1. 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

2. 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.

3. 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.

4. Background (3)
Preliminary studies in Niger on diarrhea and rotavirus ( )
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.

5. 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.

6. 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 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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 Mar 23;376(12):
Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

14. 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 Mar 23;376(12):
Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

15. 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 Mar 23;376(12):
Amadou Matar Seck, Epicentre, Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger: a randomized, controlled trial.

16. 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.

17. 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.

18. 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.