Advertisement

Meningococcal Group A, C, W, and Y Tetanus Toxoid Conjugate Vaccine: A Review of Clinical Data in Adolescents

      Abstract

      MenACWY-TT (Nimenrix) is a quadrivalent meningococcal vaccine containing polysaccharides from serogroups A, C, W, and Y conjugated to a tetanus toxoid carrier protein. MenACWY-TT is licensed in some countries as a three-dose primary series in individuals as young as 6 weeks of age and as a single dose in individuals ≥12 months of age. MenACWY-TT use is supported by long-term immunogenicity and safety across age groups, including data from several phase 2, 3, and 4 clinical studies in adolescents and young adults. Adolescents are an important population in the epidemiology, transmission, and prevention of invasive meningococcal disease, with this age-based population having the highest risk for carriage and transmission as well as one of the highest risks of disease. This age group is emerging as a target population in meningococcal vaccination programs globally, as vaccinating adolescents and young adults could potentially not only decrease disease rates directly for those vaccinated but also indirectly for unvaccinated individuals by decreasing carriage and eliciting herd protection. This review will consider available data for MenACWY-TT in adolescents, including safety and immunogenicity, booster and memory responses, persistence, and coadministration with other vaccines, with an emphasis on the rationale for use of MenACWY-TT and other quadrivalent meningococcal vaccines in adolescents to address the changing epidemiology of meningococcal disease.

      Keywords

      See Related Editorial on p. 263
      Implications and Contribution
      This review emphasizes the importance of adolescents as a target for meningococcal vaccination, owing to the high risk of carriage and disease in this age-based population. Clinical data for a meningococcal serogroup A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents are reviewed.
      Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD) [

      Centers for Disease Control and Prevention. Meningococcal disease: Technical and clinical information. Available at: http://www.cdc.gov/meningococcal/clinical-info.html. Accessed October 4, 2017.

      ], presenting most commonly as meningitis and septicemia [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ]. N meningitidis infection can occur in previously healthy individuals and has a high mortality rate [
      • Pace D
      • Pollard AJ
      Meningococcal disease: Clinical presentation and sequelae.
      ,
      • McIntosh ED
      • Carey V
      • Toneatto D
      • et al.
      Prevention of rare diseases: How revolutionary techniques can help vulnerable individuals-the example of serogroup B meningococcal infection.
      ]. Survivors may experience long-term morbidities including amputation, loss of hearing, brain damage, and neurologic impairments [

      Centers for Disease Control and Prevention. Meningococcal disease: Technical and clinical information. Available at: http://www.cdc.gov/meningococcal/clinical-info.html. Accessed October 4, 2017.

      ,
      • Pace D
      • Pollard AJ
      Meningococcal disease: Clinical presentation and sequelae.
      ].
      Meningococcal disease is a global concern [
      • Tan LK
      • Carlone GM
      • Borrow R
      Advances in the development of vaccines against Neisseria meningitidis .
      ] due to the ability of the pathogen to cause rapid, severe, and epidemic disease [
      • Pace D
      • Pollard AJ
      Meningococcal disease: Clinical presentation and sequelae.
      ,
      • Jafri RZ
      • Ali A
      • Messonnier NE
      • et al.
      Global epidemiology of invasive meningococcal disease.
      ]. In industrialized countries, IMD cases are typically sporadic although outbreaks can also occur [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      • Tan LK
      • Carlone GM
      • Borrow R
      Advances in the development of vaccines against Neisseria meningitidis .
      ,

      European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe. Available at: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/Surveillance%20of%20IBD%20in %20Europe%202012.pdf. Accessed July 20, 2017.

      ]. The major endemic disease burden is in developing regions, which are characterized by frequent epidemics and poor outcomes [
      • Jafri RZ
      • Ali A
      • Messonnier NE
      • et al.
      Global epidemiology of invasive meningococcal disease.
      ,
      • Edmond K
      • Clark A
      • Korczak VS
      • et al.
      Global and regional risk of disabling sequelae from bacterial meningitis: A systematic review and meta-analysis.
      ].
      Adolescents and young adults are an important population in IMD epidemiology, transmission, and prevention. In many regions, this population is at highest risk for carriage and transmission [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      • Christensen H
      • May M
      • Bowen L
      • et al.
      Meningococcal carriage by age: A systematic review and meta-analysis.
      ,
      • Vetter V
      • Baxter R
      • Denizer G
      • et al.
      Routinely vaccinating adolescents against meningococcus: Targeting transmission & disease.
      ] and has the highest disease risk after infants and young children [

      European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe. Available at: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/Surveillance%20of%20IBD%20in %20Europe%202012.pdf. Accessed July 20, 2017.

      ,
      • Crum-Cianflone N
      • Sullivan E
      Meningococcal vaccinations.
      ]. Adolescents are also at increased disease risk during meningococcal outbreaks [
      • Brooks R
      • Woods CW
      • Benjamin Jr., DK
      • et al.
      Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994-2002.
      ] and adolescent survivors of IMD are at risk of long-term debilitating sequelae [
      • Borg J
      • Christie D
      • Coen PG
      • et al.
      Outcomes of meningococcal disease in adolescence: Prospective, matched-cohort study.
      ]. Increased carriage and disease risk in adolescents are thought to be attributed to social behaviors that result in close physical contact that promotes transmission [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      • Vetter V
      • Baxter R
      • Denizer G
      • et al.
      Routinely vaccinating adolescents against meningococcus: Targeting transmission & disease.
      ,
      • Soriano-Gabarro M
      • Wolter J
      • Hogea C
      • et al.
      Carriage of Neisseria meningitidis in Europe: A review of studies undertaken in the region.
      ], including living and interacting in crowded communities and engaging in increased social mixing [
      • Crum-Cianflone N
      • Sullivan E
      Meningococcal vaccinations.
      ,
      • Soriano-Gabarro M
      • Wolter J
      • Hogea C
      • et al.
      Carriage of Neisseria meningitidis in Europe: A review of studies undertaken in the region.
      ]. Carriage can lead to transmission, a prerequisite for IMD [
      • Vetter V
      • Baxter R
      • Denizer G
      • et al.
      Routinely vaccinating adolescents against meningococcus: Targeting transmission & disease.
      ], making adolescents an important target for disease control through vaccination.
      Of the 12 meningococcal serogroups, most IMD is caused by serogroups A, B, C, W, X, and Y [
      • Harrison OB
      • Claus H
      • Jiang Y
      • et al.
      Description and nomenclature of Neisseria meningitidis capsule locus.
      ]. However, the prevalence of these disease-causing serogroups can vary over time, geographically, and by age [
      • Rouphael NG
      • Stephens DS
      Neisseria meningitidis: biology, microbiology, and epidemiology.
      ]. For example, in adolescents and young adults, meningococcal serogroups B, C, and Y are most commonly associated with meningococcal disease in the United States [

      Centers for Disease Control and Prevention. Enhanced Meningococcal Disease Surveillance Report, 2016.

      ], and serogroups B and C are most commonly associated with IMD in this population in Europe [

      European Centre for Disease Prevention and Control. Surveillance atlas of infectious diseases. Available at: https://ecdc.europa.eu/en/surveillance-atlas-infectious-diseases. Accessed August 15, 2017.

      ]. However, an increase in meningococcal serogroup W disease has been observed across age groups in Europe since 2011, including in individuals aged 15–24 years, with the greatest burden of serogroup W disease reported in the United Kingdom (.33 cases/ 100,000 persons in the United Kingdom vs. .06 cases/ 100,000 persons in Europe in 2015) [

      European Centre for Disease Prevention and Control. Surveillance atlas of infectious diseases. Available at: https://ecdc.europa.eu/en/surveillance-atlas-infectious-diseases. Accessed August 15, 2017.

      ]. This increase in serogroup W disease in the United Kingdom is attributed to endemic expansion of a single and highly virulent type 11 clonal complex (cc11) [
      • Lucidarme J
      • Hill DM
      • Bratcher HB
      • et al.
      Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.
      ], which has resulted in an increased number of cases among individuals aged 5–19 years (three cases in 2008–2009 vs. 16 cases in 2013–2014) [
      • Ladhani SN
      • Beebeejaun K
      • Lucidarme J
      • et al.
      Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.
      ]. Mass gathering events have also been associated with recent meningococcal serogroup W outbreaks in adolescents. For instance, at the 2015 World Scout Jamboree in Japan, meningococcal serogroup W cc11 cases were reported among five attendees and one close contact from the United Kingdom and Sweden [
      • Smith-Palmer A
      • Oates K
      • Webster D
      • et al.
      Outbreak of Neisseria meningitidis capsular group W among scouts returning from the World Scout Jamboree, Japan, 2015.
      ]. Notably, none of the individuals had received meningococcal vaccination prior to attending the jamboree.
      Vaccination is currently the best means to prevent IMD [
      • Hedari CP
      • Khinkarly RW
      • Dbaibo GS
      Meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine: A new conjugate vaccine against invasive meningococcal disease.
      ,
      • Stephens DS
      • Greenwood B
      • Brandtzaeg P
      Epidemic meningitis, meningococcaemia, and Neisseria meningitidis .
      ]. A number of vaccines are available to prevent infection with disease-causing serogroups, either targeting single serogroups or a combination of multiple serogroups [

      World Health Organization. Meningococcal meningitis fact sheet no 141. Available at: http://www.who.int/mediacentre/factsheets/fs141/en/#. Accessed March 27, 2017.

      ]. Multivalent meningococcal vaccines provide broad coverage and have the potential to protect individuals in countries with several predominant disease-causing serogroups and may also reduce disease risk from newly emergent serogroups [
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ,
      • Cohn A
      • MacNeil J
      The changing epidemiology of meningococcal disease.
      ]. For instance, although quadrivalent vaccines protecting against serogroups A, C, W, and Y were available, a meningococcal serogroup C booster dose for adolescents previously vaccinated with a monovalent serogroup C vaccine was introduced in the United Kingdom to maintain herd protection in those vaccinated in infancy and early childhood [
      • Lucidarme J
      • Hill DM
      • Bratcher HB
      • et al.
      Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.
      ]. However, the endemic increase in serogroup W cc11 disease has led to revisions to the recommendations whereby quadrivalent meningococcal vaccines are being offered to adolescents. This approach addressing the changing epidemiology of meningococcal disease is supported by data indicating that a booster dose of quadrivalent meningococcal vaccines is immunogenic and protective in adolescents who had previously received a meningococcal serogroup C vaccine in childhood [
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      ,
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      ].
      MenACWY-TT (Nimenrix; Pfizer Ltd, Sandwich, Kent, United Kingdom), a meningococcal serogroup A, C, W, and Y tetanus toxoid conjugate vaccine, is one of the available quadrivalent meningococcal vaccines. This review considers clinical data for MenACWY-TT in adolescents, including safety and immunogenicity, booster and memory responses, persistence, and coadministration with other vaccines. The rationale for use of MenACWY-TT and other quadrivalent meningococcal vaccines in adolescents to address the changing epidemiology of meningococcal disease will be described.

