Issues in evaluating the impact of a new meningococcal B vaccine
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Issues in evaluating the impact of a new meningococcal B vaccine

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Professor Ray Borrow, Head of Vaccine Evaluation Unit, Public Health England, Manchester

Professor Ray Borrow, Head of Vaccine Evaluation Unit, Public Health England, Manchester

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Issues in evaluating the impact of a new meningococcal B vaccine Presentation Transcript

  • 1. Issues in evaluating the impact of a new meningococcal B vaccine Ray Borrow Professor of Vaccine Preventable Diseases, Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary, Manchester, UK ray.borrow@phe.gov.uk
  • 2. UK and the serogroup B challenge, introduction • MenB polysaccharide is polysialic acid, a compound identical to that found on the surface of human neuronal cells. • Consequently; (i) Poorly immunogenic. (ii) Potential to induce an autoimmune response. • Use subcapsular antigens, which are; (i) Surface exposed. (ii) Conserved. (iii) Induce bactericidal activity.
  • 3. http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero • Bexsero (previously known as 4CMenB or rMenB+OMV) contains 4 main antigens. • Three recombinant proteins discovered by genome mining/reverse vaccinology combined with OMV from the New Zealand outbreak strain (NZ 98/254). Novartis investigational MenB 4CMenB vaccine (Bexsero® ) PorA (presented as part of an OMV) NadAfHBP 1 NHBA
  • 4. Bexsero (Novartis) clinical program • Phase 3 studies in infant, toddlers and adolescents complete. • Over 5000 infants/toddlers and 2000 adolescents/adults vaccinated. • Acceptable safety and tolerability profile in all age groups. • Co-administered infant vaccines elicit expected immune responses when given with Bexsero. Bai X, Findlow J & Borrow R. Expert Opin Biol Ther 2011;11:969-85.
  • 5. Bexsero: Proposed immunisation schedules by population *The safety and immunogenicity of 4CMenB in individuals older than 50 years have not been studied. The safety and immunogenicity of 4CMenB in individuals older than 50 years have not been studied. The proposed UK infant immunisation schedule is a primary series at 2,3 and 4 months with a booster at 12 months of age Information provided by Novartis Vaccines
  • 6. Potential UK schedules Infant schedule? Infant schedule and catch-up? Not recommended? Infant & adolescent schedule? Infant schedule, catch-up and adolescent schedule? Adolescent schedule?
  • 7. Predicting strain coverage Polysaccharide based vaccines •Simply calculated as the proportion of isolates with given polysaccharide. •Genotypic typing information alone is insufficient to calculate coverage.  Pfizer and Novartis have both developed assays to determine coverage of their respective vaccines. 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.
  • 8. Meningococcal Antigen Typing System (MATS) concept (Novartis) Are any of the Bexsero components in the circulating strains: (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 determines the minimum amount of recognisable antigen needed to result in bacterial killing for each of the four components
  • 9. Meningococcal Antigen Typing System (MATS) Donnelly J et al. PNAS. 2010;107:19490-5.
  • 10. Using MATS to predict whether strains are covered by 4CMenB. Positive Bactericidal Thresholds (PBT): Example - fHbp 10  Shown are the 36 fHbp expressing strains in which NadA, NHBA and PorA are either absent or mismatched Donnelly J et al. PNAS. 2010;107:19490-5.
  • 11. Killed in SBA: infant serum pool titer ≥ 8 Not killed in SBA  Serum pools from 13-month-olds immunised with 4CMenB were tested in SBA against diverse MenB strains.  The PBT is defined as the value above which ≥ 80% strains are killed in SBA, maximising statistical predictive power.  Separate PBT for each antigen based on corresponding subsets of strains with 3 of 4 antigens absent or mismatched. Donnelly J et al. PNAS. 2010;107:19490-5. Using MATS to predict whether strains are covered by 4CMenB. Positive Bactericidal Thresholds (PBT): Example - fHbp
  • 12. Coverage by the PorA (OMV) component of the vaccine is determined by conventional typing, it presence by either serotyping or genotyping of PorA P1.4 PorA coverage PorA P1.4 (presented as part of an OMV) 37 different variants of P1.4 (P1.4, P1.4-1 etc) From PorA sequenced case isolates submitted to PHE MRU (1985 to 2008), 492 belonged to P1.4 family. P1.4 n = 478 (97.2%) All mab +ve P1.4-1 n = 13 (2.6%) All mab -ve P1.4-5 n = 1 (0.2%) Mab -ve
  • 13. Distribution of MATS relative potency for fHbp among different invasive MenB strains sorted by fHbp variant and peptide: Europe 2007/8 PBT with 95% CI Box and whiskers denote quartile ranges for each distribution. VARIANT 1 VARIANT 2 VARIANT 3 Family B Family A Strains with fHbp peptides belonging to variant 1 generally had MATS RPs > PBT. Strains with fHbp belonging to variants 2 and 3 had MATS RPs < PBT. Vogel U et al. Lancet Infect Dis 2013;13:416-25.
