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents.
      • Saez-Llorens X.
      • Beltran-Rodriguez J.
      • Novoa Pizarro J.M.
      • Mensi I.
      • Keshavan P.
      • Toneatto D.
      Four-year antibody persistence and response to a booster dose of a pentavalent MenABCWY vaccine administered to healthy adolescents and young adults.
      • Welsch J.A.
      • Senders S.
      • Essink B.
      • et al.
      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.
      In the first of these studies in 495 healthy adolescents (494 were vaccinated and 485 completed the study), two doses of an OMV-containing MenABCWY vaccine formulation, given 2 months apart, induced substantial immune responses against all serogroups (co-primary outcome measure); all candidate vaccines had acceptable safety profiles (co-primary outcome measure based on solicited local and systemic reactions and adverse events).
      • Saez-Llorens X.
      • Aguilera Vaca D.C.
      • Abarca K.
      • et al.
      Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents.
      In extension studies, booster doses were evaluated and antibodies against serogroups A, C, W and Y persisted but decreased over 4 years, and levels of antibodies against serogroup B test strains also waned over 4 years post-vaccination, but remained above pre-vaccination concentrations for some strains. Exposure to a booster dose elicited an anamnestic response in adolescents previously exposed to either MenABCWY or a different quadrivalent meningococcal vaccine.
      • Saez-Llorens X.
      • Beltran-Rodriguez J.
      • Novoa Pizarro J.M.
      • Mensi I.
      • Keshavan P.
      • Toneatto D.
      Four-year antibody persistence and response to a booster dose of a pentavalent MenABCWY vaccine administered to healthy adolescents and young adults.
      In another randomised, phase 2 study of 484 healthy participants aged 10–25 years, as expected, seroresponse rates for serogroups A, C, W, and Y were superior after vaccination with two investigational MenABCWY formulations (two doses) compared with after one dose of MenACWY-CRM; prespecified immunological non-inferiority criteria (primary outcome measure) were met. Both formulations also induced substantial immune responses (albeit to a lesser extent than 4CMenB) against MenB test strains and had similar desirability indices (co-primary outcome measure based on immunogenicity and reactogenicity parameters). In addition, reactogenicity profiles were similar to each other and to that of 4CMenB, and there were no reported vaccine-related serious adverse events.
      • Block S.L.
      • Szenborn L.
      • Daly W.
      • et al.
      A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: results of a phase 2 randomized, controlled trial.
      In a subsequent randomised, phase 2 study (490 adolescents) investigating the complement-mediated bactericidal activity induced by MenABCWY vaccine against a randomly selected panel of 110 endemic US serogroup B IMD strains, MenABCWY (two and three doses) was found to be immunogenic with a clinically acceptable safety profile in adolescents, and the results suggest that the MenABCWY vaccine offered broad breadth of coverage (67% [95% CI: 65, 69] after 2 doses and 71% [95% CI: 69, 73] after 3 doses; primary objective) that could provide protection against most endemic US serogroup B strains.
      • Welsch J.A.
      • Senders S.
      • Essink B.
      • et al.
      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.
      Based on the results of these studies, the pentavalent MenABCWY vaccine is currently being evaluated in a phase 3 trial (estimated primary completion date September 2022) including 3650 healthy participants aged 10–25 years (NCT04502693).

      Clinicaltrials.gov. NCT04502693. Study to assess effectiveness of GlaxoSmithKline's (GSK's) meningococcal Group B and combined ABCWY vaccines in healthy adolescents and young adults. Avaialble at: https://clinicaltrials.gov/ct2/show/NCT04502693 (accessed 28 February, 2022).

      The trial will evaluate the effectiveness, safety, tolerability and immunogenicity of MenABCWY compared with 4CMenB and MenACWY-CRM. The primary outcome measures include the percentage of patient samples without bactericidal serum activity against each of the endemic US N. meningitidis serogroup A, B, C, W and Y strains, percentage of participants whose sera is effective against ≥70% of the strains tested using hSBA at 1 month after different vaccination schedules, and the percentage of patients achieving ≥4-fold rise in hSBA titres from baseline for ACWY and MenB test strains. The safety profile of MenABCWY will also be examined in relation to 4CMenB and MenACWY-CRM.

