Post on 16-Nov-2014
description
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 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 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
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 implementation10
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 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
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
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 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 Monitoring MenB vaccines following implementation
Use of the MRF whole genome library to determine PorA strain coverage
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
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-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
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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
0
20
40
60
80
100
120
140
160 PorA vs cc vs year among MenB (2010/11 to 2012/13) other
P1.4
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 Monitoring MenB vaccines following implementation
England and Wales
France Germany Italy Norway Combined0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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 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
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 Monitoring MenB vaccines following implementation
Laboratory Confirmed Cases of Meningococcal Disease (All serogroups) England and Wales
1998/99
1999/2000
2000/2001
2001/2002
2002/2003
2003/2004
2004/20052005/2006
2006/2007
2007/2008
2008/20092009/2010
2010/20112011/2012
2012/2013
2013/2014 (to May 12)
0
500
1000
1500
2000
2500
3000
1017 990778
639474 432 388 356 327 322 253 223 287 240 260 236
742 712
553
463
325 402323 304
237 259 292185
218161 184
104
1044 1110
1089
870
678 655708
608580
672632
504560
397 364
252
PCR only
Culture and PCR
Culture only
no
of
case
s
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
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
Early penicillin treatment- Good for patients, bad for epidemiologists?
17 Monitoring MenB vaccines following implementation
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
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
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 P1.4 Not PorA P1.4
Genotype PorA
Carriage isolate
Yes
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 press3Vogel U et al., Lancet Infect Dis 2013;13:416-25.
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 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
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
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
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.