Amadou Matar SECK, MD 19 May 2017 Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomised, controlled trial Amadou Matar SECK, MD 19 May 2017

Background (1) Studies of rotavirus vaccines in low-income countries show variable efficacy (17 – 63%) Substantial public health benefit in these settings because of the very high disease burden Available licensed and WHO-prequalified vaccines Require cold chain Large storage volume Supply constrained High price for countries graduating out of GAVI or not included Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Background (2) Landscape review of vaccines in development and manufacturers Oral recombinant vaccine (BRV-PV) Serum Institute of India (SIIL) 5 genotypes Stable up to 1 year at 37°C Lyophilized: obtained by rapid freezing and dehydration of the vaccine under high vacuum Phase II data: good immunogenicity and safety No efficacy, safety or immunogenicity data from Africa Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Background (3) Preliminary studies in Niger on diarrhea and rotavirus (2008-2012) Health care seeking behavior for diarrhea Etiology of diarrhea Rotavirus causes 30% of diarrhea cases Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Primary objective To assess the efficacy and safety of BRV-PV against severe rotavirus gastroenteritis in Niger Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Study design Randomized (1:1), double-blind, placebo-controlled Madarounfa, Niger (single center, multi-site) Intervention: 3 doses of BRV-PV or placebo administered at health centers at 6, 10, and 14 weeks of age (with EPI vaccinations) 2-8C from transport to arrival in Maradi Stored at temperatures not exceeding 25°C in Maradi Ambient temperature at dispatch to vaccination sites Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Study population Inclusion criteria: Exclusion criteria: 6-8 weeks of age Resident in study area Intend to stay for 2 years Able to swallow Written informed consent Exclusion criteria: Serious medical conditions Congenital abdominal disorders History of intussusception or abdominal surgery Previous rotavirus vaccination Corticosteroid treatment History of blood / blood product transfusion Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Sample Size Relatively novel design aimed to produce results faster Event-driven trial: Assumptions: 2% attack rate of severe rotavirus gastroenteritis (SRVGE), 50% true vaccine efficacy and a 20% participant non-assessibility, 90% power Primary analysis triggered after 117 cases of SRVGE after 28 days post-dose 3 Allows for detection of vaccine efficacy with the lower bound 95%CI > 0% 7770 children targeted for enrollment Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Definitions Gastroenteritis: ≥3 looser-than-normal stools in a 24h period with or without vomiting. Rotavirus: ELISA-confirmed in stool Severe: ≥ 11 on Vesikari clinical scoring system Very severe: ≥ 15 on Vesikari clinical scoring system Lewis K. Vesikari Clinical Severity Scoring System manual. Seattle: PATH, 2011. Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Surveillance and safety Facility-based surveillance 2 hospitals, 5 health centers and 12 health posts Clinical exam and stool collection for diarrhea: ≥1 stool sample per episode Home-based surveillance Village-based community health worker assigned to 30 children Safety 30 minutes observation after each dose Adverse events for 28 days post-dose 3 Serious adverse events until 2 years of age Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Ethical, Safety and Monitoring considerations Ethical Review Boards Comité Consultatif National d’Ethique, Niger Comité de Protection des Personnes Ile-de-France, France Hôpitaux Universitaires de Genève, Switzerland Western Institutional Review Board, USA World Health Organization, Switzerland Data and Safety Monitoring Board Independent intussusception adjudication committee GCP, GCLP compliant with external monitoring of clinical, study, lab and data procedures Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Trial Initiation Activities All ERB approvals and authorizations obtained in Q2 2014 Preparations March – July, 2014: Training on SOPs, CRFs and protocol Data management and monitoring GCP refresher Community discussions Religious and traditional authorities Pilot phase June-August 2014 We confirm we have permission to use images from participants included in this presentation. Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Results: Baseline characteristics BRV-PV N = 2044 Placebo N = 2047 Age, mean week (SD) At dose 1 6.8 (0.7) At dose 2 10.8 (0.8) 10.9 (0.9) At dose 3 15.0 (1.6) 14.9 (1.3) At end of efficacy follow-up 58.0 (17.8) 58.7 (17.8) Male sex, n (%) 1030 (50.4) 1004 (49.1) Weight (kg), mean (SD) 4.5 (0.7) Length (cm), mean (SD) 54.3 (2.6) 54.4 (2.5) Isanaka S, N Engl J Med. 2017 Mar 23;376(12):1121-1130. Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Efficacy against rotavirus gastroenteritis BRV-PV Placebo Cases (n) Rate (per 100 child-years) Vaccine Efficacy, % (95% CI) Per-protocol population All RVGE 121 8.71 172 13.29 34.5 (17.3 – 48.1) Severe 31 2.14 87 6.44 66.7 (49.9 – 77.9) Very severe 6 0.41 27 1.93 78.8 (48.6 – 91.2) Intention-to-treat population 165 7.76 271 11.59 33.0 (18.7 – 44.8) 35 1.56 125 5.05 69.1 (55.0 – 78.7) 7 0.31 1.37 77.4 (49.0 – 89.9) Isanaka S, N Engl J Med. 2017 Mar 23;376(12):1121-1130. Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Safety BRV-PV N = 2044 Placebo N = 2047 P Value   BRV-PV N = 2044 Placebo N = 2047 P Value Infants with ≥ 1 Serious Adverse Event (SAE) Hospitalization 149 175 0.15 Death 27 22 0.48 Confirmed Intussusception NA Infants with ≥ 1 SAE, by system organ class Infections or infestations 140 166 0.14 Blood and lymphatic system disorders 28 66 <0.001 Metabolism and nutrition disorders 52 57 0.70 Isanaka S, N Engl J Med. 2017 Mar 23;376(12):1121-1130. Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

What did we learn? Vaccine is efficacious No safety concerns Heat stability of vaccine means more flexible use Example of how research can be done in difficult contexts Capacity building benefits for HR pool in the Sahel Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Next steps Continue follow-up for long-term efficacy and safety outcomes Immunogenicity analysis to inform discussion about use of oral vaccines in vulnerable populations Examine possibility of dose-reduction Ensure vaccine is available for those who want to use it Vaccine licensed on 23 December 2016 in India: Rotasiil® WHO Prequalification in process Licensure in Niger in process Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

Acknowledgments Families, community and participants AARSH Study scientific committee DiagnoSearch Life Sciences Serum Institute of India Pvt Ltd provided vaccine and placebo WHO Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.