Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial

Abstract

Background Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed for developing countries. Methods In a double-blind placebo controlled multicentre trial, 6799 infants aged 6 to 7 weeks were randomised to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. Primary outcome was severe (≥11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. Findings At analyses, the median age was 17·2 months; over 96% subjects received all three doses of the vaccine/placebo and ~1% were lost to follow up. 4532 and 2267 subjects were randomly assigned to receive vaccine and placebo, respectively. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. 71 events of severe rotavirus gastroenteritis were reported in 4752 person years among the vaccinees compared to 76 events in 2360 person years in the placebo recipients; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0–66·9; P<0·001) and 56·4% (95% CI 36·6–70·1; P <0·001) in the first year of life. The number of infants needed to be immunized to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37–97). The incidence of severe rotavirus gastroenteritis/100 person years was 1·5 in vaccine and 3·2 in placebo group and an incidence rate ratio of 0·46 (95% CI 0·33–0·65). The absolute rate reduction for severe rotavirus gastroenteritis was 1·7 (95% CI 2·5–0·9). Efficacy against severe gastroenteritis of any aetiology was 18·6% (95% CI 1·9–32·3); it was 24·1% (95% CI 5·8–38·7) in the first year of life. The prevalence of immediate, solicited, and serious adverse events were similar in both groups. There were six cases of intussusception amongst 4532 vaccinees and two amongst 2267 placebo recipients (P=0·73). All intussusception cases occurred after the third dose. Among vaccine and placebo recipients, the minimum interval between dosing and intussusception was 112 and 36 days, respectively. Interpretation The monovalent human-bovine (116E) rotavirus vaccine is effective and well-tolerated in Indian infants.

Options for improving effectiveness of rotavirus vaccines in developing countries

“…2 Similar findings have been reported in clinical trials using other live oral rotavirus vaccines, including the original rhesus-reassortant tetravalent (RRV-TV) and the monovalent Indian human-bovine G9P [11] strain vaccine 116E. 2,6,7 Hypotheses proposed to explain why rotavirus vaccines are less effective in the developing country setting are grouped broadly between increased exposure of children to rotavirus infection and reduced host immune responses to administered vaccines. 8,9 This review will examine a range of strategies that have been studied to target the issue of reduced efficacy and effectiveness of oral rotavirus vaccines in developing countries.…”

“…The vaccine is administered as 3 infant doses commencing at 6-12 weeks of age and was licensed for use in India in early 2014. 6 In Phase III trials, ROTAVAC Ò reduced severe rotavirus gastroenteritis by 56.4% in the first year of life, a similar efficacy rate as that of RV5 and RV1 in developing countries. 6 Another neonatal rotavirus vaccine candidate in clinical development, RV3-BB, is based on an attenuated G3P [6] human strain identified in asymptomatic Australian newborns.…”

“…6 In Phase III trials, ROTAVAC Ò reduced severe rotavirus gastroenteritis by 56.4% in the first year of life, a similar efficacy rate as that of RV5 and RV1 in developing countries. 6 Another neonatal rotavirus vaccine candidate in clinical development, RV3-BB, is based on an attenuated G3P [6] human strain identified in asymptomatic Australian newborns. Phase II safety and immunogenicity trials in New Zealand demonstrated high levels of vaccine take in a developed setting following the administration of 3 doses commencing either in the first week of life or at 6-12 weeks of age.…”

“…The development of neonatal vaccine candidates may also present another potential time point for increasing the number of vaccine doses. 6,48 …”

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges

“…1 Two RV vaccines are commercially available globally (Rotarix Ò , GlaxoSmithKlein Biologicals, Rixensart, Belgium; RotaTeq Ò , Merck Research, Pennsylvania, USA), have been WHO pre-qualified, and are being introduced in many countries worldwide. A new RV vaccine, RotaVac TM (Bharat Biotech International Ltd, Hyderabad, India) has recently been licensed in India based on good safety and efficacy data 2 although it is not yet WHO pre-qualified for the GAVI market.…”