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Evaluating the impact of a new
meningococcal B vaccine and use of the
MRF Meningococcal genome library.
ray.borrow@phe.gov...
2 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of v...
3 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of v...
4
Novartis MenB vaccine (Bexsero®)1
NadAfHbp NHBA
OMVs from the New Zealand
outbreak strain (NZ 98/254).
Three recombinant...
5 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of v...
Meningococcal polysaccharide based vaccines
 Simply calculated as the proportion of isolates with given polysaccharide.
...
Meningococcal Antigen Typing
System (MATS)
Are any of the Bexsero components in the
test strain:
(i) Expressed to a suffic...
8 Monitoring MenB vaccines following implementation
188
794
P1.4 other
Use of the MRF whole genome library to
determine Po...
Use of the MRF whole genome library to
determine PorAstrain coverage
9 Monitoring MenB vaccines following implementation
0...
MATS relative potency (RP) distribution for
NHBA, among European MenB strains from
2007/8, by NHBA peptide
PBT with 95% CI...
11 Monitoring MenB vaccines following implementation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
England and
Wales
France ...
12 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of ...
13
MenC disease confirmation and
monitoring of MenC vaccines in the UK
1) Confirmation of
invasive
meningococcal
disease M...
Laboratory Confirmed Cases of
Meningococcal Disease (All serogroups)
England and Wales
14 Monitoring MenB vaccines followi...
15 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of ...
16
Non-B capsular groups
- Should they be considered in
MATS and if positive as a
vaccine failure?
How could we monitor th...
Early penicillin treatment- Good for
patients, bad for epidemiologists?
17 Monitoring MenB vaccines following implementati...
Cartwright KA, Jones DM. Value of throat swabs
from index cases of meningococcal meningitis. J
Clin Pathol 1990;43:438.
Ea...
Nasopharyngeal isolates from
meningococcal cases
* HPZone is a web based support tool designed to provide local Health Pro...
20
How could we monitor the impact of
Bexsero® (2)
1) Confirmation of
invasive
meningococcal
disease
Culture (+ PCR)PCR (o...
21 Monitoring MenB vaccines following implementation
Considerations for monitoring the impact
of Bexsero®
MATS
 “Conserva...
Descriptive and effectiveness studies
Descriptive studies
 Summary of epidemiology of meningococcal disease by vaccinatio...
23 Monitoring MenB vaccines following implementation
 Background information
 Bexsero and epidemiology
 Calculation of ...
Summary and conclusions (1)
 The key issue regarding monitoring of Bexsero is how to categorise each case as
either a vac...
Summary and conclusions (2)
 Monitoring will be difficult in PCR confirmed cases where no invasive isolate has
been cultu...
Acknowledgements
26 Monitoring MenB vaccines following implementation
Vaccine Evaluation Unit,
Public Health England, Manc...
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Evaluating the impact of a new MenB vaccine and use of MRF genome library

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

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Transcript of "Evaluating the impact of a new MenB vaccine and use of MRF genome library"

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 17. Early penicillin treatment- Good for patients, bad for epidemiologists? 17 Monitoring MenB vaccines following implementation
  18. 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. 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. 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. 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. 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. 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. 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. 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. 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.
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