Abstract
In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero® is based on surface protein antigens expressed by about 80 % of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero® in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.
STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20–30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5–10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100–200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the index case.
Zusammenfassung
Seit Dezember 2013 ist der Impfstoff Bexsero® zum Schutz vor Meningokokken der Serogruppe B (MenB) in Deutschland verfügbar. Seit August 2015 empfiehlt die Ständige Impfkommission (STIKO) die Anwendung dieser Impfung bei Personen mit erhöhtem Risiko für Meningokokken-Erkrankungen. Diese Begründung fasst die Evidenz zusammen, die der STIKO-Empfehlung zugrunde lag. Bexsero® basiert auf Oberflächenproteinantigenen, die von ca. 80 % der in Deutschland zirkulierenden MenB-Stämme exprimiert werden. Es wird ein Überblick über die Immunogenität und Sicherheit des Impfstoffs bei gesunden Kindern und Jugendlichen präsentiert; entsprechende Daten von Personen mit Grunderkrankungen sowie zur Wirksamkeit in Bezug auf Schutz vor klinischen Endpunkten stehen derzeit noch aus.
Die STIKO empfiehlt eine Impfung mit Bexsero® nach individueller Risikoabschätzung für folgende Personen: 1) Gesundheitlich gefährdete Personen mit angeborener oder erworbener Immundefizienz bzw. -suppression. Von diesen haben Personen mit terminalen Komplementdefekten, einschließlich bei Therapie mit Eculizumab, sowie mit Properdindefizienz, das höchste Risiko für eine invasive Meningokokken-Erkrankung (IME); es liegt bis zu 10.000-fach höher als in der Allgemeinbevölkerung. Das Erkrankungsrisiko für Personen mit Asplenie ist ca. 20- bis 30-fach erhöht und liegt für Personen mit anderen Immundefekten, z. B. mit HIV-Infektion oder Hypogammaglobulinämie wahrscheinlich nicht mehr als 5- bis 10-fach erhöht gegenüber der Hintergrundinzidenz. 2) Laborpersonal, das ein Risiko für Kontakt mit N.-meningitidis-Aerosolen hat. Für diese Gruppe wurde ein bis zu 271-fach erhöhtes Risiko für IME berichtet. 3) Ungeimpfte Haushaltskontakte oder enge Kontakte mit haushaltsähnlichem Charakter einer Person mit einer IME durch MenB. Diese haben trotz Erhalt einer Chemoprophylaxe ein ca. 100–200-fach erhöhtes Risiko für IME in den 14 bis 365 Tagen nach dem Kontakt, wobei das Risiko in den ersten 3 Monaten am höchsten ist. Daher, und weil der vollständige Impfschutz insbesondere bei Säuglingen und Kleinkindern mehrere Impfdosen benötigt, sollte die MenB-Impfung der Kontaktperson so bald wie möglich nach gesicherter Serogruppenbestimmung erfolgen.
Article PDF
References
STIKO (2014) Standard Operating Procedure of the German Standing Committee on Vaccinations (STIKO) for the systematic development of vaccination recommendations. Version 2. February 6, 2014. http://www.rki.de/DE/Content/Kommissionen/STIKO/Aufgaben_Methoden/SOP.pdf?__blob=publicationFile. Accessed 1 Sept 2015
Hoek M, Christensen H, Hellenbrand W, Stefanoff P, HOWITZ M, Stuart J (2008) Effectiveness of vaccinating household contacts in addition to chemoprophylaxis after a case of meningococcal disease: a systematic review. Epidemiol Infect 136(11):1441–1447
STIKO (2009) Mitteilung der Ständigen Impfkommission (STIKO) am Robert Koch-Institut. Empfehlung und Begründung einer postexpositionellen Meningokokken-Impfung. Epid Bull 31:314–317
Boutet R, Stuart JM, Kaczmarski EB, Gray SJ, Jones DM, Andrews N (2001) Risk of laboratory-acquired meningococcal disease. J Hosp Infect 49(4):282–284
Sejvar JJ, Johnson D, Popovic T, Miller JM, Downes F, Somsel P, Weyant R, Stephens DS, Perkins BA, Rosenstein NE (2005) Assessing the risk of laboratory-acquired meningococcal disease. J Clin Microbiol 43(9):4811–4814
Rote Liste ServiceGmbH (2014) Fachinformation (Zusammenfassung der Merkmale des Arzneimittels): Bexsero, Novartis Vaccines. Rote Liste ServiceGmbH, Frankfurt
European Medicines Agency (2013) European Public Assessment Report: Bexsero In. London. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Summary_for_the_public/human/002333/WC500137857.pdf. Accessed 1 Sept 2015
Ram S, Lewis LA, Rice PA (2010) Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev 23(4):740–780
Lewis LA, Ram S (2014) Meningococcal disease and the complement system. Virulence 5(1):98–126
Cohen C, Singh E, Wu HM, Martin S, de Gouveia L, Klugman KP, Meiring S, Govender N, von Gottberg A, for the Group for Enteric R et al (2010) Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa. AIDS 24(9):1351–1360
Pollard AJ, Frasch C (2001) Development of natural immunity to Neisseria meningitidis. Vaccine 19(11–12):1327–1346
Kelly H, Attia J, Andrews R, Heller RF (2004) The number needed to vaccinate (NNV) and population extensions of the NNV: comparison of influenza and pneumococcal vaccine programmes for people aged 65 years and over. Vaccine 22(17–18):2192–2198
Harrison OB, Claus H, Jiang Y, Bennett JS, Bratcher HB, Jolley KA, Corton C, Care R, Poolman JT, Zollinger WD et al (2013) Description and nomenclature of Neisseria meningitidis capsule locus. Emerg Infect Dis 19(4):566–573
Christensen H, May M, Bowen L, Hickman M, Trotter CL (2010) Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infect Dis 10(12):853–861
Andersen P, Berthelsen L, Bech Jensen B, Lind I (1998) Dynamics of the meningococcal carrier state and characteristics of the carrier strains: a longitudinal study within three cohorts of military recruits. Epidemiol Infect 121:85–94
Pether JV, Lightfoot NF, Scott RJ, Morgan J, Stelle-Perkins AP, Sheard SC (1988) Carriage of Neisseria meningitidis: investigations in a military establishment. Epidemiol Infect 101:21–42
Ala’Aldeen DAA, Oldfield NJ, Bidmos FA, Abouseada NA, Ahmed NW, Turner DPJ, Neal KR, Bayliss CD (2011) Carriage of meningococci by university students, United Kingdom [letter]. Emerg Infect Dis 17(9):1761–1763
Claus H, Maiden MJC, Wilson DJ, McCarthy NDJ, Urwin R, Hessler F, Frosch M, Vogel U (2005) Genetic analysis of meningococci carried by children and young adults. J Infect Dis 191:1263–1271
Faur YC, Wilson ME, May PS (1981) Isolation of N. meningitidis from patients in a gonorrhea screen program: a four-year survey in New York City. Am J Public Health 71(1):53–58
Janda WM, Bohnhoff M, Morello JA, Lerner SA (1980) Prevalence and site-pathogen studies of Neisseria meningitidis and N. gonorrhoeae in homosexual men. JAMA 244(18):2060–2064
Coen PG, Tully J, Stuart JM, Ashby D, Viner RM, Booy R (2006) Is it exposure to cigarette smoke or to smokers which increases the risk of meningococcal disease in teenagers? Int J Epidemiol 35(2):330–336
