RESEARCH AND DEVELOPMENT OF VACCINES AGAINST MENINGOCOCCAL DISEASE- How can Norway contribute? Einar Rosenqvist Norwegian Institute of Public Health

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1 RESEARCH AND DEVELOPMENT OF VACCINES AGAINST MENINGOCOCCAL DISEASE- How can Norway contribute? Einar Rosenqvist Norwegian Institute of Public Health GLOBVAC International Symposium Building Partnership in vaccination research Oslo 5th-6th March 2008

2 Meningococcal disease in Norway

3 Neisseria meningitidis Capsular polysaccharides determines meningococcal serogroups. Outer membrane proteins determines serotypes and subtypes Serogroups: A, B, C, W135 and Y causing nearly all disease cases worldwide. Polysaccharide vaccines against A, C, Y and W are introduced Serogroup B-PS is not immunogenic in man. Other vaccine alternatives have to be tried against serogroup B!

4 Outer membrane vesicle (OMV) vaccines PorA (Class 1) Subtype Outer membrane vesicles derived from a group A meningococcal strain Opc (Class 5c) Rmp (Class 4) LPS PorB (Class 3) Serotype Based on figure by Audun Aase, NIPH 2002 Tg_2-99. EM photo by Ellen Namork, NIPH. Scale bar is 100 nm.

5 OMVs from strain 44/76 (B15:P1.7,16) separated in SDS-gel, Mw 44/76 94 kd 67 kd TdfH Omp85 FetA 43 kd Por A Por B Rmp 30 kd OpcA OpaJ 20.1kD

6 Clinical development of MenBvac Phase I trial: 1987 Phase II trials: Phase III trials: A total of 25 clinical trials have been performed with MenBvac (18 in Norway, Iceland, Chile, USA, UK, New Zealand)

7 Efficacy trial of MenBvac in secondary schools DESIGN: Double-blind, placebo-controlled, school-randomised study students, years of age, 1. MenBvac: students ; 690 schools 2. Placebo: students; 645 schools 3. Non-participants: students 2 doses of 25 mcg, 6 weeks apart 29 months follow-up period (October 1998-May ) RESULTS: Protection rate (P) after 29 months follow-up: 57% Estimated protection rate after 10 months: 87 %

8 Questions-Next steps: Why did the vaccine work, and why did it not work in all cases? Can/should the MenBvac be used in Norway or in other countries? Are we prepared to produce similar vaccines against new upcoming epidemics (new strains/clones)? Development of an universal OMV vaccine against all group B meningococcal disease?

9 New vaccine building at NIPH (1995) Vaccine Research: Antigen purification (proteins, LPS, PS) Immunological assays Serum bactericidal assays Opsonophagocytic assays Mucosal immunity Preclinical vaccine studies Pilot plant vaccine production Clinical studies (phase I, II)

10 Meningococcal OMV vaccines the evidence Safe and effective against clonal serogroup B epidemics Induce serum bactericidal IgG in all age groups Norway 1983 New Zealand 2002 France Sequence type ST32 ST41 ST32 Phenotype B:15:P1.7,16 B:4:P1.7-2,4 B:14:P1.7,16 Rate per 100, No case 1-5 cases 23 cases

11 OMVs from Norwegian (44/6) and New Zealand (NZ98/254) strain Mw standard 44/76 NZ 98/ kd 67 kd TdfH Omp85 FetA 43 kd 30 kd Por A Por B FbpA Rmp OpcA OpaJ 20.1 kd NspA

12 Experiences from clinical trials in Norway, Chile, Iceland and New Zealand The OMV vaccines are safe and protective % seroconversion against homologous strains Good SBA responses against homologous strains also in infants Age dependent (5-60%) seroconversion against heterologous strains PorA is the dominant antigen

13 Conclusions: OMV vaccines are still the only viable option for controlling clonal outbreaks of group B meningococcal disease. The production process can be transferred and up-scaled to industrial level in order to meet an increasing demand. The localized outbreak in Normandy illustrates the importance of detailed surveillance and regional action plans. The concept of OMV vaccines deserves more attention and active involvement from international regulatory authorities.

