Peter Aaby , professor 1 2 , Ane B Fisker , associate professor 1 2 3 , Anders Björkman , professor 4 , Christine Stabell Benn , professor 1 2 3 5 1Bandim Health Project, INDEPTH Network, Apartado 861, Bissau, Guinea-Bissau 2Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark 3OPEN, Odense Patient data Explorative Network, Institute of Clinical Research, Odense University Hospital/ University of Southern Denmark 4Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden 5Danish Institute of Advanced Science, University of Southern Denmark Correspondence to: C S Benn cbenn{at}health.sdu.dk

Key messages Phase III trials of the RTS,S malaria vaccine identified three safety concerns: higher risks of meningitis, cerebral malaria, and doubled female mortality

These safety concerns are now being investigated in pilot implementation studies with 720 000 participating children in Ghana, Kenya, and Malawi, planned to last 4-5 years

Owing to the urgency of improving malaria control, the World Health Organization intends to decide on extending the vaccine to other African countries after only 24 months using the prevention of “severe malaria” as a surrogate marker for overall mortality

Severe malaria is not a good marker for all cause mortality; it is not even a good marker for malaria mortality, as data indicate that case fatality from severe malaria might be higher in the malaria vaccine group

An early decision after 24 months might be biased in favour of the vaccine, which was more efficacious in the first year of follow-up in the phase III trials; the relative risks of both cerebral malaria and female mortality increased after the booster dose at 20 months

We recommend that the pilot studies use “overall mortality” to assess vaccine performance and that study populations are followed for the full 4-5 years of the study before a decision on rollout is made

World malaria day on 23 April 2019 saw the start of the first routine malaria vaccine programme in Africa—a pilot study in Malawi. Ghana and Kenya have now followed. The RTS,S/AS01 malaria vaccine has been under development by GlaxoSmithKline for 30 years and is the first malaria vaccine to receive regulatory approval for human use. The pilot study aims to enrol 720 000 children in vaccination and control clusters over a two year period; it is planned to last about 50 months.

Media and leading medical journals have celebrated the news,1234 …