Neisseria meningitidis- groups Neisseria meningitidis strains are classified into 12 groups. The polysaccharide capsule is used to identify the different groups. B A C Five main groups cause the majority (95%) of all meningococcal disease Polysaccharide Capsule around the world – A, B, C, W and Y. W Y
Meningococcal disease-global epidemiology Canada B Europe C 53% 21% Japan B 90% B B Y 57%USA Y 25% 21% 37% A C W 12% 29% African 17% B Meningitis W 50% Belt A W Taiwan 78% 35% 84% Saudi Arabia B Y Columbia 50% Brazil 40% Australia B 22% C A 71% 23% B C 80% Argentina 20% B B 67% 41% C 11% South New Africa Zealand B 82%
Laboratory confirmed cases of MenC disease in England and Wales 1995 to 2012 (calendar year) 1000 900 800 700 No of confirmed cases 600 500 Public health impact since 1999 400 300 Prevention of > 12,000 cases Prevention of > 1200 deaths 200 100 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)Health Protection Agency Meningococcal Reference Unit- Unpublished data
Laboratory confirmed cases of MenB disease in England and Wales 1995 to 2012 (calendar year) 1800 1600 Natural fluctuation? 1400 No of confirmed cases 1200 1000 800 600 400 200 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)Health Protection Agency Meningococcal Reference Unit- Unpublished data
Laboratory confirmed cases of MenW disease in England and Wales 1995 to 2012 (calendar year) 140 Outbreak 120 100 No of confirmed cases 80 60 40 20 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)Health Protection Agency Meningococcal Reference Unit- Unpublished data
International Hajj associated MenW outbreak 2000* Netherlands: 9 Scotland: 1 Norway: 1 England & Wales: 50 Sweden: 2 Finland: 2 Belgium: 1 Denmark: 1 Germany: 10 France: 21 Kuwait: 3 USA: 4 Morocco: 3 Singapore: 4 Indonesia: 14 Burkina Faso (2002), 13,000 S. Arabia: 241*cases Apr to Dec 2000, WHO Oman: 18
Laboratory confirmed cases of MenY disease in England and Wales 1995 to 2012 (calendar year) 100 90 80 70 No of confirmed cases 60 50 40 30 20 10 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)Health Protection Agency Meningococcal Reference Unit- Unpublished data
Emergence of MenYin Europe Increases in disease due to MenY has been observed in a number of Countries across Europe France Sweden Germany Switzerland Finland Norway Reference: EMGM May 2011 England and Wales Czech RepublicGray SJ, et al. Presented at: EMGM . Ljubljana, Slovenia. May 18–20, 2011.
Laboratory confirmed cases of MenY disease in England and Wales by age group and yearLadhani et al., Emerg Infect Dis 2012;18:63-70
Laboratory confirmed cases of meningococcaldisease in England and Wales in2012 (calendar year) Y other W 10% 2% 3% C 3% B 82%Health Protection Agency Meningococcal Reference Unit- Unpublished data
Laboratory confirmed cases of meningococcal disease (all groups) in England and Wales 1995 to 2012 (calendar year) 3000 2500 2000 No of confirmed cases 1500 1000 500 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)Health Protection Agency Meningococcal Reference Unit- Unpublished data
Average annual number of laboratory confirmedcases of meningococcal disease in children <2years of age by capsular group and age(2006/2007 to 2009/2010)~54% of disease <1 year annualis within the first 6 months Average of age number of laboratory confirmed cases of all Meningococcal disease in under-2s by serogroup and month of age (2006-07 to 2009-10) 40.0 35.0 Other groups Ungrouped 30.0 ACWY Number of reports B 25.0 20.0 15.0 10.0 5.0 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age (months)Ladhani et al., Vaccine 2012;30:3710-6
Average annual number of invasive meningococcaldisease cases by capsular group in children andyoung adults in England and Wales(2006/07 to 2009/10) 300 ACWY 250 Ungrouped Other groups B Number of reports 200 150 100 50 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Age (years)Ladhani et al., Vaccine 2012;30:3710-6
Meningococcal conjugate vaccineproduction Polysaccharide capsule C 1999 VaccineA C Y W 2010 A 2010 B ?
