Browsing by Author "Ciarlet, M."
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Item Analyses of health outcomes from the 5 sites participating in the Africa and Asia clinical efficacy trials of the oral pentavalent rotavirus vaccine(Vaccine, 2012-04) Breiman, R.F.; Zaman, K.; Armah, G.; Sow, S.O.; Anh, D.D.; Victor, J.C.; Hille, D.; Ciarlet, M.; Neuzil, K.M.Background: Efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq®, against severe rotavirus gastroenteritis (RVGE) was evaluated in two double-blind, placebo-controlled, multicenter Phase III clinical trials conducted in GAVI-eligible countries in Africa (Ghana, Kenya, and Mali) and in Asia (Bangladesh and Vietnam) from March 2007 through March 2009. The findings from each continent have been analyzed and presented separately, according to a single identical protocol. Ad hoc analyses combining data from the five sites were performed to further assess the impact of PRV. Methods: 6674 infants (4705 infants from Africa and 1969 infants from Asia), randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age according to each country's EPI schedule, were included in the per protocol efficacy analysis. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed. Episodes of gastroenteritis (GE) in infants who presented to study facilities were captured and scored using the 20-point Vesikari scale. Stool samples were analyzed by rotavirus-specific EIA to detect presence of rotavirus antigen and RT-PCR to determine the G/P genotypes. We assessed efficacy to prevent all-cause GE and RVGE at a variety of cut-off points (score ≥ 11, severe; score ≥ 15, very severe). Results: Vaccine efficacy (VE) against RVGE, regardless of serotype, through the entire follow-up period for any severity, severe (score ≥ 11), and very severe (score ≥ 15) was 33.9%, 95% CI (22.7, 43.5), 42.5%, 95% CI (27.4, 54.6), and 51.2%, 95% CI (26.3, 68.2), respectively. Through the first year of life, VE against severe RVGE was 58.9%, 95% CI (40.0, 72.3) and against all-cause severe GE was 23.0%, 95% CI (5.4, 37.3). VE against severe RVGE caused by non-vaccine G serotypes, G8 and G9, through the entire follow-up period was 87.5%, 95% CI (6.8, 99.7) and 48.0%, 95% CI (-5.5, 75.6), respectively. All G8 strains were associated with P2A[6] (a P-type not contained in PRV), while the majority of the G9 strains were associated with P1A[8] (a P-type contained in PRV). Conclusions: Combining data from the 5 sites strengthens the precision of VE estimates and reveals rising VE with increased RVGE severity. Extrapolating data from VE against severe GE and RVGE suggest that 39% of severe GE episodes during the first year of life were due to rotavirus, highlighting substantial, potentially preventable, public health burden of RVGE. PRV provides protection against non-vaccine serotypes (G8P2A[6]). © 2011.Item Comparison of two clinical severity scoring systems in two multi-center, developing country rotavirus vaccine trials in Africa and Asia(Vaccine, 2012-04) Lewis, K.D.C.; Dallas, M.J.; Victor, J.C.; Ciarlet, M.; Mast, T.C.; Ji, M.; Armah, G.; Zaman, K.; Ferraro, A.; Neuzil, K.M.Background: Clinical severity scoring systems are used in rotavirus vaccine efficacy and effectiveness studies to define the primary endpoint, severe rotavirus gastroenteritis (RVGE). Understanding how scoring systems perform in diverse settings is critical for proper design and interpretation. This investigation aims to understand how the Vesikari scoring system (VSS) and Clark scoring system (CSS) categorize severe disease among children under 2 years of age using data from two Phase III efficacy trials conducted in five developing countries in Africa and Asia. Methods: Signs and symptoms were collected on trial participants who presented to a medical facility with study-defined gastroenteritis. Severity scores were calculated using pre-established VSS and CSS criteria and compared to identify differences in the proportions of severe RVGE within regions and sites, and by gender and age. Results: In Africa and Asia, 40.6% and 56.0% of rotavirus-positive episodes were severe according to the VSS, while 9.5% and 6.3% of episodes were severe according to the CSS (Fisher's Exact, p≤ 0.001). Using the mean scores in these trials (VSS: ≥10 Africa, ≥11 Asia; CSS: Africa and Asia ≥10) as the severity thresholds, agreement between scoring system severity classifications improved substantially within each region (Africa: kappa = 0.67; Asia: kappa = 0.78) as compared to the original severity classification (Africa: kappa = 0.27; Asia: kappa = 0.10). Using the mean score, 17.1% and 9.5% of severe VSS cases in Africa and Asia, respectively, were classified as not severe according to the CSS and 14.7% and 9.5% of severe CSS cases in Africa and Asia were classified as not severe according to the VSS. Conclusion: The two scoring systems performed differently among developing country populations in Africa and Asia, with the VSS classifying more cases as severe in both regions. One accurate and reliable scoring system should be developed and implemented for all trials so that results may be more comparable. © 2011 Elsevier Ltd.Item Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial(Lancet, 