The Malaria Vaccine Pilot Evaluation An evaluation of the cluster-randomised pilot implementation of RTS,S/AS01 through routine health systems in moderate to high malaria transmission settings in sub-Saharan Africa: a post- authorization observational study M A S T E R P R O T O C O L RTS,S MVIP v9.0 22Apr2020 PASS information Title An evaluation of the cluster-randomised pilot implementation of RTS,S/AS01 through routine health systems in moderate to high malaria transmission settings in Sub-Saharan Africa: A Post-Authorization Observational Study Protocol version identifier RTSS_MVIP_v9 22 April 2020 Date of last version of protocol 19 October 2018 EU PAS register number Study not registered Active substance RTS,S antigen and AS01E Adjuvant Medicinal product Mosquirix™ Product reference EMEA/H/W/002300 Procedure number Not applicable Study sponsor World Health Organization Joint PASS No Research question and Primary impact objectives objectives The primary objectives of the impact evaluation are to estimate the effect of the routine delivery of RTS,S/AS01 on.: • all-cause mortality (excluding accidents); • the incidence of hospital admission with severe malaria; overall and each country. Primary safety objectives The primary objectives with regard to safety are to estimate the effect of RTS,S/AS01 introduction on: the incidence of hospital admission with: • meningitis • cerebral malaria (data pooled across the three countries). and on all-cause mortality in boys and girls, to determine whether there is any evidence that RTS,S/AS01 increases mortality in girls, overall and in each country Pilot implementation of RTS,S/AS01 2 Primary feasibility objectives The primary objectives with regard to feasibility are to estimate: • the proportion of children aged 12-23 months who received three doses of RTS,S/AS01 by 12 months of age (in each country) • the proportion of children aged 27-38 months who received their fourth dose of RTS,S/AS01 by 27 months of age (in each country) Country(-ies) of study Three moderate to high malaria endemicity countries of sub-Saharan Africa: Ghana, Kenya and Malawi Author David Schellenberg World Health Organization 20 Avenue Appia, 1211 Geneve, Switzerland Revisions Date: April 22, 2020 Revisions made by: David Schellenberg Mary J Hamel Paul Milligan Scientific opinion holder Scientific opinion holder GlaxoSmithKline Biologicals Rue de l’Institut 89, 1330 Rixensart, Belgium RTS,S/AS01 Malaria Vaccine Pilot Evaluation RTS,S MVIP v9.0 22 Apr2020 3 1 Table of contents Primary impact objectives .................................................................................................... 2 Primary safety objectives ..................................................................................................... 2 Primary feasibility objectives ................................................................................................ 3 1 Table of contents .......................................................................................................................... 4 2 List of abbreviations ...................................................................................................................... 8 3 Responsible parties ..................................................................................................................... 11 4 Abstract ....................................................................................................................................... 12 5 Amendments and updates .......................................................................................................... 17 6 Milestones ................................................................................................................................... 19 7 Rationale and background .......................................................................................................... 20 7.1 Efficacy of RTS,S/AS01 ........................................................................................................ 20 7.2 Safety of RTS,S/AS01 .......................................................................................................... 21 7.2.1 SAEs in the phase 3 trial ...................................................................................... 21 7.2.2 Febrile convulsions .............................................................................................. 22 7.2.3 Meningitis............................................................................................................ 22 7.2.4 Cerebral malaria .................................................................................................. 23 7.2.5 Mortality and gender .......................................................................................... 23 7.2.6 Summary of Safety .............................................................................................. 24 7.3 International regulatory and policy review ........................................................................ 24 7.4 Alignment of the Malaria Vaccine Pilot Evaluation and the Phase 4 evaluation ............... 24 7.5 Selection of countries for the pilot programme ................................................................. 25 7.6 Overview of RTS,S/AS01 delivery and evaluation .............................................................. 25 7.6.1 Approach to delivery of RTS,S/AS01 ................................................................... 25 7.6.2 Evaluation Design ................................................................................................ 26 7.6.3 Study dates .......................................................................................................... 27 7.6.4 Vaccination Schedule .......................................................................................... 28 7.6.5 Evaluation of RTS,S/AS01 .................................................................................... 28 7.6.6 MVIP and decision-making for vaccine roll out .................................................. 30 8 Research questions and objectives ............................................................................................. 33 8.1 Key questions on impact, safety and feasibility ................................................................. 33 8.2 Objectives related to impact and community-based surveillance ..................................... 34 8.2.1 Primary impact objectives ................................................................................... 34 8.2.2 Secondary impact objectives .............................................................................. 34 8.3 Objectives related to safety and surveillance in sentinel hospitals ................................... 34 8.3.1 Primary safety objectives .................................................................................... 34 8.3.2 Secondary safety objectives ................................................................................ 35 8.4 Analysis populations ........................................................................................................... 35 8.5 Objectives related to feasibility .......................................................................................... 35 8.5.1 Primary feasibility objectives .............................................................................. 35 8.5.2 Secondary feasibility objectives .......................................................................... 35 9 Research Methods for Impact Evaluation .................................................................................. 37 9.1 Study design ....................................................................................................................... 37 RTS,S/AS01 Malaria Vaccine Pilot Evaluation RTS,S MVIP v9.0 22 Apr2020 4 9.2 Setting ................................................................................................................................. 37 9.2.1 Surveillance population and surveillance period ................................................ 37 9.2.2 Community-based surveillance ........................................................................... 37 9.2.3 Community sensitisation ..................................................................................... 38 9.2.4 Identification and training of Village Reporters .................................................. 38 9.2.5 Identification and training of supervisors for Village Reporters ......................... 38 9.2.6 Identification of deaths ....................................................................................... 39 9.2.7 Expected numbers of events ............................................................................... 39 9.2.8 Case definitions ................................................................................................... 40 9.3 Variables ............................................................................................................................. 40 9.4 Data sources ....................................................................................................................... 41 9.5 Study size ............................................................................................................................ 42 9.6 Data management .............................................................................................................. 44 9.7 Data analysis ......................................................................................................................