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Meningococcal serogroup B defeated?

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Presentation on theme: "Meningococcal serogroup B defeated?"— Presentation transcript:

1 Meningococcal serogroup B defeated?
Ray Borrow Vaccine Evaluation Unit, Health Protection Agency, Manchester Royal Infirmary, Manchester, U.K.

2

3 Novel vaccine antigens
Classification Capsule e.g. A, B, C, Y, W135 Serotype PorB e.g. 2a, 4, 15 DNA: e.g. MLST, PorA, porB Serosubtype PorA e.g. P1.16, P1.4 Novel vaccine antigens

4 Laboratory confirmed cases of meningococcal disease
England & Wales Five Weekly Moving Averages: 1997 to 2009 (up to March 14th 2009)

5 Clonal complexes of serogroup B meningococcal case isolates submitted to the Health Protection Agency MRU in January 2008 (n = 87) N = 189 N = 97 N = 90 ST32 ST213 ST41/44 ST269 1151 group B cases out of a total of 1278 meningococcal cases in 2008

6 PorA subtypes of serogroup B meningococcal case isolates submitted to the Health Protection Agency MRU in January 2008 (n = 87)

7 Correlates of protection
Immunogenicity studies, rather than efficacy studies, are sufficient for licensure of ‘group B’ meningococcal vaccines. Elevated serum bactericidal antibody (SBA) titres against a broad range of representative strains. If no SBA activity, efficacy studies will be required. Borrow R et al. Neisseria meningitidis Group B Correlates of Protection and Assay Standardization – International Meeting Report, Atlanta USA, March Vaccine 2006;24:

8 Meningococcal outer membrane vesicle OMV trials
Estimated efficacy 4:P1.15+C years 83% 3 months - 6 years 47-74% Norway 15:P1.16 57% Chile 15:P1.3+C 1 - 21 51% Year Age group Vaccine Cuba Brazil

9 Meningococcal OMV Vaccines for New Zealand
2002 Due to B:4:P1.7-2,4

10 Vaccine Implementation
Epidemic strain meningococcal disease rates Northern region by year and age-group 1st full year Vaccine Implementation Used with permission of Dr. D. Martin

11 Proportion of children aged 16 to 24 months who have seroconverted in the serum bactericidal antibody assay to their vaccine strain or a heterologous strain following either 3 doses of MeNZB or MenBvac P1.7-2,4 P1.7,16 Adapted from Wong et al. Pediatr Infect Dis J 2007;26:345-50

12 Neisseria lactamica % Subjects with a ≥4 fold rise in SBA titre (post 3 doses) Comparison of MenBvac with N. lactamica OMV Health Protection Agency

13 PorA OMP Meningococci are classified into serosubtypes based upon variation in VR1 & VR2. Mabs against VR1 & VR2 are bactericidal and protective in animal protection studies. Have long been perceived as potential vaccine components despite variation. Efficacy studies of OMV vaccines have shown a link between PorA antibodies & SBA activity.

14 Dutch Meningococcal PorA recombinant vaccine design
serosubtype P1.7,16,5-1,2-2,19,15-1 P1.7 / PorA \ P1.16 P1.5-1 / PorA \ P1.2-2 PorB PorA / P1.7 \ P1.19 / PorA \ HEXAVALENT VACCINE P1.16 P1.15-1 RmpM P1.5-2 OpA / PorA \ P1.10 serosubtype P1.7,16 P1.12-1 / PorA \ P1.13 PorA / P1.7-2 \ P1.4 serosubtype P1.5-2,10,12-1,13,7-2,4

15 Geometric mean serum bactericidal titres of 2 to 4 month old infants following vaccination with a RIVM recombinant hexavalent PorA OMV vaccine Bactericidal titre 1000 MENC11 (P1.7-1,4) TR52 (P1.5,2) 100 TR15 (P1.15) TR1213 (P1.12,13) TR4 (P1.7-8,4) TR10 (P1.5-2,10) 10 H44/76 (P1.7,16) 1 2 3 4 5 14 15 Age months Cartwright KAV et al. Vaccine 1999;17:

16 NONAMEN RIVM PorA approach serosubtype P1.7,16
/ PorA \ P1.16 / P1.5-1 PorA \ P1.2-2 PorA / \ P1.19 P1.15-1 serosubtype P1.22,14;7-1,1;18-1,3 P1.7 P1.16 / \ OpA RmpM PorA PorB serosubtype P1.7,16 P1.22 / NONAMEN PorA \ P1.14 / P1.7-1 PorA \ P1.1 PorA / \ P1.18-1 P1.3 P1.5-2 / PorA \ P1.10 / P1.12-1 PorA \ P1.13 PorA / \ P1.7-2 P1.4 serosubtype P1.5-2,10,12-1,13,7-2,4

