Serum samples from children immunized with a meningococcal serogroup B vaccine demonstrated potent serum bactericidal antibody activity against the hypervirulent Neisseria meningitidis serogroup W strain circulating in England. The recent introduction of this vaccine into the United Kingdom national immunization program should also help protect infants against this endemic strain

Alessia Biolchi

Araya

Campbell

Christensen

Comanducci

Frosi

Gossger

Hahné

Isaacs

Jamie Findlow

Jay Lucidarme

Kazim Beebeejaun

Ladhani

Mariagrazia Pizza

Mary E. Ramsay

Marzia Monica Giuliani

Parent du Châtelet

Ray Borrow

Read

Shamez N. Ladhani

Vogel

Emerging Infectious Diseases

PubMed

Ladhani, SN

Giuliani, MM

Biolchi, A

Pizza, M

Beebeejaun, K

Lucidarme, J

Findlow, J

Ramsay, ME

Borrow, R

St George's Online Research Archive

Shamez N. Ladhani, Marzia Monica Giuliani, Alessia Biolchi, Mariagrazia Pizza,  Kazim Beebeejaun, Jay Lucidarme,  Jamie Findlow, Mary E. Ramsay, Ray BorrowSerum samples from children immunized with a meningo-coccal serogroup B vaccine demonstrated potent serum bactericidal antibody activity against the hypervirulent Neis-seria meningitidis serogroup W strain circulating in England. The	recent	introduction	of	this	vaccine	into	the	United	King-dom national immunization program should also help pro-tect infants against this endemic strain.Invasive meningococcal disease (IMD) has been declin-ing in the United Kingdom since the early 2000s (1). His-torically, serogroup W Neisseria meningitides meningo-cocci (MenW) have been causal organisms for 1%–2% of IMD cases annually. An increase in invasive MenW disease associated with travel to the Hajj pilgrimage route during 2000–2002 was rapidly controlled after the introduction of mandatory vaccination for pilgrims (2). Since 2009, how-ever, laboratory-confirmed MenW cases in England have increased each year across all age groups after rapid spread of a single endemic hypervirulent sequence type (ST) 11 clonal complex (MenW:cc11) strain (3). This strain has caused severe illness with unusual clinical manifestations and, for the first time in more than a decade, was associated with fatal outcomes among infants and young children.Since the Hajj outbreak, several countries in Latin America, Africa, and the Far East have reported an increase in MenW disease and ongoing endemic transmission (3). In Chile, MenW has replaced serogroup B (MenB) as the most prevalent cause of IMD, identified in 58% of cases in 2012 (4). In Europe, an increase in MenW disease has not been observed in other countries although, in 2012, a clus-ter of cases related to MenW:cc11 in France was associated with travel to sub-Saharan Africa (5).In England, the meningococcal quadrivalent conju-gate vaccine (MenACWY, covering serogroups A, C, W, and Y) has historically been recommended for high-risk persons and travelers to disease-endemic regions and for controlling outbreaks (6). Beginning on September 1, 2015, a novel, protein-based, multicomponent vaccine, Bexsero (GSK Vaccines, Siena, Italy), has been offered as part of the routine immunization program in the United Kingdom; the vaccine is given to infants in 3 doses at 2, 4, and 12 months of age (https://www.gov.uk/government/publications/menb-vaccination-introduction-from-1-sep-tember-2015). Bexsero is composed of NHBA (neisserial heparin binding antigen), NadA (Neisseria adhesin A) and fHbp (factor H binding protein), with meningococ-cal outer membrane vesicles from an MenB strain from an outbreak in New Zealand (7). Immunization with Bex-sero induces bactericidal antibodies against all vaccine antigens (8). Although this vaccine has been licensed for prevention of MenB disease (the most prevalent capsu-lar group causing IMD in Europe), alleles for some or all of the vaccine antigens are also found among non-MenB meningococci, independently of the capsule. Therefore, antibodies raised by these antigens could induce comple-ment-mediated killing of other meningococcal groups, in-cluding the endemic MenW cc11 strain. Recently, we reported the predominance of non–cross-protective PorA (P1.5,2) and fHbp variants (variant 2 peptide 22) among endemic MenW:cc11 isolates (3). The other primary Bexsero antigens (NadA and NHBA), however, could potentially afford protection. We