Professor Ray Borrow's presentation at Meningitis Research Foundation's 2014 Meningitis Symposium http://www.meningitis.org/symposium2014

1. Evaluating the impact of a new
meningococcal B vaccine and use of the
MRF Meningococcal genome library.
ray.borrow@phe.gov.uk
Vaccine Evaluation Unit, Public Health England, Manchester, UK.
Ray Borrow

2. 2 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of vaccine strain coverage
 Monitoring of Meningococcal vaccines
 Meningococcal group C (MenC) vaccines
 Meningococcal group B (MenB) subcapsular vaccine/Bexsero
 Summary and conclusions.
Presentation overview

3. 3 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of vaccine strain coverage
 Monitoring of Meningococcal vaccines
 Meningococcal group C (MenC) vaccines
 Meningococcal group B (MenB) subcapsular vaccine/Bexsero
 Summary and conclusions.
Presentation overview

4. 4
Novartis MenB vaccine (Bexsero®)1
NadAfHbp NHBA
OMVs from the New Zealand
outbreak strain (NZ 98/254).
Three recombinant proteins discovered by reverse vaccinology.
+
PorA (P1.4)
1http://www.inpharm.com/news/101223/novartis-meningococcal-
vaccine-bexsero
Monitoring MenB vaccines following implementation
Variant
1
Variants
2 & 3
Variants
1-3
Variants
4-6
249 VR1 variants3
649 VR2 variants4
2 2 2
2Vogel U et al., Lancet Infect Dis 2013;13:416-25.
3Pubmlst.org- last updated 05/07/2013 (accessed 15/08/13).
4Pubmlst.org- last updated 26/07/2013 (accessed 15/08/13).
Variant contained within vaccine.
Expression of proteins
is variable

5. 5 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of vaccine strain coverage
 Monitoring of Meningococcal vaccines
 Meningococcal group C (MenC) vaccines
 Meningococcal group B (MenB) subcapsular vaccine/Bexsero
 Summary and conclusions.
Presentation overview

6. Meningococcal polysaccharide based vaccines
 Simply calculated as the proportion of isolates with given polysaccharide.
 Genotypic typing information alone is insufficient to calculate coverage.
 Novartis have developed an assay to determine strain coverage of Bexsero.
Subcapsular vaccines
 More complicated due to:
• Multiple protein variants (vaccine induced antibody is not equally cross-
reactive against all variants).
• Protein expression differs between isolates.
• Not all isolates harbor genes.
How to predict vaccine strain coverage?
6 Monitoring MenB vaccines following implementation

7. Meningococcal Antigen Typing
System (MATS)
Are any of the Bexsero components in the
test strain:
(i) Expressed to a sufficient degree?
and
(ii) Similar enough to the antigens in the
vaccine such that the antibodies
generated by Bexsero will kill the
bacteria?
MATS ELISA determines the minimum amount of recognisable antigen needed to
result in bacterial killing for each of fHbp, Nad A and NHBA (PorA characterised by
sero/genotyping).
For a strain to be ‘covered’, at least one antigen must be greater than the positive
bactericidal threshold (PBT) or possess homologous PorA (P1.4).
7 Monitoring MenB vaccines following implementation

8. 8 Monitoring MenB vaccines following implementation
188
794
P1.4 other
Use of the MRF whole genome library to
determine PorA strain coverage:
PorA vs cc among MenB (2010/11 to
2012/13)
19%

9. Use of the MRF whole genome library to
determine PorAstrain coverage
9 Monitoring MenB vaccines following implementation
0
20
40
60
80
100
120
140
160
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
2010-11
2011-12
2012-13
cc103 cc11 cc1157 cc162 cc167 cc18 cc213 cc22 cc254 cc269 cc282 cc32 cc35 cc41/44 cc461 cc60 cc865 UA
PorA vs cc vs year among MenB (2010/11 to 2012/13) other
P1.4

10. MATS relative potency (RP) distribution for
NHBA, among European MenB strains from
2007/8, by NHBA peptide
PBT with 95% CI
Box and whiskers
denote quartile
ranges for each
distribution.
10 Monitoring MenB vaccines following implementation
Vogel U et al., Lancet Infect Dis 2013;13:416-25.
 Within each variant, MATS RP varied over a 5-10 fold range, indicating significant
differences in expression.
 Genotypic information alone (including ST/CC) is insufficient to determine if a
strain will be “covered”.