      History of Quadrivalent Meningococcal Vaccination in Adolescents

      Meningococcal polysaccharide vaccine development began with monovalent vaccines against serogroup C and has since progressed to quadrivalent polysaccharide and conjugate vaccines against serogroups A, C, W, and Y (Table 1) [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ,
      Mencevax (MenACWY-PS)
      Product information Australia full prescribing information.
      ,
      • Vipond C
      • Care R
      • Feavers IM
      History of meningococcal vaccines and their serological correlates of protection.
      ].
      Table 1Currently Available Quadrivalent Meningococcal Vaccines
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      FormulationTrade name (manufacturer)TypeSerogroupsLicensed age range
      MenACWY-TTNimenrix (Pfizer Ltd; Sandwich, Kent, United Kingdom)ConjugateA, C, W, Y≥6 weeks
      MenACWY-DMenactra (Sanofi Pasteur Inc; Swiftwater, PA)ConjugateA, C, W, Y9 months–55 years
      MenACWY-CRMMenveo (Novartis Vaccines and Diagnostics S.r.l; Sovicille, Italy)ConjugateA, C, W, Y2–55 years
      Meningococcal polysaccharide vaccines have been available for >40 years [
      • Vipond C
      • Care R
      • Feavers IM
      History of meningococcal vaccines and their serological correlates of protection.
      ]. These vaccines have a well characterized safety and effectiveness profile and a long history of use [
      • Harrison LH
      Prospects for vaccine prevention of meningococcal infection.
      ,
      • Ali A
      • Jafri RZ
      • Messonnier N
      • et al.
      Global practices of meningococcal vaccine use and impact on invasive disease.
      ], including successful implementation in outbreaks and for mass and routine vaccination [
      • Vipond C
      • Care R
      • Feavers IM
      History of meningococcal vaccines and their serological correlates of protection.
      ]. However, widespread use has been restricted by limitations that include poor immunogenicity in children aged <2 years, lack of immunologic memory and booster response, short duration of protection, minimal effect on carriage, and immunologic hyporesponsiveness with repeated vaccination [
      • Vipond C
      • Care R
      • Feavers IM
      History of meningococcal vaccines and their serological correlates of protection.
      ,
      • Harrison LH
      Prospects for vaccine prevention of meningococcal infection.
      ].
      These limitations have spurred development of meningococcal conjugate vaccines [
      • Harrison LH
      Prospects for vaccine prevention of meningococcal infection.
      ], which covalently link the capsular polysaccharide to a carrier protein, resulting in increased immunogenicity in infants, immunologic memory at re-exposure, possible carriage reductions, herd protection [
      • Hedari CP
      • Khinkarly RW
      • Dbaibo GS
      Meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine: A new conjugate vaccine against invasive meningococcal disease.
      ,
      • Vipond C
      • Care R
      • Feavers IM
      History of meningococcal vaccines and their serological correlates of protection.
      ,
      • Ali A
      • Jafri RZ
      • Messonnier N
      • et al.
      Global practices of meningococcal vaccine use and impact on invasive disease.
      ,
      • Maiden MC
      • Ibarz-Pavon AB
      • Urwin R
      • et al.
      Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity.
      ,
      • Read RC
      • Baxter D
      • Chadwick DR
      • 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.
      ,
      • Daugla DM
      • Gami JP
      • 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 [corrected].
      ], booster response, and ability to overcome immune hyporesponsiveness [
      • Harrison LH
      Prospects for vaccine prevention of meningococcal infection.
      ]. Meningococcal conjugate polysaccharide vaccines have been available since 1999 with the introduction of the meningococcal serogroup C conjugate vaccine in the United Kingdom [
      • Ali A
      • Jafri RZ
      • Messonnier N
      • et al.
      Global practices of meningococcal vaccine use and impact on invasive disease.
      ,
      • Ishola Jr., DA
      • Borrow R
      • Findlow H
      • et al.
      Prevalence of serum bactericidal antibody to serogroup C Neisseria meningitidis in England a decade after vaccine introduction.
      ]. For the reasons listed above, these vaccines have since replaced unconjugated polysaccharide vaccines. Although surveillance data have shown the acceptable safety profile and effectiveness of these vaccines [
      • Ali A
      • Jafri RZ
      • Messonnier N
      • et al.
      Global practices of meningococcal vaccine use and impact on invasive disease.
      ], continued monitoring is important to identify the emergence of newly prevalent serogroups.
      The first licensed quadrivalent meningococcal conjugate vaccine was MenACWY-D (Menactra; Sanofi Pasteur Inc., Swiftwater, PA), which is conjugated to diphtheria toxin [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,

      Menactra (MCV4). Full prescribing information, Sanofi Pasteur Inc., Swiftwater, PA, 2014.

      ]. MenACWY-D was licensed in 2005 in the United States for individuals aged 11–55 years [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ]. Licensure in the same age group of a MenACWY vaccine conjugated to CRM197 (MenACWY-CRM; Menveo; Novartis Vaccines and Diagnostics S.r.l., Sovicille, Italy) followed in 2010. MenACWY-D and MenACWY-CRM are now licensed in the United States for individuals aged 9 months through 55 years and 2 months through 55 years, respectively [

      Menactra (MCV4). Full prescribing information, Sanofi Pasteur Inc., Swiftwater, PA, 2014.

      ,

      Menveo (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine). Full prescribing information, Novartis Vaccines and Diagnostics, Inc., Sovicille, Italy, 2011.

      ]. Both vaccines have been reported to be safe and immunogenic [
      • Ali A
      • Jafri RZ
      • Messonnier N
      • et al.
      Global practices of meningococcal vaccine use and impact on invasive disease.
      ,

      Menactra (MCV4). Full prescribing information, Sanofi Pasteur Inc., Swiftwater, PA, 2014.

      ,

      Menveo (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine). Full prescribing information, Novartis Vaccines and Diagnostics, Inc., Sovicille, Italy, 2011.

      ]. MenACWY-D is not licensed in Europe [

      Public Health England. Meningococcal: the Green Book, Chapter 22. Available at: https://www.gov.uk/government/publications/meningococcal-the-green-book-chapter-22. Accessed March 27, 2017.

      ], while MenACWY-CRM is licensed in Europe in individuals from 2 years of age as a single dose [

      Menveo (Meningococcal Group A, C, W135 and Y conjugate vaccine) Summary of product characteristics full prescribing information, GlaxoSmithKline UK, Uxbridge, Middlesex, UK, 2015.

      ].
      MenACWY-TT, a quadrivalent meningococcal vaccine conjugated to a tetanus toxoid carrier protein, was licensed in Europe in 2012 for children >12 months of age [
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ]. The indication was extended to infants aged ≥6 weeks in 2016 [

      European Medicines Agency. Summary of opinion (post authorisation). EMA/CHMP/512584/2016. Nimenrix (Meningococcal group A, C, W-135 and Y conjugate vaccine), 2016.

      ]. The MenACWY-TT clinical data in adolescents are discussed in more detail below.

      Recommendations for Quadrivalent Meningococcal Vaccines for Adolescents in Response to the Changing Epidemiology of Meningococcal Disease

      The World Health Organization recommends that meningococcal vaccination programs be introduced in countries with intermediate to high endemic rates of disease or with frequent epidemics [
      World Health Organization
      Meningococcal vaccines: WHO position paper, November 2011.
      ]. Initial mass vaccination of young children and adolescents is a recommended strategy, depending on the specific age distribution of disease of a given country, followed by routine vaccination as part of childhood vaccination programs [
      World Health Organization
      Meningococcal vaccines: WHO position paper, November 2011.
      ]. An alternative strategy is mass meningococcal conjugate vaccine use followed every 3–5 years by supplementary vaccination activities (e.g., for outbreaks or through private vaccination services) for at-risk age-based populations.
      The variable prevalence of meningococcal serogroups among adolescents, coupled with the potential breadth of coverage afforded by multivalent vaccines, has led to the modification of several national and regional recommendations for meningococcal vaccination in adolescents (Table 2) [

      Queensland Health. Queensland immunisation schedule. Available at: https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/immunisation/schedule#acwy. Accessed October 2, 2017.

      ,

      NSW Government Health. NSW meningococcal W response program fact sheet. Available at: http://www.health.nsw.gov.au/Infectious/diseases/Pages/meningococcal-w.aspx. Accessed October 2, 2017.

      ,

      Victoria State Government. Meningococcal ACWY vaccine for adolescents. Available at: https://www2.health.vic.gov.au/public-health/immunisation/vaccination-adolescents/meningococcal-acwy. Accessed October 2, 2017.

      , ,

      Government of Western Australia Department of Health. Meningococcal disease. Available at: http://healthywa.wa.gov.au/Articles/J_M/Meningococcal-vaccine. Accessed October 2, 2017.

      ,

      BC Centre for Disease Control. HealthLinkBC. Meningococcal quadrivalent vaccines. Number 23b. Available at: https://www.healthlinkbc.ca/healthlinkbc-files/meningococcal-quadrivalent-vaccines. Accessed October 3, 2017.

      ,

      Alberta Health. Routine immunization schedule. Available at: www.health.alberta.ca/health-info/imm-routine-schedule.html. Accessed October 3, 2017.

      ,

      Government of Saskatchewan. Immunization services. Available at: www. saskatchewan.ca/residents/health/accessing-health-care-services/immuniza tion-services. Accessed October 2, 2017.

      ,

      Government of Ontario. Publicly funded immunization schedules for Ontario - –December 2016. Available at: http://www.health.gov.on.ca/en/pro/ programs/immunization/docs/immunization_schedule.pdf. Accessed October 3, 2017.

      ,

      Government of New Brunswick. Routine immunization schedule. Available at: http://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/CDC/ Immunization/RoutineImmunizationSchedule.pdf. Accessed October 3, 2017.

      ,

      Government of Prince Edward Island. Adult and child immunization in PEI. Available at: www.princeedwardisland.ca/en/information/health-and- wellness/adult-and-child-immunization-pei. Accessed October 2, 2017.

      ,

      Government of Nova Scotia. School immunization schedule. Available at: https://novascotia.ca/dhw/cdpc/immunization.asp. Accessed October 3, 2017.

      ,

      Government of Newfoundland and Labrador. Meningococcal disease. Available at: http://www.health.gov.nl.ca/health/publichealth/cdc/pdf/Meningococcal_Vaccine_Fact_Sheet.pdf. Accessed October 3, 2017.

      ,

      Ministero della Salute Italia. The vaccination schedule of the National Vaccine Prevention Plan 2017–2019. Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf. Accessed July 8, 2017.

      ,
      Public Health England
      Guidance for the public health management of meningococcal disease in the UK (updated February 2018).
      ,

      The Netherlands Ministry of Health, Welfare and Sport. Meningococcal ACWY vaccination guideline. Available at: https://lci.rivm.nl/richtlijnen/meningo kokken-acwy-vaccinatie. Accessed March 22, 2018.

      ]. For instance, although the Australian vaccination guidelines recommend meningococcal serogroup B vaccination of individuals aged 15–19 years [

      Australian Government Department of Health. The Australian Immunisation Handbook. 10th Edition (updated August 2017). Canberra, Australia 2017.

      ], five states in Australia are currently providing conjugate MenACWY vaccination to adolescents (Queensland, New South Wales, Victoria, Western Australia) or to individuals ≥2 months of age (Ceduna Region, South Australia) beginning in the 2017 school year and continuing in some states until 2018/2019 in response to increased prevalence of serogroup W disease [

      Queensland Health. Queensland immunisation schedule. Available at: https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/immunisation/schedule#acwy. Accessed October 2, 2017.

      ,

      NSW Government Health. NSW meningococcal W response program fact sheet. Available at: http://www.health.nsw.gov.au/Infectious/diseases/Pages/meningococcal-w.aspx. Accessed October 2, 2017.

      ,

      Victoria State Government. Meningococcal ACWY vaccine for adolescents. Available at: https://www2.health.vic.gov.au/public-health/immunisation/vaccination-adolescents/meningococcal-acwy. Accessed October 2, 2017.

