Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis

Summary

Background

Rotavirus is the most common cause of acute childhood gastroenteritis. Vaccination with live oral heterologous rotavirus vaccines may prevent rotavirus gastroenteritis. We assessed the efficacy of rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) against severe rotavirus gastroenteritis in Finnish children in a randomised placebo-controlled double-blind trial.

Methods

Placebo or RRV-TV (titre 4·10⁵ plaque-forming units) was given to infants at ages 2, 3, and 5 months. The children were followed up for one or two rotavirus epidemic seasons. The main outcome measure was protection against severe rotavirus gastroenteritis (score ⩾11 on a 20-point severity scale). 2398 children were enrolled and received at least one dose of RRV-TV (n=1191) or placebo (n=1207). The primary efficacy analysis was based on children who received three doses of RRV-TV (n=1128) or placebo (n=1145).

Findings

256 episodes of rotavirus gastroenteritis occurred at any time during the study; 65 were among 1191 RRV-TV recipients, and 191 among 1207 placebo recipients (vaccine efficacy 66% [95% Cl 55–74]; intention-to-treat analysis). 226 episodes were included in the primary efficacy analysis of fully vaccinated children (54 among 1128 RRV-TV recipients, 172 among 1145 placebo recipients; vaccine efficacy 68% [57–76]). 100 episodes were severe, eight in RRV-TV recipients and 92 in placebo recipients (vaccine efficacy 91% [82–96]).

Interpretation

RRV-TV vaccine was highly effective against severe rotavirus gastroenteritis in young children. Incorporation of this vaccine into routine immunisation schedules of infants could reduce severe rotavirus gastroenteritis by 90% and severe gastroenteritis of all causes in young children by 60%.

Introduction

Rotavirus is a major cause of diarrhoeal disease mortality in children in developing countries: it may be the cause in 600 000 of the 3 million deaths from diarrhoea annually.¹ In developed countries rotavirus is an important cause of morbidity; the disease burden can be seen as peaks of hospital admissions, and some deaths, due to acute gastroenteritis in the winter epidemic period.2, 3

Clinical trials of a live oral heterologous rotavirus vaccine (bovine rotavirus candidate vaccine RIT 4237) showed 50% efficacy for any and 80–90% efficacy for severe rotavirus gastroenteritis in Finland,4, 5, 6 but the vaccine was not developed further because of insufficient efficacy in developing countries.7, 8 Similarly, bovine rotavirus vaccine WC3 was effective in the USA⁹ but not in Africa.¹⁰

Rhesus rotavirus (RRV) is less attenuated¹¹ and more immunogenic for humans than are bovine rotaviruses.¹² However, in clinical trials RRV vaccine showed varying efficacy, for reasons that remain unclear.13, 14, 15, 16, 17, 18

Rhesus-human reassortant rotaviruses were developed to improve the immunogenicity of RRV against human rotaviruses.¹⁹ In these reassortants the RNA segment encoding the VP7 (G-type) surface protein is replaced by the corresponding genome segment of a human rotavirus, so that the resulting reassortant expresses human rotavirus VP7 on the surface of rhesus rotavirus. Single G-type 1 and 2 rhesus-human reassortant vaccines have been found effective,15, 20 and a tetravalent vaccine containing three reassortants for human rotavirus G-types 1, 2, and 4 plus rhesus rotavirus itself (G-type 3) has been developed.21, 22 The rhesus-human assortant rotavirus tetravalent vaccine (RRV-TV) has been tested in two multicentre efficacy trials in the USA, with promising results.23, 24

Our study had the specific objective of evaluating the efficacy of RRV-TV for severe rotavirus gastroenteritis. The study conditions closely resembled real-life situations in that the study vaccine was administered at the same time as other childhood immunisations, and the enrolment period covered a calendar year. The follow-up period included one or two rotavirus epidemic seasons, depending on the time of enrolment in the study.