there-fore assessed 1) the NadA and NHBA genotypic status of endemic MenW:cc11 isolates, and 2) the serum bacteri-cidal antibody (SBA) activity against clinical MenW:cc11 isolates using serum samples from infants immunized with Bexsero.The StudyA total of 73 invasive MenW:cc11 isolates from England and Wales were received by the Public Health England Me-ningococcal Reference Unit during July 2010–June 2013. These isolates were queried within the Meningitis Research Foundation Meningococcus Genome Library (http://pubmlst.org/perl/bigsdb/bigsdb.pl?db = pubmlst_neisse-ria_mrfgenomes) for nadA and nhba and, where present, their respective allelic and peptide variants.Effectiveness of Meningococcal B Vaccine against Endemic Hypervirulent  Neisseria meningitidis W Strain, England	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	22,	No.	2,	February	2016	 309Author	affiliations:	St.	George’s	University	of	London	Paediatric	Infectious	Diseases	Research	Group,	London,	UK	(S.N.	Ladhani);	Public	Health	England,	London	(S.N.	Ladhani,	K.	Beebeejaun,	M.E.	Ramsay);	GSK	Vaccines,	Siena,	Italy	(M.M.	Giuliani,	 A.	Biolchi,	M.	Pizza);	Public	Health	England,	Manchester,	UK	 (J.	Lucidarme,	J.	Findlow,	R.	Borrow)DOI:	http://dx.doi.org/10.3201/eid2202.150369DISPATCHESWe used an SBA using human complement (hSBA) against 6 invasive MenW:cc11 isolates from patients 4 months–91 years of age in whom meningitis or septicemia was diagnosed in different regions of England and Wales during 2011–2012. SBA titers were expressed as the recipro-cal of the serum dilution corresponding to >50% bacterial killing. We used pooled serum samples from phase 2 clinical trials involving infants immunized with Bexsero at 2, 3, and 4 months or 2, 4, and 6 months and after administration of a booster at 12, 18, or 24 months (8). Pooled prevaccination serum samples from 180 infants were used as negative con-trols, and pooled serum samples from 10 randomly selected adolescents who received a single MenACWY conjugate vaccine (GSK Vaccines) dose as positive controls.Of the 6 isolates tested, 4 possessed nadA allele 5 (for peptide NadA-2/3.6) and nhba allele 17 (for NHBA peptide 29). Of the remaining 2 isolates, 1 isolate had a nadA allele (allele 146) that differed at a single nucleotide (C476A), causing a single amino acid change (T159K; peptide NadA-2/3.130); the other isolate had an nhba allele (allele 72) that differed at a single nucleotide (A376C), causing a single amino acid change (T126P; peptide 96).hSBA titers were high and were >1:32 against all 6 MenW isolates, independently of the immunization sched-ule (Table). After the booster, higher hSBA titers were ob-tained than those from primary immunization, and similar responses were comparable to those among adolescents who had received a single MenACWY dose. Preimmuni-zation serum samples showed no detectable hSBA titers against any of the 6 isolates (Table).ConclusionsThe ability of the antibodies raised by Bexsero antigens to induce SBA activity against any given meningococcal isolate depends on the presence, level of surface expres-sion, and sequence diversity of the respective antigens. Bexsero strain coverage can be predicted by using the Meningococcal Antigen Typing System, an ELISA which measures the level of antigen expression and antigenic di-versity compared with the antigen in the vaccine (9). How-ever, the correlation between the relative potency estimated by this typing system and the ability of a meningococcal isolate to be killed by serum from immunized persons has only been defined for MenB strains. We found that MenW:cc11 isolates causing invasive disease in England and Wales possessed alleles for NadA-2/3 peptide variants that are predicted to be highly cross-pro-tective with the Bexsero NadA variant (10). The isolates also possessed alleles for NHBA peptide 29 which, although dif-ferent from peptide 2 in Bexsero, has the potential to induce cross-protection even if NHBA-containing cross-protective epitopes have not been defined yet. Antibodies against Bexsero antigens can act synergistically and, therefore, the complement-mediated bactericidal killing observed could be mediated by antibodies against NadA, NHBA, or both.In England, the ongoing MenW increase is similar to the MenC:cc11 outbreak in the mid-1990s, which was eventually