      Conclusions

      Several types of meningococcal vaccine are approved, recommended and widely available. They have demonstrated effectiveness in preventing IMD in infants, adolescents and young adults. Initial meningococcal vaccines were monovalent and covered one serogroup (i.e. A or C), but quadrivalent meningococcal vaccines, such as MenACWY-CRM, have been used for more than a decade and are effective in helping reduce and control the incidence of IMD caused by the serogroups covered, and in helping to reduce meningococcal carriage. Currently, protection against the most frequent serogroups requires the administration of two vaccines (MenB and MenACWY), and this is reflected in the most comprehensive meningococcal vaccination programmes that cover MenACWY and MenB separately. The requirement for separate vaccine administration on two schedules has led to suboptimal vaccination coverage.
      The continuing development of the pentavalent MenABCWY vaccine that combines the antigenic components of two approved vaccines, MenACWY-CRM and serogroup B-targeted 4CMenB, will provide broad and complementary serogroup coverage. There have been significant advances in MenB vaccination in recent years, with implementation of 4CMenB in more NIPs based on long-term, real-world data on its effectiveness and safety, alongside data on its global healthcare impact.
      • Martinon-Torres F.
      • Banzhoff A.
      • Azzari C.
      • et al.
      Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.
      Moreover, increased understanding of the relative importance of the 4CMenB components has provided an important platform for the design of a combination vaccine that comprises these key components and those of MenACWY-CRM. A pentavalent vaccine is expected to fulfil an unmet public health need to improve meningococcal prevention through protection against a broad serogroup profile that is enhanced by reduced vaccination visits, streamlined schedules, and potential improvements in vaccination coverage. In addition, the wider global public health impact of protection against gonorrhoeal infection is a further potential benefit.
      • Ruiz Garcia Y.
      • Sohn W.Y.
      • Seib K.L.
      • et al.
      Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.
      ,
      • Longtin J.
      • Dion R.
      • Simard M.
      • et al.
      Possible impacts of wide-scale vaccination against serogroup B Neisseria meningitiditis on gonorrhoea incidence rates in one region of Quebec, Canada.
      ,
      • Whittles L.K.
      • Didelot X.
      • White PJ.
      Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis.
      ,
      • Ong J.J.
      • Unemo M.
      • Choong A.L.
      • Zhao V.
      • Chow EP.
      Is the end of gonorrhoea in sight?.
      Overall, this potential global impact on public health would represent a major step toward reducing the global meningococcal disease burden and bringing us closer to a meningococcal-free world.
      The ongoing WHO-led initiative encompasses a multi-organisational partnership with the aim of defeating meningitis by the Year 2030, with visionary goals that include elimination of IMD epidemics and reduction of cases of vaccine-preventable bacterial meningitis by 50% and deaths by 70% .6 A key strategic goal for prevention and epidemic control is higher vaccination coverage among the population, and this initiative will cover the organisms responsible for most acute bacterial meningitis, including N. meningitidis.

      World Health Organisation Initiatives. Defeating meningitis by 2030: A global road map. Available at: https://www.who.int/publications/m/item/defeating-meningitis-by-2030-a-global-road-map (accessed 28 February, 2022).

      Combining components of approved IMD vaccines is an innovation that provides a more accessible pentavalent vaccine that will simplify and streamline vaccination schedules by eliminating the need to administer two vaccines separately. Recent surveys have shown that over two-thirds of parents/guardians of US adolescents were unaware of separate MenACWY and MenB vaccines, (80% were unaware of an MenB vaccine) despite being aware of meningococcal vaccines in general,
      • Basta N.E.
      • Becker A.B.
      • Li Q.
      • Nederhoff D.
      Parental awareness of Meningococcal B vaccines and willingness to vaccinate their teens.
      and very few (7%) were aware that the MenB vaccine protects against a serogroup not covered by MenACWY
      • Srivastava A.
      • Dempsey A.
      • Galitsky A.
      • Fahimi M.
      • Huang L.
      Parental awareness and utilization of meningococcal serogroup B vaccines in the United States.
      ; nonetheless, 36% stated they would be interested in receiving more information from their HCP.
      • Srivastava A.
      • Dempsey A.
      • Galitsky A.
      • Fahimi M.
      • Huang L.
      Parental awareness and utilization of meningococcal serogroup B vaccines in the United States.
      These surveys highlighted the importance of HCP recommendations for vaccination uptake. It is hoped that the MenABCWY vaccine will increase uptake by simplifying the process and also removing the obstacle of explaining the need for separate vaccination visits to include MenB.
      Based on the varied existing recommendations and prevalent practices for meningococcal vaccination in NIPs, implementing and recommending MenABCWY vaccines could help simplify and improve global IMD vaccination programmes. For example, in the US, the pentavalent MenABCWY vaccine could replace MenACWY plus MenB vaccines,
      • Mbaeyi S.
      • Bozio C.H.
      • Duffy J.
      • et al.
      Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.
      and in the UK it could replace 4CMenB plus Hib/MenC in infants and MenACWY in adolescents.

      Public Health England. Routine vaccination schedule 2020. Available at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule (accessed 28 February, 2022).

      Similarly, MenABCWY would provide an alternative, simplified IMD vaccination schedule in European countries (e.g. Austria, Czech Republic, Italy, Spain and, more recently, France) where MenB and/or MenC and MenACWY vaccines are recommended.

