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  • QUICK 23v vaccine not effective in infants, conjugate just introduced – hoped may also protect elderly indirectly.

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  • Vaccine against meningitis, current issues, what’s new & what are the future possibilities? Ray Borrow Professor of Vaccine Preventable Diseases, Vaccine Evaluation Unit, Health Protection Agency North West, Manchester Royal Infirmary, Manchester, M13 9WZ, UK [email_address] 16 th June 2011
  • Advances in meningococcal serogroup B vaccines
  • The Independent (20p version) Friday 10 th June 2011
  • Laboratory confirmed cases of meningococcal disease, E&W, Five Weekly Moving Averages: 1997 - 2011 (week 13)
  • Percentage of capsular groups of laboratory confirmed cases of meningococcal disease, E & W, 1999 to 2011 (May 14 th )
  • Increase in serogroup Y disease in England & Wales, 2007 to 2009 Meningococcal Y Strain 2007 2008 2009 All cases Y:P1.5-1, 10-1 : F4-1: ST1655 (CC23) 3 3 15 21 Y:P1.5-1, 10-4 : F4-1: ST1655 (CC23) 0 1 5 6 Y:P1.5-1, 10-10 : F4-1: ST1655 (CC23) 1 0 1 2 Y:P1.5-1, 10-12 : F4-1: ST1655 (CC23) 0 0 1 1 Total 4 4 22 30
  • Meningococcal ‘serogroup B’ vaccines
    • MenB capsule poorly immunogenic
    • Main approach in past was outer membrane vesicle vaccines
      • Efficacy shown in older trials in South America and Norway
      • Poor protection in younger children
    • Recent use in New Zealand epidemic
      • Short term effectiveness of 73% (95% CI 52 to 85)
    • No evidence of major impact on carriage
    • Subcapsular, surface exposed, conserved, induces bactericidal activity.
    • Two approaches:
    • Fractionation, protein purification, and proteomics steps - Pfizer.
    • Reverse vaccinology – Novartis
    • Final candidates have some shared component
      • If prevents acquisition of carriage, vaccination strategies including adolescents/young adults have the potential to provide indirect (herd immunity) benefits
    The solution
  • The Pfizer Investigational MenB Vaccine rLP2086
    • Investigational vaccine is based upon LP2086, a surface-exposed lipoprotein of N. meningitidis.
    • LP2086 was identified as a factor H binding protein (fHBP), important for survival of the organism in vivo.
    • The gene is present in all meningococcal serogroup B disease isolates examined.
    • fHBP in vitro surface expression has been shown in > 98% of MnB isolates – MEASURE assay.
    • fHBP also a component of Novartis vaccine.
  • Factor H (fH) binding protein (fHBP)
      • Variant or family groups:
      • Novartis Pfizer
        • Variant 1 Family B
        • Variants 2 & 3 Family A
      • Intra-family cross-reactivity good.
      • Inter-family cross reactivity poor.
    Variant 1/ Family B Variant 2 Variant 3 Family A
    • The vaccine is composed of two recombinant LP2086 proteins, one from each subfamily.
    • Early clinical studies demonstrated excellent safety profile and broad immunological response to clinical isolates representing the two subfamilies.
    • Results have been extended in three phase I/II trials in young adults and adolescents, and support continued development:
        • Acceptable safety profile
        • Robust SBA response rates against a diverse panel of MenB
        • invasive disease isolates
        • Variation with fHBP present in strain
    Clinical Development of the Pfizer Investigational MenB Vaccine
  • Immunogenicity of the Pfizer investigational MenB vaccine in adolescents (11 – 18 yrs) in 0, 2, 6 month schedule Richmond P, Marshall H et al. 17 th IPNC. Banff, Canada. September 11-16, 2010. VW04, page 37. A04 A05 B02 B03 LP2086 variant in SBA test strains % subjects with hSBA ≥ 4 Pre dose 1 1 month post dose 2 1 month post dose 3
    • Novartis has submitted its meningococcal vaccine Bexsero to European regulators for marketing approval.
    • If approved Bexsero would be the first broad-coverage vaccine for MenB.
    • Novartis 4CMenB (Bexsero ® ) contains 4 main antigens:
    Novartis 4CMenB (Bexsero ® ) PorA (presented as part of an OMV) NadA fHBP 1.1 NHBA
  • Novartis 4CMenB (Bexsero ® ) 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.