  • 14. Distribution of MATS relative potency for NHBA among different invasive MenB strains sorted by NHBA peptide: Europe 2007/8 PBT with 95% CI Box and whiskers denote quartile ranges for each distribution. Within each NHBA peptide variant, MATS RPs varied over a 5 to 10-fold range indicating significant variation in the level of NHBA expression among isolates harboring the same peptide. Vogel U et al. Lancet Infect Dis 2013;13:416-25.
  • 15. 0 27% 1 23% 2 34% 3 16% Predicted coverage of Bexsero against English and Welsh MenB isolates 2007/08 (no of antigens)* *> MATS PBT for fHBP, NadA and NHBA, and homologous serotype for PorA. Overall coverage estimate of 72.9% Novartis Meningococcal Antigen Typing System (MATS) N=535 Vogel U et al. Lancet Infect Dis 2013;13:416-25. 1 23% 0 27% 2 34% 3 16%
  • 16. 1433 1343 1107 975 981 909 753 568 489 385 391 339 349 271 249 252 276 231 144 5 148 482 576 753 638 526 398 389 325 306 274 252 309 198 210 185 174 96 13 376 888 874 1070 1108 1065 804 738 603 721 548 697 654 596 469 498 379 203 0 500 1000 1500 2000 2500 3000 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 20122013 (To June 13) noofcases PCR only Culture and PCR Culture only Laboratory Confirmed Cases of Meningococcal Disease, England & Wales - by Calendar Year 50% PCR only confirmed PHE MRU unpublished data
  • 17. If no systemic isolate? •Cannot determine expression from non-culture PCR-based techniques. •Need an isolate. •Use nasopharyngeal isolates where available.
  • 18. Nasopharyngeal isolates from cases Cartwright KA, Jones DM. Value of throat swabs from index cases of meningococcal meningitis. J Clin Pathol 1990;43:438.
  • 19. Nasopharyngeal isolates from cases NICE guides do not stipulate submission of nasopharyngeal isolates from cases. HPZone* prompts for collection of throat swabs for suspected meningococcal cases. * HPZone is a web based support tool designed to provide staff at local Health Protection Units with timely & comprehensive information on cases, outbreaks, incidents and threats.
  • 20. Typing data currently generated •For cultures: Meningitis Research Foundation whole genome project. 2010/11 514 isolates 2011/12 417 isolates •For non-culture: •PorA •fHbp
  • 21. Culture vs non-culture genotyping: PorA 7-2, 4, 37 22, 14, 36 22, 9, 35-1 19-1, 15-11, 36 18-1, 3, 38 19, 15, 36 17-1, 23, 37 22, 14-6, 36-2 12-1, 9, 35-1 18-7, 9, 35-1 7, 16, 35 7, 30, 38 19-2, 13-1, 36 5-1, 10-8, 36-2 18-1, 14, 36 5, 2, 36-2 17, 16-3, 36 21, 16, 37-1 5-1, 2-2, 36-2 7-1, 1, 35-1 12-1, 16, 37-1 18-1, 34, 38 19-1, 3-5, 38 7-2, 13-1, 35-1 Other =1 Group B case isolates 2012 (Jan-Nov) Total 223 7-2, 4, 37 22, 14, 36 22, 9, 35-1 19-1, 15-11, 36 np 18-1, 3, 38 7, 30, 38 19, 15, 36 7-1, 1, 35-1 17-1, 23, 37 5, 2, 36-2 21, 16, 37-1 22, 14-6, 36-2 5-1, 10-1, 36-2 22, 9, ? 5-1, 10-8, 36-2 7, 16, 35 17, 16-3, 36 22, 4, 37 5-1, 2-2, 36-2 12-1, 16, 37-1 18-7, 9, 35-1 other Group B PCR+ve only positive cases 2012 (Jan-Oct) Total 216
  • 22. Non-culture genotyping: fHbp •To provide a complete picture of fHbp diversity and distribution, a PCR-based sequencing assay has been developed to amplify and sequence the meningococcal DNA within non-culture confirmed samples. •A nested-PCR protocol consisting of two consecutive PCR rounds is used to increase the sensitivity and specificity of the assay. •This assay is being used in an ongoing project to determine the fHbp allele of all non-culture cases between 2011-2015.
