BACKGROUND: An effective malaria vaccine, deployed in conjunction with other 
malaria interventions, is likely to substantially reduce the malaria burden. 
Efficacy against severe malaria will be a key driver for decisions on 
implementation. An initial study of an RTS, S vaccine candidate showed promising 
efficacy against severe malaria in children in Mozambique. Further evidence of 
its protective efficacy will be gained in a pivotal, multi-centre, phase III 
study. This paper describes the case definitions of severe malaria used in this 
study and the programme for standardized assessment of severe malaria according 
to the case definition.
METHODS: Case definitions of severe malaria were developed from a literature 
review and a consensus meeting of expert consultants and the RTS, S Clinical 
Trial Partnership Committee, in collaboration with the World Health Organization 
and the Malaria Clinical Trials Alliance. The same groups, with input from an 
Independent Data Monitoring Committee, developed and implemented a programme for 
standardized data collection.The case definitions developed reflect the typical 
presentations of severe malaria in African hospitals. Markers of disease 
severity were chosen on the basis of their association with poor outcome, 
occurrence in a significant proportion of cases and on an ability to standardize 
their measurement across research centres. For the primary case definition, one 
or more clinical and/or laboratory markers of disease severity have to be 
present, four major co-morbidities (pneumonia, meningitis, bacteraemia or 
gastroenteritis with severe dehydration) are excluded, and a Plasmodium 
falciparum parasite density threshold is introduced, in order to maximize the 
specificity of the case definition. Secondary case definitions allow inclusion 
of co-morbidities and/or allow for the presence of parasitaemia at any density. 
The programmatic implementation of standardized case assessment included a 
clinical algorithm for evaluating seriously sick children, improvements to care 
delivery and a robust training and evaluation programme for clinicians.
CONCLUSIONS: The case definition developed for the pivotal phase III RTS, S 
vaccine study is consistent with WHO recommendations, is locally applicable and 
appropriately balances sensitivity and specificity in the diagnosis of severe 
malaria. Processes set up to standardize severe malaria data collection will 
allow robust assessment of the efficacy of the RTS, S vaccine against severe 
malaria, strengthen local capacity and benefit patient care for subjects in the 
trial.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619.