McCall BJ, Neill AS, Young MM (2004) Risk factors for invasive meningococcal disease in southern Queensland, 2000–2001. Intern Med J 34:464–468
Moore PS (1992) Meningococcal meningitis in sub-Saharan Africa: a model for the epidemic process. Clin Infect Dis 14(2):515–525
Tuite AR, Kinlin LM, Kuster SP, Jamieson F, Kwong JC, McGeer A, Fisman DN (2010) Respiratory virus infection and risk of invasive meningococcal disease in Central Ontario, Canada. PLoS One 5(11):e15493
Robert Koch-Institut (2014) Meningokokken-Erkrankungen. Ratgeber Infektionskrankheiten—Merkblätter für Ärzte [Meningococcal disease. Guidance on infectious disease for Physicians]. https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_Meningokokken.html. Accessed 1 Sept 2015
Bettinger JA, Scheifele DW, Le Saux N, Halperin SA, Vaudry W, Tsang R, for the Members of the Canadian Immunization Monitoring Program A (2013) The Disease burden of invasive meningococcal serogroup B disease in Canada. Pediatr Infect Dis J 32(1):e20–e25. doi:10.1097/INF.0b013e3182706b89
Gottfredsson M, Reynisson IK, Ingvarsson RF, Kristjansdottir H, Nardini MV, Sigurdsson JF, Schneerson R, Robbins JB, Miller MA (2011) Comparative long-term adverse effects elicited by invasive group B and C meningococcal infections. Clin Infect Dis 53(9):e117–e124
Howitz M, Lambertsen L, Simonsen JB, Christensen JJ, Mølbak K (2009) Morbidity, mortality and spatial distribution of meningococcal disease, 1974–2007. Epidemiol Infect 137(11):1631–1640
Viner RM, Booy R, Johnson H, Edmunds WJ, Hudson L, Bedford H, Kaczmarski E, Rajput K, Ramsay M, Christie D (2012) Outcomes of invasive meningococcal serogroup B disease in children and adolescents (MOSAIC): a case-control study. Lancet Neurol 11(9):774–783
European Centre for Disease Prevention and Control (2013) Surveillance of invasive bacterial diseases in Europe 2011. In. Stockholm. Accessed 1 Sept 2015
European Medicines Agency (2012) Summary of opinion (initial authorisation) Bexsero Meningococcal group B Vaccine (rDNA, component, adsorbed). http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002333/WC500134836.pdf. Accessed 1 Sept 2015
Finne J (1985) Polysialic acid—a glycoprotein carbohydrate involved in neural adhesion and bacterial meningitis. Trends Biochem Sci 10(3):129–132
Pizza M, Scarlato V, Masignani V, Giuliani MM, Aricò B, Comanducci M, Jennings GT, Baldi L, Bartolini E, Capecchi B et al (2000) Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287(5459):1816–1820
Arnold R, Galloway Y, McNicholas A, O’Hallahan J (2011) Effectiveness of a vaccination programme for an epidemic of meningococcal B in New Zealand. Vaccine 29(40):7100–7106
Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S, Principi N, Diez-Domingo J, Sokal E, Becker B et al (2012) Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA 307(6):573–582
Martin NG, Snape MD (2013) A multicomponent serogroup B meningococcal vaccine is licensed for use in Europe: what do we know, and what are we yet to learn? Expert Rev Vaccines 12(8):837–858
Vesikari T, Esposito S, Prymula R, Ypma E, Kohl I, Toneatto D, Dull P, Kimura A (2013) Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet 381(9869):825–835
Findlow J, Bai X, Findlow H, Newton E, Kaczmarski E, Miller E, Borrow R (2015) Safety and immunogenicity of a four-component meningococcal group B vaccine (4CMenB) and a quadrivalent meningococcal group ACWY conjugate vaccine administered concomitantly in healthy laboratory workers. Vaccine 33(29):3322–3330
Balmer P, Borrow R (2004) Serologic correlates of protection for evaluating the response to meningococcal vaccines. Expert Rev Vaccines 3(1):77–87
Frasch CE, Borrow R, Donnelly J (2009) Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease. Vaccine 27(Suppl 2):B112–B116
Donnelly J, Medini D, Boccadifuoco G, Biolchi A, Ward J, Frasch C, Moxon ER, Stella M, Comanducci M, Bambini S et al (2010) Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci U S A 107(45):19490–19495
Vogel U, Taha M-K, Vazquez JA, Findlow J, Claus H, Stefanelli P, Caugant DA, Kriz P, Abad R, Bambini S et al (2013) Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis 13(5):416–425
Claus H, Vogel U, De Paola R, Stella M, Wichmann O, Hellenbrand W (2014) Meningococcal antigen typing system (MATS) based coverage for Bexsero on invasive MenB strains isolated from infants aged less than one year in Germany 2007–2013. In: International Pathogenic Neisseria Conference. Asheville, North Carolina
Santolaya ME, OʼRyan ML, Valenzuela MT, Prado V, Vergara R, Muñoz A, Toneatto D, Graña G, Wang H, Clemens R et al (2012) Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet 379(9816):617–624
McQuaid F, Snape MD, John TM, Kelly S, Robinson H, Houlden J, Voysey M, Toneatto D, Kitte C, Dull PM et al (2014) Persistence of bactericidal antibodies to 5 years of age after immunization with serogroup B meningococcal vaccines at 6, 8, 12 and 40 months of age. Pediatr Infect Dis J 33(7):760–766. doi:10.1097/INF.0000000000000327
Snape MD, Philip J, John TM, Robinson H, Kelly S, Gossger N, Yu L-M, Kittel C, Toneatto D, Dull PM et al (2013) Bactericidal antibody persistence 2 years after immunization with 2 investigational serogroup B meningococcal vaccines at 6, 8 and 12 months and immunogenicity of preschool booster doses: a follow-on study to a randomized clinical trial. Pediatr Infect Dis J 32(10):1116–1121. doi:10.1097/INF.0b013e31829cfff2
Snape MD, Saroey P, John TM, Robinson H, Kelly S, Gossger N, Yu L-M, Wang H, Toneatto D, Dull PM et al (2013) Persistence of bactericidal antibodies following early infant vaccination with a serogroup B meningococcal vaccine and immunogenicity of a preschool booster dose. Can Med Assoc J 185(15):E715–E724
Santolaya ME, O’Ryan M, Valenzuela MT, Prado V, Vergara RF, Muñoz A, Toneatto D, Graña G, Wang H, Dull PM (2013) Persistence of antibodies in adolescents 18–24 months after immunization with one, two, or three doses of 4CMenB meningococcal serogroup B vaccine. Hum Vaccin Immunother 9(11):2304–2310
Maiden M, Ibarz-Pavon A, Urwin R, Gray S, Andrews N, Clarke S, Walker AM, Evans M, Kroll JS, Neal K et al (2008) Impact of meningococcal serogroup c conjugate vaccines on carriage and herd immunity. J Infect Dis 197(5):737–743
Campbell H, Andrews N, Borrow R, Trotter C, Miller E (2010) Updated post-licensure surveillance of meningococcal C conjugate vaccine in England and Wales: effectiveness, validation of serological correlate of protection and modelling predictions of the duration of herd immunity. Clin Vacc Immunol 17(5):840–847