      ECDC Vaccine Scheduler. Meningococcal disease: Recommended vaccinations. Available at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=48&SelectedCountryIdByDisease=-1 (accessed 28 February, 2022).

      This strategy should also improve the overall percentage of infants and adolescents vaccinated against the five serogroups. The medical advantages and societal benefits of a combined pentavalent MenABCWY vaccine, based on historical experience with combination vaccines in general, together with potential benefits specific to IMD, are summarised in Fig. 4. Thus, development of a pentavalent meningococcal vaccine represents the next logical, coherent, and major step in the evolution of meningococcal prevention by building on the successful development of quadrivalent vaccines and subsequent wealth of clinical experience generated by vaccine programmes incorporating the MenB and MenACWY vaccines. Despite the emergence of serogroup X IMD in Africa,
      • Xie O.
      • Pollard A.J.
      • Mueller J.E.
      • Norheim G.
      Emergence of serogroup X meningococcal disease in Africa: need for a vaccine.
      MenABCWY is expected to provide broad protection and prevent IMD attributed to most circulating meningococcal strains worldwide.
      Fig 4
      Fig. 4Potential medical, healthcare, and societal benefits of a pentavalent MenABCWY vaccine. AE, adverse event; IMD, invasive meningococcal disease.

      Funding details

      GlaxoSmithKline Biologicals SA funded all costs associated with the development and the publishing of the present manuscript.

      Role of the funding source

      GlaxoSmithKline Biologicals SA was involved in the writing the manuscript and in the decision to submit the article for publication.

      Disclosure statement

      RBB, EF, SP, RR, W-YS, LS, and KV are employees of the GSK group of companies and hold shares as part of their employee remuneration.

      Declaration of Competing Interest

      All authors are employees of the GSK group of companies and hold shares as part of their employee remuneration. GlaxoSmithKline Biologicals SA funded all costs associated with the development and the publishing of the present manuscript.

      Acknowledgments

      The authors thank the Open Health Medical Communications for writing support, editorial assistance, and manuscript coordination, on behalf of GSK.

      References

        • Cohn A.C.
        • MacNeil J.R.
        • Clark T.A.
        • et al.
        Prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (ACIP).
        MMWR Recomm Rep. 2013; 62: 1-28
        • Pizza M.
        • Bekkat-Berkani R.
        • Rappuoli R.
        Vaccines against meningococcal diseases.
        Microorganisms. 2020; 8
        • Wang B.
        • Santoreneos R.
        • Giles L.
        • Haji Ali Afzali H.
        • Marshall H.
        Case fatality rates of invasive meningococcal disease by serogroup and age: a systematic review and meta-analysis.
        Vaccine. 2019; 37: 2768-2782
      1. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases.

        • Jafri R.Z.
        • Ali A.
        • Messonnier N.E.
        • et al.
        Global epidemiology of invasive meningococcal disease.
        Popul Health Metr. 2013; 11: 17
      2. World Health Organisation Initiatives. Defeating meningitis by 2030. Available at: https://www.who.int/initiatives/defeating-meningitis-by-2030 (accessed 28 February, 2022).

        • Terranella A.
        • Cohn A.
        • Clark T.
        Meningococcal conjugate vaccines: optimizing global impact.
        Infect Drug Resist. 2011; 4: 161-169
        • Booy R.
        • Gentile A.
        • Nissen M.
        • Whelan J.
        • Abitbol V.
        Recent changes in the epidemiology of Neisseria meningitidis serogroup W across the world, current vaccination policy choices and possible future strategies.
        Hum Vaccin Immunother. 2019; 15: 470-480
        • Mustapha M.M.
        • Marsh J.W.
        • Harrison L.H.
        Global epidemiology of capsular group W meningococcal disease (1970-2015): Multifocal emergence and persistence of hypervirulent sequence type (ST)-11 clonal complex.
        Vaccine. 2016; 34: 1515-1523
        • Pelton S.I.
        The global evolution of meningococcal epidemiology following the introduction of meningococcal vaccines.
        J Adolesc Health. 2016; 59: S3-S11
      3. Dutch National Immunisation Programme: Meningococcal vaccine. Avaialble at: https://rijksvaccinatieprogramma.nl/english (accessed 28 February, 2022).

        • Borrow R.
        • Alarcón P.
        • Carlos J.
        • et al.
        The global meningococcal initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
        Expert Rev Vaccines. 2017; 16: 313-328
        • Campbell H.
        • Saliba V.
        • Borrow R.
        • Ramsay M.
        • Ladhani S.
        Targeted vaccination of teenagers following continued rapid endemic expansion of a single meningococcal group W clone (sequence type 11 clonal complex), United Kingdom 2015.
        Eurosurveillance. 2015; 20
      4. GSK. Bexsero Summary of Product Characteristics. EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/bexsero (accessed 28 February, 2022).

