1. Emerging Models of Protection
MenB Immunization
Emerging Models of Protection
Moderator
Shamez Ladhani, PhD, MRCPCH
St George's Hospital
University of London
London, United Kingdom
Introduction
00:00
MenB = meningococcal B

2. Kirsty le Doare, MBBS, MRCPCH
Faculty
Ulrich Heininger, MD
Head of Division of Pediatric Infectious Disease and Vaccinology
University Children's Hospital Basel, Basel, Switzerland
Kirsty le Doare, MBBS, MRCPCH
Senior Clinical Lecturer
Center of International Child Health
Imperial College London,
London, United Kingdom
00:22

3. Introduction Meningitis infection and sequelae Meningitis epidemiology
Protection against MenB infection
Examples of MenB vaccine programs
Communication strategies to address caregiver concerns about vaccination against MenB infection
00:42

4. Impact of Disease in Young Children
Neisseria meningitidis causes meningococcal disease
Invasive meningococcal disease (IMD)
Rapid progression, with an 8% to 15% case-fatality ratio[a]
Without treatment the case-fatality rate can be as high as 70%[b]
Incidence is highest in young children, with a second peak amongst adolescents and young adults[a]
Impact of Disease
00:54
N Engl J Med. 2001 May 3;344(18):
Meningococcal disease.
Rosenstein NE1, Perkins BA, Stephens DS, Popovic T, Hughes JM.
IMD = invasive meningococcal disease
a. European Centre for Disease Prevention and Control website. Factsheet about meningococcal disease.
b. CDC website. Epidemiology of meningitis.

5. Meningitis Sequelae
10% to 20% of survivors will develop major long-term sequelae
Deafness
Neurological deficit
Seizures
Limb amputation
Up to 36% of survivors may have deficits in physical, cognitive, and psychological function
01:38
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 recombinant protein vaccines. Hum Vaccin Immunother May 4;14(5): doi: / Epub 2018 Apr 30.
Villena R, et al. Hum Vaccin Immunother. 2018;14:

6. Meningitis Sequelae (cont)
02:30
Vaccine
Volume 30, Supplement 2, 30 May 2012, Pages B3-B9
Meningococcal disease: Clinical presentation and sequelae
DavidPaceaAndrew J.Pollardb
Pace D, et al. Vaccine. 2012;30(Suppl 2):B3-B9.

7. Meningitis Epidemiology by Serogroup
Serogroup A: China, India and Russia.[a] Was previously the predominant serogroup in Africa but has decreased significantly due to vaccination efforts[b]
Serogroup B: Europe, the Americas, and Australia[a,c]
Serogroups C and W: Africa, Latin America[a,c]
Serogroup Y: Nordic countries[c]
03:00
Trotter CL, et al. Impact of MenAfriVac in nine countries of the African meningitis belt, 2010–15: an analysis of surveillance data
Lancet 2017;17:
a. Harrison LH, et al. Clin Infect Dis. 2010;50:S37.
b. Trotter CL, et al. Lancet. 2017;17:
c. Peterson ME, et al. J Glob Health. 2019; 9:

8. Meningitis Epidemiology by Serogroup (cont)
B, C
A, C
B, C, Y A A
A, C, W-135, X
[04:13]
Harrison LH, The Epidemiology of Meningococcal Disease in the United States. Clin Infect Dis 2010;50:S37
Gabutti G et al. Epidemiology of Neisseria meningitidis infections: case distribution by age and relevance of carriage. J Prev Med Hyg 2015;56:E116-E120
B, C, Y
A, B, C, Y, W-135 B
B, C, W-135
Harrison LH, et al. Clin Infect Dis. 2010;50:S37.

9. Age Distribution of Meningitis Disease
Meningitis incidence is highest in infants with a second smaller peak in young adults
< 1
1-4
5-14
15-24
25-49
50-64
65+ 2 4 6 8 10
Age, y
Cases per 100,000 population
Male
Female
[04:37]
Ladhani SN, Ramsay M, Borrow R, et al. Arch Dis Child 2016;101:91–95.
Source: Country reports from Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the United Kingdom

10. How Is Meningitis Transmitted?
Neisseria meningitidis is an obligate human pathogen
Transmitted by aerosol or direct contact with respiratory secretions or saliva
Acquisition of meningococci can lead to
Transient carriage
Persistent colonization
Invasive disease
Most carriers are asymptomatic with the pathogen in their nasopharynx
Invasive meningococcal disease is rare
Carriage rates are highest in teenagers and young adults (up to 20% to 50%)
05:10
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 recombinant protein vaccines. Hum Vaccin Immunother May 4;14(5): doi: / Epub 2018 Apr 30.
Villena R et al. Hum Vaccin Immunother. 2018;14:

