Plans for enhanced surveillance and evaluation of efficacy of Bexsero http://www.meningitis.org/conference2015

1. Plans for enhanced surveillance
and evaluation of the efficacy of
Bexsero®
Ray Borrow
ray.borrow@phe.gov.uk
Meningitis Research Foundation, Meningitis & Septoicaemia in Children and
Adults, Nov 2015, London

2. 2
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/4577
23/MeningoEnhancedSurveillancePlan_01092015_v1.1.pdf

3. Local PHE HPT
informed
Suspected
case of IMD
► Throat Swab for local culture
► EDTA sample (2 mL) sent to MRU for PCR-testing
► All meningococcal positive samples to the MRU
►Check throat swab has been taken
►Check 2 mL EDTA sample has been taken
►Remind that all meningococcal positive samples should be sent to the MRU
►Collect detail needed for PH action (epi surveillance form MENSV01 or local equivalent)
PHE HPT routine surveillance
Local hospital: action according to local procedures
Flowchart: surveillance actions for
suspected and confirmed IMD cases
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/464003/surveillanceflowchart_final.pdf

4. 4
Suspected case 5 years of age or older
► Request additional EDTA sample (2 mL) to
be sent to MRU for non-culture typing of
vaccine antigens using the PHE sample
submission form.
All cases confirmed as IMD
►Ensure epi surveillance form MENSV01 is completed and uploaded to
HPZone or is returned to PHE for all confirmed cases
Suspected case under 5 years of age
► Request ACUTE serum (2 mL) and additional
EDTA sample (2 mL) for non-culture typing of
vaccine antigens be taken (ideally within 72 hours
of treatment) & stored.
►For confirmed cases; the PHE Immunisation
Team will request both samples are sent to MRU
using the PHE sample submission form.
► Request age appropriate samples are sent including stored acute serum and second EDTA sample for
confirmed cases <5 years
► Request CLINICIANS to complete the clinical questionnaire (MENSV02) for confirmed cases <5 years
► Request PHE HPTs to complete epi surveillance form MENSV01 (if not complete)
PHE HPT enhanced
surveillance
PHE Immunisation team enhanced surveillance

5. 5
Surveillance form MENSV01

6. 6
Enhanced surveillance –
sample submission form

7. Laboratory Confirmed Cases of Group B
Meningococcal Disease, England & Wales,
1998/99 to 2014/15
7
0
200
400
600
800
1000
1200
1400
1600
1800
noofcases
PCR only
Culture and PCR
Culture only
45%

8. 88
Calculating the strain coverage of
meningococcal vaccines
In healthy individuals, the meningococcus must express capsule to survive post-
invasion.
Meningococcal disease in country ‘X’
Capsular
group
Proportion of disease
(%)
A 1
B 60
C 20
W 9
Y 10
MenC
vaccine
-
-
20
-
-
Total = 20 %
MenACWY
vaccine
1
-
20
9
10
Total = 40 %
Vaccine strain coverage estimates
MenB
vaccine
-
?
-
-
-
Total = ? %
MenB
vaccine
?
?
?
?
?
Total = ? %
For Bexsero and other sub-capsular vaccines, efficacy and coverage may be
independent to the capsular group

9. 9
Cultured Isolates
In vitro Assays
 SBA Assay
 MATS
 MEASURE
Phenotyping
Serogrouping 
Serotyping 
Serosubtyping 
In vitro Assays
SBA assay ()
MEASURE ()
MATS 
PCR Analysis
MLST (7 Loci) ()
PorA ()
fHbp ()
Whole Genome Sequencing
All genes 
MLST (rMLST and
cgMLST)

Isolation of meningococci from normally sterile body site.
If none available, isolates from throat swabs can be used.

10. 10
Non-Culture Cases (PCR positives)
Phenotyping
 Grouping
 Typing (PorB)
 Subtyping (PorA)
In vitro Assays
 SBA Assay
 MATS
 MEASURE
Phenotyping
Grouping X
Typing X
Subtyping X
In vitro Assays
SBA Assay X
MEASURE X
MATS X
PCR Analysis
Genogroup 
MLST (7 Loci) ()
PorA 
fHbp 
Whole Genome Sequencing
All genes X
MLST (rMLST and
cgMLST)
X

11. 1111
Subcapsular antigen complexities
- Factor H-binding protein
Found in virtually all meningococci.
Immunogenic and elicits functional antibody.
http://pubmlst.org/neisseria/fHbp/
Variant
1
Variants
2 & 3
However:
Three main variants, variant 1, 2 and 3 but only variant 1
is in Bexsero®
As of the 4th October 2015 there were:
fHbp allele: 1109
fHbp peptide: 885
Can vary in amount of expression

12. 12
Genotypic typing information alone is insufficient to calculate coverage.
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 protein-based vaccine strain
coverage?

13. 13
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 (termed relative potency) 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).

14. 14
Distribution of relative potencies in
MATS for fHbp for different invasive
serogroup B meningococcal strains
Variant & peptide (n = 920)
PBT
4 1 37 232
Vogel U et al. Lancet Infect Dis 2013;13:416-25.

