An AW outer membrane vesicle (OMV) meningococcal vaccine trial in Ethiopia. Tesfamariam Mebrahtu Armauer Hansen Research Insitute

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1 An AW outer membrane vesicle (OMV) meningococcal vaccine trial in Ethiopia Tesfamariam Mebrahtu Armauer Hansen Research Insitute

2 BACKGROUND meningitis belt In the meningitis belt of sub-saharan Africa Epidemics of meningitis are significant cause of mortality & morbidity The incidence is peaking in the dry season every year. About 90% of the cases are caused by one of the serogroups A, B, C, Y, W and X.

3 BACKGROUND... In addition to the yearly cycles, large, multi-country epidemics recur roughly every 8-12 years. 1996, more than 250,000 individuals contracted meningococcal disease during one season and about 16,000 died After year 2000, the incidence of serogroup W (MenW) meningococcal disease has increased. & Serious epidemic occurred in Burkina Faso in 2002 with 12,600 cases and 1,500 deaths.

4 BACKGROUND... The major cause of most outbreaks in Ethiopia has been meningococci of serogroup A. Meningitis Vaccine Project (MVP) developed an affordable monovalent MenA conjugate vaccine, (MenAfriVac) This vaccine was first introduced in Burkina Faso, Mali and Niger in Dramatic effect on MenA disease was seen.

5 In Ethiopia, MenAfriVac introduction started in October (West East ) With the likely elimination of MenA, MenW may emerge as a serious problem. Following elimination of MenA epidemics, an affordable, safe and effective vaccine against all meningococcal serogroups is highly needed. A vaccine based on sub-capsular antigens is an innovative major step further towards this aim. Development of an AW OMV meningococcal candidate vaccine in collaboration between NIPH and Finlay Institute, Cuba

6 Developement of AW OMV candidate vaccine MenA strain Mk499/03, clinical isolate from Ethiopia 2003 MenW strain Mk222/02, clinical isolate from Burkina Faso 2002 Less expensive than existing multivalent conjugate vaccines Broader protection than the affordable monovalent conjugate vaccine MenAfriVac Preclinical studies (Tunheim G et al. Vaccine, 2013) Immunogenicity is non-inferior to MenAfriVac and Menveo Functional antibody titers (SBA, OPA) against A and W strains Is significantly higher in mice compared to Menveo High stability for long periods

7 Licensed OMV vaccines from N.meningitidis serogroup B Vaccine Developed at To address (strain) Applied in Doses VA-MENGOC-BC Finlay Institute, Cuba An epidemic Tested (B:4:P1.19,15) Cuba (>20 years) 40 millions MenBvac Norwegian Institute of Public Health (NIPH) An epidemic Tested (B:15:P1.7,16 (44/76)) Normandy, France in trials in France MeNZB Partnership (WHO, New Zealand government, University of Auckland, NIPH, Chiron) An epidemic Used (B:4:P1.7-2 (NZ 98/254)) New Zealand 1.2 million Bexsero Novartis To provide broad-based protection (B:4:P1.7-2 (NZ 98/254) and three recombinant antigens) Licensed in 37 countries >1 million

8 Rationale for phase II study A. Preclinical studies: AW OMV vaccine immunogenic B. Phase I clinical trial, Cuba 2013/2014: Study design phase I, Cuba 1. Safety No SAE 2. Immunogenicity See presentation 5: G. Norheim Induced antibodies against AW OMV Antibodies were bactericidal

9 Phase I clinical trial, Cuba Safe (AW OMV Vs control vaccine groups) No Serious Adverse Events No immediate adverse reactions No abnormal clinical lab test 7 days after the 1 st dose with clinical significance No significant differences in the frequency of local and general symptoms were detected. Immunogenic The AW OMV vaccine induces high levels of protective antibodies against both MenA and MenW

10 Phase II clinical trial, Ethiopia A geographical region where the vaccine is intended to be used in the next step in the development of the vaccine

11 Phase II clinical trial, Ethiopia Sponsor: NIPH Funder: Norwegian Research Council Principal Investigator (PI): Tesfamariam Mebrahtu, AHRI Vaccine production: Finlay Institute, Cuba Collaborators: Andrew Pollard, Oxford Vaccine Group Abraham Aseffa, AHRI Nejib Yusuf, Haramaya University Monitors Simon Kerridge, Oxford Vaccine Group Getnet Yimer, AHRI Statisticians Merryn Voysey, Oxford Vaccine Group

