Protocol No. 110021 - MAL 55 STUDY

A phase III, double blind (observer-blind), randomised, controlled multicenter study to evaluate, in infants and children, the efficacy of the RTS,S/AS01E candidate vaccine against malaria disease caused by P. falciparum infection, across diverse malaria transmission settings in Africa”

Study population Male and female infants and children aged 6-12 weeks and 5-17

months of age at first vaccination if eligible according to inclusion and exclusion criteria.

Study population of the extension

Male and female infants and children enrolled in Malaria-055 PRI and having received at least one dose of study or control vaccine during the primary trial phase.

Rationale for the study

This Phase III study of GSK Biologicals candidate malaria vaccine RTS,S/AS01E has been designed to address the key

safety and efficacy information required for vaccine licensure. In addition, other disease endpoints that allow the evaluation of the full public health impact and cost effectiveness of vaccine implementation are included. Co-primary objectives will

investigate the efficacy against clinical disease in children from 5- 17 months of age at first dose and the efficacy in infants 6-12 weeks of age who receive the vaccine in co-administration with EPI antigens (i.e. DTPw Hep B/Hib).

All participating centers will use standardized case definitions for efficacy endpoints and a structured approach to case-assessment.

Cases of clinical disease will be pooled across participating centers to determine the primary endpoint of efficacy against

clinical disease in each age category. Secondary objectives will assess the efficacy of the vaccine on severe malaria disease, severe anemia and malaria hospitalization. Analysis by site will allow the evaluation of efficacy under different conditions of malaria transmission and randomization to a booster dose will allow the evaluation of the duration of efficacy of a primary course and the requirement for boosting. Additional objectives include determination of efficacy of the vaccine against all medical hospitalization, non-malaria serious illness, fatal malaria and all-cause mortality. In addition immunological correlates of protection will be investigated.

Analyses are planned at the following timepoints during the trial:

 A primary analysis to investigate efficacy against clinical malaria disease after approximately 6000 children 5-17

months of age at first dose (4000 RTS,S/AS01E recipients) have completed 14 months of follow up post dose 1.

 A primary analysis to investigate efficacy against clinical malaria disease after approximately 6000 infants 6 to 12 weeks of age at first dose (4000 RTS,S/AS01E recipients) have completed 14 months of follow up post dose 1.

 A secondary analysis for evaluation of efficacy against severe disease when there are 250 accumulated cases, or at study

end, whichever occurs earlier.

 A secondary analysis for evaluation of efficacy, safety and immunogenicity when all children have completed 18 month follow-up post Dose 3 (Visit 22).

 A secondary analysis for evaluation of the antibody responses to polio serotypes 1, 2 and 3 in the 6-12 weeks age category

one month post boost (Visit 23).

 A final analysis will be carried out at the end of the trial and will include further investigations of vaccine efficacy against

a range of manifestations of malaria disease and evaluate the booster dose.

 An additional analysis will be conducted at the end of the extension including an evaluation of safety and efficacy

against clinical malaria, severe malaria and prevalent parasitemia.

Rationale for the extension

The strategy underlying the development of the RTS,S/AS01E malaria vaccine is that it would target the most vulnerable age

group: infants and young children. It would provide protection from the most severe forms of the disease whilst allowing natural

blood stage immunity to develop due to continued exposure to infections. However, there is a theoretical concern that the

protection conferred by a malaria vaccine in young children may impair their ability to acquire natural immunity to the blood stage form of P. falciparum and that, if the vaccine efficacy decreases over time, these children would become vulnerable to malaria.

This could result in a higher susceptibility to severe malaria and/or a higher frequency of clinical malaria disease in vaccinated

children compared to children of the same age that were not vaccinated. This long term follow-up probably represents the last opportunity to evaluate the duration of vaccine efficacy and the long term safety of RTS,S/AS01E relative to a control group in a large multi-country study.

Mean follow-up time: The last study visit of the extension (Visit 38) is scheduled in December 2013 (interval: Nov 2013-Jan

2014). This means a variable number of months after vaccination by individual children. Based on the actual enrolment, the mean follow-up time will be:

- 5-17 months: 49 months post Dose 1 (range: 41-55)

- 6-12 weeks: 41 months post Dose 1 (range: 32-48)