Open Access Highly Accessed Methodology

Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care

Johan Vekemans1*, Kevin Marsh2, Brian Greenwood3, Amanda Leach1, William Kabore4, Solange Soulanoudjingar5, Kwaku Poku Asante6, Daniel Ansong7, Jennifer Evans8, Jahit Sacarlal9, Philip Bejon2, Portia Kamthunzi10, Nahya Salim11, Patricia Njuguna2, Mary J Hamel12, Walter Otieno12, Samwel Gesase13, David Schellenberg142 and the Clinical Trials Partnership Committee

Author Affiliations

1 GlaxoSmithKline Biologicals, Wavre, Belgium

2 KEMRI-Wellcome Trust Research Programme, Kisumu, Kenya

3 London School of Hygiene and Tropical Medicine, University of London, London, UK

4 Institut de Recherche en Sciences de la Santé, Centre Muraz, Burkina Faso

5 Albert Schweitzer Hospital, Kumasi, Gabon

6 Kintampo Health Research Centre, Ghana Health Service, Kintampo, Ghana

7 School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

8 Kumasi Centre for Collaborative Research, Kumasi, Ghana

9 Centro de Investigação em Saúde de Manhiça, Manhiça, Mozambique

10 University of North Carolina (UNC) Project, Lilongwe, Malawi

11 Ifakara Health Institute, Ifakara, Tanzania

12 KEMRI/CDC Research and Public Health Collaboration, Kisumu, Kenya

13 National Institute of Medical Research, Dar es salaam, Tanzania

14 PATH Malaria Vaccine Initiative, Washington, USA

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Malaria Journal 2011, 10:221  doi:10.1186/1475-2875-10-221

Published: 4 August 2011

Abstract

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