Josephine van Dongen

6 Non-specific effects of human rotavirus vaccination 143 Introduction Beneficial non-specific effects have been attributed to (live attenuated) vaccines in both adults and children. 1 Non-specific effects are defined as effects of vaccines on morbidity and mor tality that are not explained by the prevention of the target diseases, 2 or as resistance towards unrelated pathogens in vaccine recipients. 3 For instance, since the introduction of the first human vaccine, Vaccinia, reductions in measles and scarlet fever were observed besides the effect on smallpox. 3 The proposed mechanism for non-specific effects on non-target infections and hospitalizations is trained immunity. 1 Trained immunity is induced by epigenetic reprogramming that results in enhanced innate immune responses to reinfection and to non-target pathogens.4 Immunological studies in infants and adults established that vaccines can induce activation of innate immune cells against other than target diseases. 5–8 The duration of these beneficial non- specific effects is thought to last between three months and one year or until the next (non- live) vaccine is given. 1,9 Epidemiologic studies suggest that bacillus Calmette-Guérin (BCG) vaccination can offer protection against respiratory infections and (recurrent) bladder cancer. 10 A recent randomized controlled trial showed that neonatal BCG vaccination prevented non-tuberculosis infectious diseases in the first six weeks of life. 11 For the Measles Mumps Rubella (MMR) vaccine, a reduction in childhood mor tality was observed mediated by prevention of respiratory infections. 12 For Oral Polio vaccine (OPV) research indicated lower hospitalization rates and protection against otitis media.1 However, conflicting repor ts on reduction in all-cause case fatality after OPV have been published. 13–15 Another observation from epidemiological studies is a non-specific effect on atopy. There are two repor ts of reduced atopy after BCG vaccination, 16,17 however a randomized controlled trial found no effect but a potential trend towards less (severe) eczema. 18 The mechanism resulting in atopy prevention is less well studied, the Th1 stimulating proper ty of live-vaccines may prevent allergic sensitization and reduce atopy (which is Th2 mediated). 17,19 Yet, two systematic reviews on routine childhood vaccinations and non-specific effects concluded that low quality studies and heterogeneity of the available evidence should raise caution in interpretation. 20,21 The World Health Organization recommends more research towards non- specific effects of vaccines. 22,23 Rotavirus vaccines are live-attenuated and orally administered, like OPV. It is hypothesized that rotavirus vaccination can therefore induce beneficial non-specific effects through similar mechanisms, but this has been little studied thus far. One study repor ted a decrease of 31% in non-rotavirus hospitalization rates in the 60 days following rotavirus vaccination, but misclassification of rotavirus infections could not be completely ruled out. 24 To our knowledge, no literature is available on non-specific effects of rotavirus vaccination on respiratory infections or atopy. We explored potential non-specific effects in a prospective cohor t of medical risk infants in the