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Effect of human rotavirus vaccine on severe diarrhea in African infants.

by Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, Ngwira B, Victor JC, Gillard PH, Cheuvart BB, Han HH, Neuzil KM
The New England journal of medicine. 2010 Jan 28;362(4):289-98

Article Abstract:

BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. METHODS: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. RESULTS: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. CONCLUSIONS: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)

Interpreting data on comparative efficacy of an intervention in settings with different base rates

By: James Scanlan - Sun 2/28/2010 PM

Based on a smaller percentage reduction in severe rotavirus gastroenteritis achieved by rotavirus vaccination in Malawi compared with South Africa, Madhi et al.[1] conclude that vaccine efficacy was lower in Malawi than South Africa. That reasoning overlooks the statistical pattern whereby, for reasons related to the shapes of normal risk distributions, a factor that reduces an outcome will tend to reduce it proportionately more in the setting with the lower base rate, while increasing the opposite outcome proportionately more in the other setting.[2,3] For example, the 49.4% reduction of severe rotavirus gastroenteritis in Malawi compared with a 79.6% reduction in South Africa noted in the abstract corresponds with a 4.2% increase in the rate of avoiding that outcome in Malawi compared with a 2.6% increase in South Africa, which had the lower base rate of severe rotavirus gastroenteritis. The statistical tendency is only part of the picture of course. But its existence requires that efforts to appraise the comparative efficacy of interventions in settings (or among groups) with different base rates must employ measures that are not affected by differing base rates.[4] See Table A to this comment,[5] which shows such a method applied to the figures just mentioned from the Madhi study. -¶References: -¶1. Madhi SA, Cunliffe NA, Steele D, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med 2010;362:289-98. -¶2. Scanlan JP. Divining difference. Chance 1994;7(4):38-9,48. (Accessed February 28, 2009, at http://jpscanlan.com/images/Divining_Differen... -¶3. Scanlan JP. Race and mortality. Society 2000;37(2):19-35. (Accessed February 28, 2009, at http://www.jpscanlan.com/images/Race_and_Mort... -¶4. Scanlan JP. Interpreting differential effects in light of fundamental statistical tendencies. Presented at 2009 Joint Statistical Meetings of the American Statistical Association, International Biometric Society, Institute for Mathematical Statistics, and Canadian Statistical Society, Washington, DC, August 1-6, 2009. (Accessed February 28, 2009, at http://www.jpscanlan.com/images/JSM_2009_ORAL... -¶5. http://www.jpscanlan.com/images/Table_to_Comm... (Accessed February 28, 2010.)

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