Campbell H, Borrow R, Salisbury D, Miller E (2009) Meningococcal C conjugate vaccine: the experience in England and Wales. Vaccine 27(Suppl 2):B20–B29
Read R, Baxter D, Chadwick D, Faust S (2013) Impact of a quadrivalent conjugate (MENACWY-CRM) or a serogroup B (4CMenB) meningococcal vaccine on meningococcal carriage in English university students. In: The 31st Meeting of the European Society for Paediatric Infectious Diseases: 2013; Milan, Italy
De Serres G, Gariépy M-C, Billard M-N, Rouleau I (2014) Rapport intérimaire de surveillance de la sécurité de la première dose du vaccin contre le méningocoque de sérogroupe B au Saguenay—Lac-Saint-Jean. In. Edited by Institut nationale santé publique du Québec. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0CCAQFjAAahUKEwjk0f_jrZnIAhVCPRQKHeIkDnY&url=https%3A%2F%2Fwww.inspq.qc.ca%2Fpdf%2Fpublications%2F1885_Vaccin_Menincogoque_SerogroupeB.pdf&usg=AFQjCNEKfOTJVE4CaEiwaEUGevc084wLdQ. Accessed 1 Sept 2015
Miller L, Arakaki L, Ramautar A, Bodach S, Braunstein SL, Kennedy J, Steiner-Sichel L, Ngai S, Shepard C, Weiss D (2014) Elevated Risk for Invasive Meningococcal Disease Among Persons With HIV. Ann Intern Med 160(1):30–37
Taniguchi LU, Correia MD, Zampieri FG (2014) Overwhelming postsplenectomy infection: narrative review of the literature. Surg Infect 15(6):686–693
Cullingford GL, Watkins DN, Watts ADJ, Mallon DF (1991) Severe late postsplenectomy infection. Br J Surg 78(6):716–721
Ejstrud P, Kristensen B, Hansen JB, Madsen KM, Schonheyder HC, Sorensen HT (2000) Risk and patterns of bacteraemia after splenectomy: a population-based study. Scand J Infect Dis 32(5):521–525
Dendle C, Sundararajan V, Spelman T, Jolley D, Woolley I (2012) Splenectomy sequelae: an analysis of infectious outcomes among adults in Victoria. Med J Aust 196:582–586
Thomsen RW, Schoonen WM, Farkas DrK, Riis A, Jacobsen J, Fryzek JP, Sørensen HT (2009) Risk for hospital contact with infection in patients with splenectomy a population-based cohort study. Ann Intern Med 151(8):546–555
Waghorn DJ (2001) Overwhelming infection in asplenic patients: current best practice preventive measures are not being followed. J Clin Pathol 54(3):214–218
Holdsworth RJ, Cuschieri A, Irving AD (1991) Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 78(9):1031–1038
Kyaw MH, Holmes EM, Toolis F, Wayne B, Chalmers J, Jones IG, Campbell H (2006) Evaluation of severe infection and survival after splenectomy. Am J Med 119(3):276.e271–276.e277
Bisharat N, Omari H, Lavi I, Raz R (2001) Risk of infection and death among post-splenectomy patients. J Infect 43(3):182–186
Loggie BW, John Hinchey E (1986) Does splenectomy predispose to meningococcal sepsis? An experimental study and clinical review. J Pediatr Surg 21(4):326–330
Statistisches Bundesamt (2014) DRG-Statistiken des Statistischen Bundesamtes. In. Edited by https://www.gbe-bund.de/gbe10/abrechnung.prc_abr_test_logon?p_uid=gast&p_aid=0&p_knoten=VR&p_sprache=D&p_suchstring=splenektomie. Accessed 1 Sept 2015 Statistisches Bundesamt, Wiesbaden
Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl S, Ritterbusch H, Baumann U, Meyer-Bahlburg A, Witte T et al (2013) The German national registry for primary immunodeficiencies (PID). Clin Exp Immunol 173:372–380
Eber S, Dickerhoff R (2014) Anämien und Hämoglobinkrankheiten bei Patienten mit Migrationshintergrund. Dtsch Med Wochenschr 139(09):434–440
Meerveld-Eggink A, de Weerdt O, de Voer R, Berbers G, van Velzen-Blad H, Vlaminckx B, Biesma D, Rijkers G (2011) Impaired antibody response to conjugated meningococcal serogroup C vaccine in asplenic patients. Eur J Clin Microbiol Infect Dis 30(5):611–618
Balmer P, Falconer M, McDonald P, Andrews N, Fuller E, Riley C, Kaczmarski E, Borrow R (2004) Immune response to meningococcal serogroup C conjugate vaccine in asplenic individuals. Infect Immun 72(1):332–337
Stoehr GA, Luecken J, Zielen S, Eber SW, Borrow R, Rose MA (2008) Mode of splenectomy and immunogenicity of meningococcal vaccination in patients with hereditary spherocytosis. Br J Surg 95(4):466–471
Mitchell R, Trück J, Pollard AJ (2013) Use of the 13-valent pneumococcal conjugate vaccine in children and adolescents aged 6–17 years. Expert Opin Biol Ther 13(10):1451–1465
Langley JM, Dodds L, Fell D, Langley GR (2010) Pneumococcal and influenza immunization in asplenic persons: a retrospective population-based cohort study 1990–2002. BMC Infect Dis 10:219
Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME (2004) Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 364:365–367
Figueroa JE, Densen P (1991) Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 4(3):359–395
Platonov AE, Beloborodov VB, Vershinina IV (1993) Meningococcal disease in patients with late complement component deficiency: studies in the U.S.S.R. Medicine (Baltimore) 72(6):374–392
Ross SC, Densen P (1984) Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore) 63(5):243–273
Densen P (1989) Interaction of complement with Neisseria meningitidis and Neisseria gonorrhoeae. Clin Microbiol Rev 2(Suppl):S11–S17
Figueroa J, Andreoni J, Densen P (1993) Complement deficiency states and meningococcal disease. Immunol Res 12(3):295–311
Fijen CAP, Kuijper EJ, te Bulte MT, Daha MR, Dankert J (1999) Assessment of complement deficiency in patients with meningococcal disease in the Netherlands. Clin Infect Dis 28(1):98–105
Fijen CP, Hannema A, Kuijper E, Sjöholm A, Van Putten JM (1989) Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups. Lancet 334(8663):585–588
Orren A, Caugant DA, Fijen CA, Dankert J, van Schalkwyk EJ, Poolman JT, Coetzee GJ (1994) Characterization of strains of Neisseria meningitidis recovered from complement-sufficient and complement-deficient patients in the Western Cape Province, South Africa. J Clin Microbiol 32(9):2185–2191
Fijen CAP, Kuijper EJ, Dankert J, Daha MR, Caugant DA (1998) Characterization of Neisseria meningitidis strains causing disease in complement-deficient and complement-sufficient patients. J Clin Microbiol 36(8):2342–2345
Bradley DT, Bourke TW, Fairley DJ, Borrow R, Shields MD, Young IS, Zipfel PF, Hughes AE (2012) Genetic susceptibility to invasive meningococcal disease: MBL2 structural polymorphisms revisited in a large case—control study and a systematic review. Int J Immunogenet 39(4):328–337
Skattum L, van Deuren M, van der Poll T, Truedsson L (2011) Complement deficiency states and associated infections. Mol Immunol 48(14):1643–1655
Sjöholm AG, Jönsson G, Braconier JH, Sturfelt G, Truedsson L (2006) Complement deficiency and disease: an update. Mol Immunol 43(1–2):78–85
Grumach AS, Kirschfink M (2014) Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol 61(2):110–117