  • 23. Approximately half of 2011 samples have been sequenced. The non-culture profile generally reflects that of the cultured isolates. There is noticeably lower incidence of fHbp peptides 2.22 (A10) and 2.25 (A15) in the non-culture samples. These peptide variants are associated with groups W and Y, respectively. Interim non-culture fHbp results 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2011 Culture Isolates 2011 Non-Culture (244 samples) Other 37 47 21 22 16 45 1 19 14 25 15 13 4 Jan to June Jan to May, Nov to Dec
  • 24. B 76.3% Y 14.8% W 5.1% C 2.5% other 1.0% cnl/NG 0.4% 2010/11 isolates B 83.8% Y 8.3% W 3.5% C 2.3% other 0.2% cnl/NG 2.0% 2010/11 allCulture only Culture/non-culture Capsular group for culture only proven versus culture/non-culture laboratory confirmed cases, 2010/11 Lucidarme J et al. The Meningitis Research Foundation Meningococcal Genome Library. Neisserialvaccines2013, Varadero, Cuba, May 2013.
  • 25. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% clonal complex (n) NK >66 26-65 16-25 6-15 3-5 2 1 <1 Y W Age (years) Clonal complex versus age group Lucidarme J et al. The Meningitis Research Foundation Meningococcal Genome Library. Neisserialvaccines2013, Varadero, Cuba, May 2013.
  • 26. Post-licensure studies of meningococcal serogroup B vaccine, Bexsero® •Descriptive studies •Effectiveness studies
  • 27. Descriptive studies •Summary of the epidemiology of meningococcal disease, by vaccination status, age, etc. •Focus on the epidemiology not only of meningococcal serogroup B, but, also include other serogroups. - evaluate cross protection against other serogroups. - any capsule replacement after introduction of the vaccine.
  • 28. Effectiveness studies •Analyses for effectiveness of 4CMenB will be performed prospectively eg by the screening method. •The screening method has been used to successfully assess meningococcal serogroup C conjugate vaccine1, Haemophilus influenzae type b conjugate vaccine2 , and influenza vaccine3 effectiveness in the UK. •The screening method is based on a comparison of the proportion vaccinated among the cases and the population and control is achieved by using an estimate of vaccine coverage. •If the screening method is inapplicable then a case control method would be used. 1. Trotter CL et al. Lancet 2004;364:365-7. 2. Ramsay ME et al. J Infect Dis 2003;188:481-5. 3. Fleming DM et al. J Epidemiol Community Health 2010;64:1062-7.
  • 29. A case of N. meningitidis is defined by culture of N. meningitidis or identification of meningococcal DNA from a normally sterile site. Cases can be further classified as: 1) A case of serogroup B N. meningitidis is defined as isolation of serogroup B N. meningitidis or positive capsular group B specific PCR from a normally sterile site. Definitions - 1
  • 30. Definitions - 2 2) A serogroup B Bexsero-vaccine-type confirmed case can be defined as either:  Isolation of serogroup B N. meningitidis with at least one vaccine antigen above the positive bactericidal threshold (PBT) as measured by the MATS assay from a normally sterile site, or Positive for meningococcal DNA and capsular group B specific PCR on a normally sterile site plus isolation from a throat swab of serogroup B N. meningitidis with at least one vaccine antigen above the PBT as measured by the MATS assay, or Positive for meningococcal DNA and capsular group B specific PCR on a normally sterile site and PorA P1.4 identified on genosubtyping.
