Safety of Oral Pentavalent Rotavirus Vaccine in Kenya, Including Among HIV-Infected Infants

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1 Safety of Oral Pentavalent Rotavirus Vaccine in Kenya, Including Among HIV-Infected Infants Geoffrey Nyambane(1), Kayla F. Laserson(1,3), Daniel R. Feikin(1,2), Daveline Nyakundi(1), Earnest Cook(1), Janet Oyieko(1), Joel Ojwando(1), Stephen B. Rivers(4), Max Ciarlet(4), Kathleen Neuzil(5), and Robert F. Breiman(1,2,3) 1)Kenya Medical Research Institute / Centers for Disease Control and Prevention, Research and Public Health Collaboration, Kenya; 2)International Emerging Infections Program, Centers for Disease Control and Prevention, Atlanta, Georgia; 3)Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia; 4)Merck Research Laboratories, North Wales, PA; 5)PATH, Seattle, WA 1

2 Background Rotavirus is the leading cause of diarrheal hospitalization and death among children < 5 years of age: associated with 25 million clinic visits, 2 million hospitalizations, and more than approximately 600,000 deaths worldwide 80% of the hospitalizations and deaths in South Asia and Sub-Saharan Africa A multicenter Phase III clinical trial was conducted in Ghana, Mali and Kenya from April 2007-March 2009 to evaluate the safety and efficacy of the Pentavalent Rotavirus Vaccine (PRV), RotaTeq, in Africa 2

3 Objectives To assess the safety of RotaTeq with respect to serious adverse events (SAEs) for all subjects within 14 days of any dose of RotaTeq or placebo in Kenya To assess the safety of RotaTeq with respect to all adverse events (AEs) with attention to vomiting, diarrhea, and elevated temperature for a subset of subjects screened for HIV infection within 42 days of any dose of RotaTeq or placebo 3

4 Methods: Study Design In rural western Kenya, 1,308 infants were randomized (1:1) to receive 3 doses of PRV or placebo at approximately 6-, 10-, and 14-weeks of age HIV counseling and testing were offered HIV infection was not an exclusion criterion 4

5 Methods: Safety Surveillance Full Cohort: All severe adverse events (SAE) at day 7 and 14 following each dose, and vaccine-related SAEs and all deaths occurring at any time Intensive Surveillance Cohort: All adverse events (AE) recorded for the first 297 participants for 42 days with attention to vomiting, diarrhea and elevated temperature. Home visits (or telephone contacts) occurred on days 3,5,7,14,21 and 42 following any vaccination There were no pre-specified safety outcomes (or prespecified associated hypotheses) Safety outcomes were compared by Mantel Haenszel test and Fisher s exact test 5

6 Non-death SAEs (full cohort) Reported among 20 of 649 vaccine recipients (3.1%) vs. 21 of 643 placebo recipients (3.3%) within 14 days following vaccination (p=0.85) The most common SAEs in the vaccinated group were pneumonia (1.7%) and gastroenteritis (1.4%) Similar frequencies for placebo recipients No case of intussusception was reported 6

7 Non-death SAEs Within 14 Days Following Vaccination (full cohort) Condition RotaTeq Placebo P-Value Subjects in the population with follow up With one or more serious adverse events With no serious adverse events N % n % (3.1 ) (96.9 ) (3.3 ) (96.7) Pneumonia 11 (1.7) 6 (0.9) 0.23 Gastroenteritis 9 (1.4) 13 (2.0) 0.38 Malaria 6 (0.9) 5 (0.8) 0.77 HIV Infection 4 (0.6) 1 (0.2) 0.37 Anaemia 1 (0.2) 0 (0.0) 1.00 Bronchopneumonia 1 (0.2) 1 (0.2) 1.00 Meningitis 0 (0.0) 1 (0.2) 0.50 Upper Respiratory Tract Infection 0 (0.0) 1 (0.2) 0.50 Soft Tissue Injury 0 (0.0) 1 (0.2) 0.50 Pneumonia Aspiration 0 (0.0) 1 (0.2) 0.50 Respiratory Distress 0 (0.0) 1 (0.2)

8 Non-death SAEs (Intensive Safety Surveillance Cohort) SAEs were reported among 14 of 147 (9.5%) vaccine recipients vs. 23 of 150 (15.3%) placebo recipients (p=0.13) Most common SAEs Pneumonia reported among 11 (7.5%) vaccine recipients vs. 8 (5.3%) placebo recipients (p=0.45) Gastroenteritis reported among 10 (6.8%) vaccine recipients vs. 17 (11.3%) placebo recipients (p=0.18) Malaria reported among 5 (3.4%) vaccine recipients vs. 8 (5.3%) placebo recipients (p=0.42) 8