14 Epidemic meningitis in Africa Number of cases 200, , , ,00092,347 80,000 60,000 40,000 20, Year 188,345 80,743 88,939 68, ,401 02

15 Meningococcal vaccine alternatives Plain polysaccharide vaccines Conjugated polysaccharide vaccines Outer membrane vesicle (OMV) vaccines Challenge: to make an affordable, effective vaccine for the meningitis belt countries, inducing long-lasting protection in all age groups against serogroups A, W-135, (+ C, Y and X)

16 Polysaccharide vaccines: Effective in outbreak situations Uncertain effectiveness in children < 2 yr No long-lasting immunity (up to 3-5 yrs) T-cell independent. No immunological memory, little or no benefit of booster dose Hyporesponsiveness with repeated doses of serogroup C no elimination of carrier state; Herd immunity not demonstrated

17 Epidemic Meningitis Trends in the Meningitis Belt. Four year moving average *. * William A. Perea. Epidemiology and Control of Meningococcal Meningitis in Africa: Recent Experiences and future Challenges. Global Forum of Vaccine, 2006.

18 Why explore OMV vaccines? Mechanisms for protection against group A MC-disease are not fully understood Antibodies to non-capsular antigens (proteins and LPS) are likely to contribute to protection Antibodies to non-capsular antigens have higher avidity than Ab to capsular ps. Efficacy of A-PS conjugate vaccine not yet known A vaccine against serogroups A+W135+Y+C+ X is needed. MenB OMV vaccines have shown good immunogenicity and safety profiles OMV vaccines are relatively simple to produce Be prepared for surprises: Don t put all your eggs in one basket

19 Gonder College of Medical Science North Gondar Zone Health Bureau Armauer Hansen Research Institute SNNPR Health Bureau Yirgalem Hospital

20 Meningitis belt meningococci, meningococcal strains analysed 78% were serogroup, of ST-5 clonal complex : A :4/21:P1.20,9 17% were serogroup W-135 (2a:P1.5,2) of ST-11 clonal complex Emerging threats: serogroup A ST-2859 serogroup W-135 ST-2881 serogroup X ST-181

21 Protein antigens in outer membrane preparations (OMVs) from serogroup B, A and W135 meningococcal strains

22 Summary OMV vaccines based on serogroup A and W135 strains induce high levels of bactericidal and opsonophagocytic antibodies. Thus, these OMV vaccines have a potential to protect against meningococcal disease caused by serogroup A subgroup III strains (A:4/21:P1.20,9), and ET-37-complex strains of serogroup C and W135 (2a:P1.5,2) in Africa. As most serogroup Y strains in Africa are 2a:P1.5,2, and most serogroup X strains are NT:P1.5, an OMV vaccine would probably also give protection against disease caused by these serogroups. A combined MenA+ MenW135 OMV vaccine may be an alternative or a supplement to polysaccharide based vaccines in Africa at an acceptable cost.

23 Collaboration between FINLAY Institute and NIPH on development of an OMV vaccine for Africa A Letter of Intent is signed by the the two institutions (June 2007) stating that: The parties declare their willingness to: Interchange of specialists in this project. Exchange of scientific information. Seek financial support for development project. To establish a Cooperation Agreement.

24 Cuban strengths in the Vaccine area Knowledge on meningococcal vaccines and clinical trials Production capacity (Finlay Institute) Human Resources State Priority regarding R&D Collaboration among the different institutions Health System A massive disposition for participating in clinical trials.

25 Phase II clinical study for immunogenicity and safety evaluation of a Brazilian OMV vaccine against meningococcus B

26 Collaboration between Biomanguinhos, Brasil (B-M) and Norwegian Institute of Public Health (NIPH) on development of a Brazilian group B meningococcal vaccine Comparison of assays used for SBA activity. Advisor on Clinical Trials Advisor on Manufacturing and Characterization of OMV vaccine Analysis of sera from Phase II in SBA Analysis of sera for opsonophagocytis activity