Edwards, Kathryn M

Mulholland, E Kim

Wu, Ken

English

LSHTM Research Online

C l i n i c a l  D e c i s i o n sT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 382;4 nejm.org January 23, 2020 379Interactive at nejm.orgChoosing a Mass Immunization Program  against Meningococcal BThis interactive feature addresses the approach to a clinical issue. A case vignette is followed by specific options, neither of which can be considered either correct or incorrect. In short essays, experts in the field then argue for each of the options. Readers can participate in forming community opinion by choosing one of the options and, if they like, providing their reasons.C ase Vignet teAn Outbreak of Meningococcal DiseaseKen Wu, M.B., B.S.You are a physician advising the national health agency in your country (comparable to the Cen-ters for Disease Control and Prevention [CDC] in the United States). An outbreak of meningitis has occurred among students in a public univer-sity. Four cases of invasive meningococcal dis-ease caused by Neisseria meningitidis serogroup B have been reported to the national health agency within the past month. All the affected patients were undergraduate students between 19 and 21 years of age who were otherwise healthy. They had had all the routine childhood immunizations recommended by the national health agency but were not immunized against meningococcal B. All four patients were hospitalized and treated successfully and had no permanent complica-tions. Reports of the outbreak have made local and national news and are trending on social media, causing a high level of anxiety among parents, especially those with children graduat-ing from high school.In the United States, there have been 10 univer-sity-based outbreaks of meningococcal B disease in seven states since 2013; these outbreaks have involved a total of 39 cases and 2 deaths.1 In response, affected universities have initiated meningococcal B vaccination campaigns, with mass vaccination of university students recom-mended in 8 of the outbreaks. Since its develop-ment, the vaccine against meningococcal B has become part of the routine immunization sched-ule in some jurisdictions; for example, it is in-cluded in the routine immunization schedule in the United Kingdom for all infants younger than 1 year of age and in the Australian state of South Australia for all infants younger than 1 year of age and for adolescents 16 to 17 years of age.2,3 The current policy of the health agency in your country regarding administration of the menin-gococcal B vaccine to adolescents and young adults 16 to 23 years of age who are not at in-creased risk is that the decision about vaccina-tion should be based on individual clinical factors.Your national health agency is asking for your advice about whether to expand immunization for meningococcal B by recommending admin-istration of the vaccine to all persons 17 to 18 years old in addition to a mass vaccination cam-paign at universities at which there is an out-break. In particular, you are asked to consider the effectiveness of the vaccine in preventing both meningococcal B disease and transmission of infection, as well as the cost-effectiveness of a mass vaccination program.Treatment Op tionsWhich one of the following choices would you recommend to the national health agency? Base your choice on the published literature, your own experience, published guidelines, and other information sources.1. Administer the meningococcal B vaccine to all 17-to-18-year-olds and to all students at uni-versities with an outbreak.2. Administer the meningococcal B vaccine only to students at universities with an outbreak.To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the issue and the points made by the experts, which approach would you choose?The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on September 29, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 382;4 nejm.org January 23, 2020380Op tion 1Administer the Meningococcal B Vaccine to All 17-to-18-Year-Olds and to All Students at Universities with an OutbreakE. Kim Mulholland, M.D.Meningococcal B disease is a curious and terrify-ing condition with unusual epidemiology. Spo-radic cases occur throughout the world, with occasional small outbreaks, but large-scale epi-demics, when they occur, can last for a decade or more. Unlike other meningococcal serogroups, meningococcal B is not amenable to the highly successful vaccine-development approach that is based on covalent binding of the capsular poly-saccharide to a carrier protein to form a poly-saccharide–protein conjugate vaccine. Vaccines developed in the Americas and in Norway in response to previous meningococcal B epidem-ics were based on the outer-membrane vesicle approach using vesicles of the bacterial mem-brane that express important epitopes, particu-larly the immunodominant PorA protein, which varies from epidemic to epidemic.4 The 1990–2005 epidemic in New Zealand was success-fully aborted by a tailor-made outer-membrane vesicle vaccine, which was administered to a high proportion of persons younger than 20 years of age in the country.5 That vaccine has since been modified to produce one of the two currently available vaccines that cover most strains of meningococcal B — 4CMenB (Bex-sero, GlaxoSmithKline). The other meningo-coccal B vaccine currently in use is MenB-FHbp (Trumenba, Pfizer) which targets factor H bind-ing protein.Although meningococcal B disease can affect