      5. GSK. Bexsero Prescribing Information 2020. Available at: https://www.fda.gov/media/90996/download (accessed 28 February, 2022).

      6. Pfizer. Trumenba Summary of Product Characteristics. EMA, 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/trumenba-epar-product-information_en.pdf (accessed 28 June, 2022).

      7. Pfizer. Trumenba Prescribing Information, 2021. Available at: https://labeling.pfizer.com/showlabeling.aspx?id=1796 (accessed 28 June, 2022).

      8. Clinicaltrials.gov. NCT04502693. Study to assess effectiveness of GlaxoSmithKline's (GSK's) meningococcal Group B and combined ABCWY vaccines in healthy adolescents and young adults. Avaialble at: https://clinicaltrials.gov/ct2/show/NCT04502693 (accessed 28 February, 2022).

        • Trotter C.L.
        • Ramsay M.E.
        Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines.
        FEMS Microbiol Rev. 2007; 31: 101-107
        • Daugla D.M.
        • Gami J.P.
        • Gamougam K.
        • et al.
        Effect of a serogroup a meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study.
        Lancet North Am Ed. 2014; 383: 40-47
        • Kristiansen P.A.
        • Diomandé F.
        • Ba A.K.
        • et al.
        Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.
        Clin Infect Dis. 2013; 56: 354-363
        • Keshavan P.
        • Pellegrini M.
        • Vadivelu-Pechai K.
        • Nissen M.
        An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine.
        Expert Rev Vaccines. 2018; 17: 865-880
        • Boisier P.
        • Nicolas P.
        • Djibo S.
        • et al.
        Meningococcal meningitis: unprecedented incidence of serogroup X-related cases in 2006 in Niger.
        Clin Infect Dis. 2007; 44: 657-663
        • Materu S.
        • Cox H.S.
        • Isaakidis P.
        • Baruani B.
        • Ogaro T.
        • Caugant DA.
        Serogroup X in meningococcal disease, Western Kenya.
        Emerg Infect Dis. 2007; 13: 944-945
        • Yazdankhah S.P.
        • Kriz P.
        • Tzanakaki G.
        • et al.
        Distribution of serogroups and genotypes among disease-associated and carried isolates of Neisseria meningitidis from the Czech Republic, Greece, and Norway.
        J Clin Microbiol. 2004; 42: 5146-5153
        • Pajon R.
        • Lujan E.
        • Granoff D.M.
        A meningococcal NOMV-FHbp vaccine for Africa elicits broader serum bactericidal antibody responses against serogroup B and non-B strains than a licensed serogroup B vaccine.
        Vaccine. 2016; 34: 643-649
        • Mbaeyi S.
        • Bozio C.H.
        • Duffy J.
        • et al.
        Meningococcal vaccination: recommendations of the advisory committee on immunization practices, United States, 2020.
        Morb Mortal Wkly Rep (MMWR). 2020; 69 (Available at) (accessed 4 July, 2022): 1-41
        • MacNeil J.R.
        • Blain A.E.
        • Wang X.
        • Cohn AC.
        Current epidemiology and trends in meningococcal disease-United States, 1996-2015.
        Clin Infect Dis. 2018; 66: 1276-1281
        • Mbaeyi S.
        • Pondo T.
        • Blain A.
        • et al.
        Incidence of meningococcal disease before and after implementation of quadrivalent meningococcal conjugate vaccine in the United States.
        JAMA Pediatr. 2020; 174: 843-851
      9. Centers for Disease Control and Prevention. Meningococcal disease surveillance data tables. Avialable at: https://www.cdc.gov/meningococcal/surveillance/surveillance-data.html#figure01 (accessed 28 February, 2022).

      10. Centers for Disease Control and Prevention. Teen vaccination coverage publications and resources. Available at: https://www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/pubs-presentations.html (accessed 28 February, 2022).

      11. GSK. Menveo Prescribing Information 2020. Available at: https://gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Menveo/pdf/MENVEO.PDF (accessed 28 February, 2022).

      12. GSK. Menveo Summary of Product Characteristics, EMA, 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/menveo (accessed 28 February, 2022).

      13. Argentina National Immunisation Calendar. Available at: https://bancos.salud.gob.ar/sites/default/files/2021-12/calendario-nacional-vacunacion-2022.pdf (accessed 28 June, 2022).

      14. CDC. Recommended child and adolescent immunization schedule for ages 18 years or younger, United States 2020. Available at: https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fschedules%2Fhcp%2Fchild-adolescent.html (accessed 28 June, 2022).

      15. Public Health England. Routine vaccination schedule 2020. Available at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule (accessed 28 February, 2022).