Hässig A, Borel JF, Ammann P, Thöni M, Bütler R (1964) Essentielle Hypokomplementämie. Pathobiology 27(4):542–547
Gathmann B, Binder N, Ehl S, Kindle G, ESID WOrking Party (2011) The European internet-based patient and research database for primary immunodeficiencies: update 2011. Clin Exp Immunol 167:479–491
Schwabe U, Paffrath D (2014) Arzneiverordnungs-Report 2014: Aktuelle Daten, Kosten, Trends und Kommentare. Springer, Berlin
Schlesinger M, Greenberg R, Levy J, Kayhty H, Levy R (1994) Killing of meningococci by neutrophils: effect of vaccination on patients with complement deficiency. J Infect Dis 170(2):449–453
Biselli R, Casapollo I, DʼAmelio R, Salvato S, Matricardi PM, Brai M (1993) Antibody response to meningococcal polysaccharides A and C in patients with complement defects. Scand J Immunol 37(6):644–650
Andreoni J, Käyhty H, Densen P (1993) Vaccination and the role of capsular polysaccharide antibody in prevention of recurrent meningococcal disease in late complement component-deficient individuals. J Infect Dis 168(1):227–231
Fijen CAP, Kuijper EJ, Drogari-Apiranthitou M, Van Leeuwen Y, Daha MR, Dankert J (1998) Protection against meningococcal serogroup ACYW disease in complement- deficient individuals vaccinated with the tetravalent meningococcal capsular polysaccharide vaccine. Clin Exp Immunol 114(3):362–369
Platonov AE, Vershinina IV, Käyhty H, Fijen CAP, Würzner R, Kuijper EJ (2003) Antibody-dependent killing of meningococci by human neutrophils in serum of late complement component-deficient patients. Int Arch Allergy Immunol 130(4):314–321
Platonov AE, Beloborodov VB, Pavlova LI, Vershinina IV, KÄYhty H (1995) Vaccination of patients deficient in a late complement component with tetravalent meningococcal capsular polysaccharide vaccine. Clin Exp Immunol 100(1):32–39
Plested JS, Granoff DM (2008) Vaccine-induced opsonophagocytic immunity to Neisseria meningitidis group B. Clin Vaccine Immunol 15(5):799–804
Plested JS, Welsch JA, Granoff DM (2009) Ex vivo model of meningococcal bacteremia using human blood for measuring vaccine-induced serum passive protective activity. Clin Vaccine Immunol 16(6):785–791
Ross SC, Rosenthal PJ, Berberich HM, Densen P (1987) Killing of Neisseria meningitidis by human neutrophils: implications for normal and complement-deficient individuals. J Infect Dis 155(6):1266–1275
Stephens DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM (1995) Sporadic meningococcal disease in adults: results of a 5-Year population-based study. Ann Intern Med 123(12):937–940
Siberry GK, Warshaw MG, Williams PL, Spector SA, Decker MD, Jean-Philippe P, Yogev R, Heckman BE, Manzella A, Roa J et al (2012) Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children. Pediatr Infect Dis J 31(1):47–52
Bertolini DV, Costa LS, van der Heijden IM, Sato HK, de Sousa Marques HH (2012) Immunogenicity of a meningococcal serogroup C conjugate vaccine in HIV-infected children, adolescents, and young adults. Vaccine 30(37):5482–5486
Frota ACC, Milagres LG, Harrison LH, Ferreira B, Barreto DM, Pereira GS, Cruz AC, Pereira-Manfro W, de Oliveira RH, Abreu TF et al (2014) Immunogenicity and safety of meningococcal C Conjugate Vaccine in children and adolescents infected and uninfected with human immunodeficiency virus in Rio de Janeiro, Brazil. Pediatr Infect Dis J 34(5)e113–e118
Lujan-Zilbermann J, Warshaw MG, Williams PL, Spector SA, Decker MD, Abzug MJ, Heckman B, Manzella A, Kabat B, Jean-Philippe P et al (2012) Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus. J Pediatr 161(4):676–681.e672
Siberry GK, Williams PL, Lujan-Zilbermann J, Warshaw MG, Spector SA, Decker MD, Heckman BE, Demske EF, Read JS, Jean-Philippe P et al (2010) Phase I/II, Open-label trial of safety and immunogenicity of meningococcal (Groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents. Pediatr Infect Dis J 29(5):391–396
Crum-Cianflone NF, Wallace MR (2014) Vaccination in HIV-Infected Adults. Aids Patient Care STDS 28(8):397–410
Lear S, Eren E, Findlow J, Borrow R, Webster D, Jolles S (2005) Meningococcal meningitis in two patients with primary antibody deficiency treated with replacement intravenous immunoglobulin. J Clin Pathol 59(11):1191–1193
Principi N, Esposito S (2014) Vaccine use in primary immunodeficiency disorders. Vaccine 32(30):3725–3731
Goldacker S, Draeger R, Warnatz K, Huzly D, Salzer U, Thiel J, Eibel H, Schlesier M, Peter HH (2007) Active vaccination in patients with common variable immunodeficiency (CVID). Clin Immunol 124(3):294–303
Ko J, Radigan L, Cunningham-Rundles C (2005) Immune competence and switched memory B cells in common variable immunodeficiency. Clin Immunol 116(1):37–41
Rezaei N, Aghamohammadi A, Siadat SD, Moin M, Pourpak Z, Nejati M, Ahmadi H, Kamali S, Norouzian D, Tabaraei B et al (2008) Serum bactericidal antibody responses to meningococcal polysaccharide vaccination as a basis for clinical classification of common variable immunodeficiency. Clin Vacc Immunol 15(4):607–611
De Wals P, Hertoghe L, Borleé-Grimée I, De Mayer-Cleempel S, Reginster-Haneuse G, Dachy A, Bouckaert A, Lechat MF (1981) Meningococcal disease in Belgium. Secondary attack rate among household, day-care nursery and pre-elementary school contacts. J Infect 3(Suppl 1):53–61
Group TMDS (1974) Meningococcal disease. Secondary attack rate and chemoprophylaxis in the United States, 1974. J Am Med Assoc 235(3):261–265
European Centre for Disease Prevention and Control (2010) Public health management of sporadic cases of invasive meningococcal disease and their contacts. In. Edited by http://ecdc.europa.eu/en/publications/Publications/Forms/ECDC_DispForm.aspx?ID=572 Eao. Stockhom. Accessed 1 Sept 2015
Ladhani SN, Cordery R, Mandal S, Christensen H, Campbell H, Borrow R, Ramsay ME (2014) Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero®). J Infect 69(5):470–480
Ladhani SN, Cordery R, Mandal S, Christensen H, Campbell H, Borrow R, Ramsay M (2014) PHE VaPiBi forum members: preventing secondary cases of invasive meningococcal capsular group B (MenB) disease: benefits of offering vaccination in addition to antibiotic chemoprophylaxis to close contacts of cases in the household, educational setting, clusters and the wider community. In., vol. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/328835/Invasive_meningococcus_secondary_case_prevention_April_2014.pdf. Public Helath England, London
Prymula R, Esposito S, Zuccotti GV, Xie F, Toneatto D, Kohl I, Dull PM (2014) A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I): effects of prophylactic paracetamol on immunogenicity and reactogenicity of routine infant vaccines and 4CMenB. Hum Vaccin Immunother 10(7):1993–2004