all ages, the two age groups at highest risk are young infants and older teenagers. The organ-ism circulates easily in the 17-to-18-year-old age group because of the ease with which persons of this age share saliva6 — a point that may be well understood by readers who are parents of teen-agers or those with fond memories of those years. Sadly, this behavior carries with it a small risk of the horrors of meningococcal B disease, which often leads to serious sequelae, such as multiple limb amputations, or to death.7 It is also believed to be the means by which menin-gococcal B circulates in a community; therefore, prevention of carriage in this age group should lead to herd immunity. Unfortunately, findings of a large study by Marshall et al. published in this issue of the Journal provide convincing evi-dence that the 4CMenB vaccine does not prevent carriage,6 so the objective of vaccination is to prevent cases. Public attention tends to focus on outbreaks among university students, who ac-count for most cases of meningococcal B disease among young adults in the United States. How-ever, cases also occur among the 62% of 18-to-24-year-olds in the United States who are not attending university.8There are two general approaches to vaccine control of meningococcal B disease. In 2015, the U.K. government began a national infant vacci-nation program with 4CMenB, with the aim of providing direct protection to one of the age groups at highest risk.9 The report by Ladhani et al., the results of which are also published in this issue of the Journal, highlights the effective-ness of that program, which is consistent with the experience in New Zealand.5,10 Others have focused attention on teenagers, the age group producing the highest numbers of meningococ-cal B cases. In the United States, limiting vac-cination to students attending universities that have reported cases may seem logical. The risk in this group may be higher, but in fact all young adults are at risk. Therefore, the most logical approach to preventing meningococcal B disease among students is to provide a vaccine for all citizens in the very-high-risk age group of 17 to 18 years, which happens to be the usual age at which students enter university — and a time that for many students includes their first dating experience. In addition, students of all ages at-tending universities in which cases have oc-curred should be offered the vaccine and encour-aged to accept it.Disclosure forms provided by the author are available at NEJM.org.From Murdoch Children’s Research Institute and the University of Melbourne Department of Paediatrics, Melbourne, VIC, Aus-tralia; and the London School of Hygiene and Tropical Medi-cine, London. The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on September 29, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. Clinical Decisionsn engl j med 382;4 nejm.org January 23, 2020 381Op tion 2Administer the Meningococcal B Vaccine Only to Students  at Universities with an OutbreakKathryn M. Edwards, M.D.The recommendation to administer meningococ-cal B vaccine only to students at universities where an outbreak has occurred is the best ap-proach for several reasons. First, rates of menin-gococcal B disease are very low in the United States; the average annual incidence is only 0.17 cases per 100,000 population. Among the 1174 total cases of meningococcal disease reported during 2014–2016, only 166 occurred in persons 18 to 24 years of age, and only 88 of those cases were due to serogroup B.11 Thus, the costs of immunizing an entire birth cohort of 4 million people with two doses of meningococcal B vac-cine to prevent these few cases would be exces-sive. A recent study showed that the incremental cost per quality-adjusted life year gained with universal meningococcal B vaccination approached nearly $14 million, as compared with the usual willingness-to-pay benchmark threshold of $150,000 per quality-adjusted life year.12The second reason that only targeted immu-nization during an outbreak is preferable is sup-ported by the study by Marshall et al. published in this issue of the Journal.6 Investigators from Australia immunized more than 20,000 15-to-18-year-old students with two doses of meningo-coccal B vaccines and showed that vaccination was not associated with a reduction in carriage — a finding that contrasts with the effect of the conjugate vaccines targeting serogroups A, C, W, and Y, which prevent colonization. Immuniza-tion with meningococcal B vaccine does not prevent transmission and does not generate herd immunity.Meningococcal B vaccines are directed against proteins expressed on meningococcal B strains, in contrast to the serogroup A, C, W, and Y vac-cines, which are directed against the polysac-charide capsules. Thus, not all infecting strains of serogroup B organisms share these proteins, and it is difficult to predict whether the vaccine strains will match the circulating strains. Data from one outbreak showed that more than 30% of participants who were vaccinated with two doses of meningococcal B vaccine had low anti-body titers, and therefore, there was no evidence of a protective response against the outbreak strain.13 The study conducted in England by Lad-hani et al. shows that vaccine effectiveness for the prevention of invasive MenB disease in infants with a universal immunization program was only 60%, with wide confidence intervals.10 Data on vaccine effectiveness from a large outbreak in