      • Short-lived fever in infants without medical consequences.
      • No excess fever in adolescents/adults.
    • Co-administered infant vaccines elicit expected immune responses when given with 4CMenB.
    • Additional studies are ongoing (i.e., 2, 3, 4 month primary vaccination, long-term persistence, carriage study in adolescents).
  • Novartis 4CMenB Phase III study in infants % of subjects with hSBA ≥ 1:5 one month after dose 3 (2, 4, 6 month schedule) Vesikari T, Esposito S, Kimura A et al. Presented at the 17 th IPNC. Banff, Canada. September 11-16, 2010. P180, page 167. fHBP NadA PorA 1.4 Baseline Post-primary N = 1149 to 1152 % Subjects with bactericidal titers ≥1:5 Antigen NHBA
  • Findlow J, Borrow R, Snape MD et al. Clin Infect Dis 2010;51:1127-37. % Subjects with SBA titres ≥1:4 fHBP NadA PorA UK infant trial: proportion of subjects with hSBA titres ≥ 4 before & after Novartis 4CMenB vaccine Strains Baseline Post 3 rd dose Pre booster Post booster
  • Summary of systemic reactogenicity after receipt of Novartis 4CMenB vaccine Findlow J, Borrow R, Snape MD et al. Clin Infect Dis 2010;51:1127-37.
  • Potential coverage of the investigational 4CMenB vaccine against group B isolates from England and Wales
  • Isolates
        • All invasive MenB isolates received at the Health Protection Agency Meningococcal Reference Unit from a single epidemiological year were selected.
        • Epidemiological year was from July 2007 to June 2008.
        • Total of 535 MenB isolates.
  • Methods - Genotypic coverage
        • All MenB isolates were genetically characterised with respect to:
            • MLST
            • fHBP
            • NHBA
            • NadA
            • PorA
  • Clonal complex of MenB isolates from 2007/2008 N = 535
  • PorA genotype of MenB isolates from 2007/2008 N = 535
  • Cumulative percentage (from n=535) 20 36 50 58 62 64 67 68 70 71 Top ten PorA genotypes of MenB isolates from 2007/2008
    • Calculation of coverage by genotypic methods does not account for,
      • Any differences in expression (or accessibility) of protein by each isolate.
      • Any differences in cross-reactivity of vaccine induced antibody to protein variants.
      • Any potential synergy between different antibody populations induced by the different components of 4CMenB.
    Discussion - genotypic coverage
    • Complications:
    • Variants of the proteins exist (vaccine induced antibody is not equally cross-reactive against all protein variants).
    • Protein expression differs between isolates.
    Meningococcal protein vaccines- evaluation of immunogenicity and coverage
    • Immunogenicity
    • Multiple (representative) strains with different antigenic repertoires are required to evaluate the breadth of protection in the SBA assay.
    • This is impractical due to the low volumes of sera gained from infant trials.
    • Coverage
    • Differences in expression and cross-reactivity of induced antibody, mean that typing information (genotypic) alone is insufficient.
  • Methodological issues- to determine expression and/or cross-reactivity? Antigen expression Cross-reactivity Combination of expression and cross-reactivity Mathematically calculated threshold of being killed by post-vaccination sera (i.e. being covered or not covered)
  • Meningococcal Antigen Typing System (MATS) Donnelly J et al. PNAS 2010;107:19490-19495
    • Each isolate is compared to a reference strain to give a relative potency (per recombinant protein).
    • For each recombinant protein a positive bactericidal threshold (PBT) which predicts SBA activity has been established.
    • Determined using serum pools from 13 month toddlers immunised with four doses of 4CMenB.
    • The PBT is the value above which >80% of strains are killed in the SBA assay.
    • This gives a binary outcome of either covered/not covered by the vaccine (per recombinant protein).
    • Coverage by the PorA (OMV) component of the vaccine is determined genotypically.
    Analysis of MATS data
  • Methods - MATS
    • The same 535 invasive MenB isolates were characterised:
    • Phenotypically using MATS for recombinant antigens (fHBP, NHBA, NadA).
    • Genotypic data for PorA was combined with MATS data to give an overall coverage prediction.