  • 31. 3) Non-serogroup B Bexsero-vaccine-type confirmed case is defined as either:  Isolation of non-B serogroup N. meningitidis with at least one vaccine antigen above the PBT as measured by the MATS assay from a normally sterile site, or Positive for meningococcal DNA and non-B serogroup specific PCR on a normally sterile site plus isolation from a throat swab of the same serogroup N. meningitidis with at least one vaccine antigen above the PBT as measured by the MATS assay, or  Positive for meningococcal DNA and non-B serogroup specific PCR on a normally sterile site and PorA P1.4 identified on genosubtyping. Definitions - 3
  • 32. Definition of a Bexsero vaccine failure A confirmed case as defined above and … … the confirmation that the patient was age appropriately and fully vaccinated as recommended and with 1 month delay for a full effect of the immunisation.
  • 33. Clinical case of N. meningitidis Reported to PHE MRU Serogroup B vaccine-type Serogroup B Non-serogroup B vaccine-type No N. meningitidis confirmation PCR only confirmed N. meningitidis from sterile site Culture confirmed N. meningitidis from sterile site MATS on throat swab PorA P1.4 genotyping MATS on sterile site Case identification
  • 34. Carriage studies - 1 Reduction in capsular group C carriage following introduction of meningococcal serogroup C conjugate vaccines 0 1 2 3 0 2 4 6 8 10 0 5 10 15 20 25 0 2 4 6 8 10 Meningococci (% of isolates) 1999 2000 2001 Serogroup C Serogroup YSerogroup B Serogroup W -71% -81% Maiden MC et al. J Infect Dis. 2008;197:737-43.
  • 35. Carriage studies - 2 •A phase III study (NCT01214850) enrolled 2968 students in 10 universities across England from September-December 2010. •Students received either one dose of a licensed quadrivalent meningococcal conjugate vaccine, Menveo® (n = 956) followed by saline placebo, or two doses of either meningococcal Bexsero® (n = 932) or Ixiaro® (n = 948). •Oropharyngeal samples were taken before vaccination and at 5 subsequent visits over one year. •Primary analysis at one month after the vaccination series did not reveal significant impact of either vaccine however across the cumulative later timepoints:  Menveo was associated with a carriage-reduction efficacy of 38.0% (95% CI: 15.9 – 54.2) against serogroup Y.  Bexsero was associated with a decrease in carriage of genogroup MenBCWY strains (24.2% [95% CI: 7.8 – 37.6]. Read R et al. ESPID 2013
  • 36. Seroprevalence studies - 1 Ishola D, Borrow R, Findlow H, et al. Clin Vaccine Immunol 2012; 19:1126-30. 0 10 20 30 40 50 60 70 80 90 100 <6mths 6-11mths 1-4yrs 5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-34yrs 35-44yrs 45-54yrs 55-64yrs 65+yrs %withSBAtitre>=8 1996-99 2000-2004 2009 Proportions of sera with MenC SBA titres ≥8 by age in England & Wales, pre and post-introduction of MCC vaccines
  • 37. Seroprevalence studies - 2 0 10 20 30 40 50 60 70 80 <0.3 0.3-0.59 0.6-0.99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920-2425-3435-4445-5455-64 65+ age (years) incidenceper100,000peryear 0% 10% 20% 30% 40% 50% 60% %withSBAtitres>=4 incidence group B per 100,000 per year SBA>=4 Age-specific incidence of group B disease compared to the percentage of individuals with SBA ≥4 against strain NZ98/254 (B:4:P1.7-2,4) Trotter C, Findlow J, Balmer P, Holland A, Barchha R, Hamer N, Andrews N, Miller E, Borrow R. Clin Vaccine Immunol 2007; May 9; 14:863-8. • For Bexsero use strains 44/76-SL (fHbp); 5/99 (NadA); NZ98/254 (PorA). • No useable strain for NHBA for seroprevalence studies though a UK NHBA MATS +ve/fHbp & NadA MATS -ve with mismatched PorA is being investigated.
  • 38. Conclusions •Approximately 50% of cases cultured confirmed thus can fully characterise utilising MATS. •Non-culture confirmed cases: - Nasopharyngeal isolates - Non-culture PorA, P1.4 - non-culture fHbp but no information on expression •Need means of quantifying expression levels direct from non-culture PCR positive samples. •Both nasopharyngeal carriage and seroprevalence need to be monitored.