2010) Armah, G.E.; Sow, S.O.; Breiman, R.F.; Dallas, M.J.; Tapia, M.D.; Feikin, D.R.; Binka, F.N.; Steele, D.A.; Laserson, K.F.; Ansah, N.A.; Levine, M.M.; Lewis, K.; Coia, M.L.; Attah-Poku, M.; Ojwando, J.; Rivers, S.B.; Victor, J.C.; Nyambane, G.; Hodgson, A.; Schödel, M.; Ciarlet, M.; Neuzil, K.M.Background Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009. Methods In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4–12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score ≥11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. Findings 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610・6 person-years in the vaccine group, compared with 129 cases in 2585・9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39・3% (95% CI 19・1–54・7, p=0・0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1・5%) of 2723 infants assigned to receive vaccine and 45 (1・7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0・6%]; placebo 17 [0・6%]). Interpretation Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO’s recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa.Item Immunogenicity of the pentavalent rotavirus vaccine in African infants(Vaccine, 2012-04) Armah, G.E.; Breiman, R.F.; Tapia, M.D.; Dallas, M.J.; Neuzil, K.M.; Binka, F.N.; Sow, S.O.; Ojwando, J.; Ciarlet, M.; Steele, A.D.We recently completed a double-blind, placebo-controlled, multicenter Phase III clinical trial of the pentavalent rotavirus vaccine (PRV) in three African countries, Ghana, Kenya, and Mali, from April 2007 to March 2009. The immunogenicity of PRV in African infants is described. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV or placebo at approximately 6, 10, and 14 weeks of age. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed, and HIV-infected infants were not excluded. Immunogenicity of PRV was assessed by measuring serum anti-rotavirus IgA responses, as well as serum neutralization antibody (SNA) to the human rotavirus serotypes G1, G2, G3, G4 and P1A[8] in approximately 150 infants per country. Sera were collected pre-dose 1 (pD1) and approximately 14 days post-dose 3 (PD3) for immunological analysis. For the sero-response rates (≥3-fold rise from pD1 to PD3), the number of subjects evaluable included those with both pD1 and PD3 data available. PRV was immunogenic in African children and significantly reduced severe RVGE in African children through the first two years of life. The pooled anti-rotavirus IgA sero-response rate was 78.3%, with consistent rates in each of the African sites: 73.8% (Kenya), 78.9% (Ghana), and 82.5% (Mali); but generally lower than that reported in Europe and USA. PD3 GMTs (28.2 dilution-units) were 5-10 times lower than those assessed in subjects in clinical trials in developed countries. SNA responses to human rotavirus serotypes G1-G4 and P1A[8] ranged from 6.3% (G3) to 26.5% (G4). PD3 SNA GMTs to G1 and P1A[8] were 4-fold and 3-fold lower respectively, when compared to the corresponding GMTs in subjects who received PRV in similar studies conducted in developed countries. PRV was immunogenic in African infants, and the anti-rotavirus IgA sero-response rates were similar across all three African sites although lower than those observed in Europe and USA. While immune correlates of protection have not been established for rotavirus, the findings are consistent with lower efficacy rates demonstrated during this trial. Further investigation is needed to understand the reason for the lower immunogenicity observed. © 2012.Item Rotavirus vaccine efficacy in African and Asian countries Reply(The Lancet, 2010-12) Breiman, R.F.; Armah, G.; Zaman, K.; Sow, S.; Anh, D.D.; Ciarlet, M.; Neuzil, K.M.The pentavalent rotavirus vaccine offers an opportunity to affect child health positively, particularly in regions of the world with high diarrhoea morbidity and mortality. Although our study focused on the prevention of severe gastroenteritis, we agree with Stephen Obaro that the vaccine might be effective against less common outcomes, including mortality. In fact, such an effect has been shown in postmarketing studies, most notably in Mexico, where introduction of a rotavirus vaccine into the national immunisation programme correlated with a significant reduction in all-cause diarrhoea mortality.1 Our studies used a passive “catchment” design to identify cases of rotavirus gastroenteritis, and, as Obaro suggests, health-care use did interfere with optimum case ascertainment. Indeed, in the Mali site, gastroenteritis episodes were managed largely by traditional healers during the first year of the study, resulting in very few cases identified and a limited capacity to contribute to vaccine efficacy calculations. When this problem was identified and addressed at the end of the first rotavirus season, the number of cases identified increased substantially.Item Secondary efficacy endpoints of the pentavalent rotavirus vaccine against gastroenteritis in sub-Saharan Africa(Vaccine, 2012-04) Tapia, M.D.; Armah, G.; Breiman, R.F.; Dallas, M.J.; Lewis, K.D.C.; Sow, S.O.; Rivers, S.B.; Levine, M.M.; Laserson, K.F.; Feikin, D.R.; Victor, J.C.; Ciarlet, M.; Neuzil, K.M.; Steele, A.D.The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq®, was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (April 2007-March 2009) in 3 low-income countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine. © 2012 Elsevier Ltd.