      16. Switzerland: Federal Office of Public Health. Swiss Vaccination Schedule Synopsis. Available at: https://www.infovac.ch/docs/public/-main/synopsis-schweizerischer-impfplan-2020.pdf (accessed 28 February, 2022).

        • Abdelnour A.
        • Silas P.E.
        • Lamas M.R.
        • et al.
        Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: results of an open-label, randomized, phase 3b controlled study in healthy infants.
        Vaccine. 2014; 32: 965-972
      17. 2021, 24-29 May, 2021 Poster number 908 Available at: https://postergskcom/poster/6550 (accessed 4 July, 2022).
        • Reisinger K.S.
        • Baxter R.
        • Block S.L.
        • Shah J.
        • Bedell L.
        • Dull P.M.
        Quadrivalent meningococcal vaccination of adults: phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra.
        Clin Vaccine Immunol. 2009; 16: 1810-1815
        • Im J.H.
        • Woo H.
        • Ha B.M.
        • Lee J.S.
        • Chung M.H.
        • Jung J.
        Effectiveness of a single dose of the quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, in the Korean Armed Forces.
        Vaccine. 2020; 38: 730-732
      18. Australian Government, Department of Health. Clinical update: National Immunisation Program (NIP) schedule changes from 1 July 2020 – advice for vaccination providers. Available at: https://www.health.gov.au/news/clinical-update-national-immunisation-program-nip-schedule-changes-from-1-july-2020-advice-for-vaccination-providers (accessed 28 February, 2022).

      19. Government of Canada: Recommended immunization schedules: Canadian Immunization Guide. Available at: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html #p1c12a2 (accessed 28 June, 2022).

      20. GSK Press Release, 23 January 2020. World's first meningitis B national infant vaccination programme shows 75% drop in cases over three years. Available at: https://www.gsk.com/en-gb/media/press-releases/world-s-first-meningitis-b-national-infant-vaccination-programme-shows-75-drop-in-cases-over-three-years/ (accessed 28 February, 2022).

        • Borrow R.
        • Taha M.K.
        • Giuliani M.M.
        • Pizza M.
        • Banzhoff A.
        • Bekkat-Berkani R.
        Methods to evaluate serogroup B meningococcal vaccines: from predictions to real-world evidence.
        J Infect. 2020; 81: 862-872
        • Rodrigues C.M.C.
        • Jolley K.A.
        • Smith A.
        • Cameron J.C.
        • Feavers I.M.
        • Maiden M.C.J.
        Meningococcal deduced vaccine antigen reactivity (MenDeVAR) index: a rapid and accessible tool that exploits genomic data in public health and clinical microbiology applications.
        J Clin Microbiol. 2020; 59
      21. ECDC Vaccine Scheduler. Meningococcal disease: Recommended vaccinations. Available at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=48&SelectedCountryIdByDisease=-1 (accessed 28 February, 2022).

        • Martinon-Torres F.
        • Banzhoff A.
        • Azzari C.
        • et al.
        Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.
        J Infect. 2021; 83: 17-26
      22. Government of South Australia. SA Health. Meningococcal B Immunisation Program. Available at: https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/conditions/immunisation/immunisation+programs/meningococcal+b+immunisation+program (accessed 28 February, 2022).

        • Alvarez Garcia F.J.
        • Cilleruelo Ortega M.J.
        • Alvarez Aldean J.
        • et al.
        [Immunisation schedule of the Spanish association of paediatrics: 2020 recommendations].
        An Pediatr (Engl Ed). 2020; 92 (e51-52 e10): 52
      23. Haute Autorite de Sante (HAS). Vaccination strategy for the prevention of invasive meningococcal infections: Serogroup B and the place of Bexsero. https://www.has-sante.fr/jcms/p_3066921/fr/strategie-de-vaccination-pour-la-prevention-des-infections-invasives-a-meningocoques-le-serogroupe-b-et-la-place-de-bexser (accessed 28 February, 2022).

