Non-specific effects of rabies vaccine on the incidence of common infectious disease episodes: study protocol for a randomized controlled trial

Abstract

Background: Vaccines may cause non-specific effects (NSEs) on morbidity and mortality through immune-mediated mechanisms that are not explained by the prevention of the targeted disease. Much of the evidence for NSEs comes from observational studies with a high risk of bias, and there is a clear need for new data from randomised controlled trials. Recently, it was proposed that rabies vaccine has protective NSEs in people and in animals. The aim of the proposed study is to determine if rabies vaccine reduces the incidence rate of episodes of common infectious disease syndromes in a population of veterinary students on the island of St. Kitts.Methods: The trial design is a single-site, two-arm, parallel-group, participant-blinded, randomized, placebo-controlled, two-sided comparative study, with an internal pilot study for blinded sample size re-estimation. Allocation to study arm is by block randomization stratified by sex within cohort with a 1:1 allocation ratio. The primary study endpoint is the number of new weekly episodes of common infectious diseases including respiratory, diarrheal, and febrile illnesses. A vaccine efficacy ancillary study is planned.Discussion: Demonstration of a non-specific protective effect of rabies vaccine against unrelated respiratory, gastrointestinal and febrile illnesses would provide supportive evidence for the design of similar studies in children in populations with a high burden of these illnesses.Trial registration: ClinicalTrials.gov, NCT03656198. Registered 24 August 2018.

Non-specific effects of maternal and offspring rabies vaccination on mortality and antibiotic use in a Danish pig herd: A randomized trial

“…The 2-fold excess female mortality among RTS,S recipients also seen for the youngest participants [8] cannot be explained, however, by potential beneficial NSE of rabies vaccine, as the meningococcal vaccine was used as the comparator for this age group [7]. A very recent randomized controlled trial of non-live Rabivax-S vaccine in human adult volunteers [44] did not find an overall effect on self-reported infectious disease symptoms, although rabies vaccine was associated with a lower incidence of self-reported diarrhea episodes in males but not females. The study was underpowered, however, to support an interaction analysis with sex (Knobel D, manuscript in revision).…”