controlled through mass vaccination (11). The increase in MenW cases has led to the rapid introduction of a national adolescent MenACWY conjugate vaccination program in August 2015 (https://www.gov.uk/government/news/new-meningococcal-vaccination-programme-ex-pected-to-save-lives). In adolescents, a single MenACWY dose would provide direct protection and, by targeting the age group most likely to carry meningococci (12), could also provide indirect protection against MenW (Figure) and the other 3 capsular groups by reducing carriage and onward transmission to others.310	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	22,	No.	2,	February	2016   Table. Bactericidal antibody titers in pooled serum samples from	infants	vaccinated	with	Bexsero	and	adolescents	immunized	with	Menveo	against	6	invasive	clinical	Neisseria meningitidis serogroup	W	isolates	in	England	and	Wales,	UK,	during	2011–2012* Isolate Adolescents receiving Menveo  Infants	receiving	Bexsero Positive control† Negative	control‡ Pool	1§ Pool	2¶ Pool 3# Pool	4** Before After M11–240417 <16 256  <2 64 128 >128 >128 M11–240427 <16 128  <2 32 32 64 64 M11–240802 <16 512  <2 32 >64 >64 >64 M12–240016 <16 256  <2 32 32 64 128 M11–240798 <16 512  <2 >64 >64 >64 >64 M12–240754 <16 256  <2 64 64 >64 >64 *Human	serum	bactericidal	antibody	titers	against	6	meningococcal	group	W	clinical	isolates	belonging	to	ST-11	clonal	complex	using	pooled	serum	from	adolescents	immunized	with	the	MenACWY	conjugate	vaccine,	Menveo,	and	from	infants	immunized	with	the	protein-based, multicomponent meningococcal vaccine,	Bexsero. †Pooled serum samples from adolescents 11–17	years	of	age	before	and	1	month	after	receiving	a	single	dose	of	MenACWY	(Menveo)	conjugate	vaccine	(n	=	10). ‡Pooled prevaccination serum samples from infants at 2 months of age (n = 180) (control). §Pooled	serum	samples	from	infants	who	received	3	doses	of	vaccine	at	2,	3,	and	4	months	of	age	and	had	a	blood	sample	taken	1	month	after	the	last	dose	of	vaccine	(n	=	56). ¶Pooled	serum	samples	from	infants	who	received	3	doses	of	vaccine	at	2,	4,	and	6	months	of	age	and	had	a	blood	sample	taken	1	month	after	the	last	dose	of	vaccine	(n	=	47). #Pooled	serum	samples	from	infants	who	received	3	doses	of	vaccine	at	2,	4,	and	6	months	of	age	plus	a	booster	at	12	months	and had a	blood	sample	taken	1	month	after	the	booster	(n	=	72). **Pooled	serum	samples	from	an	additional	cohort	of	infants	who	also	received	3	doses	of	vaccine	at	2,	4,	and	6	months	of	age plus a booster	at	12	months	and	had	a	blood	sample	taken	1	month	after	the	booster	(n	=	94).  Meningococcal B Vaccine, EnglandConversely, infants would require >2 MenACWY dos-es starting at 2 months of age, because MenW cases increase from birth and peak at 7 months of age before declining. Bexsero, which is predicted to protect against 73%–88% of invasive MenB isolates in England and Wales (9,13), could offer additional protection against MenB, which causes more cases among infants and toddlers than the other meningococ-cal serogroups. Among infants (<1 year of age), 101 MenB cases were reported during 2014–2015, compared with 21 MenW, 4 MenY, and 1 MenC; among toddlers, (1–4 years of age), 139 MenB cases were reported, compared with 18 MenW, 5 MenY, and 0 MenC. The difference in adolescents (15–19 years of age) is less pronounced, but 36 MenB cases were reported in this age group during 2014–2015, com-pared with 25 MenW, 14 MenY and 3 MenC cases (https://www.gov.uk/government/uploads/system/uploads/attach-ment_data/file/476989/hpr38-3915.pdf). However, the ef-fectiveness of Bexsero against meningococcal carriage and, therefore, its ability to provide herd protection, which is a major objective of an adolescent programme, is less certain than with conjugate vaccines (14). These observations and our results support the recent implementation of both the adolescent MenACWY conjugate and infant MenB immu-nization programmes in the UK.J.F. and R.B. perform contract research on behalf of Public Health England for GSK, Novartis, Pfizer, Sanofi Pasteur and Sanofi Pasteur MSD, and S.N.L. performs contract research for the same companies on behalf of St. George’s University of  London. None of the authors have received any personal  remuneration. M.M.G., A.B., and M.P. are employees of GSK Vaccines, which manufactures the MenB vaccine, Bexsero.Dr. Ladhani is a pediatric infectious disease consultant and a clinical epidemiologist at Public Health England, London, United Kingdom. He is the clinical lead for enhanced national surveillance of several vaccine-preventable infections in England and Wales and has a particular research interest in the direct and indirect population impact of conjugate and other vaccines.References  1. Ladhani SN, Flood JS, Ramsay ME, Campbell H, Gray SJ,  Kaczmarski EB, et al. Invasive meningococcal disease in England and Wales: implications for the introduction of new vaccines. Vaccine. 