How do we use meningococcalvaccines to achieve optimalprotection? Infants Indirect protectionAdolescents
Meningococcal conjugatevaccines Vaccine Active Manufacturer Carrier protein constituents Mengitec C Pfizer CRM197 Menjugate C Novartis CRM197 NeisVac-C C Baxter Tetanus toxoid Menactra A, C, W + Y Sanofi Pasteur Diphtheria toxoid Menveo A, C, W + Y Novartis CRM197 Nimenrix A, C, W + Y GSK Tetanus toxoid Menitorix C + Hib GSK Tetanus toxoid MenHibrix C + Y + Hib GSK Tetanus toxoid MenAfriVax A Serum Institute of Tetanus toxoid India No licensed MenB vaccine available
Why is there currently noMenB vaccine available? MenB polysaccharide is polysialic acid, a compound identical to thatfound 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. Downside of approach = Diversity
Subcapsular approaches Development of subcapsular antigen vaccines has broadly followedtwo pathways-(i) Outer membrane vesicles (OMVs) (ii) Individual proteins Used successfully to combat single clone epidemics of MenB disease. Immune response is primarily Purified or recombinant outer directed against the PorA membrane proteins Blebbing Purified OMVs protein, resulting in limited cross-
The Pfizer Investigational MenBvaccine rLP2086 Investigational vaccine based upon rLP2086, a surface-exposedlipoprotein of N. meningitidis. Discovered by traditional vaccine development procedure(fractionation, protein purification and proteomic steps). LP2086 has since been renamed as factor H binding protein (fHBP). fHBP is important for survival of the organism in vivo. The gene is present in all meningococcal MenB disease isolates examined. fHBP also a component of the Novartis vaccine.
fHBP Variant or family groups Variant 1 Family BNovartis PfizerVariant 1 Family BVariants 2 & 3 Family A Variant 2Intra-family cross-reactivity good. Family AInter-family cross reactivity poor. Variant 3
Clinical development of the Pfizerinvestigational MenB vaccine The vaccine is composed of two recombinant LP2086/fHBP proteins, one from each family. Promising results have been achieved in three phase I/II trials in young adults and adolescents, and support continued development: (i) Acceptable safety profile. (ii) Robust serum bactericidal antibody (SBA) response rates. Current situation Evaluation continuing through later phase trials. Will be targeted for an adolescent indication.Anderson AS, Jansen KU & Eiden J. Expert Rev Vaccines 2010;10:617-34.
Novel antigens discovered byreverse vaccinology Based on the genome sequence of MC58, ~350 proteins successfully expressed in 570 ORFs that potentially encoded novel surface E.coli, purified, and used to immunise mice exposed or exported proteins were identified 1 IHT-A 2,200,000 100,000 2,100,000 200,000 2,000,000 300,000 expression IHT-C 1,900,000 400,000 and 1,800,000 500,000 purification 1,700,000 IHT-B 600,000 purified proteins 1,600,000 700,000 1,500,000 800,000 1,400,000 900,000 1,300,000 1,000,000 1,200,000 1,100,000 Sera used to confirm surface exposure of immunisations novel proteins Bexsero® 28 novel protein antigens identified Slide provided by Novartis Vaccines
Novartis investigational MenB ®4CMenB vaccine(Bexsero ) Bexsero (previously known as 4CMenB or rMenB+OMV) contains 4 main antigens. Three recombinant proteins discovered by reverse vaccinology. OMVs from the New Zealand outbreak strain (NZ 98/254). fHBP NadA NHBA PorA (Variant 1) (presented as part of an OMV)http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero
Bexsero (Novartis Vaccines) 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. Current situation Novartis has submitted for marketing approval (licensure) to European regulators (EMA). Decision is predicted during 2012. Ongoing trial in English University students to investigate any impact on carriage (herd protection).Bai X, Findlow J & Borrow R. Expert Opin Biol Ther 2011;11:969-85.
Alternative MenB vaccineapproaches Pre-clinical Numerous approaches using other surface exposed antigens mostly in the form of OMVs. Walter Reed Army Institute of Research (WRAIR) Three genetically modified strains used to produce native OMVs. Genes responsible for three reactogenic components have been “knocked out”. Each OMV has an extra gene for a different PorA inserted (therefore each OMV has two different PorA proteins). Increased expression of selected proteins including fHBP (Family A and B), OpcA, and NadA. Early phase trials have been successfully undertaken which have demonstrated good immunogenicity with a good safety profile. Novartis Vaccines Combined vaccine of Bexsero and Menveo (ClinicalTrials.gov Identifier: NCT01210885).