Borrow R, Findlow J, Gray S, Taylor S, Kaczmarski E (2014) Safe laboratory handling of Neisseria meningitidis. J Infect 68(4):305–312
Guibourdenche M, Darchis JP, Boisivon A, Collatz E, Riou JY (1994) Enzyme electrophoresis, sero- and subtyping, and outer membrane protein characterization of two Neisseria meningitidis strains involved in laboratory-acquired infections. J Clin Microbiol 32(3):701–704
Channing DS, Harriman K, Zipprich J, Louie JK, Probert WS, Horowitz M, Prudhomme JC, Gold D, Mayer L (2014) Fatal meningococcal disease in a laboratory worker—California, 2012. Morb Mortal Weekly Rep 63(35):770–772
Kessler AT, Stephens DS, Somani J (2007) Laboratory-acquired serogroup A meningococcal meningitis. J Occup Health 49(5):399–401
Snape MD, Dawson T, Oster P, Evans A, John TM, Ohene-Kena B, Findlow J, Yu LM, Borrow R, Ypma E et al (2010) Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial. Pediatr Infect Dis J 29(11):e71–e79
Esposito S, Prymula R, Zuccotti GV, Xie F, Barone M, Dull PM, Toneatto D (2014) A phase 2 II randomized controlled trial of a multicomponent meningococcal serogroup B vaccine, 4CMenB, in infants (II): effects of variations of the OMV and protein content on immunogenicity and reactogenicity. Hum Vaccin Immunother 10(7):2005–2014
Findlow J, Borrow R, Snape MD, Dawson T, Holland A, John TM, Evans A, Telford KL, Ypma E, Toneatto D et al (2010) Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis 51(10):1127–1137
Toneatto D, Ismaili S, Ypma E, Vienken K, Oster P, Dull P (2011) The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans. Hum Vaccin 7(6):646–653
Toneatto D, Oster P, deBoer ACW, Emerson A, Santos GF, Ypma E, DeTora L, Pizza M, Kimura A, Dull P (2011) Early clinical experience with a candidate meningococcal B recombinant vaccine (rMenB) in healthy adults. Hum Vaccin 7(7):781–791
Kimura A, Toneatto D, Kleinschmidt A, Wang H, Dull P (2011) Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates. Clin Vacc Immunol 18(3):483–486
Read RC, Baxter D, Chadwick DR, Faust SN, Finn A, Gordon SB, Heath PT, Lewis DJM, Pollard AJ, Turner DPJ et al (2014) 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 384(9960):2123–2131
Vesikari T, Esposito S, Prymula R, Ypma E, Kleinschmidt A, Toneatto D, Kimura A, Dull P (2011) Use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in a clinical trial in 3630 infants. Arch Dis Child 96(Suppl 1):A3–A3
Anonymous (2014) Princeton University can import vaccine to combat meningitis outbreak. Clin Infect Dis 58(3):i. (United States)
Dull P, Pizza, M, Toneatto D, De Tora L, Ypma E, Kleinschmidt A, Kimura A (2010) Early clinical development of a novel, multicomponent meningococcal serogroup B vaccine (4CMenB). Can J Infect Dis Med Microbiol 21(4):183–184
Dull P, Wang H, Annett Kleinschmidt A, Toneatto D, Kimura A, Dull P, Wang H (2010) Immunogenicity and safety of a recombinant meningococcal serogroup B vaccine and a quadrivalent conjugate vaccine in laboratory workers. Can J Infect Dis Med Microbiol 21(4):182–183
Esposito S, Vesikari T, Kimura A, Ypma E, Toneatto D, Dull P (2010) Tolerability of a three-dose schedule of an investigational, multicomponent meningococcal serogroup B vaccine and routine infant vaccines in a lot consistency trial. Can J Infect Dis Med Microbiol 21(4):183
Thorel M, Fummi C, Chavade D, Massy N, Dagostino C, Andréjak M, Gras V (2014) A new signal of pharmacovigilance: persistent indurations with meningococcal B vaccine. Fundam Clin Pharmacol 28:98
Vesikari TE, Esposito S, Kimura A, Kleinschmidt A, Ypma, E, Toneatto D, Dull P (2010) Immunogenicity of an investigational multicomponent meningococcal serogroup B vaccine in healthy infants at 2, 4 and 6 months of age. Can J Infect Dis Med Microbiol 21(4):183
Vesikari TE, Esposito S, Prymula R, Ypma, E, Kleinschmidt, A, Toneatto D, Kimura A, Dull P (2011) Use of an investigational multicomponent meningococcal serogroup B vaccine (4cmenb) in a clinical trial in 3630 infants. Arch Dis Child 96:3
Vesikari TE, Esposito S, Prymula R (2013) Erratum: Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. (Lancet (2013) 381 (825–836)). Lancet 381(9869):804
Wassil J, McIntosh EDG, Serruto D, DeTora L, Bröker M, Kimura A (2012) The early clinical development of a multicomponent vaccine against meningococcal serogroup B. Clin Investig 2(5):503–517
De Serres G, Gariépy M-C, Billard M-N, Rouleau I, Buolianne N, Toth E, Gagné H, Bilodeau C, Dubé E, Vivion M et al (2014) Preliminary surveillance report on the safety of meningococcal serogroup B vaccination in Saguenay—Lac-Saint-Jean. Abstract and Poster at the Canadian Immunization Conference 2014. Ottawa
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
W. Hellenbrand, J. Koch, T. Harder, C. Bogdan, U. Heininger, T. Tenenbaum, M. Terhardt, O. Wichmann, R. von Kries declare no conflict of interest. U. Vogel receives kits from GSK to perform MATS testing on German strains for scientific collaboration as well as for timely testing of circulating strains to determine vaccine strain coverage.
Appendices
Annex 1
Key results on immunogenicity of 4CMenB (Bexsero®) vaccination as reported in licensure studies
Annex 2
Evaluation of the reactogenicity and safety of the 4CMenB vaccine (Bexsero®)
Methods
To perform a systematic review of the reactogenicity and safety of 4CMenB vaccine, we defined “PICO” (Population, Intervention, Comparator and patient relevant outcomes) according to the recommendations of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. Persons of all ages were defined as the population for inclusion, vaccination with 4CMenB was defined as the intervention, vaccination with placebo or with another vaccine or no vaccination were defined as comparators. Outcomes were classified according to their importance for decision making, using a scale of 1–9. Outcomes rated from 7 to 9 and 4 to 6 were classified as “critical” and “important”, respectively. In infants and toddlers, fever, seizures, Kawasaki syndrome and hospitalization for clarification/treatment of adverse events (AE) were classified as critical outcomes. Severe local pain and vomiting were classified as important outcomes. In adolescents and adults, seizures, Guillain-Barré syndrome (GBS), juvenile arthritis (JA), seizures and acute disseminated encephalomyelitis (ADEM) were classified as critical, and fever, severe local pain and headache as important. The working group decided to define a temperature threshold for comparing intervention and comparator groups after taking into account the location of temperature measurements and thresholds used in available studies retrieved in the literature search.