      , ,

      Government of Western Australia Department of Health. Meningococcal disease. Available at: http://healthywa.wa.gov.au/Articles/J_M/Meningococcal-vaccine. Accessed October 2, 2017.

      ].
      Table 2Recommendations for Quadrivalent Meningococcal Vaccines for Adolescents in Response to the Changing Epidemiology of Meningococcal Disease
      CountryRecommendation
      Australia
      Queensland

      Queensland Health. Queensland immunisation schedule. Available at: https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/immunisation/schedule#acwy. Accessed October 2, 2017.

      MenACWY available without charge to:
      • Year 10 students (∼14–15 years) in 2017
      • Individuals 15–19 years from June 2017 to May 2018 who can access the vaccine via their doctor or immunization provider
      New South Wales

      NSW Government Health. NSW meningococcal W response program fact sheet. Available at: http://www.health.nsw.gov.au/Infectious/diseases/Pages/meningococcal-w.aspx. Accessed October 2, 2017.

      MenACWY available without charge to:
      • Year 11 and 12 students in 2017 through the New South Wales School-based Vaccination Program
      • Adolescents in 2017 who have left school through their GP
      Victoria

      Victoria State Government. Meningococcal ACWY vaccine for adolescents. Available at: https://www2.health.vic.gov.au/public-health/immunisation/vaccination-adolescents/meningococcal-acwy. Accessed October 2, 2017.

      MenACWY-D available without charge to:
      • Individuals 15–19 years from April 18 to December 2017 through the secondary school immunization program or a clinical setting
      South Australia (Ceduna Region) MenACWY available without charge to:
      • Individuals ≥2 months from March to June 2017 living in the Ceduna region
      • MenACWY-CRM to be used for infants (2–11 months) and MenACWY-TT or MenACWY-CRM for individuals ≥12 months
      Western Australia

      Government of Western Australia Department of Health. Meningococcal disease. Available at: http://healthywa.wa.gov.au/Articles/J_M/Meningococcal-vaccine. Accessed October 2, 2017.

      MenACWY-TT available without charge to:
      • Individuals 15–19 years through the current meningococcal immunization program and to be administered through schools or through healthcare providers
      • All aboriginal and/or Torres Strait Islander individuals 15–19 years can receive the vaccine throughout 2017; the vaccine will be available to incoming Year 10 students (∼14–15 years) only in 2018 and 2019
      Canada
      MenACWY conjugate vaccine available without charge to children by school grade
      Grade 4, 6, 7, and 9 corresponds to children approximately 9–10, 11–12, 12–13, and 14–15years of age, respectively.
      Grade 4Grade 5Grade 6Grade 7Grade 8Grade 9
      British Columbia
      Includes MenACWY-CRM, MenACWY-D, and MenACWY-TT [51,86,87].

      BC Centre for Disease Control. HealthLinkBC. Meningococcal quadrivalent vaccines. Number 23b. Available at: https://www.healthlinkbc.ca/healthlinkbc-files/meningococcal-quadrivalent-vaccines. Accessed October 3, 2017.

      Alberta
      Includes MenACWY-CRM, MenACWY-D, and MenACWY-TT [51,86,87].

      Alberta Health. Routine immunization schedule. Available at: www.health.alberta.ca/health-info/imm-routine-schedule.html. Accessed October 3, 2017.

      Saskatchewan
      Includes MenACWY-CRM, MenACWY-D, and MenACWY-TT [51,86,87].

      Government of Saskatchewan. Immunization services. Available at: www. saskatchewan.ca/residents/health/accessing-health-care-services/immuniza tion-services. Accessed October 2, 2017.

      Ontario
      Includes MenACWY-D [52,54].

      Government of Ontario. Publicly funded immunization schedules for Ontario - –December 2016. Available at: http://www.health.gov.on.ca/en/pro/ programs/immunization/docs/immunization_schedule.pdf. Accessed October 3, 2017.

      New Brunswick

      Government of New Brunswick. Routine immunization schedule. Available at: http://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/CDC/ Immunization/RoutineImmunizationSchedule.pdf. Accessed October 3, 2017.

      Prince Edward Island
      Includes MenACWY-D [52,54].

      Government of Prince Edward Island. Adult and child immunization in PEI. Available at: www.princeedwardisland.ca/en/information/health-and- wellness/adult-and-child-immunization-pei. Accessed October 2, 2017.

      Nova Scotia

      Government of Nova Scotia. School immunization schedule. Available at: https://novascotia.ca/dhw/cdpc/immunization.asp. Accessed October 3, 2017.

      Newfoundland and Labrador

      Government of Newfoundland and Labrador. Meningococcal disease. Available at: http://www.health.gov.nl.ca/health/publichealth/cdc/pdf/Meningococcal_Vaccine_Fact_Sheet.pdf. Accessed October 3, 2017.

      Italy

      Ministero della Salute Italia. The vaccination schedule of the National Vaccine Prevention Plan 2017–2019. Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf. Accessed July 8, 2017.

      • MenACWY conjugate vaccine for individuals aged 12–18 years
      The Netherlands

      The Netherlands Ministry of Health, Welfare and Sport. Meningococcal ACWY vaccination guideline. Available at: https://lci.rivm.nl/richtlijnen/meningo kokken-acwy-vaccinatie. Accessed March 22, 2018.

      • Beginning in 2018, MenACWY conjugate vaccine
      Includes MenACWY-D and MenACWY-TT [58,59].
      to be offered to adolescents aged 12–14 years
      United Kingdom
      Public Health England
      Guidance for the public health management of meningococcal disease in the UK (updated February 2018).
      • Beginning August 2015, MenACWY conjugate vaccined for individuals aged 13–14 years and new university entrants ≤25 years
      • From 2015 to 2017, catch-up MenACWY conjugate vaccine for individuals aged 14–18 years in 2015
      Data are current as of October 2017.
      a Grade 4, 6, 7, and 9 corresponds to children approximately 9–10, 11–12, 12–13, and 14–15 years of age, respectively.
      b Includes MenACWY-CRM, MenACWY-D, and MenACWY-TT

      Government of Saskatchewan. Immunization services. Available at: www. saskatchewan.ca/residents/health/accessing-health-care-services/immuniza tion-services. Accessed October 2, 2017.

      ,

      BC Centre for Disease Control. Part 4 - Biological Products. Available at: http://www.bccdc.ca/health-professionals/clinical-resources/communicable- disease-control-manual/immunization/biological-products. Accessed October 3, 2017.

      ,

      Alberta Health. Meningococcal conjugate (groups A, C, Y and W-135) vaccine (MenC-ACYW). Available at: https://open.alberta.ca/dataset/aip/resource/7ea6d5c9-f644-4db1-b600-635d3e0033fb/download/AIP-BP-MenC-ACYW.pdf. Accessed October 3, 2017.

      .
      c Includes MenACWY-D

      Government of Ontario. Publicly funded immunization schedules for Ontario - –December 2016. Available at: http://www.health.gov.on.ca/en/pro/ programs/immunization/docs/immunization_schedule.pdf. Accessed October 3, 2017.

      ,

      Government of Prince Edward Island. Adult and child immunization in PEI. Available at: www.princeedwardisland.ca/en/information/health-and- wellness/adult-and-child-immunization-pei. Accessed October 2, 2017.

      .
      d Includes MenACWY-D and MenACWY-TT
      Public Health England
      Guidance for the public health management of meningococcal disease in the UK (updated February 2018).
      ,

      The Netherlands Ministry of Health, Welfare and Sport. Meningococcal ACWY vaccination guideline. Available at: https://lci.rivm.nl/richtlijnen/meningo kokken-acwy-vaccinatie. Accessed March 22, 2018.

      .
      In Canada, the national vaccination guide recommends either a conjugated meningococcal C or MenACWY vaccine be administered to healthy adolescents and young adults aged 12–24 years []. However, eight Canadian provinces have also elected to provide conjugate MenACWY vaccines without charge to children and adolescents in grades 4 (9–10 years of age; Newfoundland and Labrador), 6 (11–12 years of age; Saskatchewan), 7 (12–13 years of age; Ontario, Nova Scotia), and 9 (14–15 years of age; British Columbia, Alberta, New Brunswick, Prince Edward Island) in response to the increase in cases covered by the quadrivalent vaccine [

      BC Centre for Disease Control. HealthLinkBC. Meningococcal quadrivalent vaccines. Number 23b. Available at: https://www.healthlinkbc.ca/healthlinkbc-files/meningococcal-quadrivalent-vaccines. Accessed October 3, 2017.

      ,

      Alberta Health. Routine immunization schedule. Available at: www.health.alberta.ca/health-info/imm-routine-schedule.html. Accessed October 3, 2017.

      ,

      Government of Saskatchewan. Immunization services. Available at: www. saskatchewan.ca/residents/health/accessing-health-care-services/immuniza tion-services. Accessed October 2, 2017.

      ,

      Government of Ontario. Publicly funded immunization schedules for Ontario - –December 2016. Available at: http://www.health.gov.on.ca/en/pro/ programs/immunization/docs/immunization_schedule.pdf. Accessed October 3, 2017.

      ,

      Government of New Brunswick. Routine immunization schedule. Available at: http://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/CDC/ Immunization/RoutineImmunizationSchedule.pdf. Accessed October 3, 2017.

      ,

      Government of Prince Edward Island. Adult and child immunization in PEI. Available at: www.princeedwardisland.ca/en/information/health-and- wellness/adult-and-child-immunization-pei. Accessed October 2, 2017.

      ,

      Government of Nova Scotia. School immunization schedule. Available at: https://novascotia.ca/dhw/cdpc/immunization.asp. Accessed October 3, 2017.

      ,

      Government of Newfoundland and Labrador. Meningococcal disease. Available at: http://www.health.gov.nl.ca/health/publichealth/cdc/pdf/Meningococcal_Vaccine_Fact_Sheet.pdf. Accessed October 3, 2017.

      ].
      The increase in meningococcal serogroup W cases in some European countries has also resulted in modified vaccine recommendations among adolescents. For instance, in 2015 the United Kingdom included conjugate MenACWY vaccines (i.e., MenACWY-TT and MenACWY-D) in the national immunization program for adolescents aged 13–14 and for new university entrants up to 25 years of age in response to a national serogroup W outbreak [
      Public Health England
      Guidance for the public health management of meningococcal disease in the UK (updated February 2018).
      ]. Catch-up vaccination for adolescents aged 14–18 years at the beginning of the program was also offered from 2015 to 2017. Similarly, the Ministry of Health, Welfare, and Sport in the Netherlands began offering MenACWY conjugate vaccines in 2018 to adolescents aged 12–14 years in response to the increase in serogroup W cases [

      The Netherlands Ministry of Health, Welfare and Sport. Meningococcal ACWY vaccination guideline. Available at: https://lci.rivm.nl/richtlijnen/meningo kokken-acwy-vaccinatie. Accessed March 22, 2018.

      ]. In Italy, conjugate MenACWY vaccination is provided for adolescents aged 12–18 years [

      Ministero della Salute Italia. The vaccination schedule of the National Vaccine Prevention Plan 2017–2019. Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf. Accessed July 8, 2017.

      ].
      The success of such programs requires adapting to the variable nature of meningococcal disease so that vaccines targeting currently prevalent disease-causing serogroups are recommended. As multiple MenACWY vaccine options are often available, the choice of which quadrivalent meningococcal vaccine to use requires consideration of the properties, licensure, dosing and administration, immunogenicity, antibody persistence, and safety and tolerability profile of the particular vaccine in a specific population. These characteristics of MenACWY-TT are described in more detail in the following sections.