        • Parikh S.R.
        • Newbold L.
        • Slater S.
        • et al.
        Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.
        Lancet Infect Dis. 2017; 17: 754-762
        • Ladhani S.N.
        • Andrews N.
        • Parikh S.R.
        • et al.
        Vaccination of Infants with meningococcal group B vaccine (4CMenB) in England.
        N Engl J Med. 2020; 382: 309-317
        • Parikh S.R.
        • Andrews N.J.
        • Beebeejaun K.
        • et al.
        Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study.
        Lancet. 2016; 388: 2775-2782
        • Azzari C.
        • Moriondo M.
        • Nieddu F.
        • et al.
        Effectiveness and impact of the 4CMenB vaccine against group B meningococcal disease in two italian regions using different vaccination schedules: a five-year retrospective observational study (2014-2018).
        Vaccines. 2020; 8 (Basel)
        • Rodrigues F.M.P.
        • Marlow R.
        • Simoes M.J.
        • Danon L.
        • Ladhani S.
        • Finn A.
        Association of use of a meningococcus group B vaccine with group B invasive meningococcal disease among children in Portugal.
        JAMA. 2020; 324: 2187-2194
        • De Wals P.
        • Deceuninck G.
        • Lefebvre B.
        • et al.
        Impact of an immunization campaign to control an increased incidence of serogroup b meningococcal disease in one region of Quebec, Canada.
        Clin Infect Dis. 2017; 64: 1263-1267
        • Ruiz Garcia Y.
        • Sohn W.Y.
        • Seib K.L.
        • et al.
        Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.
        NPJ Vaccines. 2021; 6: 130
        • Vincent L.R.
        • Jerse A.E.
        Biological feasibility and importance of a gonorrhea vaccine for global public health.
        Vaccine. 2019; 37: 7419-7426
        • Longtin J.
        • Dion R.
        • Simard M.
        • et al.
        Possible impacts of wide-scale vaccination against serogroup B Neisseria meningitiditis on gonorrhoea incidence rates in one region of Quebec, Canada.
        Open Forum Infect Dis. 2017; 4: S734-S735https://doi.org/10.1093/ofid/ofx1180.1002
        • Petousis-Harris H.
        Impact of meningococcal group B OMV vaccines, beyond their brief.
        Hum Vaccin Immunother. 2018; 14: 1058-1063
        • Abara W.E.
        • Bernstein K.T.
        • Lewis F.M.T.
        • et al.
        Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study.
        Lancet Infect Dis. 2022;
        • Wang B.
        • Giles L.
        • Andraweera P.
        • et al.
        Effectiveness and impact of the 4CMenB vaccine against invasive serogroup B meningococcal disease and gonorrhoea in an infant, child, and adolescent programme: an observational cohort and case-control study.
        Lancet Infect Dis. 2022;
        • Whittles L.K.
        • Didelot X.
        • White PJ.
        Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis.
        Lancet Infect Dis. 2022;
        • Chiu N.C.
        • Huang L.M.
        • Willemsen A.
        • et al.
        Safety and immunogenicity of a meningococcal B recombinant vaccine when administered with routine vaccines to healthy infants in Taiwan: A phase 3, open-label, randomized study.
        Hum Vaccin Immunother. 2018; 14: 1075-1083
        • Gossger N.
        • Snape M.D.
        • Yu L.M.
        • et al.
        Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial.
        JAMA. 2012; 307: 573-582
        • Bryan P.
        • Seabroke S.
        • Wong J.
        • et al.
        Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study.
        Lancet Child Adolesc Health. 2018; 2: 395-403
        • Folaranmi T.
        • Rubin L.
        • Martin S.W.
        • Patel M.
        • MacNeil J.R.
        Use of serogroup B meningococcal vaccines in persons aged ≥10 years at increased risk for serogroup B meningococcal disease: recommendations of the advisory committee on immunization practices.
        MMWR Morb Mortal Wkly Rep. 2015; 64 (2015): 608-612
        • Basta N.E.
        • Becker A.B.
        • Li Q.
        • Nederhoff D.
        Parental awareness of Meningococcal B vaccines and willingness to vaccinate their teens.
        Vaccine. 2019; 37: 670-676
        • Kempe A.
        • Allison M.A.
        • MacNeil J.R.
        • et al.
        Adoption of serogroup B meningococcal vaccine recommendations.
        Pediatrics. 2018; 142
        • Morrone T.
        • Napolitano F.
        • Albano L.
        • Di Giuseppe G.
        Meningococcal serogroup B vaccine: knowledge and acceptability among parents in Italy.
        Hum Vaccin Immunother. 2017; 13: 1921-1927
        • Ponticelli D.
        • D'Ambrosio A.
        • Cancellieri M.
        • Agozzino E.
        Do HCWs adequately know about meningitis and 4CMenB vaccine and recommend its use to parents? A cross sectional analysis in Campania Region, Italy.
        J Prev Med Hyg. 2019; 60: E147-E157
      24. Centers for Disease Control and Prevention. Group settings as a risk factor. https://www.cdc.gov/meningococcal/about/risk-community.html (accessed 28 February, 2022).