Relevant studies published since 2010 addressing outcomes classified as “critical” or “important” were identified according to evidence-based criteria in a systematic literature search via the DIMDI portal using the searchstring “f ((MenB vaccin? or 4CMenB or Bexsero) or (meningococc? and (serogroup B) and (vaccin? or immuni?ation))) AND PY > 2009”.The literature search was performed using the following databases: Cochrane, MEDLINE, EMBASE, SciSearch, GLOBAL Health, BIOSIS Previews.
Two reviewers independently screened the titles and abstracts of the retrieved references. All full texts of publications considered relevant by at least one of the two reviewers were examined in detail and a consensus then reached regarding their inclusion.
Relevant data were systematically extracted using a standardized form, and the internal and external validity of the included studies assessed. Data pertaining to outcomes classified as “critical” or “important” were extracted from the studies and entered into the Review Management Software Review Manager (Version 5.2, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). When data were available from several studies without significant heterogeneity these were pooled for meta-analysis. The data were imported into the computer software GRADEprofiler (version 3.6) to create a GRADE evidence profile that was also used for calculation of the risk differences. The quality of evidence of all included studies was assessed for each outcome according to the following criteria: study design, heterogeneity, precision, indirect evidence, strength of effect and publication bias. The lowest quality of evidence for any of the critical outcomes was used to classify to overall level of quality of the evidence.
Results
4.1 Systematic literature search
A total of 576 abstracts were retrieved in our literature search after removal of duplicates. Screening of the titles and abstracts led to identification of 25 potentially relevant publications [35, 37, 44–48, 116, 121, 122, 124–137]. Of these, 5 fulfilled the inclusion criteria [35, 37, 44, 116, 128]. Fig. 3 shows the results of the literature search as a flowchart. None of the included studies reported on the safety of 4CMenB in persons with an increased risk for invasive meningococcal disease (IMD) related to underlying medical conditions.
4.2 Description of included studies
All five studies included in the review of reactogenicity and safety were randomized controlled studies funded by Novartis Vaccines. With the exception of a sub-study in [37] and the adolescent study [44], the study participants (or their parents) knew which vaccines were administered. Blinding may also have been incomplete in the adolescent study since the study staff administering the vaccines was aware of the group assignments. Key aspects of the studies included in this review are summarized in Tables 5 and 6. As data was not available in all studies on all outcomes classified as “important” or “critical”, we considered further, related outcomes for descriptive analysis: Thus, in addition to hospitalization, we looked at the outcome “Medical treatment for vaccination reactions” (see Table 5 and 6). In addition, we considered the outcome “Administration of antipyretics and analgesics”, as we considered this relevant for the interpretation of the data on febrile reactions and pain. Data on some of the outcomes classified as critical were not or only incompletely addressed in the 5 included studies– sometimes presumably because they did not occur. For instance, studies did not report consistently on how long after vaccination the few reported seizures occurred. In addition differentiation between febrile and non-febrile seizures was not always clear. For these reasons, and because study sizes did not permit assessment of very rare AE, it was not possible to evaluate the outcomes seizures, KS, hospitalizations for AE, JA, GBS and ADEM based on GRADE. Relevant available data were therefore not included in the GRADE profile, but only listed in Tables 5 and 6.
Data on the outcomes fever, severe local pain and vomiting in infants and toddlers were included in the GRADE profile [35, 37]. Both studies allowed comparison between reactogenicity after 4CMenB plus routine vaccinations versus after routine vaccinations alone at the ages of 2, 4 and 6 months. Vesikari et al. [37] presented the number of study participants who had experienced the respective safety outcome after at least one of the received vaccine doses, while Gossger et al. [35] presented the number of events per dose administered. Because the incidence of the safety outcomes after each of the three doses in the Gossger study was similar (see Fig. 4), only the number of events after the 1st dose were considered in the review to enable use of the same denominator (number of study subjects and not number of all administered doses) for data from both studies. In addition, the study by Gossger et al. [35] permitted the comparison between 4CMenB alone at ages of 2, 4 and 6 months and routine vaccinations alone at ages of 3, 5 and 7 months. In Vesikari et al. [37], a fourth 4CMenB dose was also administered at age 12 months with or without MMRV, but without a comparator group. The objective of the 3rd, much smaller study by Prymula et al. [116], was to evaluate the immunogenicity and reactogenicity of 4CMenB + routine vaccines with and without prophylactic administration of paracetamol; thus an appropriate comparator group was lacking and the study could not be included in our evaluation. None of the 3 studies allowed a comparison between 4CMenB alone and placebo, which would have been necessary for a completely unbiased description of the reactogenicity of 4CMenB.
A single study each in adolescents [44] and adults [128] was included for evaluation of the outcomes fever, severe local pain and headache after administration of 2–3 doses of 4CMenB alone versus placebo. In the adult study, one comparator group received 2 doses of the Japanese encephalitis vaccine Ixiaro®. The other comparator group received the quadrivalent meningococcal conjugate vaccine as a first dose and placebo as a 2nd dose. Therefore, safety outcomes observed in recipients of the 2nd 4CMenB dose were compared with those observed in recipients of the placebo dose.
4.3 Evaluation of the reactogenicity and safety of 4CMenB in infants and toddlers
The results of the two studies included for evaluation of reactogenicity and safety outcomes in infants and toddlers showed that vaccination with 4CMenB+ routine vaccinations was associated with increased reactogenicity, particularly due to fever. Compared to vaccination with routine vaccines alone, the risk for fever, severe local pain and vomiting was significantly increased (see Forest plots Fig. 5 and GRADE profile Table 7). Because of significant heterogeneity of the absolute frequencies and relative and absolute risks for severe pain as well as for vomiting in Vesikari et al. [37] and in Gossger et al. [35] (see below) the data for these outcomes were not pooled. Fever following 4CMenB+ routine vaccinations occurred very frequently after 4CMenB plus routine vaccines (in 74 % of the vaccine doses), but only after 40 % of the vaccine doses with routine vaccinations alone. Thus if 1000 infants were to receive 4CMenB+ routine vaccinations, 335 (95 % CI: 254–419) more febrile reactions would occur than in 1000 children receiving routine vaccines only. Severe pain also occurred more frequently after 4CMenB + routine vaccinations than after routine vaccinations alone (see Fig. 5 and Table 7), but to a greater extent in the study by Vesikari et al. (29.2 vs. 7.7 %) than in the study by Gossger et al. (13.3 vs. 2.6 %). Vomiting occurred more frequently after 4CMenB+ routine vaccinations than after routine vaccinations alone only in the study by Vesikari et al. (26.7 vs. 17.5 %, see Fig. 5 and Table 7).