      MenACWY-TT Development

      MenACWY-TT is an intramuscular, quadrivalent meningococcal vaccine conjugated to a tetanus toxoid carrier protein [
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ]. One .5-mL reconstituted dose of MenACWY-TT contains 5 μg each of serogroup A, C, W, and Y polysaccharides conjugated to 44 μg of tetanus toxoid carrier protein [
      • Hedari CP
      • Khinkarly RW
      • Dbaibo GS
      Meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine: A new conjugate vaccine against invasive meningococcal disease.
      ]. Serogroups A and C polysaccharides are conjugated with a spacer molecule and indirectly conjugated to the tetanus toxoid carrier protein; serogroups W and Y polysaccharides are conjugated directly to the carrier protein.
      MenACWY-TT is licensed in the European Union and has been launched in 43 additional countries (as of October 2017) including those in Africa (18 countries), Asia (seven countries), Eastern Europe (three countries), the Middle East (eight countries), North America (two countries), Oceania (two countries), and South America (three countries). MenACWY-TT is not currently licensed in the United States. In Europe and other countries, MenACWY-TT is indicated as a three-dose series for infants beginning between the ages of 6 and 12 weeks, with the second dose administered 2 months later and the third dose given at 12 months of age [
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ]. MenACWY-TT is administered as a single dose for previously unvaccinated children older than 12 months, adolescents, and adults. A booster dose can be given to individuals who have previously received conjugated or polysaccharide meningococcal vaccines and continue to be at risk of meningococcal disease. Of note, booster dosing of adolescents with meningococcal conjugate vaccines, including MenACWY-TT, is currently included in the United Kingdom national immunization program [
      Public Health England (PHE)
      Meningococcal ACWY immunisation programme for adolescents (information for healthcare professionals).
      ]. In some countries, including Canada and Australia, MenACWY-TT is indicated for individuals aged 12 months to 55 years [
      • Bethea J
      • Makki S
      • Gray S
      • et al.
      Clinical characteristics and public health management of invasive meningococcal group W disease in the East Midlands region of England, United Kingdom, 2011 to 2013.
      ,
      NIMENRIX
      (Meningococcal polysaccharide serogroups A, C, W-135 and Y conjugate vaccine). Full prescribing information.
      ]. MenACWY-TT is the first conjugated meningococcal vaccine that has been investigated in individuals aged >56 years [
      • Dhillon S
      • Pace D
      Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix®): A review.
      ].
      MenACWY-TT safety and immunogenicity were established or continue to be investigated in several phase 2 and 3 clinical studies in infants, toddlers, children, adolescents, and adults. Similar to development programs for other meningococcal vaccines, the low incidence of meningococcal disease has precluded conduct of large vaccine efficacy studies for MenACWY-TT [
      • Jafri RZ
      • Ali A
      • Messonnier NE
      • et al.
      Global epidemiology of invasive meningococcal disease.
      ,

      Vaccines and Related Biologic Products Advisory Committee. Approaches to licensure of meningococcal vaccines for prevention of serogroup B invasive meningococcal disease. Briefing document for the Vaccines and Related Biologic Products Advisory Committee Meeting. April 7, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiological ProductsAdvisoryCommittee/UCM248586.pdf. Accessed April 10, 2017.

      ]. Serum bactericidal assays (SBAs), which measure vaccine-elicited serum bactericidal antibody responses, are used as a surrogate of efficacy using either human (hSBA) or rabbit complement (rSBA) [
      • Borrow R
      • Balmer P
      • Miller E
      Meningococcal surrogates of protection–serum bactericidal antibody activity.
      ]. An hSBA titer ≥1:4 is the accepted correlate of protection [

      Vaccines and Related Biologic Products Advisory Committee. Approaches to licensure of meningococcal vaccines for prevention of serogroup B invasive meningococcal disease. Briefing document for the Vaccines and Related Biologic Products Advisory Committee Meeting. April 7, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiological ProductsAdvisoryCommittee/UCM248586.pdf. Accessed April 10, 2017.

      ,
      • Borrow R
      • Balmer P
      • Miller E
      Meningococcal surrogates of protection–serum bactericidal antibody activity.
      ,
      • Goldschneider I
      • Gotschlich EC
      • Artenstein MS
      Human immunity to the meningococcus. I. The role of humoral antibodies.
      ,
      • Andrews N
      • Borrow R
      • Miller E
      Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England.
      ], whereas rSBA titers ≥1:8 to 1:64 are considered protective [
      • Vipond C
      • Care R
      • Feavers IM
      History of meningococcal vaccines and their serological correlates of protection.
      ,
      • Andrews N
      • Borrow R
      • Miller E
      Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England.
      ,
      • Frasch CE
      • Borrow R
      • Donnelly J
      Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease.
      ,
      • Borrow R
      • Andrews N
      • Goldblatt D
      • et al.
      Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: Reevaluation of correlates of protection.
      ].
      The MenACWY-TT safety profile includes pooled data from >10,000 subjects, including infants (6–12 weeks at first dose), toddlers (12–23 months), children (2–10 years), adolescents (11– 17 years), and adults (18–55 and >55 years) [
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ]. The most common local reactions reported after MenACWY-TT vaccination across age groups (>12 months) are pain, redness, and swelling (Table S1 [
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ]). In toddlers and young children (12 months–5 years), irritability, drowsiness, appetite loss, and fever are most commonly reported. In older age groups, headache, fatigue, gastrointestinal symptoms, and fever are most common.
      The MenACWY-TT clinical study program has demonstrated the immunogenicity, safety, and persistence of immune responses of a primary dose of the vaccine across various age groups and of MenACWY-TT given as a booster dose in individuals previously vaccinated with a conjugate or polysaccharide meningococcal vaccine [
      • Dhillon S
      • Pace D
      Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix®): A review.
      ,
      • Assaf-Casals A
      • Dbaibo G
      Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT, Nimenrix): A review of its immunogenicity, safety, co-administration, and antibody persistence.
      ]. MenACWY-TT is also the only meningococcal conjugate vaccine licensed in infants from 6 weeks of age and the first to be investigated in older individuals aged 56 years and older. Thus, MenACWY-TT is a vaccine that can be used across all age groups and is an important option for the prevention of IMD in individuals who are at high risk of infection or carriage. Because adolescents and young adults are often at highest risk for meningococcal carriage, have one of the highest IMD rates of any age group [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,

      European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe. Available at: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/Surveillance%20of%20IBD%20in %20Europe%202012.pdf. Accessed July 20, 2017.

      ,
      • Christensen H
      • May M
      • Bowen L
      • et al.
      Meningococcal carriage by age: A systematic review and meta-analysis.
      ,
      • Crum-Cianflone N
      • Sullivan E
      Meningococcal vaccinations.
      ], and are emerging as a target population in meningococcal vaccination programs globally, a summary of MenACWY-TT clinical studies in this age group is described in detail in the following section.

      MenACWY-TT Clinical Data in Adolescents

      The MenACWY-TT clinical trial program includes several phase 2, 3, and 4 studies in adolescents and young adults (Table 3) [
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ,
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      ,
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      ,
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      ,
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      ,
      • Ostergaard L
      • Van der Wielen M
      • Bianco V
      • et al.
      Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
      ,
      • Ostergaard L
      • Silfverdal SA
      • Berglund J
      • et al.
      A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
      ,
      • Quiambao BP
      • Bavdekar A
      • Dubey AP
      • et al.
      Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
      ,
      • Halperin SA
      • Baine Y
      • Domachowske JB
      • et al.
      Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Kolhe D
      • et al.
      Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
      ,
      • Lupisan S
      • Limkittikul K
      • Sosa N
      • et al.
      Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
      ,

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      ]. Antibody persistence after primary MenACWY-TT vaccination and coadministration of MenACWY-TT with vaccines commonly administered in this population have also been assessed or are ongoing.
      Table 3Overview of MenACWY-TT Clinical Trial Program in Adolescents and Young Adults Including Study Phase, Design, Population, Country of Investigation, and Status
      StudyClinicalTrials.gov identifierDesignParticipantsLocationDuration/Status
      003 (phase 2)
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      NCT00196950Comparison of MenACWY-TT to MenACWY-PS50 participants aged 18–25 yearsBelgiumSeptember 2003–September 2006/Completed
      009 (phase 2)

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      NCT00196963Comparison of four formulations of MenACWY-TT to MenACWY-PS125 participants aged 15–19 yearsBelgiumMarch–July 2005/Completed
      012 (phase 2)
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      NCT00126945Comparison of five formulations of MenACWY-TT to MenACWY-PS125 participants aged 15–19 yearsDenmarkAugust 2005–October 2005/Completed
      015 (phase 2b)
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      NCT00356369Comparison of MenACWY-TT to MenACWY-PS500 participants aged 11–55 yearsSaudi Arabia, PhilippinesDecember 2006–August 2010/Completed
      020 (phase 2b)
      • Borja-Tabora CF
      • Montalban C
      • Memish ZA
      • et al.
      Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.
      NCT00356369Extension of study 015 to evaluate long-term antibody persistence of response of MenACWY-TT 5 years after primary vaccination404
      The number of participants at the longest follow-up period is shown.
      participants aged 11–55 years
      Saudi Arabia, PhilippinesDecember 2006–February 2013/Completed
      021 (phase 2)

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      NCT00661557Comparison of MenACWY-TT in those who received prior MenACWY-PS versus those who are meningococcal vaccine naive272 participants aged 4.5–34 yearsLebanonMay–June 2009/Completed
      024, 025, 026 (phase 2)
      • Ostergaard L
      • Van der Wielen M
      • Bianco V
      • et al.
      Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
      NCT00390143Extension of study 012 to evaluate persistence of response of MenACWY-TT46a participants aged 15–19 yearsDenmarkFebruary 2007–May 2009/Completed
      036 (phase 3)
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      NCT00464815Comparison of MenACWY-TT and MenACWY-PS1,025 participants aged 11–17 yearsIndia, Philippines, TaiwanMay 2007–September 2008/Completed
      037 (phase 3)
      • Ostergaard L
      • Silfverdal SA
      • Berglund J
      • et al.
      A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
      NCT00465816Comparison of MenACWY-TT given with and without HepA/B vaccine611 participants aged 11–17 yearsDenmark, SwedenApril 2007–April 2008/Completed
      043 (phase 3)
      • Quiambao BP
      • Bavdekar A
      • Dubey AP
      • et al.
      Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
      NCT00974363Extension of study 036 to evaluate long-term antibody persistence of MenACWY-TT478a participants aged 11–17 yearsIndia, PhilippinesAugust 2010–April 2013/Completed
      052 (phase 2)
      • Halperin SA
      • Baine Y
      • Domachowske JB
      • et al.
      Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
      NCT01165242Comparison of MenACWY-TT to MenACWY-D1,011 participants aged 10–25 yearsUnited States, CanadaAugust 2010–March 2011/Completed
      Baxter et al. (phase 2)
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      NCT00454909Comparison of MenACWY-TT to MenACWY-D872 participants aged 10–25 yearsUnited StatesApril 2007–April 2008/Completed
      054 (phase 3)

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      NCT01755689Assessment of MenACWY-TT given with and without HPV and DTP vaccine1,300 female participants aged 9–25 yearsDominican Republic, Estonia, ThailandJanuary 2013–April 2014/Completed
      059 (phase 2)
      • Baxter R
      • Baine Y
      • Kolhe D
      • et al.
      Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
      NCT00715910Extension of study 052 to evaluate long-term antibody persistence of MenACWY-TT 1, 3, and 5 years after vaccination312a participants aged 10–31 yearsUnited StatesAugust 2008–September 2013/Completed
      084 (phase 3)