Proportions of sera with MenC SBA titres ≥8 byage in England & Wales, pre and post-introduction of MCC vaccines Consequently, need to introduce a 1996-99 2009 booster dose for MenC to 100 (i) Provide direct protection 90 (ii) Maintain herd protection 80 70 % with SBA titre >=8 60 50 40 30 20 10 0 6-11 mths <6 mths 10-14 yrs 15-19 yrs 20-24 yrs 35-44 yrs 45-54 yrs 55-64 yrs 65+ yrs 25-34 yrs 1-4 yrs 5-9 yrs1996-9 data: Trotter CL et al., Clin Vaccine Immunol 2008;15:1694-8. 2009 data: Ishola D et al., Clin Vaccine Immunol 2012;19:1126-30
“The committee noted that clinical trial data shows that a singledose of meningococcal C vaccines (NeisvacC® or Menjugate®)provided sufficient immunity in infancy until the booster dose ofHib/MenC at 12 months of age. Given this evidence and the advicefrom the sub-committee that a dose of meningococcal C should beconsidered in adolescence to maintain individual and herdprotection, the committee advised that a cost-neutral approachcould be to remove a dose from the infant schedule and replace itwith an adolescent dose of meningococcal C vaccine.JCVI asked that its adolescent sub-committee look at options forthe timing of an adolescent dose of meningococcal C vaccine.Action: committee and sub-committee to consider the timingof an adolescent dose of meningococcal C vaccine.”
MenC booster“the meningococcal C immune response of quadrivalent meningococcal ACWY vaccine wasuncertain and may be inferior to the monovalent vaccine. In the absence of carriage data the impactof use of quadrivalent vaccine on meningococcal Y carriage is also uncertain. For these reasonsthe sub-committee agreed with the advice of the JCVI meningococcal sub-committee that themonovalent meningococcal C vaccine should be used as a booster dose”“noting that there is uncertainty about when the expected increase in meningococcal C diseasemay arise, considered that a booster dose should be introduced as soon as practicable onprecautionary grounds. It was noted that the suggested use was outside of the current marketauthorisations for the vaccines.”“The vaccine could be given concomitantly with the current tetanus, diphtheria and polio (Td/IPV)booster. Evidence that would be discussed later in the agenda suggested that the booster wouldprobably most effectively be delivered in schools. Whilst a booster dose at age 15 years (schoolyear 11) may be optimal given that it may have a larger immediate impact on carriage, issuesaround implementation of a booster dose at that age need to be considered and would bediscussed later in the agenda. An alternative strategy that would have a similar impact on carriagewould be to introduce routine vaccination in younger adolescents with a time limited catch-upcampaign for older ages, although this option would be more costly overall. It would also beimportant to review new carriage data that may be available later in the year, which may informscheduling considerations.”
Quadrivalent meningococcal vaccines“The committee noted the recent market authorisation of a new quadrivalent meningococcal ACWYconjugate vaccine (Nimenrix® produced by GSK) for children from one year of age and adults. CurrentGreen Book guidance covers use of another quadrivalent meningococcal ACWY conjugate vaccine(Menveo® produced by Novartis) in certain risk groups and as a travel vaccine. The current marketauthorisation for Menveo® is for use in children from 11 years of age and adults. However, JCVI hadadvised that it should be used in certain younger children outside of its market authorisation. It wasnoted that the market authorisation for Menveo® may change in relation to use in younger children.31. The committee agreed that Green Book guidance should be changed to specify that eitherMenveo® or Nimenrix® may be used in certain risk groups and as a travel vaccine in individuals fromone year of age. Only Menveo® should be used in children under one year of age as there are somedata on its use in that age group (there are no data on use of Nimenrix® in this age group) and theamount of tetanus toxoid in Nimenrix® could potentially give rise to greater reactogenicity in infants.32. The committee also noted that the summary of product characteristics of both vaccines suggested abooster dose of vaccine after one year in individuals that remain at risk of exposure to serogroup Ameningococci bacteria because of evidence of waning immunity against this strain. However, it wasconsidered that the data on waning meningococcal A immunity may be unreliable due to the type ofassay (human complement serum bactericidal assay) used in clinical trials. It was agreed that a boosterdose after five years may be more appropriate for individuals at continued risk from serogroup Ameningococci, in line with that5 of the meningococcal ACWY polysaccharide vaccines.”