The definition for high fever varied in the included studies. In Gossger et al. [35] 11.5 % (72/624) of infants developed an axillary temperature of ≥ 39.0 °C after the 1st dose of 4CMenB + routine vaccinations in the 7 days following vaccination, while this was the case in only 3.5 % (11/311) of infants who received routine vaccinations alone (RR = 3.26, 95 % CI: 1.76–6.06; risk difference (RD) = 100/1000, 95 % CI: 80–130). In Vesikari et al. [37] 1.2 % of infants developed a rectal temperature ≥ 40.0 °C after at least one of the doses of 4CMenB + routine vaccinations in the 6 h following the vaccination while this was the case for none (0/659) of the children who received routine vaccinations alone (RR = 15.77, 95 % CI: 0.96–257.78); RD = 10/1000, 95 % CI: − 10–30). In addition to varying temperature thresholds and observation periods in the two studies, the frequent receipt of antipyretics in Vesikari et al. (see Table 5) might also explain the more seldom occurrence of high fever; however data on receipt of antipyretics are lacking in Gossger et al.
Data from Gossger et al. [35] also permitted a comparison between infants who were vaccinated with 4CMenB only and infants vaccinated with routine vaccinations only. For this comparison, the risk of fever after the 1st dose of 4CMenB was 38.0 % (238/627), still significantly higher than after routine vaccinations (30.9 % (96/311) RR = 1.23, 95%CI: 1.01–1.49). The absolute risk was, however, markedly lower than with concomitant vaccination (74 %, see above). After 4CMenB alone the risk for severe pain in the vaccinated extremity was 10.2 % (64/626), also significantly higher than after routine vaccinations alone (2.6 % (8/310) RR = 4.0, 96 % CI 1.9–8.2). This absolute risk of 10.2 % as well as the risk difference (76/1000, 95 % CI: 47–106), were, however, somewhat lower than for the comparison of concomitant vaccination with routine vaccines alone (13.3 % and 110/1000, respectively, see Fig. 5 and Table 5). No significant difference was observed in the occurrence of vomiting after 4CMenB alone and routine vaccinations alone (14.2 vs. 13.6 %). Although the evidence from these two studies was rated low quality due to a number of methodological weaknesses (see below), these results do suggest that 4CMenB vaccination of infants is associated with higher reactogenicity as shown in the more frequent occurrence of local pain and fever than vaccination with routine vaccines. The reactogenicity of concomitant vaccination with 4CMenB + routine vaccinations was higher still, reflected particularly in a high rate of febrile reactions that occurred in over 70 % of vaccinated infants. In both studies, temperature peaked after 6 h and had normalized 2 days after vaccination in the majority of cases [35, 37].
The evidence quality of all considered outcomes was downgraded by one level in the included infant studies due to indirectness (simultaneous administration of other vaccinations as well as lack of placebo comparison). In addition, the reactogenicity outcomes were measured/observed by the parents. Together with their knowledge of what vaccines their child received (with the exception of a subgroup of parents in Vesikari et al.; in this case, however, the vaccinating staff was not blinded), this increased the risk of bias and therefore led to downgrading of the evidence quality for all outcomes by an additional level. Finally, the studies showed major heterogeneity for the outcomes “severe local pain” and “vomiting” (I2 = 84 % and 79 % respectively). Thus the data could not be pooled and the quality of evidence was further downgraded for these outcomes. The overall evidence underlying the review for infants and toddlers was therefore rated as “low” (see Table 7).
The 3 additional outcomes seizures, Kawasaki syndrome and hospitalization, all rated as critical, were not included in a GRADE profile for reasons outlined above (and see Table 5). Data on medical consultations (Table 5) for fever were available in Vesikari et al. and revealed a lower treatment rate in the non-blinded than in the observer-blinded sub-study. The medical consultation rate for fever after 4CMenB plus routine vaccinations was higher (5.3 %) than after routine vaccinations plus MenC vaccination (2.8 %, p = 0.07 (Fischer exact) only in the observer-blinded sub-study. Although febrile convulsions or seizures with fever were reported more frequently after 4CMenB (+/− routine vaccines) than after routine vaccines (see Table 5), the small number of observed febrile convulsions after 4CMenB vaccination does not suggest a highly elevated risk of seizures due to the 4CMenB vaccination. However, the frequent receipt of paracetamol could have influenced the risk for seizures. Furthermore, to ensure sufficient power for detection of increased risk for very rare AE, a much higher case number would have been necessary. Consequently, as detailed in the Risk Management Plan (RMP), EMA requires more precise investigation of the risk for anaphylaxis/anaphylactic shock, Kawasaki syndrome, seizures and febrile seizures in a post-licensure observational safety surveillance study (V72_36OB [7].
4.4 Evaluation of the reactogenicity and safety of the 4CMenB vaccine in adolescents and adults
The 2 studies with results on reactogenicity and safety in adolescents [44] and adults [128] were considered separately because they were conducted on different continents, there was no overlap in the ages of the enrolled study subjects, and the reported frequencies of reactogenicity outcomes differed markedly. In the adolescent study, safety outcomes were presented as the total number of events in relation to the total number of vaccine doses administered and not, as in the other studies, in relation to the number of vaccinated study subjects. Thus vaccine doses administered to the same study participant were regarded as independent events, effectively tripling case numbers and leading to unduly narrow confidence intervals.
Fever, severe local pain and headache occurred significantly more frequently compared to placebo vaccination after 4CMenB vaccination in adolescents, while in adults this applied only to the latter two outcomes (see Fig. 6 and 7; Tables 8 and 9). As in the infant studies, the use of antipyretics was relevant to the interpretation of febrile reactions in the studies: In the adult study [128], 4 % of vaccine recipients took antipyretics prophylactically for the 1st dose of 4CMenB and 9 % for the 2nd dose and a further 19 and 21 %, respectively, took antipyretics therapeutically. For the placebo dose, 3 % took antipyretics prophylactically and 6 % therapeutically. In the adolescent study [44] antipyretic use was reported by 4 and 2 % of the adolescents vaccinated with 4CMenB or placebo, respectively. This difference possibly explains the higher rate of fever after the 4CMenB vaccination in adolescents (3.7 %) vs. adults (1.9 %). In any case, at < 4 %, the rates of fever in adolescents and adults were very much lower than in infants. Severe local pain also occurred somewhat less often than in infants, following 16.9 % (adolescents) of 4CMenB doses in adolescents and in 8.3 % of adults. Again, the lower incidence of severe pain in the adult study might be due to their more frequent use of antipyretics. The risk differences between the 4CMenB and the placebo groups were markedly increased in both adolescents and adults for severe pain (131 and 64 more events/1000 vaccinations) and headache (with 154 and 91 more events/1000 vaccinations, see Table 8 & 9).
In addition to fever, local pain and headache seizures, GBS and ADEM, and JA were also classified as critical outcomes for older children and adults when PICO were defined. Of the latter four, only seizures and JA were mentioned in the two available studies [44, 128]; thus presumably none of the other 2 safety outcomes was observed. In the 1622 adolescents vaccinated with ≥ 1 dose of 4CMenB, 1 convulsion was observed in a participant after the first 4CMenB dose; this participant reported a family history of epilepsy. In addition, also in the adolescent study, 2 cases of JA occurred 170–198 days following a 3rd dose of 4CMenB; in the 1st case, joint pain and tendinitis had occurred once before in the past. No cases occurred after placebo vaccination. A causal association with the vaccine was therefore assessed by the authors as possible for the 2nd case and probable for the 1st. A much larger study would be necessary to demonstrate a statistically significant association. It should be noted in this context, however, that arthralgia occurred after approximately. 24 % of the administered 4CMenB doses, but only after approximately. 13 % of the placebo doses (percent values taken from Fig. 5 taken in [44]). Additional serious adverse events (SAE) observed in the studies are listed in Table 10.
