Design of a phase III multicenter trial to evaluate the efficacy of the RTS,S/AS01 malaria vaccine in children across diverse transmission settings in Africa

Table 5 Case definitions of secondary efficacy endpoints

	Definition 1	Other definitions
Incident severe anaemia ¹	Hb <5.0 g/dL identified on morbidity surveillance in association with P falciparum parasitaemia >5000 parasites/μL	Hb <5.0 g/dL identified on morbidity surveillance PLUS 1. P falciparum parasitaemia >0 parasites/μL OR 2. No parasitaemia
Prevalent anaemia ¹	Hb <5.0 g/dL identified at cross sectional survey	Hb <8.0 g/dL identified at cross sectional survey
Malaria hospitalization	Medical hospitalisation² in association with P falciparum parasitaemia >5000 parasites/μL	P falciparum infection is sole or major cause of hospitalization on investigators' clinical judgement
All hospitalization	Medical hospitalization²
Bacteremia/Sepsis	Positive blood culture⁷
Pneumonia	Cough or difficulty breathing (on history) Tachypnoea (≥50 breaths per minute in children <1 year, ≥40 breaths per minute in children ≥1 year) Lower chest wall in-drawing	As definition 1, PLUS 1. Chest X-ray consolidation or pleural effusion on a chest X-ray taken within 72 h of admission OR 2. Chest X-ray consolidation or pleural effusion or other infiltrates on a chest X-ray taken within 72 h of admission OR 3. Oxygen saturation <90%
Fatal malaria	Fatal case of severe malaria according to primary case definition 3,4	Fatal case of severe malaria according to secondary definitions 3,4
All-cause mortality	Death due to any cause5	Death due to medical cause5,6

¹ Severe anaemia is defined as Hb <8 g/dL and very severe anaemia is defined as Hb <5 g/dL according to WHO/IVR report (WHO/IVR Malaria Vaccine Advisory Committee meeting 2004)
² Excludes planned, surgical and trauma related admissions
³ Refer to [23] for primary and secondary definitions of severe malaria
⁴ Restricted to children fully evaluated as inpatients and excludes diagnoses made by verbal autopsy
⁵ Includes deaths in hospital and in the community
⁶ Excludes trauma, which may be diagnosed by verbal autopsy
⁷ A blood culture taken within 72 h of admission is considered positive if: a definite pathogen is isolated or a bacteria that could be either a pathogen or a contaminant is isolated within 48 hours of incubation and is considered clinically to be a likely pathogen [23].

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