Cumulative weekly number of reports of Invasive PneumococcalDisease due to any of the six serotypes IN Prevenar13™ but not inPCV7 : Children aged < 2 years in England and Wales byEpidemiological Year: July-June (2006- To Date) 250 06-07 07-08 08-09 09-10 10-11 11-12 200 PCV13 introduced WHITE LINE Week 13 2010Number of Reports 150 100 Introduction of Prevenar™ BLUE LINE Week 36 2006 50 Vaccine effectiveness of additional 6 serotypes = 80% 0 Week
Cumulative weekly number of reports of Invasive PneumococcalDisease due to any of the serotypes NOT IN Prevenar13™ : Childrenaged < 2 Years in England and Wales by Epidemiological Year: July-June (2006- To Date) 06-07 07-08 08-09 09-10 10-11 11-12 140 120 PCV13 introduced WHITE LINE Week 13 2010 100 Number of Reports 80 60 Introduction of Prevenar™ 40 BLUE LINE Week 36 2006 20 0 Week Unclear whether there is an increase in non PCV13 serotypes as yet in children
Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the six serotypes IN Prevenar13™ but not in PCV7 : Persons aged >5 Years in England and Wales by Epidemiological Year: July-June (2006- To Date) 2500 06-07 07-08 08-09 09-10 10-11 11-12 PCV13 introduced WHITE LINE Week 13 2010 2000Number of Reports 1500 1000 Introduction of Prevenar™ BLUE LINE Week 36 2006 Early evidence of 500 herd protection (within 18 months of implementation) 0 Week
Cumulative weekly number of reports of Invasive PneumococcalDisease due to any of the serotypes NOT IN Prevenar13™ :Persons aged >5 Years in England and Wales by EpidemiologicalYear: July-June (2006- To Date) 3000 06-07 07-08 08-09 09-10 10-11 11-12 2500 PCV13 introduced WHITE LINE Week 13 2010 2000Number of Reports 1500 Introduction of Prevenar™ 1000 BLUE LINE Week 36 2006 500 0 Week Unclear whether there is an increase in non PCV13 serotypes as yet in >5 year olds
Pneumococcal vaccines“The committee agreed with the sub-committee that it would not be effective nor cost effective tointroduce a programme in the UK to offer PCV13 to those in clinical risk groups or to older adultsgiven the evidence of accumulating indirect protection of the population from the childhoodimmunisation programme. However, certain groups with a greatly increased risk of death from IPDfrom PCV13 serotypes would continue to benefit, but only in the short-term, from PCV13 given underthe supervision of a secondary care physician. Given the expected disappearance of PCV13serotypes within a small number of years, use of PCV13 outside of the routine childhoodimmunisation programme would become ineffective even in these groups. It was noted that severalmedical professional bodies had recommended use of PCV13 in certain clinical risk groups.Action: the committee and sub-committee to produce a more detailed statement with thisadvice.18. In addition, the committee also accepted the advice of the sub-committee:• to revise the definition of chronic kidney disease for the purposes of pneumococcal vaccination;• that there should be no changes currently to guidance on the use of pneumococcal polysaccharidevaccine (PPV23);• the use of PPV23 should be reviewed within two years to determine whether it remains effectiveand cost effective in light of the changing epidemiology of invasive pneumococcal disease andfurther analysis of the accumulating UK data on the effectiveness of PPV23.”
Summary (1) Meningococcal epidemiology In England and Wales we are currently in a period of comparativelylower meningococcal disease incidence. The number of MenY disease cases has risen over recent yearsand is associated with pneumonia in older age groups. MenB is currently responsible for ~85% of meningococcal diseasein and is currently unpreventable by vaccination. The peak incidence of MenB disease is at 5 months of age. Vaccination strategies can be designed to provide indirectprotection in addition to direct protection.
Summary (2) MenB vaccines There are two MenB vaccines in the later stages of development. Bexsero (Novartis Vaccines) is currently being reviewed by theEMA. If licensed this would result in the first broad coverage vaccinefor MenB becoming available. Licensure of Bexsero does not necessarily equate torecommendation/implementation into the UK schedule which is basedupon multiple considerations. It is probable that other broad coverage MenB vaccines willsubsequently become available over the next decade.
Summary (3) Future schedule changes (meningococcal vaccines) We will be changing from a two dose MCC priming schedule to asingle dose priming schedule in the near future. In a “cost neutral” approach, this MCC dose will re-scheduled tobecome an adolescent booster. A second quadrivalent meningococcal polysaccharide vaccine(Nimenrix, GSK) has been recently licensed by the EMA. The “Green book” will be updated shortly to include Nimenrix.
Summary (4) Pneumococcal epidemiology and vaccination Excellent direct impact of PCV13 in targeted age groups, with overall vaccine effectiveness of the additional 6 serotypes covered by PCV13 ~80%. Early evidence of rapid herd protection with PCV13 (within 18 months) despite no catch up. The JCVI have recommended no changes to the use of PPV23 in clinical at-risk groups (except those with a very high risk of contracting disease).
What the papers say 10th June 2011 or 2012 30th Sept 2012 2013?
Acknowledgements Vaccine Evaluation Unit, HPA, Manchester Ray Borrow. Meningococcal Reference Unit, HPA, Manchester Ed Kaczmarski, Steve Gray and Tony Carr. Immunisation Department, HPA, Colindale Liz Miller, Pauline Kaye, Shamez Ladhani and Rashmi Malkani.