The quality of evidence of the adolescent study was downgraded by one level due to the increased risk of bias present due to non-blinding of the personnel administering the vaccines. Because the reactogenicity outcomes were presented in relation to the total number of doses and not to study subjects, the quality of evidence was further downgraded to “low”, due to indirectness.
Since in the adult study only 600 study participants were included for observation of reactogenicity and safety, confidence intervals for the RR pertaining to the outcomes fever and headache were very wide (and spanned 1 for fever) due to low event counts. Therefore, the quality of evidence was downgraded due to imprecision. Due to an additional elevated risk of bias attributed to non-blinding of the study personnel administering the vaccines, quality of evidence was further downgraded to “low” for all outcomes.
In the Risk Management Plan, EMA stipulated that—in addition to the aforementioned safety-relevant outcomes of anaphylaxis/anaphylactic shock, Kawasaki syndrome, seizures and febrile seizures for infants and toddlers—the risk of GBS and ADEM after 4CMenB vaccination should be evaluated more precisely by means of a post-licensure observational safety surveillance study (V72_36OB) [7].
Postmarketing Surveillance
No publications reporting on postmarketing surveillance of Bexsero® following licensure were identified in the literature search. However, through communication with colleagues, a report on active surveillance of possible AE following a vaccination campaign in Saguenay-Lac-St-Jean, Québec (Canada) with longstanding increased incidence of MenB IMD caused by a ST-269 meningococcal B clone was identified. AE were ascertained in the 7 days following MenB vaccination in 0–20-year-old persons. [53]. Of 43,740 persons who had received a dose of 4CMenB in May and June 2014, 28 % completed a questionnaire on the occurrence of AE. The primary objective of the survey was to determine in real time the frequency of absences from work/school/day care and medical consultations attributable to the vaccine in the 7 days after vaccination. In addition, the questionnaire was designed to ascertain the frequency of vaccine-related fever, the effect of prophylactic antipyretics on the risk of fever, febrile convulsions and severe arthralgias. Finally, the influence of AE on the responders’ intention to obtain the second dose of Bexsero® was investigated. Active surveillance was supplemented by the already established passive surveillance system for the reporting of adverse drug reactions, through which physicians were legally obliged to report, all unusual clinical manifestations following vaccinations.
The interpretation of the reported AE must take into account that antipyretics (most commonly as paracetamol) were taken prophylactically by 70 % of all study subjects. Use of antipyretics was highest at 93 % in vaccine recipients under 2 years of age, and declined with age to 43 % in > 17-year-olds.
In participants of the active surveillance study, fever within 7 days after 4CMenB vaccination occurred in 10.9 % of vaccine recipients; most often in < 2-year-olds at 14 %, followed by 12 % in 2–4-year-olds and 6.8 % in older children and adolescents. In < 2-year-olds, fever occurred more often when 4CMenB was administered concomitantly with other vaccines (19 vs. 13 %, p = 0.09). The incidence of fever following the 4CMenB vaccination in children < 2 years of age was lower in those who had taken antipyretics than in those who had had not: 14 % versus 31 % in 2–11-month-old children and 13 versus 23 % in 2–11-month-olds, p < 0.001. Two or more doses of antipyretic led to a greater reduction than only one dose, but only in children under 2 years of age. In children aged 5 and over, antipyretics were no longer associated with a reduction in the occurrence of fever. In children < 2 years of age with co-administration of other vaccines, fever was reported in 7/11 (64 %) children who had not received any antipyretics, in 22/64 (34 %) who had received one dose of antipyretics and in 38/268 (14 %) who had received ≥ 2 doses (p < 0.001). The highest mean temperature was 38.9 °C and did not vary significantly with age. Less than 1 % reported fever ≥ 40.5 °C (rectal). The median duration of fever was 2 days. One febrile convulsion was recorded in a 1-year-old child through active surveillance and an additional febrile convulsion in a 6-month-old child through passive surveillance in a total of 3886 with children < 2 years of age vaccinated with 4CMenB. This was fewer cases than expected based on the incidence of febrile convulsions in the licensure studies after 4CMenB. The almost universal prophylaxis with antipyretics may have played a role here.
Arthralgia was reported by 113 vaccine recipients; however, following contact with a nurse, only 5 of these were rated as severe. None of these were associated with warmth, reddening or swelling, signs suggestive of arthritis. However, the observation period was too short to exclude the occurrence of later-onset arthritis with certainty.
Absenteeism of the vaccine recipient or their carers due to fever, malaise or local side effects that occurred within 7 days after vaccination were reported by 6.0 % of responders and 1.2 % reported having consulted a physician because of an AE in this time interval. In addition, 4 hospitalizations > 24 h duration were reported after the 1st 4CMenB dose, but none apparently causally associated with the vaccine. Of all responders, 99 % reported that they intended to receive the 2nd 4CMenB vaccination dose, but this proportion was lower among those who had reported medical consultations or absences due to the 4CMenB vaccination at 92 %.
No cases of GBS, ADEM or Kawasaki-syndrome (KS) were ascertained through the active or the the passive surveillance system. As the authors discuss, however, with only 12,500 vaccinated children ≤ 5 years of age, an expected KS incidence in Saguenay-lac-St. Jean of < 8/100,000 children ≤ 5 years of age and the short observation time in both surveillance systems, the power of the study was insufficient to exclude a slightly increased risk of KS through the vaccine [53].
Further results on the monitoring following additional 4CMenB vaccine doses in Saguenay-Lac-St-Jean were presented in the final report of the active surveillance study [139]. The observations after a 2nd dose of Bexsero® differed as follows from those after the 1st dose: Fever occurred more frequently (11 vs. 9 %, p < 0.001). While after the 1st dose, vaccine recipients taking antipyretics reported fever 49 % less frequently than vaccine recipients who had not taken antipyretics, after the 2nd dose this the case for only 35 % of those taking antipyretics. Absences or medical consultations due to AE occurring in the 7 days after vaccination were reported more frequently after the 2nd dose (9.0 %) than after the 1st dose (6.0 %). After the 2nd dose, there were 4 reported hospitalizations, for conditions possibly related to the vaccine: One case of anaphylaxis following concomitant vaccination with hepatitis A vaccine and Bexsero® and one febrile convulsion following vaccination with Bexsero®.
Since availability of Bexsero® in Germany, a total of 770 AE were reported to PEI on 218 vaccine recipients via the passive reporting system, including 8 seizures (of these 4 febrile convulsions) and one anaphylactic shock reaction. No significant safety signals for Bexsero® were detected in the routine analyses performed at PEI on AE reports after vaccinations (Keller, May 2015, personal communication).
Rights and permissions
About this article
Cite this article
Hellenbrand, W., Koch, J., Harder, T. et al. Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease. Bundesgesundheitsbl. 58, 1314–1343 (2015). https://doi.org/10.1007/s00103-015-2253-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00103-015-2253-z