11. The Development of the MenB Vaccine
The Challenge
Capsular polysaccharide of serogroup B is poorly immunogenic due to its antigenic structure
Resembles glycosylated neural cell adhesion molecule, which is expressed in the developing human brain
Immunological tolerance
Antigenic mimicry raises the potential for the induction of autoimmunity
MenB Vaccines
06:25
Villena R, et al. Hum Vaccin Immunother. 2018;14:

12. Earlier versions Current versions MenB Vaccines
MeNZB® – meningococcal OMV vaccine
Current versions
Target MenB antigens: outer membrane proteins (OMPs); Por A
4CMenB
MenB-FHbp (or rLP2086)
07:14
OMP = outer membrane protein
Villena R et al. Hum Vaccin Immunother. 2018;14:

13. 4CMenB Vaccine
3 primary recombinant antigens obtained by "reverse vaccinology"
Factor H binding protein (fHbp)
Neisserial adhesin A (NadA)
Neisseria heparin binding antigen (NHBA)
+ OMV expressing PorA from the New Zealand strain, NZ PorA P1.4
07:32
fHbp = factor H binding protein
EMA = European Medicines Agency
NadA = neisserial adhesin A
NHBA = Neisseria heparin binding antigen
OMV = outer membrane vesicle
EMA 2013
Approved for infants ≥ 2 months old (3-dose schedule) Approved for children, adolescents, and adults (2-dose schedule)
Villena R, et al. Hum Vaccin Immunother. 2018;14:

14. MenB-FHbp Vaccine
Includes 2 variants of the surface-exposed fHpb protein
EMA 2017
Approved for ≥ 10 years old
(2-dose schedule, 0 and 6 months) or
(3-dose schedule, 0, 1 to 2, and 6 months) for persons with higher risk of infection
07:58
Villena R, et al. Hum Vaccin Immunother. 2018;14:

15. WHO: Defeating Meningitis by 2030 -- Call for Action
Prevention and epidemic control
Diagnosis and treatment
Disease surveillance
Support and care for patients and families
Advocacy and engagement
08:30
WHO website. Meningococcal meningitis.

16. WHO: Defeating Meningitis by 2030 -- Call for Action (cont)
Healthier Populations
1 billion more people enjoying better health and well-being
Health Emergencies
1 billion more people better protected from health emergencies
Universal Health Coverage
1 billion more people benefitting from universal health coverage
Engage civil societies and communities
Address country priorities through
evidence to policy and impact
Detect meningitis epidemics
through strengthened surveillance
Control meningitis
epidemics
Preserve human capital by preventing
and treating meningitis sequelae
Strong immunization programs
Increased access to care
and meningitis treatment
09:04
Promote and connect R&D to regulatory and policy to enable
global access to diagnostics, medicines and vaccines
WHO website. Defeating bacterial meningitis by 2030.

17. 4CMenB -- United Kingdom Program
The United Kingdom was the first country to offer national, routine, publicly funded MenB vaccine
4CMenB is licensed for pediatric population (from 2 months onwards), whereas MenB-FHbp is licensed for 10 years old and above
4CMenB – The United Kingdom Experience
09:19

18. United Kingdom MenB Vaccine Impact -- 3 Years35 30 25 20 15 10 5
2011/12
2012/13
2013/14
2014/15
2015/16
2016/17
2017/18
0 to 8 wk
Count 40
9 to 17 wk
160
140
120
100 80 60
18 to 52 wk
1 y olds 45 50
3 y olds
4 y olds
Drop 28% (1 to 48%)
PART TARGET
Drop 70% (51 to 81%)
ALL TARGET
Drop 77% (62 to 82%)
ALL TARGET
09:30
Ladhani S. Meningococcal Protein Vaccines – where next? Presented at 37th Annual Meeting of European Society of Paediatric Infectious Diseases; May 6-11, 2019; Ljubljana, Slovenia. ESPID Symposium 11
Drop 57% (34 to 72%)
PART TARGET
Drop 80% (64 to 89%)
ALLTARGET
Ladhani S. ESPID ESPID Symposium 11.