        • Packnett E.R.
        • Zimmerman N.M.
        • Kim G.
        • et al.
        A real-world claims data analysis of meningococcal serogroup B vaccine series completion and potential missed opportunities in the United States.
        Pediatr Infect Dis J. 2022;
        • Packnett E.
        • Irwin D.E.
        • Novy P.
        • et al.
        Meningococcal-group B (MenB) vaccine series completion and adherence to dosing schedule in the United States: a retrospective analysis by vaccine and payer type.
        Vaccine. 2019; 37: 5899-5908
        • Gallagher K.E.
        • Kadokura E.
        • Eckert L.O.
        • et al.
        Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.
        BMC Public Health. 2016; 16: 172
        • Macdonald V.
        • Dore G.J.
        • Amin J.
        • van Beek I.
        Predictors of completion of a hepatitis B vaccination schedule in attendees at a primary health care centre.
        Sex Health. 2007; 4: 27-30
        • Beck E.
        • Klint J.
        • Garcia S.
        • et al.
        Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: an application to England.
        Vaccine. 2020; 38: 7558-7568
        • Obando-Pacheco P.
        • Rivero-Calle I.
        • Gomez-Rial J.
        • Rodriguez-Tenreiro Sanchez C.
        • Martinon-Torres F.
        New perspectives for hexavalent vaccines.
        Vaccine. 2018; 36: 5485-5494
        • Maman K.
        • Zollner Y.
        • Greco D.
        • Duru G.
        • Sendyona S.
        • Remy V.
        The value of childhood combination vaccines: from beliefs to evidence.
        Hum Vaccin Immunother. 2015; 11: 2132-2141
        • Miller E.
        • Salisbury D.
        • Ramsay M.
        Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story.
        Vaccine. 2001; 20: S58-S67
      25. Centers for Disease Control and Prevention. Health, United States, 2018 - Data Finder. Available at: https://www.cdc.gov/nchs/hus/contents2018.htm#Table_032 (accessed 28 February, 2022).

        • Cheng W.Y.
        • Chang R.
        • Novy P.
        • O'Connor C.
        • Duh M.S.
        • Hogea C.S.
        Determinants of meningococcal ACWY vaccination in adolescents in the US: completion and compliance with the CDC recommendations.
        Hum Vaccin Immunother. 2020; 16: 176-188
        • Walker T.Y.
        • Elam-Evans L.D.
        • Yankey D.
        • et al.
        National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years - United States, 2018.
        MMWR Morb Mortal Wkly Rep. 2019; 68: 718-723
        • Huang L.
        • Snedecor S.J.
        • Balmer P.
        • Srivastava A.
        Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.
        Postgrad Med. 2021; : 1-8
        • Huang L.
        • Goren A.
        • Lee L.K.
        • Li V.W.
        • Dempsey A.
        • Srivastava A.
        Disparities in healthcare providers' interpretations and implementations of ACIP's meningococcal vaccine recommendations.
        Hum Vaccin Immunother. 2020; 16: 933-944
        • Elam-Evans L.D.
        • Yankey D.
        • Singleton J.A.
        • et al.
        National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 Years - United States, 2019.
        MMWR Morb Mortal Wkly Rep. 2020; 69: 1109-1116
        • Haimowitz R.
        • Torres R.
        • Caleb S.
        • et al.
        Serogroup B meningococcal vaccination practice patterns on college campuses.
        Vaccine. 2020; 38: 7350-7356
        • La E.M.
        • Garbinsky D.
        • Hunter S.
        • Poston S.
        • Novy P.
        • Ghaswalla P.K.
        Meningococcal B vaccination coverage among older adolescents in the United States.
        Vaccine. 2021; (In press)
        • Ackerson B.K.
        • Sy L.S.
        • Yao J.F.
        • Cheetham C.T.
        • Jacobsen S.J.
        Impact of MMRV combination vaccine on childhood vaccination compliance.
        Am J Manag Care. 2012; 18: e440-e445
        • MacDonald S.E.
        • Tough S.
        • Guo X.
        • Kellner JD.
        Impact of combination MMRV vaccine on first-dose coverage for measles and varicella: a population-based study.
        J Public Health. 2020;
        • Vie le Sage F.
        • Gaudelus J.
        • Lert F.
        • et al.
        Public health impact of Infanrix hexa (DTPa-HBV-IPV/Hib) reimbursement: a study programme in France. Part 2: evolution of the acceptability of infants' vaccination against hepatitis B in general and pediatric practices - the PRALINE study.
        Rev Epidemiol Sante Publique. 2016; 64: 185-194
        • Lee G.M.
        • Kleinman K.
        • Pelton S.
        • et al.
        Immunization, antibiotic use, and pneumococcal colonization over a 15-year period.
        Pediatrics. 2017; 140e20170001
        • Block S.L.
        • Szenborn L.
        • Daly W.
        • et al.
        A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: results of a phase 2 randomized, controlled trial.
        Vaccine. 2015; 33: 2500-2510
        • Saez-Llorens X.
        • Aguilera Vaca D.C.
        • Abarca K.
        • et al.
        Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents.
        Hum Vaccin Immunother. 2015; 11: 1507-1517
        • Saez-Llorens X.
        • Beltran-Rodriguez J.
        • Novoa Pizarro J.M.
        • Mensi I.
        • Keshavan P.
        • Toneatto D.
        Four-year antibody persistence and response to a booster dose of a pentavalent MenABCWY vaccine administered to healthy adolescents and young adults.
        Hum Vaccin Immunother. 2018; 14: 1161-1174
        • Welsch J.A.
        • Senders S.
        • Essink B.
        • et al.
        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.
        Vaccine. 2018; 36: 5309-5317
        • Ong J.J.
        • Unemo M.
        • Choong A.L.
        • Zhao V.
        • Chow EP.
        Is the end of gonorrhoea in sight?.
        Lancet Infect Dis. 2022;
      26. World Health Organisation Initiatives. Defeating meningitis by 2030: A global road map. Available at: https://www.who.int/publications/m/item/defeating-meningitis-by-2030-a-global-road-map (accessed 28 February, 2022).