    • fHBP
    • All (34/34) isolates with the vaccine homologous fHBP 1.1 had positive MATS phenotype.
    • Of the fHBP 1.1 variants, there were up to a 6 fold difference in MATS RP.
    • Of the 63% of strains with fHBP positive phenotype,
      • 6% were variant 1.1.
      • 57% were fHBP variants other than 1.1.
    • NadA
    • Only three isolates had positive MATS phenotype.
    • All were ST-11 isolates harbouring variant 2 proteins.
    Results - MATS
    • NHBA
    • 131/133 (98%) of isolates with vaccine homologous P0002 NHBA had positive MATS phenotype.
    • MATS RP ranged from <1% to ~200%.
    • Of the 55% of isolates with positive NHBA phenotype,
      • 25% were variant P0002.
      • 30% were variants other than the vaccine homologous variant.
    Results - MATS
    • Overall coverage estimates are heavily influenced by the proportion of isolates with variant 1 fHBP and low numbers with cross-reactive NadAs.
    • As 50% and 16% of isolates are covered by 2 and 3 antigens, respectively, this has the potential to reduce the likelihood of vaccine escape mutants.
    • The MATS PBT and hence subsequent coverage estimates are based upon immunological cross-reactivity in 13-month olds following a 3 + 1 schedule .
    • Immunogenicity data have demonstrated that cross-reactivity of induced antibody to fHBP increases with age.
    • Therefore, it is likely that the coverage estimate will overestimate coverage in infants and underestimate that of adults.
    • Antibody populations induced by the OMV may act synergistically making coverage potentially higher.
    Discussion - MATS results
    • Using MenB isolates from the epidemiological year 2007/2008, we predict that 4CMenB would have a coverage of 72.9 % (95% CI 59.8-89.6) in England and Wales.
    • Coverage of 50% of isolates would be afforded by at least two antigens in 4CMenB decreases the likelihood of vaccine escape mutants occurring .
    • We conclude that 4CMenB has the potential to protect against a significant proportion of MenB disease in England and Wales.
    MenB coverage conclusion
  • Identifier: NCT01214850 A phase 3 to evaluate the effect of Novartis vaccine's 4CMenB and Menveo on pharyngeal carriage of N. meningitidis in young adults, n = 3,000. Group 1: Subjects in this arm will receive 2 doses of Novartis 4CMenB vaccine. Group 2: Subjects in this arm will receive one dose of Menveo. Group 3: Control arm-subjects in this arm will receive 2 doses of IXIARO (Japanese encephalitis). Sheffield, Manchester, Liverpool, Nottingham, Bristol, Middlesbrough, Oxford, Southampton, London
  • Pneumo
  • Incidence of Invasive pneumococcal disease per 100,000 population by age England & Wales 1998-2006
  • Pneumococcal vaccination programme in England and Wales
    • Pneumococcal 23-valent polysaccharide vaccine (PPV23)
    • Pre-2003: PPV23 only used in at risk groups.
    • 2003 to date: PPV23 recommended for all elderly:
      • From August 2003: ≥ 80 yr olds
      • From April 2004: 75 to 79 yr olds
      • From April 2005: 65 to 74 yr olds
    • Pneumococcal conjugate vaccines (PCV)
    • From 2002, PCV7 for at risk children under 2 years of age.
    • September 2006: PCV7 introduced for all infants + catch-up up to 2 years of age.
    • April 2010: PCV13 replaced PCV7 for all infants.
  • Pneumococcal Vaccines
    • PCV7, 7-valent conjugate vaccine (Prevenar™ ) contains serotypes
    • 14 18C 19F 23F 4 6B 9V
    There are over 90 serotypes of Streptococcus pneumoniae PPV23, the 23- valent polysaccharide vaccine (Pneumovax™ ) contains 14 18C 19F 23F 4 6B 9V 7F 5 1 3 19A 9N 8 33F 22F 20 2 17F 15B 12F 11A 10A Six additional serotypes added for Prevenar13 TM , PCV13 7F 5 1 3 19A 6A
  • Vaccine efficacy estimates for each age cohort , 62 to 80+ years, are being determined. These new data will inform as to the pneumococcal vaccination of those 65 years+. The use of PPV23 in at risk groups also being looked in to. PPV23 (Pneumovax ™)
  • PCV7 introduced in England & Wales on September 4 th 2006
    • Children aged > 13 months & < 2 years, born between 5/9/04 & 3/8/05
    • 1 dose of PCV 7.