19. United Kingdom Program MenB Summary
Overall, 169 cases confirmed and 277 cases prevented in the vaccine-eligible cohort after 3 years, irrespective of:
Vaccine coverage in the population
Number of vaccine doses received by the infants
MATS coverage of the MenB strains causing IMD cases
Vaccine effectiveness against invasive MenB disease
10:00
MATS = Meningococcal Antigen Typing System 
Ladhani S. ESPID ESPID Symposium 11.

20. 4CMenB -- Safety
Reactogenicity was higher for concomitant vaccines administration, but not concerning
Injection site pain/tenderness
Fever in infants, and injection site pain, malaise
Headache in adolescents are relatively common
10:45

21. 4CMenB and Prophylactic Paracetamol
Using prophylactic paracetamol reduced post-vaccination reactions without clinically relevant negative consequences on vaccine immunogenicity
Study Group
4CMenB
4CMenB+Paracetamol
MenC
Dose
1st
2nd
3rd
4th
n =
182
181
155
Max. rectal temperature
< 38.0 °C 29 23 43 30 47 63 41 76 61 74 31
38.0 °C to 38.9 °C 49 62 50 48 51 34 46
39.0 °C to °C 20 15 7 19 4 5 3 10 1
≥ 40 °C
Medically attended fever (within 3 d)
4 (2)
1 (1)
2 (1)
3 (2)
11:20
Prymula R, et al. Hum Vaccin Immunother. 2014;10:

22. Parents' Attitudes Toward MenB Vaccination
Successful implementation of MenB vaccinations depends on parental acceptance
Survey of 60 parents of children < 2 years of age
Knowledge of meningitis B poor
Parents concerned about fever
Most parents had paracetamol at home, and were willing to administer after MenB vaccination
Some parents preferred spreading two visits at age 12 months
11:33
Jackson C, et al. BMJ Open. 2017;7:e

23. United Kingdom Recommendations for Paracetamol Use After MenB Vaccination
A total of 3 doses of 2.5 mL (60 mg) is recommended following MenB vaccination, according the schedule below:
Age of Baby
Up to 6 months (Usually at 2 and 4 months)
Dose 1
One 2.5 mL (60 mg) dose as soon as possible after vaccination
Dose 2
One 2.5 mL (60 mg) dose 4 to 6 hours after first dose
Dose 3
One 2.5 mL (60 mg) dose 4 to 6 hours after second dose
11:50
When MenB vaccines are given alone, paracetamol is not recommended because fever rates are not as high as when given with routine vaccines
UK National Health Service. Paracetamol to prevent and treat fever after MenB vaccination.

24. Vaccine Safety: United Kingdom Data -- Expert Perspective
3 million doses given to children so far
Concerns before vaccine introduction
Kawasaki Disease – very rare in < 6 months, no evidence of increase
Seizures -- no evidence of increase in any kind of seizure
Less likely to have subsequent vaccination – no evidence (97% to 98% return for their subsequent vaccines)
Primary care consultations for fever
Small increase in infants attending general practitioner for fever post-vaccination with 4CMenB
12:30
Ladhani S. ESPID ESPID Symposium 11.

25. Vaccine Safety: United Kingdom Data -- Expert Perspective (cont)
Secondary care consultations for fever
Small increase in infants attending the ED for fever post-vaccination
Hospitalizations for fever
Around half the infants attending the ED have septic screens ± antibiotics
Did the parents give prophylactic paracetamol as recommended?
13:19
ED = emergency department
Ladhani S. ESPID ESPID Symposium 11.

26. Distribution of Confirmed Invasive Meningococcal Disease Cases in 2017
Country
Confirmed Cases
Rate*
Reported Cases
United Kingdom
772
1.2
775
Germany
281
0.3
283
France
545
0.8
546
Spain
268
0.6
304
Italy
197
Netherlands
198
Belgium 96
Lithuania 68
2.4 81
Czech Republic 67
13:38
*Rates per population.
European Centre for Disease Prevention and Control website.
Invasive meningococcal disease Annual Epidemiology Report for 2017.

27. Other Countries That Have Introduced MenB Into Their National Immunization Programs
Countries with high IMD incidence rates have introduced a MenB vaccine into the national immunization program
Cuba[a]
New Zealand[b]
Italy[c]
United Kingdom[c]
Ireland[c]
Austria*[c]
Czech Republic*[c]
Saxony, Germany*[c]
14:07
European Centre for Disease Prevention and Control. Expert opinion on the introduction of the meningococcal B (4CMenB) vaccine in the EU/EEA. Stockholm: ECDC; 2017
*Recommended but without funding. a. Rodriguez AP, et al. Mem Insti Oswaldo Cruz. 1999; 94: ; b. Holst J, et al. Hum Vaccine Immunother. 2013;9: ; c. European Centre for Disease Prevention and Control. Expert opinion on the introduction of the meningococcal B (4CMenB) vaccine in the EU/EEA. Stockholm: ECDC; 2017.