15. 15
Epidemiological year 2014/15: baseline
for Bexsero® introduction - serogroup B
invasive disease isolates from England & Wales
253 serogroup B isolates
PHE MRU unpublished data

16. 16
PHE MRU unpublished data
MATS coverage of invasive disease
serogroup B isolates by antigen, 2014/15
2014/15 serogroup B strain coverage = 67% [52, 81]

17. 17
MATS strain coverage of invasive
serogroup B isolates from England & Wales
for epidemiological years 2007/8 vs 2014/15

18. 1818
Non-culture confirmed cases
Other
PCR (only)
MenB
Amplify & sequence: PorA fHbp
Covered: P1.4 1, 4, 37, 232
Vaccine Failure if fully vaccinated
Determine vaccine history
?

19. 19
NICE guidelines [CG102] Bacterial meningitis and meningococcal septicaemia
Review decision:
We checked this guideline and decided that it should not be updated at this
time. For details, see the update decision and the process for deciding if an
update is needed. We have also removed reference to throat swabs from
recommendation 1.3.14, to bring it into line with Public Health
England’s Guidance for public health management of meningococcal
disease in the UK.
Throat swabs
If PCR meningococcal positive but no blood/CSF isolate,
Isolates from throat swab are very useful.
Can then perform MATS and whole genome sequencing.

20. 20
•Confirmed case – capsular group B-vaccine-type:
 Isolate with ≥ 1 vaccine antigen above PBT by MATS or PorA P1.4 from a
normally sterile site (MATS-positive), or
 PCR on a normally sterile site + B isolation from throat swab with ≥ 1 vaccine
antigen above PBT by MATS or PorA P1.4 (MATS-positive), or
 PCR on a normally sterile site + PorA P1.4 identified on genosubtyping
•Probable case – capsular group B-vaccine-type:
 PCR on a normally sterile site + fHBP sub-variant 1, 4, 37, 232
Definitions

21. 2121
Risk groups for Bexsero® in the UK
Asplenia, splenic dysfunction; Complement disorders/deficiencies; Lab staff
Two cases of serogroup B disease in vaccinated patients receiving Eculizumab
Case 1
A young adult on Soliris therapy received two doses of Bexsero vaccine 6 weeks
part (in April 2014 and May 2014) and a single dose of Menveo (in March 2014).
Onset of disease was Dec 2014.Had stopped antibiotic prophylaxis.
No isolate, PCR genogroup B; fHbp gene encodes for peptide 23 (variant 2).
porA P1.7-1;1;35-1
Case 2
A young adult on Soliris therapy received two doses of Bexsero vaccine 4 weeks
part (in April 2015 and May 2015) and a single dose of Menveo (in March 2015).
Onset of disease was Sept 2015. Compliant with Pen V prophylaxis.
B:NT:P1.14 Penicillin resistant Isolate submitted for WGS

22. Do non-culture confirmed cases
reflect culture confirmed?
22
• PCR-based assay used to sequence fHbp from non-culture DNA
extracts received between Jan 2011 and Dec 2013*.
• fHbp peptide data for isolates received during same period downloaded
from MRF Meningococcus Genome Library.
(http://www.meningitis.org/research/genome).
• Group and age data (where available) also compiled.
• MLST data from isolates used to assess associations between fHbp
and clonal complexes.
* Clark SA et al. PLoS ONE, 2014;9:e89921.

23. 23
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
C NC C NC C NC C NC C NC C NC
<1 1-10 11-25 26-64 65+ Combined
%ofsubset
Age Group (Yrs) / Culture (C) or Non-Culture (NC) Cases
Capsular Group in E&W by Age
and Culture Status: 2011-2013

24. 24
0
5
10
15
20
25
4/B16 13/B09 15/B44 19/A22 14/B03 1/B24 45/A05
%ofdataset(e.g.2011culture)
fHbp Peptide Variant
2011 Culture
2011 Non-culture
2012 Culture
2012 Non-culture
2013 Culture
2013 Non-culture
Combined Culture
Combined Non-culture
Common fHbp peptides among
serogroup B cases (by year)
p= <0.05 after adjusting for year received
91% of 15/B44-harbouring strains belong to ST-269 cluster (cc269)

25. 25
Conclusions
•Meningococcal serogroup B cases now at 438 cases (58%) for 2014/15.
•45% of serogroup B cases confirmed by PCR alone.
•Serogroup B strain coverage by MATS for 2014/15 is 67%.
•Case definitions defined for serogroup B ‘vaccine failures’.
•Serogroup W & Y cases more commonly confirmed by culture than non-
culture in all age groups.
•fHbp 15/B44 or ST-269 more commonly confirmed by non-culture than
culture.

26. 26
Acknowledgements
(http://www.meningitis.org/research/genome).
PHE Manchester: Stephen Clark, Jamie Findlow, Stephen Gray, Aiswarya
Lekshmi, Jay Lucidarme, Lynne Newbold, Stephanie Slater.
PHE Colindale: Helen Campbell, Shamez Ladhani, Mary Ramsay
University of Oxford: Martin Maiden, Keith Jolley, Dorothea Hill, Odile Harrison,
Carina Brehony, Holly Bratcher.
GSK: Monica Moschioni, Rosita De Paola, Elizabeth Merrall
Pfizer: Annaliesa Anderson, How Tsao, Li Hao