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      NCT01641042Assessment of MenACWY-TT in at-risk participants86 participants aged 1–17 yearsCzech Republic, United StatesSeptember 2012–March 2015/Completed
      093 (phase 3)
      • Lupisan S
      • Limkittikul K
      • Sosa N
      • et al.
      Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
      NCT01154088Comparison of MenACWY-TT and MenACWY-PS1,170 participants aged 18–25 yearsPanama, Philippines, ThailandAugust–December 2010/Completed
      098 (phase 3)

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      NCT01767376Assessment of MenACWY-TT coadministered with DTP692 participants aged 11–25 yearsRepublic of Korea, Germany, Dominican RepublicJanuary 2013–January 2014/Completed
      099 (phase 3)

      U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

      NCT01934140Comparison of the long-term antibody persistence of MenACWY-TT to MenACWY-PS from 6 to 10 years after primary vaccination336 participants aged 17–66 yearsPhilippinesApril 2014–September 2018/Ongoing
      Ishola et al. (phase 2/3)
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      NCT01192997Comparison of MenACWY-TT and MenACWY-CRM booster in adolescents previously vaccinated with MenC at 3.5 to 5.9 years93 participants aged 16–19 yearsUnited KingdomJune 2012–March 2014/Completed
      van Ravenhorst et al. (phase 4)
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      EudraCT number: 2013-001823-38Comparison of MenA, MenW, and MenY antibody levels of MenACWY-TT and MenC-TT booster doses in adolescents previously vaccinated with MenC-TT at 14 months to 3 years246 participants aged 10 (n = 83), 12 (n = 82), and 15 (n = 81) yearsThe Netherlands
      DTP = diphtheria, pertussis, and tetanus; HepA/B = hepatitis A/B; HPV = human papilloma virus.
      a The number of participants at the longest follow-up period is shown.

      Immunogenicity

      MenACWY-TT use in adolescents and young adults was first evaluated in two phase 2 studies comparing different formulations of MenACWY-TT (varying by polysaccharide concentration and conjugation method) to MenACWY-PS (Mencevax; Pfizer Australia Pty Ltd, Ryde, New South Wales, Australia) in 125 participants aged 15–19 years and 50 participants aged 18–25 years (Table 4) [
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ,
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      ,
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      ,
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      ,
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      ,
      • Ostergaard L
      • Van der Wielen M
      • Bianco V
      • et al.
      Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
      ,
      • Ostergaard L
      • Silfverdal SA
      • Berglund J
      • et al.
      A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
      ,
      • Quiambao BP
      • Bavdekar A
      • Dubey AP
      • et al.
      Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
      ,
      • Halperin SA
      • Baine Y
      • Domachowske JB
      • et al.
      Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Kolhe D
      • et al.
      Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
      ,
      • Lupisan S
      • Limkittikul K
      • Sosa N
      • et al.
      Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
      ,
      • Borja-Tabora CF
      • Montalban C
      • Memish ZA
      • et al.
      Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.
      ]. In this study by Ostergaard and colleagues, all participants receiving MenACWY-TT demonstrated rSBA titers ≥1:8 across all serogroups 1 month after vaccination.
      Table 4Overview of Published MenACWY-TT Clinical Studies in Adolescents and Young Adults
      StudyDesignImmunogenicitySafety
      Phase 2 studies
      Ostergaard et al. (study 012 and 003; 024, 025, and 026 [extension])
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      ,
      • Ostergaard L
      • Van der Wielen M
      • Bianco V
      • et al.
      Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
      MenACWY-TT versus MenACWY-PS (study 012: aged 15–19 years [n = 125]; study 003: aged 18–25 years [n = 50])Vaccine response
      For initially seronegative subjects, postvaccination antibody titer ≥1:32; for initially seropositive subjects, antibody titer ≥4-fold the prevaccination antibody titer.
      (aged 15–19 years)
      Most common local event: pain
      1 month: 72.0%–100% versus 78.3%–96.0%Most common systemic event: fatigue, headache
      42 months
      Included 50 participants who were vaccinated in study 012; values are rSBA titers ≥1:8.
      : 100% versus 88.2%
      SAEs
      As reported 8days after vaccination.
      : 1 (urticaria) versus 0; considered related and completely resolved
      rSBA ≥1:8 (aged 18–25 years)
      1 month: 100% versus 100%
      36 months: 100% versus 91.7%–100%
      Baxter et al.
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Kolhe D
      • et al.
      Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
      MenACWY-TT (aged 11–25 years, n = 587) versus MenACWY-D (aged 11–25 years, n = 197) versus MenACWY-TT (aged 10 years, n = 88) Booster dose administered at 5 yearshSBA ≥1:4Primary dose
      1 month: ≥83.0% versus ≥70.7% versus ≥89.9%Most common local event: pain (54.9% versus 54.1% versus 55.8%)
      1 year: 30.3%–98.5% versus 31.5%–86.6% versus 29.8%–100%Most common systemic event: headache (33.0% versus 37.1% versus 34.9%)
      3 years: 39.2%–95.9% versus 47.4%–88.6% versus 45.1%–98.1%SAEs: .9% versus 1.0% versus 2.3%; no SAEs related to vaccination reported ≤5 years after vaccination
      5 years
      At 5 years, a booster dose was administered to 218, 56, and 38 participants in the MenACWY-TT (aged 11–25 years), MenACWY-D (aged 11–25 years), and MenACWY (aged 10 years) groups, respectively.
      : 52.5%–95.7% versus 44.4%–90.9% versus 37.5%–92.3%
      Booster dose
      Most common local event: pain (58.8% vs. 54.1% vs. 60.4%)
      Most common systemic event: headache (35.9% vs. 27.0% vs. 24.2%)
      Halperin et al. (study 052)
      • Halperin SA
      • Baine Y
      • Domachowske JB
      • et al.
      Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
      MenACWY-TT (n = 673) versus MenACWY-D (n = 338) (aged 10–25 years)hSBA ≥1:8Most common local event: pain (51.1% vs. 55.4%)
      1 month: 51.0%–82.5% versus 39.0%–76.3%Most common systemic event: fatigue (28.9% vs. 27.3%)
      SAEs: 8 (asthma [n = 2 events], tooth infection, appendicitis, influenza, pneumonia [n = 2 events], hypoxia) versus 2 (jaw fracture, postprocedural hematoma); none considered related
      Borja-Tabora et al. (study 015 and 020 [extension])
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      ,
      • Borja-Tabora CF
      • Montalban C
      • Memish ZA
      • et al.
      Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.
      MenACWY-TT (n = 225) versus MenACWY-PS (n = 76) (aged 11–17 years)rSBA ≥1:8Most common local event: pain (38.6% vs. 32.3%)
      1 month: 99.7%–100% versus 100%Most common general event: headache (17.5% vs. 12.0%)
      1 year: 99.7%–100% versus 99.1%–100%SAEs: 2 (costochondritis, mental disorder) versus 0; none considered related; 0 vaccine-related events reported ≤5 years after vaccination
      2 years: 99.4%–99.7% versus 90.1%–99.1%
      3 years: 99.1%–100% versus 86.7%–100%
      4 years: 76.5%–88.7% versus 20.0%–82.7%
      5 years: 74.0%–92.8% versus 23.7%–80.3%
      Phase 3 and 4 studies
      Bermal et al. and Quiambo et al. (study 036 and 043 [extension])
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ,
      • Quiambao BP
      • Bavdekar A
      • Dubey AP
      • et al.
      Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
      MenACWY-TT (n = 768) versus MenACWY-PS (n = 257) (aged 11–17 years)rSBA ≥1:8Any general symptoms 4 days postvaccination (10–18 years): 25.4% (195/768) versus 24.5% (63/257)
      1 month: 99.7%–100% versus 99.6%–100%Grade 3 general symptoms 4 days postvaccination (10–18 years): 1.6% (12/768) versus .4% (1/257)
      3 years (n = 643): 82.0%–93.1% versus 30.0%–86.0%
      4 years (n = 541): 77.2%–94.1% versus 26.9%–86.9%
      5 years (n = 478): 86.0%–97.5% versus 34.9%–93.0%
      Lupisan et al.
      • Lupisan S
      • Limkittikul K
      • Sosa N
      • et al.
      Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
      MenACWY-TT (n = 780) versus MenACWY-PS (n = 390) (18–25 years)Vaccine response
      For initially seronegative subjects (rSBA titer <1:8), postvaccination titer ≥1:32; for initially seropositive subjects (rSBA titer ≥1:8), postvaccination titer ≥4times the prevaccination antibody titer.
      Most common local event: pain (53.9%–54.7% vs. 36.8%)
      1 month: 79.1%–97.0% versus 73.7%–94.1%Most common general event: fatigue (28.6%–30.3%), headache (26.9%–31.0%)
      SAEs: 1 (blighted ovum; potentially related) versus 1 (appendicitis; not related); all resolved
      Ostergaard et al. (study 037)
      • Ostergaard L
      • Silfverdal SA
      • Berglund J
      • et al.
      A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
      MenACWY + HepA/B (n = 367) versus MenACWY alone (n = 122) versus HepA/B alone (n = 122) (aged 11–17 years)rSBA ≥1:8Most common local event: pain (49.6% vs. 48.7% vs. NA
      Occurring after MenACWY-TT administration.
      ; 39.2% vs. NA vs. 43.0%
      Occurring after the first HepA/B administration.
      )
      1 month: 99.7%–100% versus 99.1%–100% versus NAMost common general event: fatigue and headache
      7 months: 99.4%–100% versus 98.2%–100% versus NASAEs: 1.1% versus 0 versus .8%
      Seroconversion rates for hepatitis A
      1 month after third HepA/B dose: 100%
      Percentage of subjects with concentration above the specified cutoff (HepA: 15.0 mIU/mL; HepB: 10.0 mIU/mL).
      versus NA versus 100%
      Seroconversion rates for hepatitis B
      1 month after third HepA/B dose: 99.1%
      Percentage of subjects with concentration above the specified cutoff (HepA: 15.0 mIU/mL; HepB: 10.0 mIU/mL).
      versus NA versus 100%
      Ishola et al.
      Phase 2/3 study.
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      MenACWY-TT booster versus MenACWY-CRM booster (aged 16–19 years; previously vaccinated with MenC at 3.5–5.9 years)rSBA ≥1:8Local or general events: similar between groups; severe redness and muscle pain more common with MenACWY-CRM and severe tiredness more common with MenACWY-TT
      Prebooster: 11%–49% versus 7%–30%SAEs: 1 (appendicitis) versus 3 (ulcerative colitis, hospitalization for transient disorientation likely from spiked social drinks, hospitalization for tonsillitis)
      1 month: 98%–100% versus 100%
      6 months: 91%–100% versus 95%–100%
      9 months: 100% versus 96%–100%
      van Ravenhorst et al.
      Phase 4 study.
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      MenACWY-TT booster versus MenC-TT booster (aged 10, 12, and 15 years; previously vaccinated with MenC-TT at 14 months–3 years)rSBA ≥1:8
      Does not include meningococcal serogroup C.
      NR
      Baseline: 15.1%–32.0% versus NR
      1 month: 94.5%–100% versus NR
      1 year: 94.5%–100% versus NR
      HepA/B = hepatitis A/B; hSBA = serum bactericidal assay using human complement; NA = not applicable; NR = not reported; rSBA = serum bactericidal assay using rabbit complement; SAE = serious adverse event.
      a For initially seronegative subjects, postvaccination antibody titer ≥1:32; for initially seropositive subjects, antibody titer ≥4-fold the prevaccination antibody titer.
      b Included 50 participants who were vaccinated in study 012; values are rSBA titers ≥1:8.
      c As reported 8 days after vaccination.
      d At 5 years, a booster dose was administered to 218, 56, and 38 participants in the MenACWY-TT (aged 11–25 years), MenACWY-D (aged 11–25 years), and MenACWY (aged 10 years) groups, respectively.
      e For initially seronegative subjects (rSBA titer <1:8), postvaccination titer ≥1:32; for initially seropositive subjects (rSBA titer ≥1:8), postvaccination titer ≥4 times the prevaccination antibody titer.
      f Percentage of subjects with concentration above the specified cutoff (HepA: 15.0 mIU/mL; HepB: 10.0 mIU/mL).
      g Occurring after MenACWY-TT administration.
      h Occurring after the first HepA/B administration.
      i Phase 2/3 study.
      j Phase 4 study.
      k Does not include meningococcal serogroup C.
      Another phase 2 study, which included 872 participants aged 10–25 years, compared MenACWY-TT with MenACWY-D [
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      ]. In this study by Baxter and colleagues, MenACWY-TT was immunogenic in those aged 11–25 years (n = 784), and immunogenicity in those aged 10 years was comparable with that in older adolescents (Table 4). For both vaccines, a high proportion of participants had hSBA titers ≥1:4 for all serogroups 1 month postvaccination. An exploratory assessment found that the proportion of participants with hSBA titers ≥1:8 for serogroups A, W, and Y was higher after MenACWY-TT vaccination compared with MenACWY-D.
      MenACWY-TT has also been evaluated in adolescent and young adult populations from Asia. In a phase 3 study by Bermal and colleagues in 1,025 participants aged 11–17 years conducted in India, the Philippines, and Taiwan, the noninferiority of MenACWY-TT immunogenicity to MenACWY-PS was assessed [
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ]. MenACWY-TT induced a vaccine response against each serogroup in ≥85% of participants (Table 4). Significantly higher rSBA vaccine response rates were observed in MenACWY-TT recipients for serogroups A, W, and Y as compared with MenACWY-PS recipients. Consistent findings were also reported in a phase 3 study by Lupisan and colleagues conducted in Panama, the Philippines, and Thailand in 1,170 participants aged 18–25 years, which compared two lots of MenACWY-TT with MenACWY-PS [
      • Lupisan S
      • Limkittikul K
      • Sosa N
      • et al.
      Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
      ].
      A phase 2 study in 500 adolescents and adults aged 11–55 years conducted in the Philippines and Saudi Arabia compared MenACWY-TT with MenACWY-PS [
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      ]. In this study by Borja-Tabora and colleagues, noninferiority of the immune response induced by MenACWY-TT compared with MenACWY-PS was met for all serogroups (Table 4). Significantly higher rSBA vaccine response rates for serogroups A and Y after administration of MenACWY-TT compared with administration of MenACWY-PS were observed in exploratory analyses.