2012;30:3710–6. http://dx.doi.org/10.1016/j.vaccine.2012.03.011  2. Hahné SJ, Gray SJ, Aguilera JF, Crowcroft NS, Nichols T,  Kaczmarski EB, et al. W135 meningococcal disease in England and Wales associated with Hajj 2000 and 2001. Lancet. 2002;359:582–3. http://dx.doi.org/10.1016/S0140-6736(02)07716-4  3. Ladhani SN, Beebeejaun K, Lucidarme J, Campbell H, Gray S, Kaczmarski E, 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. 2014; 578–85. http://dx.doi.org/10.1093/cid/ciu881   4. Araya P, Fernandez J, Del CF, Seoane M, Ibarz-Pavon AB,  Barra G, et al. Neisseria meningitidis ST-11 clonal complex, Chile 2012. Emerg Infect Dis. 2015;21:339–41. http://dx.doi.org/ 10.3201/eid2102.140746  5. Parent du Châtelet I, Barboza P, Taha MK. W135 invasive  meningococcal infections imported from Sub-Saharan Africa to France, January to April 2012. Euro Surveill. 2012;17.   6. Department of Health. Pneumococcal. In: Salisbury D, Ramsay M,  Noakes K, editors. Immunisation against infectious disease.  Norwick (UK): The Stationery Office; 2006 [updated 2011].  p. 295–313  7. Isaacs D, McVernon J. Introducing a new group B meningococcus vaccine. BMJ. 2014;348:g2415. http://dx.doi.org/10.1136/bmj.g2415  8. Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S,  et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine  infant vaccinations according to different immunization schedules:  a randomized controlled trial. JAMA. 2012;307:573–82.  http://dx.doi.org/10.1001/jama.2012.85  9. Vogel U, Taha MK, Vazquez JA, Findlow J, Claus H, Stefanelli P, et al. Predicted strain coverage of a meningococcal  multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis. 2013;13:416–25.  http://dx.doi.org/ 10.1016/S1473-3099(13)70006-910. Comanducci M, Bambini S, Brunelli B, Adu-Bobie J, Arico B, Capecchi B, et al. NadA, a novel vaccine candidate of  Neisseria meningitidis. J Exp Med. 2002;195:1445–54.  http://dx.doi.org/10.1084/jem.2002040711. Campbell H, Borrow R, Salisbury D, Miller E. Meningococcal  C conjugate vaccine: the experience in England and Wales.  Vaccine. 2009;27(Suppl 2):B20–9. http://dx.doi.org/10.1016/ j.vaccine.2009.04.06712. Christensen H, May M, Bowen L, Hickman M, Trotter CL.  Meningococcal carriage by age: a systematic review and  meta-analysis. Lancet Infect Dis. 2010;10:853–61. http://dx.doi.org/10.1016/S1473-3099(10)70251-613. Frosi G, Biolchi A, Sapio ML, Rigat F, Gilchrist S, Lucidarme J,  et al. Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS  underestimates 4CMenB vaccine strain coverage. Vaccine. 2013;31:4968–74. http://dx.doi.org/10.1016/j.vaccine.2013.08.00614. Read RC, Baxter D, Chadwick DR, Faust SN, Finn A, Gordon SB, 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;384:2123–31. http://dx.doi.org/10.1016/S0140-6736(14)60842-4Address for correspondence: Shamez Ladhani, Immunisation Department, Public Health England, 61 Colindale Ave, London NW9 5EQ, UK; email: shamez.ladhani@phe.gov.uk	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	22,	No.	2,	February	2016	 311Figure.	Age	distribution	of	all	laboratory-confirmed,	invasive	Neisseria meningitidis	serogroup	W	disease	cases	identified	in	England	during	July	2009–December	2014.

Effectiveness of Meningococcal B Vaccine against Endemic Hypervirulent Neisseria meningitidis W Strain, England

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Effectiveness of Meningococcal B Vaccine against Endemic Hypervirulent<i>Neisseria</i><i>meningitidis</i>W Strain, England

Shamez Ladhani

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Effectiveness of Meningococcal B Vaccine against Endemic Hypervirulent Neisseria meningitidis W Strain, England

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