9 Deaths (full cohort) 66 participants died during the study: 36 (5.5%) vaccine recipients and 30 (4.7%) placebo recipients (p=0.47) Leading cause of death was gastroenteritis (n=23) 13 among vaccine recipients and 10 among placebo recipients (p=0.54) 9

10 AEs (Intensive Safety Surveillance Cohort) AEs were experienced by 137 of 147 (93.2%) vaccine recipients vs. 147 of 150 (98.0%) placebo recipients (p=0.04) 10

11 AEs in the Intensive Safety Surveillance Cohort within 42 Days of Vaccination Condition RotaTeq Placebo P- Value Subjects in Population with Follow up With one or mere adverse events With no adverse Events n % n % (93.2) (6.8) (98.0) (2.0) Pyrexia 96 (65.3) 97 (64.7) 0.91 Cough 88 (59.9) 89 (59.3) 0.93 Diarrhea 71 (48.3) 64 (42.7) 0.39 Rash 56 (38.1) 55 (36.7) 0.80 Rhinitis 52 (35.4) 62 (41.3) 0.29 Gastroenteritis 46 (31.3) 56 (37.3) 0.27 Vomiting 35 (23.8) 30 (20.0) 0.43 Rhinorrhoea 30 (20.4) 18 (12.0) 0.49 Malaria 27 (18.4) 40 (26.7) 0.09 Pneumonia 26 (17.7) 25 (16.7) 0.82 Dyspnoea 22 (15.0) 23 (15.3) 0.93 Oral Candidiasis 16 (10.9) 13 (8.7) 0.52 Conjunctivitis 10 (6.8) 13 (8.7)

12 Safety of PRV among HIV-Infected Infants in Kenya (full cohort) All participants offered HIV counseling and testing 89.2% were tested 19 of 587 (3.2%) vaccine recipients and 11 of 580 (1.9%) placebo recipients were HIVinfected 12

13 Safety of PRV among HIV-Infected Infants in Kenya (Cont d) Among the 30 HIV-infected infants, 5/19 (26%) vaccine recipients and 1/11(9.1%) placebo recipients reported a nondeath SAE (p=0.37) In total, 11 deaths occurred among HIV-infected infants 8 (42%) of 19 vaccine recipients vs. 3 (27%) of 11* placebo recipients (p=0.47) 2 of the 8 vaccine recipient deaths were gastroenteritis-related vs. 2 of the 3 placebo recipient deaths (p=0.49) 13

14 Discussion SAEs did not occur significantly more frequently in vaccine recipients compared to placebo recipients. There were significantly more AEs reported among placebo recipients HIV-infected infants given PRV did not have significantly more SAEs or AEs than HIV uninfected infants; however the number of HIVinfected participants in the trial was small, limiting conclusions 14

15 Conclusion Results suggest that PRV is a safe intervention against rotavirus gastroenteritis among infants Given efficacy data, PRV will likely be an effective tool to diminish large public health burden of rotavirus diarrhea in infants Post-licensure surveillance would be helpful to characterize effectiveness during routine use and to evaluate whether there are associated serious adverse events too rare to be documented during the trial 15

16 Acknowledgments Kenya Investigators and Study Coordinators Robert Breiman (PI) Daniel Feikin Kayla Laserson Joel Ojwando Ernest Cook Geoffrey M. Nyambane Daveline Nyakundi Ben Ochieng Janet Oyieko Study Participants The Karemo Community KEMRI/CDC Merck Max Ciarlet Michael J. Dallas Michele L. Coia Stephen J. Rivers Donna Hyatt Fay DiCandilo Florian Schödel DSMB King Holmes (Chair) Wasif Ali Khan (Bangladesh) Edward T. Agbenyega (Ghana) Grace Irimu (Kenya) Mamadou M. Keita (Mali) Dinh Sy Hien (Vietnam) Nik Zarifah Reed (WHO) Janet Wittes (statistician) PATH Kathleen Neuzil J. Chris Victor Kristen Lewis A. Duncan Steele This trial was funded by PATH s Rotavirus Vaccine Program, established in 2003 with a generous grant from the GAVI Alliance. The trial was sponsored by Merck & Co., Inc

17 AHSANTE SANA!! 17