      Safety following primary vaccination

      A pooled analysis of the safety and reactogenicity profile of MenACWY-TT in adolescents following primary vaccination is not available, and assessment is reliant on data from the clinical studies conducted in this population.
      In the two phase 2 studies comparing different MenACWY-TT formulations with MenACWY-PS, MenACWY-TT was well tolerated, with reactogenicity profiles consistent with MenACWY-PS (Table 4) [
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      ]. Pain was the most common local event and fatigue and headache the most common systemic events with both vaccines. A serious adverse event (SAE) of urticaria was reported in a recipient who received MenACWY-TT. The event occurred eight days after vaccination, was considered causally related to vaccination, and completely resolved. Similar findings were reported in a phase 2 study in adolescents and adults aged 11–55 years comparing MenACWY-TT with MenACWY-PS, with both vaccines found to be well tolerated and showing generally comparable safety and reactogenicity profiles [
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      ].
      In the phase 2 study comparing MenACWY-TT with MenACWY-D, MenACWY-TT was found to have an acceptable and generally comparable reactogenicity and safety profile to MenACWY-D, with pain and headache the most frequently reported reactogenicity events with both vaccines [
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      ]. Most reactogenicity events were mild to moderate in intensity, of short duration, and resolved spontaneously. Consistent findings were observed in another phase 2 study comparing two lots of MenACWY-TT with MenACWY-D in adolescents and young adults [
      • Halperin SA
      • Baine Y
      • Domachowske JB
      • et al.
      Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
      ].

      Booster and memory responses and persistence

      A 3.5-year follow-up of 46 adolescents from a study by Ostergaard and colleagues, which compared MenACWY-TT with MenACWY-PS in participants aged 15–19 years, found that all adolescents vaccinated with MenACWY-TT had rSBA titers ≥1:8 against all serogroups up to 42 months postvaccination (Table 4) [
      • Ostergaard L
      • Van der Wielen M
      • Bianco V
      • et al.
      Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
      ]. In those vaccinated with MenACWY-PS, all participants had rSBA titers ≥1:8 for serogroups A, W, and Y, and only 88% had titers ≥1:8 for serogroup C. No vaccine-related SAEs or IMD cases were reported ≤42 months postvaccination. For young adults (aged 18–25 years) from the companion phase 2 study, all participants who received MenACWY-TT and 91.7%–100% of participants who received MenACWY-PS achieved rSBA titers ≥1:8 across serogroups A, C, W, and Y at 36 months [
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      ].
      Five-year antibody persistence has been reported from the phase 2 study by Baxter and colleagues that included 872 participants aged 10–25 years and compared MenACWY-TT with MenACWY-D [
      • Baxter R
      • Baine Y
      • Kolhe D
      • et al.
      Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
      ]. The extension study also evaluated safety and immunogenicity of a MenACWY-TT booster dose given 5 years after primary vaccination. Overall, 312 participants were assessed for persistence of antibody response, and a booster dose of MenACWY-TT was administered to 322 participants at 5 years. Most participants vaccinated with MenACWY-TT or MenACWY-D retained hSBA antibody titers ≥1:8 up to year 5 for serogroups C, W, and Y (Table 4). Rapid waning in the proportion of participants retaining hSBA titers ≥1:8 for serogroup A was observed with both vaccines. Exploratory analyses of a MenACWY-TT booster dose to participants who had received primary vaccination with MenACWY-TT or MenACWY-D suggested that vaccine responses for all four serogroups were higher than in those who had not received the primary vaccine. Vaccine responses to serogroups A and W induced by the booster dose were also potentially higher in participants who received primary MenACWY-TT vaccination compared with those who received primary MenACWY-D vaccination, although statistical significance was not examined. Reactogenicity events were similar after administration of booster and primary MenACWY-TT doses. These findings support induction of immunologic memory with MenACWY-TT and boosting of primary vaccination responses by MenACWY-TT or Men-ACWY-D and suggest that MenACWY-TT can be used interchangeably with MenACWY-D as a booster dose when primary vaccination with MenACWY-D was used.
      A phase 3 study by Bermal and colleagues of 1,025 participants aged 11–17 years conducted in India, the Philippines, and Taiwan that compared MenACWY-TT with MenACWY-PS [
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ] included an extension phase assessing antibody persistence of MenACWY-TT up to 5 years after primary vaccination [
      • Quiambao BP
      • Bavdekar A
      • Dubey AP
      • et al.
      Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
      ]. Of note, participants from Taiwan were excluded from the extension phase of the study owing to the small sample size recruited from the two corresponding centers in the primary study. Among participants 16–23 years of age 5 years after primary vaccination, antibody persistence was sustained up to 5 years postvaccination with at least 86% of recipients maintaining rSBA titers ≥1:8 for each serogroup (Table 4). Antibody titers against serogroup A were higher among those receiving MenACWY-TT compared with MenACWY-PS, and a small increase in antibody titers was observed in both groups between years 4 and 5 for serogroups A, W, and Y.
      Persistence of antibody responses 5 years after vaccination was assessed in a phase 2 study by Borja-Tabora and colleagues in 500 adolescents and adults aged 11–55 years conducted in the Philippines and Saudi Arabia that compared immunogenicity and safety of MenACWY-TT with MenACWY-PS [
      • Borja-Tabora CF
      • Montalban C
      • Memish ZA
      • et al.
      Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.
      ]. Overall, 404 participants were included in the year 5 assessment; of these, 284 were aged 11–17 years. Five years after primary vaccination, the percentage of adolescents with rSBA titers ≥1:8 was 74%–93% in the MenACWY-TT group and 24%–80% in the MenACWY-PS group (Table 4). Immunogenicity findings for adolescents were consistent with data for the total population. No vaccine-related SAEs were reported ≤5 years after vaccination.
      Two studies reported the effect of a booster dose of quadrivalent meningococcal vaccines in adolescents who had been primed with a meningococcal C vaccine at preschool age [
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      ,
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      ]. In the first study, conducted in the United Kingdom, 93 participants aged 16–19 years previously randomized to receive a meningococcal C vaccine at the ages of 3–6 years were randomized to receive a booster dose of MenACWY-TT or MenACWY-CRM (Table 4 [
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      ]). Both MenACWY-TT and MenACWY-CRM yielded protective functional antibody titers against all serogroups in adolescents who were primed >10 years prior with a meningococcal C vaccine irrespective of the primary vaccine received. In the second study, a phase 4 study conducted in the Netherlands, children and adolescents aged 10, 12, and 15 years previously primed with a meningococcal C conjugate vaccine at 14 months–3 years of age were randomized to receive a booster dose of MenACWY-TT or a meningococcal C vaccine [
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      ]. MenACWY-TT elicited robust antibody responses against serogroups A, W, and Y and 95% maintained protective titers 1 year after vaccination; data for serogroup C were not reported. The findings from these studies suggest that a booster dose of MenACWY-TT is a viable option for adolescents who previously received a meningococcal C vaccine in childhood.

      Coadministration with other vaccines

      Coadministration of MenACWY-TT with other vaccines in adolescents has been reported. In a phase 3 study that included 611 adolescents aged 11–17 years, coadministration of MenACWY-TT with the hepatitis A/B (HepA/B) vaccine was assessed [
      • Ostergaard L
      • Silfverdal SA
      • Berglund J
      • et al.
      A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
      ]. Participants received either a single MenACWY-TT dose administered with HepA/B vaccine (0-, 1-, 6-month administration), MenACWY alone, or HepA/B vaccine alone. Noninferiority of the immunogenicity of coadministration to the single administration of each vaccine was assessed 1 and 7 months after vaccination. MenACWY-TT coadministered with HepA/B vaccine was noninferior to the administration of MenACWY-TT alone (Table 4). HepA/B vaccine coadministered with MenACWY-TT was also shown to be noninferior to the administration of HepA/B vaccine alone. The authors suggested that the ability to administer MenACWY-TT with the HepA/B vaccine could simplify immunization schedules of adolescent travelers to endemic regions and national immunization programs in countries in which these diseases are endemic. Studies assessing coadministration of MenACWY-TT with other vaccines given in adolescence are also being completed, including coadministration of MenACWY-TT with the tetanus, diphtheria, and pertussis vaccine and with the human papilloma virus vaccine (Table 3).