17 Novel Antigens Identified by Reverse Vaccinology
Based on the genome sequence of MC58, ORFs that potentially encoded novel surface exposed or exported proteins were identified 100,000 200,000 300,000 400,000 500,000 600,000 700,000 800,000 900,000 1,000,000 1,100,000 1,200,000 1,300,000 1,400,000 1,500,000 1,600,000 1,700,000 1,800,000 1,900,000 2,000,000 2,100,000 2,200,000 IHT-A IHT-B IHT-C 1 ~350 proteins successfully expressed in E.coli, purified, and used to immunize mice purified proteins expression and purification immunizations Sera used to confirm surface exposure of novel proteins 28 novel protein antigens with bactericidal activity were identified Novartis Vaccines

18 Novartis MenB vaccine contains 4 main antigens
fHBP 1.1 NadA GNA2132 PorA (presented as part of an OMV)

19 Target strains used in the SBA assay
Antigen Designation PorA fHBP NadA NZ 98/254 P1.7-2,4 1.10 - 5/99 P1.5,2 2.8 + 44/76-SL P1.7,16 1.1

20 UK infant trial rMenB vaccine with or without OMV at 2, 4, 6 and 12 months of age. Control group received a single dose of rMenB at 12 months of age. Miller E, Pollard AJ, Borrow R, Findlow J, Dawson T, Morant A, John T, Snape M, Southern J, Morris R, Cartwright K, Oster P. 26th Meeting of the European Society for paediatric Infectious diseases – ESPID, Graz, Austria, 14th May 2008

21 Proportion of subjects with hSBA titres ≥1:4 before & after rMenB+OMV vaccine
Baseline Post 3rd dose Pre booster Post booster % Subjects with SBA titres ≥1:4 44/76-SL 5/99 NZ98/254 Strains

22 Geometric mean hSBA titres after rMenB+OMV vaccine for: 5/99 (NadA)
hSBA GMTs & 95% CIs Baseline Post nd dose Post rd dose Pre booster Control pre* Post booster Control post* n = 42 40 46 22 43 21 *Control group = A single dose of rMenB + OMV at 12 months.

23 Geometric mean hSBA titres after rMenB+OMV vaccine for: 44/76-SL (fHBP)
hSBA GMTs & 95% CIs Baseline Post nd dose Post rd dose Pre booster Control pre* Post booster Control post* n = 47 44 45 22 *Control group = A single dose of rMenB + OMV at 12 months.

24 Geometric mean hSBA titres after rMenB+OMV vaccine for: NZ98/254 (PorA P1.4)
hSBA GMTs & 95% CIs Baseline Post nd dose Post rd dose Pre booster Control pre* Post booster Control post* n = 48 44 47 22 *Control group = A single dose of rMenB + OMV at 12 months.

25 Wyeth rLP2086 vaccine LP2086 recombinantly expressed in E. coli and purified to homogeneity. Vaccine formulation developed for clinical studies contains two rLP2086 proteins- one from Subfamily A and one from Subfamily B. Induce bactericidal antibodies cross-reactive against all fHbp variants, depending on expression level. Phase I and Phase II (18 to 25 year olds, 8 to 14 year olds and 18 to 36 month olds).

26 Wyeth MenB Encouraging phase 1 trial results
Vaccine relatively well tolerated Dose-dependent reactogenicity & SBA responses % of responders approaching 100% for some strains, varied by definition of responder, and by strain tested GMTs varied by strain tested, expression critical Moving ahead with Phase 2 studies 16th International Pathogenic Neisseria Conference, Sept 2008, Rotterdam, the Netherlands

27 Multivalent group B meningococcal vaccine based on outer membrane vesicles
Walter Reed Army Institute of Research, Maryland, USA Native OMVs Each strain modified to express a different PorA, a different core LOS and an increased expression of one conserved antigen (fHbp1, fHbp2, NadA, Opc). - Phase I completed, safe and induced SBA GSK - Recombinant OMV technology Upregulate key protective antigens Down regulate variable immunodominant antigens Modify LOS

28 What is the potential coverage of these new vaccines eg PorA?
29 different variants of P1.4 (P1.4, P1.4-1 etc)* From PorA sequenced case isolates submitted to HPA 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 From Jan 2008 the % of isolates with P1.4 = 20% * #NIBSC code 02/148

29 fHbp variants for England & Wales case isolates in Jan 2008
Antigens variants - fHbp fHbp variants for England & Wales case isolates in Jan 2008 V1 V2 V3 }B B A }A Present in all case strains, genetic diversity, expression variable Present in all case strains, genetic diversity, expression variable

30 Incidence of serogroup B disease for 2006 for England, Wales and Northern Ireland
No. of B cases for 2008:

31 Age- and Serogroup-Specific Meningococcal Disease Incidence United States, 1993–2002
0-4 mos 5-11 mos 1 yr 2-4 yrs 5-10 yrs 11-17 yrs 18-22 yrs 23-32 yrs 1 2 3 4 5 6 7 Incidence per 100,000 Serogroup B Serogroup C Serogroup Y Serogroup W-135 Other Shepard CW, et al. Pediatrics. 2005;115:

32 X X How will they work? Immunise infants for direct protection?
Immunise adolescents for indirect protection?

33 Conclusions Group B vaccine trials are underway after a hiatus of a decade. Need to determine immunogenicity to predict effectiveness. Need to determine potential coverage. Which age groups should be vaccinated? Are carriage studies required?


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