    • Children aged 8 months to 13 months, born between 4/8/05 & 3/2/06
        • 1 dose PCV7 at routine 13 month visit.
    • Children aged > 2 months & < 8 months, born between 4/2/06 & 3/7/06
    • 2 doses of PCV 7 separated by 2 months, with a further dose at routine 13 month visit.
    CATCH – UP Campaign
  • HPA Enhanced Surveillance of IPD Microbiology Labs in England and Wales Hospitals in England and Wales S pneumoniae Isolates sent for serotyping to RSIL Reports of S. pneumoniae isolates sent to CFI via CoSurv Electronic data imported into CFI systems Rapid telephone follow to get PCV vaccination status Clinical advice sent to GP and paediatrician sends blood to HPA Manchester DATA SHARED ON JOINT DATABASE AT CFI Antibody results HPA Manchester Feed back results with further advice
  • CASES OF IPD FOLLOWED UP to 14 th June 2011
    • 2254 cases of IPD in children born since 04/09/2004
    • 2052 (91%) serotyped – i.e. isolate sent to RSIL
            • Remainder are from CoSurv reports to Centre for Infections but no isolate sent to RSIL for serotyping
        • Immunisation status obtained for 99%.
        • 317 of total serotyped (15%) have a PCV7 serotype.
        • 1105 of total serotyped (53%) have a PCV13 (but not in 7) serotype.
    • 127 children have died.
            • Around (75%) attributable to pneumococcal sepsis.
    • 503 children (22%) had pneumococcal meningitis.
            • Case fatality rate of meningitis was 12%.
        • 1,424 bloods sent to HPA Manchester for serotype-specific IgG responses for measurement post-disease or post-completion of PCV immunisation.
  • The impact on Invasive Pneumococcal Disease Children Under 5 yrs: Serotypes contained in PCV7
  • The impact on Invasive Pneumococcal Disease Children Under 5 yrs: Serotypes NOT contained in PCV7
  • The impact on Invasive Pneumococcal Disease Persons ≥ 5 yrs: Serotypes contained in PCV7
  • The impact on Invasive Pneumococcal Disease Persons ≥ 5 yrs: Serotypes NOT contained in PCV7
  • Incidence of invasive pneumococcal disease per 100,000 population by age England & Wales 1998-2010
  • Cumulative weekly number of reports of Invasive Pneumococcal Disease Serotypes in PCV 13 but not in PCV 7 Children aged <2 years in England and Wales by Epidemiological Year:
  • Pneumococcal conclusions
    • Little impact seen from PPV23 vaccination programme in the elderly.
    • Estimates show excellent vaccine efficacy with PCV7 in the targeted age groups.
    • Evidence of a herd immunity effect from PCV7 introduction has been seen.
    • Despite replacement disease, the reduction in IPD in children is substantial.
    • The phenomenon of replacement needs to be confronted and investigated.
    • Evidence of direct impact of PCV13 in under 2 year olds.
    • There is a role for higher valency conjugate vaccines.
  • Acknowledgements
    • Meningococcal acknowledgements
    • HPA Manchester
    • Jamie Findlow, Jay Lucidarme, Xilian Bai, Stefanie Gilchrist, Danielle Thompson, Lynne Newbold, Steve Gray, Ed Kaczmarski
    • Immunisation Department, HPA Centre for Infections, Colindale
    • Shamez Ladhani, Mary Ramsay
    • Pneumococcal acknowledgements
    • Immunisation Department, HPA Centre for Infections, Colindale
    • Pauline Kaye, Liz Miller, Rashmi Malkani, Shamez Ladhani, Nick Andrews, Stefan Flasche
    • Respiratory & Systemic Infection Laboratory, HPA Centre for Infections, Colindale
    • Robert George, Mary Slack, Androulla Efstratiou, Siobhan Martin, Christine More
    • HPA Manchester
    • Elaine Stanford
    • Infectious Diseases and Clinical Microbiology, University of Oxford, UK
    • David Griffiths, Derrick Crook