      Discussion and Summary

      Meningococcal disease is a serious global health concern and a priority for prevention owing to the rapid onset of symptoms and the high mortality rate, even after treatment [
      • Pace D
      • Pollard AJ
      Meningococcal disease: Clinical presentation and sequelae.
      ,
      • Tan LK
      • Carlone GM
      • Borrow R
      Advances in the development of vaccines against Neisseria meningitidis .
      ,
      • Jafri RZ
      • Ali A
      • Messonnier NE
      • et al.
      Global epidemiology of invasive meningococcal disease.
      ]. Vaccines are available to effectively prevent infection by most disease-causing meningococcal serogroups. However, the epidemiology and cyclic nature of IMD require continuous surveillance to identify populations most at risk of disease and carriage and the causative serogroups in a region at a particular time [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      • Jafri RZ
      • Ali A
      • Messonnier NE
      • et al.
      Global epidemiology of invasive meningococcal disease.
      ,
      • Stephens DS
      • Greenwood B
      • Brandtzaeg P
      Epidemic meningitis, meningococcaemia, and Neisseria meningitidis .
      ,
      • Chang Q
      • Tzeng YL
      • Stephens DS
      Meningococcal disease: Changes in epidemiology and prevention.
      ,

      Centers for Disease Control and Prevention. 2016 Yellow Book Travelers' Health. 2016.

      ]. Therefore, successful vaccination programs should adapt to the variable nature of meningococcal disease. Such programs focus on recommending effective and safe vaccines that target currently prevalent disease-causing serogroups and strive to achieve high coverage potential in the target population.
      Adolescents and young adults in many countries are at highest risk for meningococcal carriage and have one of the highest IMD rates of any age group [
      • Cohn AC
      • MacNeil JR
      • Clark TA
      • et al.
      Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,

      European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe. Available at: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/Surveillance%20of%20IBD%20in %20Europe%202012.pdf. Accessed July 20, 2017.

      ,
      • Christensen H
      • May M
      • Bowen L
      • et al.
      Meningococcal carriage by age: A systematic review and meta-analysis.
      ,
      • Crum-Cianflone N
      • Sullivan E
      Meningococcal vaccinations.
      ]. Thus, adolescents and young adults are emerging as a target of meningococcal vaccination programs globally. The goal of this initiative is to directly decrease disease rates for those vaccinated and indirectly reduce disease by decreasing carriage and creating herd protection in unvaccinated individuals [
      • Vetter V
      • Baxter R
      • Denizer G
      • et al.
      Routinely vaccinating adolescents against meningococcus: Targeting transmission & disease.
      ].
      MenACWY-TT is a single-dose quadrivalent meningococcal vaccine supported by long-term immunogenicity and safety data across age groups [
      Summary of Product Characteristics
      NIMENRIX full prescribing information.
      ,

      Menveo (Meningococcal Group A, C, W135 and Y conjugate vaccine) Summary of product characteristics full prescribing information, GlaxoSmithKline UK, Uxbridge, Middlesex, UK, 2015.

      ,
      • Assaf-Casals A
      • Dbaibo G
      Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT, Nimenrix): A review of its immunogenicity, safety, co-administration, and antibody persistence.
      ]. In adolescents and young adults, MenACWY-TT has been investigated in several completed and ongoing clinical studies. Based on available data in adolescents and young adults comparing MenACWY-TT with other available polysaccharide and conjugate quadrivalent meningococcal vaccines, MenACWY-TT has shown robust and sustained immunogenic responses [
      • Bermal N
      • Huang LM
      • Dubey A
      • et al.
      Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
      ,
      • Ostergaard L
      • Lebacq E
      • Poolman J
      • et al.
      Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
      ,
      • Borja-Tabora C
      • Montalban C
      • Memish ZA
      • et al.
      Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
      ,
      • Ostergaard L
      • Van der Wielen M
      • Bianco V
      • et al.
      Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
      ,
      • Ostergaard L
      • Silfverdal SA
      • Berglund J
      • et al.
      A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
      ,
      • Quiambao BP
      • Bavdekar A
      • Dubey AP
      • et al.
      Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
      ,
      • Halperin SA
      • Baine Y
      • Domachowske JB
      • et al.
      Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Ensor K
      • et al.
      Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
      ,
      • Baxter R
      • Baine Y
      • Kolhe D
      • et al.
      Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
      ,
      • Lupisan S
      • Limkittikul K
      • Sosa N
      • et al.
      Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
      ,
      • Borja-Tabora CF
      • Montalban C
      • Memish ZA
      • et al.
      Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.
      ]. An acceptable tolerability profile was also demonstrated when MenACWY-TT was administered alone or in combination with vaccines that might also be administered in this age group.
      To address the changing epidemiology of meningococcal disease in which serogroup W cases have recently emerged, data are also available supporting the use of a booster dose of MenACWY-TT in adolescents previously vaccinated with a meningococcal serogroup C vaccine in childhood [
      • van Ravenhorst MB
      • van der Klis FRM
      • van Rooijen DM
      • et al.
      Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
      ,
      • Ishola DA
      • Andrews N
      • Waight P
      • et al.
      Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
      ]. These and forthcoming data in this population at high risk of carriage and/or meningococcal disease, coupled with its increased use and inclusion in vaccination programs, suggest that MenACWY-TT will contribute significantly to meningococcal disease prevention.

      Acknowledgments

      Writing support was provided by Tricia Newell, Ph.D., of Complete Healthcare Communications, LLC (West Chester, PA) and was funded by Pfizer Inc.

      Funding Sources

      This work was supported by Pfizer Inc.

      Appendix. Supplementary materials

      References

      1. Centers for Disease Control and Prevention. Meningococcal disease: Technical and clinical information. Available at: http://www.cdc.gov/meningococcal/clinical-info.html. Accessed October 4, 2017.

        • Cohn AC
        • MacNeil JR
        • Clark TA
        • et al.
        Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2013; 62 (DOI: rr6202a1 [pii]): 1-28
        • Pace D
        • Pollard AJ
        Meningococcal disease: Clinical presentation and sequelae.
        Vaccine. 2012; 30: B3-B9https://doi.org/10.1016/j.vaccine.2011.12.062
        • McIntosh ED
        • Carey V
        • Toneatto D
        • et al.
        Prevention of rare diseases: How revolutionary techniques can help vulnerable individuals-the example of serogroup B meningococcal infection.
        Ther Adv Vaccines. 2015; 3: 13-23
        • Tan LK
        • Carlone GM
        • Borrow R
        Advances in the development of vaccines against Neisseria meningitidis .
        N Engl J Med. 2010; 362: 1511-1520https://doi.org/10.1056/NEJMra0906357
        • Jafri RZ
        • Ali A
        • Messonnier NE
        • et al.
        Global epidemiology of invasive meningococcal disease.
        Popul Health Metr. 2013; 11: 11-17https://doi.org/10.1186/1478-7954-11-17
      2. European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe. Available at: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/Surveillance%20of%20IBD%20in %20Europe%202012.pdf. Accessed July 20, 2017.

        • Edmond K
        • Clark A
        • Korczak VS
        • et al.
        Global and regional risk of disabling sequelae from bacterial meningitis: A systematic review and meta-analysis.
        Lancet Infect Dis. 2010; 10: 317-328https://doi.org/10.1016/S1473-3099(10)70048-7
        • Christensen H
        • May M
        • Bowen L
        • et al.
        Meningococcal carriage by age: A systematic review and meta-analysis.
        Lancet Infect Dis. 2010; 10: 853-861
        • Vetter V
        • Baxter R
        • Denizer G
        • et al.
        Routinely vaccinating adolescents against meningococcus: Targeting transmission & disease.
        Expert Rev Vaccines. 2016; 15: 641-658https://doi.org/10.1586/14760584.2016.1130628
        • Crum-Cianflone N
        • Sullivan E
        Meningococcal vaccinations.
        Infect Dis Ther. 2016; 5: 89-112https://doi.org/10.1007/s40121-016-0107-0
        • Brooks R
        • Woods CW
        • Benjamin Jr., DK
        • et al.
        Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994-2002.
        Clin Infect Dis. 2006; 43: 49-54
        • Borg J
        • Christie D
        • Coen PG
        • et al.
        Outcomes of meningococcal disease in adolescence: Prospective, matched-cohort study.
        Pediatrics. 2009; 123: e502-e509
        • Soriano-Gabarro M
        • Wolter J
        • Hogea C
        • et al.
        Carriage of Neisseria meningitidis in Europe: A review of studies undertaken in the region.
        Expert Rev Anti Infect Ther. 2011; 9: 761-774
        • Harrison OB
        • Claus H
        • Jiang Y
        • et al.
        Description and nomenclature of Neisseria meningitidis capsule locus.
        Emerg Infect Dis. 2013; 19: 566-573https://doi.org/10.3201/eid1904.111799
        • Rouphael NG
        • Stephens DS
        Neisseria meningitidis: biology, microbiology, and epidemiology.
        Methods Mol Biol. 2012; 799: 1-20
      3. Centers for Disease Control and Prevention. Enhanced Meningococcal Disease Surveillance Report, 2016.

      4. European Centre for Disease Prevention and Control. Surveillance atlas of infectious diseases. Available at: https://ecdc.europa.eu/en/surveillance-atlas-infectious-diseases. Accessed August 15, 2017.

        • Lucidarme J
        • Hill DM
        • Bratcher HB
        • et al.
        Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.
        J Infect. 2015; 71: 544-552
        • Ladhani SN
        • Beebeejaun K
        • Lucidarme J
        • et al.
        Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.
        Clin Infect Dis. 2015; 60: 578-585https://doi.org/10.1093/cid/ciu881
        • Smith-Palmer A
        • Oates K
        • Webster D
        • et al.
        Outbreak of Neisseria meningitidis capsular group W among scouts returning from the World Scout Jamboree, Japan, 2015.
        Euro Surveill. 2016; 21https://doi.org/10.2807/1560-7917.ES.2016.21.45.30392
        • Hedari CP
        • Khinkarly RW
        • Dbaibo GS
        Meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine: A new conjugate vaccine against invasive meningococcal disease.
        Infect Drug Resist. 2014; 7: 85-99https://doi.org/10.2147/IDR.S36243
        • Stephens DS
        • Greenwood B
        • Brandtzaeg P
        Epidemic meningitis, meningococcaemia, and Neisseria meningitidis .
        Lancet. 2007; 369: 2196-2210
      5. World Health Organization. Meningococcal meningitis fact sheet no 141. Available at: http://www.who.int/mediacentre/factsheets/fs141/en/#. Accessed March 27, 2017.

        • Bermal N
        • Huang LM
        • Dubey A
        • et al.
        Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults.
        Hum Vaccin. 2011; 7: 239-247
        • Cohn A
        • MacNeil J
        The changing epidemiology of meningococcal disease.
        Infect Dis Clin North Am. 2015; 29: 667-677
        • van Ravenhorst MB
        • van der Klis FRM
        • van Rooijen DM
        • et al.
        Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.
        Vaccine. 2017; 35: 4753-4760https://doi.org/10.1016/j.vaccine.2017.06.007
        • Ishola DA
        • Andrews N
        • Waight P
        • et al.
        Randomized trial to compare the immunogenicity and safety of a CRM or TT conjugated quadrivalent meningococcal vaccine in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age.
        Pediatr Infect Dis J. 2015; 34: 865-874
        • Summary of Product Characteristics
        NIMENRIX full prescribing information.
        Pfizer Limited, Sandwich, Kent, UK2017
        • Mencevax (MenACWY-PS)
        Product information Australia full prescribing information.
        Pfizer Australia Pty Ltd, West Ryde, NSW, Australia2016
        • Vipond C
        • Care R
        • Feavers IM
        History of meningococcal vaccines and their serological correlates of protection.
        Vaccine. 2012; 30: B10-B17
        • Harrison LH
        Prospects for vaccine prevention of meningococcal infection.
        Clin Microbiol Rev. 2006; 19: 142-164https://doi.org/10.1128/CMR.19.1.142-164.2006
        • Ali A
        • Jafri RZ
        • Messonnier N
        • et al.
        Global practices of meningococcal vaccine use and impact on invasive disease.
        Pathog Glob Health. 2014; 108: 11-20
        • Maiden MC
        • Ibarz-Pavon AB
        • Urwin R
        • et al.
        Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity.
        J Infect Dis. 2008; 197: 737-743
        • Read RC
        • Baxter D
        • Chadwick DR
        • 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
        • Daugla DM
        • Gami JP
        • 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 [corrected].
        Lancet. 2014; 383: 40-47
        • Ishola Jr., DA
        • Borrow R
        • Findlow H
        • et al.
        Prevalence of serum bactericidal antibody to serogroup C Neisseria meningitidis in England a decade after vaccine introduction.
        Clin Vaccine Immunol. 2012; 19: 1126-1130https://doi.org/10.1128/CVI.05655-11
      6. Menactra (MCV4). Full prescribing information, Sanofi Pasteur Inc., Swiftwater, PA, 2014.