Quebec, where more than 80% of nearly 60,000 older persons were immunized, showed similar rates.14 In addition, reports of vaccine failures in fully immunized adolescents during outbreaks supports the notion that the effectiveness of this vaccine falls short of that of other vaccines, such as measles or bacterial conjugate vaccines.15Finally, rapid waning of vaccine-induced im-munity has been clearly shown in serologic stud-ies,16 a finding that has led to the recent recom-mendation by the CDC Advisory Committee on Immunization Practices that persons at high risk for meningococcal serogroup B disease should be given a booster dose of vaccine at 1 year after the primary series. Even if the entire birth co-hort were immunized with meningococcal B vaccine, immunity for longer than a year could not be ensured.Thus, for all the reasons outlined above, the best approach is to immunize only the students enrolled at the university with the outbreak. With robust use of the media to publicize the need for vaccination and with multiple partici-pating clinics, the vaccine can be delivered to a large percentage of the university community.Disclosure forms provided by the author are available at NEJM.org.From the Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville.This article was updated on February 20, 2020, at NEJM.org. 1. Soeters HM, McNamara LA, Blain AE, et al. University-based outbreaks of meningococcal disease caused by serogroup B, United States, 2013-2018. Emerg Infect Dis 2019; 25: 434-40.2. Meningococcal B Immunisation Program. Adelaide: Depart-ment of Health and Wellbeing, Government of South Australia, 2019 (https://www .sahealth .sa .gov .au/ wps/ wcm/ connect/ public+ content/ sa+health+internet/ health+topics/ health+conditions+ prevention+and+treatment/ immunisation/ immunisation+ programs/ meningococcal+b+immunisation+program).3. The routine immunisation schedule from autumn 2019. Public Health England, 2019 (https://assets .publishing .service .gov .uk/ government/ uploads/ system/ uploads/ attachment_data/ The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on September 29, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. Clinical Decisionsn engl j med 382;4 nejm.org January 23, 2020382f ile/ 824542/ PHE_complete_immunisation_schedule_autumn _2019 .pdf).4. Villena R, Safadi MAP, Valenzuela MT, Torres JP, Finn A, O’Ryan M. Global epidemiology of serogroup B meningococcal disease and opportunities for prevention with novel recombi-nant protein vaccines. Hum Vaccin Immunother 2018; 14: 1042-57.5. Arnold R, Galloway Y, McNicholas A, O’Hallahan J. Effec-tiveness of a vaccination programme for an epidemic of menin-gococcal B in New Zealand. Vaccine 2011; 29: 7100-6.6. Marshall HS, McMillan M, Koehler AP, et al. Meningococcal B vaccine and meningococcal carriage in adolescents in Austra-lia. N Engl J Med 2020; 382:318-27.7. Olbrich KJ, Müller D, Schumacher S, Beck E, Meszaros K, Koerber F. Systematic review of invasive meningococcal disease: sequelae and quality of life impact on patients and their care-givers. Infect Dis Ther 2018; 7: 421-38.8. Enhanced meningococcal disease surveillance report, 2017. Atlanta: Centers for Disease Control and Prevention, 2017 (https://www .cdc .gov/ meningococcal/ downloads/ NCIRD - EMS - Report - 2017 .pdf).9. JCVI position statement on use of Bexsero® meningococcal B vaccine in the UK. Public Health England, March 2014 (https://assets .publishing .service .gov .uk/ government/ uploads/ system/ uploads/ attachment_data/ file/ 294245/ JCVI_Statement_on_MenB .pdf).10. Ladhani SN, Andrews N, Parikh SR, et al. Vaccination of infants with meningococcal group B vaccine (4CMenB) in Eng-land. N Engl J Med 2020; 382:309-17.11. Mbaeyi SA, Joseph SJ, Blain A, Wang X, Hariri S, MacNeil JR. Meningococcal disease among college-aged young adults: 2014-2016. Pediatrics 2019; 143(1): e20182130.12. Leeds IL, Namasivayam V, Bamogo A, Sankhla P, Thayer WM. Cost effectiveness of meningococcal serogroup B vaccina-tion in college-aged young adults. Am J Prev Med 2019; 56: 196-204.13. Basta NE, Mahmoud AAF, Wolfson J, et al. Immunogenicity of a meningococcal B vaccine during a university outbreak. N Engl J Med 2016; 375: 220-8.14. De Wals P, Deceuninck G, Lefebvre B, et al. Impact of an immunization campaign to control an increased incidence of serogroup B meningococcal disease in one region of Quebec, Canada. Clin Infect Dis 2017; 64: 1263-7.15. Mbaeyi S. Serogroup B meningococcal vaccine booster doses. Atlanta: Centers for Disease Control and Prevention, June 27, 2019 (https://www .cdc .gov/ vaccines/ acip/ meetings/ downloads/ slides - 2019 - 06/ Meningococcal - 2 - Mbaeyi - 508 .pdf).16. Marshall HS, Richmond PC, Beeslaar J, et al. Meningococcal serogroup B-specific responses after vaccination with bivalent rLP2086: 4 year follow-up of a randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 2017; 17: 58-67.DOI: 10.1056/NEJMclde1916746Copyright © 2020 Massachusetts Medical Society.The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on September 29, 2020. For personal use only. No other uses without permission.  Copyright © 2020 Massachusetts Medical Society. All rights reserved. 

Choosing a Mass Immunization Program against Meningococcal B.

https://researchonline.lshtm.ac.uk/id/eprint/4657887/15/Wu-etal-2020-Choosing_a_Mass_Immunization_Program.pdf

Choosing a Mass Immunization Program against Meningococcal B.

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