11. 11 Monitoring MenB vaccines following implementation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
England and
Wales
France Germany Italy Norway Combined
4Ag>PBT*
3Ag>PBT*
2Ag>PBT*
1Ag>PBT*
Vogel U et al., Lancet Infect Dis 2013;13:416-25.
*> MATS PBT for
fHBP, NadA and
NHBA/homologous
PorA serotype.
MATS predicted coverage of European
MenB isolates from 2007/08
MATS concept is to predict strain
coverage and is “conservative”- does not
account for any antibody synergy,
differences in age-related responses to
Bexsero or responses to minor OMV
components.
Donnelly J et al., Proc Natl Acad Sci USA 2010;107:19490-5.
Frosi G et al., Vaccine 2013: in press

12. 12 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of vaccine strain coverage
 Monitoring of Meningococcal vaccines
 Meningococcal group C (MenC) vaccines
 Meningococcal group B (MenB) subcapsular vaccine/Bexsero
 Summary and conclusions.
Presentation overview

13. 13
MenC disease confirmation and
monitoring of MenC vaccines in the UK
1) Confirmation of
invasive
meningococcal
disease MenCOther Other
3) Monitoring
vaccine
effectiveness Vaccine Failure
- Fully vaccinated
Non-vaccine failure
- Partially vaccinated
- Not vaccinated
- Insufficient time for immunity
Molecular
-Group
-MLST
-PorA
-WGS
Serological
-Group
-PorA
-PorB
2) Additional
typing and
monitoring of
epidemiology
Determine vaccine history
Culture (+ PCR)PCR (only)
Further typing
Reliance on three key principals
1) Grouping target (MenC capsule) is
the vaccine antigen.
2) MenC capsule expression is required
for invasive disease.
3) MenC vaccination provides immunity
against most MenC strains.
Monitoring MenB vaccines following implementation
MenC

14. Laboratory Confirmed Cases of
Meningococcal Disease (All serogroups)
England and Wales
14 Monitoring MenB vaccines following implementation
1017 990
778
639
474 432 388 356 327 322 253 223 287 240 260 236
742 712
553
463
325 402
323 304
237 259
292
185
218
161 184
104
1044 1110
1089
870
678 655
708
608
580
672
632
504
560
397 364
252
0
500
1000
1500
2000
2500
3000
noofcases
PCR only
Culture and PCR
Culture only

15. 15 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of vaccine strain coverage
 Monitoring of Meningococcal vaccines
 Meningococcal group C (MenC) vaccines
 Meningococcal group B (MenB) subcapsular vaccine/Bexsero
 Summary and conclusions.
Presentation overview

16. 16
Non-B capsular groups
- Should they be considered in
MATS and if positive as a
vaccine failure?
How could we monitor the impact of
Bexsero® (1)
1) Confirmation of
invasive
meningococcal
disease Other
Culture (+ PCR)PCR (only)
Molecular
-Group
-MLST
-PorA
-fHbp
-WGS
Serological
-Group
-PorA
-PorB
2) Additional
typing and
monitoring of
epidemiology
OtherMenB
Further typing
3) Monitoring
vaccine
effectiveness Vaccine Failure
- Fully vaccinated
Non-vaccine failure
- Partially vaccinated
- Not vaccinated
- Insufficient time for immunity
Determine vaccine history
MATS
-fHbp
-NadA
-NHBA
-PorA
“Covered”
MenB
“Covered” includes
genotyped PorA P1.4.
“Not Covered”
- PBT may not be applicable to
non-MenB strains. Evaluation of
PBT’s is ongoing.
- Non-culture PorA and fHbp
sequencing implemented at PHE
MRU.
- Possibility of non-culture WGS?
Monitoring MenB vaccines following implementation
PCR confirmed only
- Do we ignore these cases?
- Not covered by vaccine
All
covered
by MRF
WGS
library

17. Early penicillin treatment- Good for
patients, bad for epidemiologists?
17 Monitoring MenB vaccines following implementation

18. Cartwright KA, Jones DM. Value of throat swabs
from index cases of meningococcal meningitis. J
Clin Pathol 1990;43:438.
Early penicillin treatment- Good for
patients, bad for epidemiologists? (2)
18 Monitoring MenB vaccines following implementation

19. Nasopharyngeal isolates from
meningococcal cases
* HPZone is a web based support tool designed to provide local Health Protection Units with timely & comprehensive
information on cases, outbreaks, incidents and threats.
 UK NICE guidelines do not stipulate submission
of nasopharyngeal isolates from cases.
 However, HPZone* prompts for collection in
suspected meningococcal cases.
 Feasible to use throat swabs/carriage isolates from cases in MATS to determine if
“covered”/vaccine failure (where no invasive isolate available).
 Prudent to cross-check any typing data between isolate and clinical sample (e.g.
group, PorA and fHbp).
 Need to evaluate if PBTs apply to carriage isolates (including comparison of
expression between matched invasive and carriage isolates).
19 Monitoring MenB vaccines following implementation