12 Study design, phase II trial in Ethiopia

13 Study design Primary Objective To evaluate the immunogenicity and safety of two doses of the AW OMV meningococcal candidate vaccine administered as 50 µg protein/dose Secondary Objective To further explore the safety and functional response of antibodies against serogroups A and W of N. meningitidis strains, before vaccination and after administration of two doses of the bivalent AW OMV meningococcal candidate vaccine and one dose of the control vaccines

14 Study design Random assignment of the vaccines: 2:1:1 AW OMV meningococcal candidate vaccine MenAfriVac control vaccine Menveo control vaccine Blood sampling: Week -2/0, 0, 8, 16, 34, 60 Saliva sampling: Week 0, 8, 16, 34, 60

15 Statistical analyses Sample size: 240 subjects will be enrolled in the study There is no statistical (null) hypothesis associated with the immunogenicity objective due to the statistical power considerations. Analyses will be run descriptively

16 Blinding Double Blinding For the study candidate vaccine & Control Vaccine Nursing staff in charge of administering the vaccines Physicians Lab Personnel Pharmacists PI and Collaborating staffs Data management staff Sponsors Participants And All investigating team Should be blinded

17 At AHRI, Blinding procedure Two persons will prepare opaque individual bags. These bags will correspond to the number of participants included in the study. They will identify each bag with a vaccine code At the study site: One nurse is responsible for the preparation of the vaccines. Another nurse is responsible for administration of the vaccines The blinding nurse: retrieves the assigned vaccine code for each participant code from the randomization list.

18 AW OMV vaccine production Manufactured at Finlay Institute, Cuba Good manufacturing practices (GMP) GMP site license GMP certificate of analysis Batch release certificate Export permission CECMED Import permission FMHACA Stability data report

19 Control vaccines MenAfriVac, Serum Institute India Serogroup A conjugate vaccine 1 dose, second dose: saline Menveo, Novartis Vaccines Serogroups ACYW conjugate vaccine 1 dose, second dose: saline

20 Study visits Visit Main activity Week* Visit 1 Screening -2/0 Visit 2 Vaccination (1. dose), sampling and clinical evaluation visits (day 1, 2, 3 and 0 7 after vaccination) Visit 3 Vaccination (2. dose),sampling and clinical evaluation visits (day 1, 2, 3 and 8 (±5d) 7) after vaccination Visit 4 Sampling and clinical evaluation 16 (±11d) Visit 5 Sampling and clinical evaluation 34 (±23d) Visit 6 Sampling 60 (±42d)

21 Preparation of the phase II clinical trial Synopsis and protocol development (June 2014) Ethical and Regulatory authorities approvals: REC, Norway AAERC, Ethiopia IRB Haramaya, Ethiopia NRERC, Ethiopia FMHACA, Ethiopia AAERC REC NRERC IRB Haramaya FMHACA

22 Clinical study site Hiwot Fana Specialized Hospital, Haramaya University

23 Clinical study site

24 Recruitment A list of houses with persons aged 18 to 29 is be prepared by Kersa DSS (Demographic Surveillance Site) Participants will be recruited Harar DSS from 6 Kebeles SEX Age group Female Male Total 2-3 HEW in each Kebele 0-4 years 989 1,070 2, years 1,441 1,485 2, years 1,503 1,474 2, years 1,815 1,560 3,375 The total population of these years 1,778 1,371 3, years 2,015 1,479 3, years 1,461 1,523 2,984 sites is estimated to be 30, years 1,232 1,364 2, years 805 1,065 1, years , years , years years years years years years: years: years: 4078 Total 15,617 14,612 30, Harar-DSS Males Percentages Females

25 Data collection Paper Case Report Form (CRF) Source documents Data entry into OpenClinica Web based software for collating clinical trial data OpenClinica Database Design at AHRI, captures all data according to the protocol Double data entry in Haramaya Monitor and Manage Data module, allows the monitor to oversee and validate data

26 Site preparation Preparation of Haramaya clinical trial site SOP development Clinical trial flowchart and logistics Shipment and logistics Laboratory analysis Site initiation visit Monitoring and GCP training plan Trial master file (TMF)

27 Implementation plan Preparation phase Study site preparation Ethical approval Staff training GCP training AW OMV vaccine production Site initiation visit Study start MenAfriVac vaccination Haramaya March/April 2015 Nov 2015 Clinical study visits Screening 1 st dose 2 nd dose Week -2/0 Week 0 Week 8 Week 16 Week 34 Week 60 Blood and saliva sampling

28 Acknowledgement NIPH, Norway Sponsor AHRI, Ethiopia PI: Tesfamariam Mebrahtu, AHRI Haramaya University Hiwot Fana Specialized Hospital Finlay Institute, Cuba Vaccine production Oxford Vaccine Group Monitor Collaborator

29 THANK YOU