28. MenB Vaccine Effectiveness in Outbreak Settings
In 2015, the MenB-FHbp was used during a MenB IMD outbreak in a college in Rhode Island, United States. A 94% coverage rate was achieved for the first dose, and subsequent cases of meningitis B disease have been prevented[a]
4CMenB vaccine used following an outbreak at a university in New Jersey, United States (9 cases between 2013 and 2014). 89.1% of the target population were vaccinated, and no meningococcal disease occurred in persons who received 4CMenB vaccine[b]
14:43
McNamara LA, Shumate AM, Johnsen P, et al. First use of a serogroup
B meningococcal vaccine in the US in response to a university
outbreak. Pediatrics. 2015;135:798–804.
Vetter V, Baxter R, Denizer G, et al. Routinely vaccinating adolescents
against meningococcus: targeting transmission & disease.
Expert Rev Vaccines. 2016;15:641–658.
a. Fiorito TM, et al. J Am Coll Health. 2017;65: ; b. McNamara LA, et al. Pediatrics. 2015;135:

29. How Would You Help Parents Make a Decision?
Serious disease, rare, but likelihood of contracting disease is unpredictable
Pediatrician role -- advice from physicians is the most important factor in parents decisions
If the physician is convinced, they are confident in their recommendation
Communication Strategies with Parents about the MenB Vaccines
17:11

30. Age Distribution of IMD by Serogroup and Age
Infants are the most vulnerable, and the second peak are teenagers 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Age, y
Number of Cases Over 10 Y (2005/06 to )
500
1000
1500
2000
2500
Other
MenY
MenW
MenC
MenB
19:40
Ladhani SN, Ramsay M, Borrow R, et al
Enter B and W: two new meningococcal vaccine programmes launched
Archives of Disease in Childhood 2016;101:91-95.
Age distribution of lab confirmed IMD cases by serogroup in England 2004/ /2015
Ladhani SN, et al. Arch Dis Child. 2016;101:91-95.

31. Parental Attitudes Towards Immunization
6025 participants
95% named their pediatrician as the most important source of information regarding immunization
22.6% of survey participants felt that immunizations are administered "too early" in life
21.0% thought that overload of the child's immune system would be a side effect of immunization
12.2% thought induction of allergies would be side effects of immunizations
20:13
Heininger U, et al. Vaccine. 2006;24:

32. MenB Vaccine: Protection Against Other Meningococcal Groups
MenB vaccines are composed of proteins present in other meningococcal serogroups and Neisseria species[a]
4CMenB has been reported to induce bactericidal antibodies against serogroup X[b], and serogroups C, Y, and W[c]
MenB-FHbp has been reported to induce bactericidal responses against serogroups C, W, Y, X, and A strains[d]
22:30
4cmenb, a multicomponent meningococcal vaccine developed for serogroup b meningococci elicits cross-reactive immunity also against serogroups c, w and y
a. Toneatto D, et al. Exp Rev Vaccines. 2017;16: ; b. Hong E, et al. Vaccine. 2013;31: ; c. Pizza M, et al. ESPID [Abstract ]; d. Harris SL, et al. Vaccine. 2018;36:

33. MeNZB Protection Against Gonorrhea
14,730 cases and controls for analysis
Vaccinated individuals were less likely to be cases than controls (41% vs 51%, adjusted OR 0.69 [95% CI: 0.61, 0.79]; P < .0001
Estimated MeNZB effectiveness against gonorrhea: 31% (95% CI: 21, 39)
24:00
Pertousis-Harris H, et al. Lancet. 2017;390:

34. Conclusions
There is a need to protect the pediatric population from MenB through vaccinations
Not all countries have implemented MenB vaccination as part of a national program; however, we do have successful examples of how this has worked in the United Kingdom
Education and communication between the pediatrician, primary care practitioner, and caregiver in order to overcome potential barriers for MenB vaccination
Conclusion
24:53

35. Abbreviations
ED = emergency department EMA = European Medicines Agency fHbp = factor H binding protein IMD = invasive meningococcal disease MATS = Meningococcal Antigen Typing System MenB = meningococcal B NadA = neisserial adhesin A NHBA = Neisseria heparin binding antigen OMP = outer membrane protein OMV = outer membrane vesicle