20. 20
How could we monitor the impact of
Bexsero® (2)
1) Confirmation of
invasive
meningococcal
disease
Culture (+ PCR)PCR (only)
Molecular
-Group
-MLST
-PorA
-FetA
-WGS
Serological
-Group
-PorA
-PorB
2) Additional
typing and
monitoring of
epidemiology
OtherMenB
Further typing
3) Monitoring
vaccine
effectiveness Vaccine Failure
- Fully vaccinated
Non-vaccine failure
- Partially vaccinated
- Not vaccinated
- Insufficient time for immunity
- Not covered by vaccine
Determine vaccine history
MATS
-fHbp
-NadA
-NHBA
-PorA
“Covered”
MenB
“Not Covered”
Monitoring MenB vaccines following implementation
No
Unknown
(of if not fully
vaccinated, non-
vaccine failure)
Other
PorA P1.4Not PorA P1.4
Genotype PorA
Carriage isolate
Yes

21. 21 Monitoring MenB vaccines following implementation
Considerations for monitoring the impact
of Bexsero®
MATS
 “Conservative” results not accounting for any antibody synergy, age related-
responses or responses against minor OMV components.1,2
 Currently un-validated for carriage isolates or non-MenB strains.
 MATS may underestimate NadA expression due NadR repression during the in-
vitro assay growth conditions.1,3
“Unknowns” (vaccine failure or non-vaccine failure)
 If you are unable to determine a case as a vaccine failure or not, how do you
accurately calculate vaccine efficacy?
Educated guesses
 In some cases you will have partial genotypic information.
e.g. Non-culture PorA genotype indicative of a lineage which has thus far
always been “non-covered”. Assume it is not a vaccine failure?
1Donnelly J et al., Proc Natl Acad Sci USA 2010;107:19490-5.
2Frosi G et al., Vaccine 2013: in press
3Vogel U et al., Lancet Infect Dis 2013;13:416-25.

22. Descriptive and effectiveness studies
Descriptive studies
 Summary of epidemiology of meningococcal disease by vaccination status, age,
etc.
 Focus on both MenB and non-MenB cases to evaluate cross-protection and any
replacement.
Effectiveness studies
 Prospectively determined using the screening method as successfully undertaken
in the UK for MenC1, Haemophilus influenzae type b2, and influenza vaccines3.
 Screening method is based on the proportion of vaccinated among cases and the
population and control achieved by using vaccine coverage estimates.
 If the screening method is inapplicable then a case control method could be
utilised.
22 Monitoring MenB vaccines following implementation
1Trotter CL et al., Lancet 2004;364:365-7.
2Ramsay ME et al., J Infect Dis 2003;188:481-5.
3Fleming DM et al., J Epidemiol Community Health 2010;64:1062-7.

23. 23 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of vaccine strain coverage
 Monitoring of Meningococcal vaccines
 Meningococcal group C (MenC) vaccines
 Meningococcal group B (MenB) subcapsular vaccine/Bexsero
 Summary and conclusions.
Presentation overview

24. Summary and conclusions (1)
 The key issue regarding monitoring of Bexsero is how to categorise each case as
either a vaccine failure or non-vaccine failure.
 Whole genome sequencing provides all necessary molecular typing.
 However, methods previously undertaken for MenC (or MenAWY) and genotypic
information alone are insufficient for monitoring subcapsular vaccines such as
Bexsero®.
 Based on protein expression and accounting for any variation in the protein, MATS
is currently the only way to predict if a strain is likely to be “covered” by Bexsero®
and hence a vaccine failure.
 Although MATS is currently only validated for MenB invasive isolates, its use on
non-MenB isolates and matched carriage isolates seems a sensible adaptation.
24 Monitoring MenB vaccines following implementation

25. Summary and conclusions (2)
 Monitoring will be difficult in PCR confirmed cases where no invasive isolate has
been cultured.
 MATS on nasopharyngeal isolates from the case is one way to address this
issue.
 Other methods to determine protein expression in non-culture cases would be
beneficial.
 There is likely to be a considerable number of cases in vaccinated individuals
which would fit into an “unknown” category.
 Other considerations are important when monitoring impact, such as waning
immunity and any underlying conditions such as complement deficiencies.
25 Monitoring MenB vaccines following implementation

26. Acknowledgements
26 Monitoring MenB vaccines following implementation
Vaccine Evaluation Unit,
Public Health England, Manchester
Jamie Findlow, Jay Lucidarme, Stephen Clark.
Meningococcal Reference Unit,
Public Health England, Manchester
Lynne Newbold, Steve Gray and Tony Carr.
Immunisation Department,
Public Health England, Colindale, London
Mary Ramsay, Shamez Ladhani.