        • Srivastava A.
        • Dempsey A.
        • Galitsky A.
        • Fahimi M.
        • Huang L.
        Parental awareness and utilization of meningococcal serogroup B vaccines in the United States.
        BMC Public Health. 2020; 20: 1109
        • Xie O.
        • Pollard A.J.
        • Mueller J.E.
        • Norheim G.
        Emergence of serogroup X meningococcal disease in Africa: need for a vaccine.
        Vaccine. 2013; 31: 2852-2861
        • Masignani V.
        • Pizza M.
        • Moxon E.R.
        The development of a vaccine against meningococcus B using reverse vaccinology.
        Front Immunol. 2019; 10: 751
      27. Ireland National Immunisation Office. Immunisation schedule. Available at: https://www.hse.ie/eng/health/immunisation/pubinfo/pcischedule/immschedule/ (accessed 28 February, 2022).

      28. Italy Ministry of Health. Piano Nazionale Prevenzione Vaccinale, PNPV 2017-2019. Available at: https://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf (accessed 28 February, 2022).

      29. Ministry of Health of the Republic of Lithuania. Official: children in Lithuania will be vaccinated against type B meningococcus. Available at: https://sam.lrv.lt/en/news/minister-of-health-aurelijus-veryga-signed-an-order-by-which-vaccines-against-type-b-meningococcus-are-to-be-included-in-the-schedule-for-the-preventive-vaccination-of-children-the-start-of-the-vaccination-is-scheduled-as-of-july-this-year (accessed 28 February, 2022).

      30. Government of Malta. National immunisation schedule. Available at: https://deputyprimeminister.gov.mt/en/phc/pchyhi/Pages/National-Immunisation-Schedule.aspx (February 28, 2022).

      31. SAÚDE. Gabinete do Secretário de Estado da Saúde. Despacho n.° 12434/2019. Available at: https://dre.pt/application/conteudo/127608823 (accessed 28 February, 2022).

        • Deceuninck G.
        • Lefebvre B.
        • Tsang R.
        • Betala-Belinga J.F.
        • De Serres G.
        • De Wals P.
        Impact of a mass vaccination campaign against Serogroup B meningococcal disease in the Saguenay-Lac-Saint-Jean region of Quebec four years after its launch.
        Vaccine. 2019; 37: 4243-4245
        • Ladhani S.N.
        • Campbell H.
        • Andrews N.
        • et al.
        First real world evidence of meningococcal group B vaccine, 4CMenB, protection against meningococcal group W disease; prospective enhanced national surveillance, England.
        Clin Infect Dis. 2020; 73: e1661-e1668
        • Hall G.C.
        • Douglas I.
        • Heath P.T.
        • et al.
        Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program.
        Vaccine. 2021; 39: 3296-3303
        • Stowe J.
        • Andrews N.J.
        • Turner P.J.
        • Miller E.
        The risk of Kawasaki disease after pneumococcal conjugate & meningococcal B vaccine in England: a self-controlled case-series analysis.
        Vaccine. 2020; 38: 4935-4939
        • Mentzer D.
        • Oberle D.
        • Keller-Stanislawski B.
        Adverse events following immunisation with a meningococcal serogroup B vaccine: report from post-marketing surveillance, Germany, 2013 to 2016.
        Euro Surveill. 2018; 23
        • Read R.C.
        • Baxter D.
        • Chadwick D.R.
        • et al.
        Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.
        Lancet. 2014; 384: 2123-2131
        • Tipton M.
        • Daly W.
        • Senders S.
        • et al.
        MenACWY-CRM conjugate vaccine booster dose given 4–6 years after priming: Results from a phase IIIb, multicenter, open label study in adolescents and adults.
        Vaccine. 2019; 37: 6171-6179
        • Yoo B.W.
        • Jung H.L.
        • Byeon Y.S.
        • et al.
        Results from a large post-marketing safety surveillance study in the Republic of Korea with a quadrivalent meningococcal CRM-conjugate vaccine in individuals aged 2 months-55 years.
        Hum Vaccin Immunother. 2020; 16: 1260-1267