      7. Menveo (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine). Full prescribing information, Novartis Vaccines and Diagnostics, Inc., Sovicille, Italy, 2011.

      8. Public Health England. Meningococcal: the Green Book, Chapter 22. Available at: https://www.gov.uk/government/publications/meningococcal-the-green-book-chapter-22. Accessed March 27, 2017.

      9. Menveo (Meningococcal Group A, C, W135 and Y conjugate vaccine) Summary of product characteristics full prescribing information, GlaxoSmithKline UK, Uxbridge, Middlesex, UK, 2015.

      10. European Medicines Agency. Summary of opinion (post authorisation). EMA/CHMP/512584/2016. Nimenrix (Meningococcal group A, C, W-135 and Y conjugate vaccine), 2016.

        • World Health Organization
        Meningococcal vaccines: WHO position paper, November 2011.
        Wkly Epidemiol Rec. 2011; 86: 521-539
      11. Queensland Health. Queensland immunisation schedule. Available at: https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/immunisation/schedule#acwy. Accessed October 2, 2017.

      12. NSW Government Health. NSW meningococcal W response program fact sheet. Available at: http://www.health.nsw.gov.au/Infectious/diseases/Pages/meningococcal-w.aspx. Accessed October 2, 2017.

      13. Victoria State Government. Meningococcal ACWY vaccine for adolescents. Available at: https://www2.health.vic.gov.au/public-health/immunisation/vaccination-adolescents/meningococcal-acwy. Accessed October 2, 2017.

      14. SA Health. Ceduna region meningococcal W vaccination program. Frequently asked questions. Available at: http://www.sahealth.sa.gov.au/wps/wcm/ connect/public+content/sa+health+internet/health+topics/health+conditions+prevention+and+treatment/immunisation/immunisation+programs/ceduna+region+meningococcal+w+vaccination+program/ceduna+region+meningo coccal+w+vaccination+program. Accessed October 2, 2017.

      15. Government of Western Australia Department of Health. Meningococcal disease. Available at: http://healthywa.wa.gov.au/Articles/J_M/Meningococcal-vaccine. Accessed October 2, 2017.

      16. BC Centre for Disease Control. HealthLinkBC. Meningococcal quadrivalent vaccines. Number 23b. Available at: https://www.healthlinkbc.ca/healthlinkbc-files/meningococcal-quadrivalent-vaccines. Accessed October 3, 2017.

      17. Alberta Health. Routine immunization schedule. Available at: www.health.alberta.ca/health-info/imm-routine-schedule.html. Accessed October 3, 2017.

      18. Government of Saskatchewan. Immunization services. Available at: www. saskatchewan.ca/residents/health/accessing-health-care-services/immuniza tion-services. Accessed October 2, 2017.

      19. Government of Ontario. Publicly funded immunization schedules for Ontario - –December 2016. Available at: http://www.health.gov.on.ca/en/pro/ programs/immunization/docs/immunization_schedule.pdf. Accessed October 3, 2017.

      20. Government of New Brunswick. Routine immunization schedule. Available at: http://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/CDC/ Immunization/RoutineImmunizationSchedule.pdf. Accessed October 3, 2017.

      21. Government of Prince Edward Island. Adult and child immunization in PEI. Available at: www.princeedwardisland.ca/en/information/health-and- wellness/adult-and-child-immunization-pei. Accessed October 2, 2017.

      22. Government of Nova Scotia. School immunization schedule. Available at: https://novascotia.ca/dhw/cdpc/immunization.asp. Accessed October 3, 2017.

      23. Government of Newfoundland and Labrador. Meningococcal disease. Available at: http://www.health.gov.nl.ca/health/publichealth/cdc/pdf/Meningococcal_Vaccine_Fact_Sheet.pdf. Accessed October 3, 2017.

      24. Ministero della Salute Italia. The vaccination schedule of the National Vaccine Prevention Plan 2017–2019. Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf. Accessed July 8, 2017.

        • Public Health England
        Guidance for the public health management of meningococcal disease in the UK (updated February 2018).
        PHE Publications, London2018
      25. The Netherlands Ministry of Health, Welfare and Sport. Meningococcal ACWY vaccination guideline. Available at: https://lci.rivm.nl/richtlijnen/meningo kokken-acwy-vaccinatie. Accessed March 22, 2018.

      26. Australian Government Department of Health. The Australian Immunisation Handbook. 10th Edition (updated August 2017). Canberra, Australia 2017.

      27. Canadian Immunization Guide. Part 4. Active vaccines. Available at: https://www.canada.ca/en/public-health/services/publications/healthy-living/ canadian-immunization-guide-part-4-active-vaccines.html. Accessed October 26, 2017.

        • Public Health England (PHE)
        Meningococcal ACWY immunisation programme for adolescents (information for healthcare professionals).
        PHE Publications, London2016 (October 2016)
        • Bethea J
        • Makki S
        • Gray S
        • et al.
        Clinical characteristics and public health management of invasive meningococcal group W disease in the East Midlands region of England, United Kingdom, 2011 to 2013.
        Euro Surveill. 2016; 21https://doi.org/10.2807/1560-7917.ES.2016.21.24.30259
        • NIMENRIX
        (Meningococcal polysaccharide serogroups A, C, W-135 and Y conjugate vaccine). Full prescribing information.
        Pfizer Australia Pty Ltd, West Ryde NSW, Australia2016
        • Dhillon S
        • Pace D
        Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix®): A review.
        Drugs. 2017; 77: 1881-1896https://doi.org/10.1007/s40265-017-0828-8
      28. Vaccines and Related Biologic Products Advisory Committee. Approaches to licensure of meningococcal vaccines for prevention of serogroup B invasive meningococcal disease. Briefing document for the Vaccines and Related Biologic Products Advisory Committee Meeting. April 7, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiological ProductsAdvisoryCommittee/UCM248586.pdf. Accessed April 10, 2017.

        • Borrow R
        • Balmer P
        • Miller E
        Meningococcal surrogates of protection–serum bactericidal antibody activity.
        Vaccine. 2005; 23: 2222-2227https://doi.org/10.1016/j.vaccine.2005.01.051
        • Goldschneider I
        • Gotschlich EC
        • Artenstein MS
        Human immunity to the meningococcus. I. The role of humoral antibodies.
        J Exp Med. 1969; 129: 1307-1326
        • Andrews N
        • Borrow R
        • Miller E
        Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England.
        Clin Diagn Lab Immunol. 2003; 10: 780-786
        • Frasch CE
        • Borrow R
        • Donnelly J
        Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease.
        Vaccine. 2009; 27: B112-B116https://doi.org/10.1016/j.vaccine.2009.04.065
        • Borrow R
        • Andrews N
        • Goldblatt D
        • et al.
        Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: Reevaluation of correlates of protection.
        Infect Immun. 2001; 69: 1568-1573https://doi.org/10.1128/IAI.69.3.1568-1573.2001
        • Assaf-Casals A
        • Dbaibo G
        Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT, Nimenrix): A review of its immunogenicity, safety, co-administration, and antibody persistence.
        Hum Vaccin Immunother. 2016; 12: 1825-1837https://doi.org/10.1080/21645515.2016.1143157
        • Ostergaard L
        • Lebacq E
        • Poolman J
        • et al.
        Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15-25 years.
        Vaccine. 2009; 27: 161-168https://doi.org/10.1016/j.vaccine. 2008.08.075
        • Borja-Tabora C
        • Montalban C
        • Memish ZA
        • et al.
        Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: Results of an open, randomised, controlled study.
        BMC Infect Dis. 2013; 13: 116
        • Ostergaard L
        • Van der Wielen M
        • Bianco V
        • et al.
        Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT).
        Int J Infect Dis. 2013; 17: e173-e176
        • Ostergaard L
        • Silfverdal SA
        • Berglund J
        • et al.
        A tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-administered with Twinrix® in subjects aged 11-17 years: an open, randomised, controlled trial.
        Vaccine. 2012; 30: 774-783https://doi.org/10.1016/j.vaccine.2011.11.051
        • Quiambao BP
        • Bavdekar A
        • Dubey AP
        • et al.
        Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.
        Hum Vaccin Immunother. 2017; 13: 636-644https://doi.org/10.1080/21645515.2016.1248009
        • Halperin SA
        • Baine Y
        • Domachowske JB
        • et al.
        Comparison of the safety and immunogenicity of a novel quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine and a marketed quadrivalent meningococcal ACWY-diphtheria toxoid conjugate vaccine in healthy individuals 10-25 years of age.
        J Pediatric Infect Dis Soc. 2014; 3: 33-42
        • Baxter R
        • Baine Y
        • Ensor K
        • et al.
        Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.
        Pediatr Infect Dis J. 2011; 30: e41-e48https://doi.org/10.1097/INF.0b013e3182054ab9
        • Baxter R
        • Baine Y
        • Kolhe D
        • et al.
        Five-year antibody persistence and booster response to a single dose of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in adolescents and young adults: An open, randomized trial.
        Pediatr Infect Dis J. 2015; 34: 1236-1243https://doi.org/10.1097/INF.0000000000000866
        • Lupisan S
        • Limkittikul K
        • Sosa N
        • et al.
        Meningococcal polysaccharide A O-acetylation levels do not impact the immunogenicity of the quadrivalent meningococcal tetanus toxoid conjugate vaccine: results from a randomized, controlled phase III study of healthy adults aged 18 to 25 years.
        Clin Vaccine Immunol. 2013; 20: 1499-1507https://doi.org/10.1128/CVI.00162-13
      29. U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/. Accessed October 26, 2017.

        • Borja-Tabora CF
        • Montalban C
        • Memish ZA
        • et al.
        Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.
        BMC Infect Dis. 2015; 15: 409https://doi.org/10.1186/s12879-015-1138-y
        • Chang Q
        • Tzeng YL
        • Stephens DS
        Meningococcal disease: Changes in epidemiology and prevention.
        Clin Epidemiol. 2012; 4: 237-245
      30. Centers for Disease Control and Prevention. 2016 Yellow Book Travelers' Health. 2016.

      31. BC Centre for Disease Control. Part 4 - Biological Products. Available at: http://www.bccdc.ca/health-professionals/clinical-resources/communicable- disease-control-manual/immunization/biological-products. Accessed October 3, 2017.

      32. Alberta Health. Meningococcal conjugate (groups A, C, Y and W-135) vaccine (MenC-ACYW). Available at: https://open.alberta.ca/dataset/aip/resource/7ea6d5c9-f644-4db1-b600-635d3e0033fb/download/AIP-BP-MenC-ACYW.pdf. Accessed October 3, 2017.

      Linked Article