Why children?

Malaria remains a major killer of children in Africa, where over 90% of cases occur. The RTS,S malaria vaccine was shown in a large phase-3 trial to be efficacious, with an acceptable safety profile. Modeling estimates indicate that its addition to current malaria-control measures could save tens of thousands of lives. Its wide implementation is delayed by a lack of data on effectiveness and safety when delivered through the national Expanded Programs on Immunization (EPI). The World Health Organization (WHO) recommended pilot introduction to evaluate feasibility, impact and safety, with emphasis on the safety signals observed in the phase-3 trial, in routine use to inform a global policy recommendation. Through the WHO-coordinated Malaria Vaccine Implementation Programme (MVIP), pilot implementation of RTS,S is well underway in three African countries, with more than 700,000 children vaccinated.

Independent of vaccine implementation is the ongoing evaluation to measure feasibility of reaching children with the recommended four-dose schedule requiring immunization contact and vaccine impact and safety in routine use. The evaluation component of the MVIP is referred to as the Malaria Vaccine Programme Evaluation (MVPE)

The surveillance established for the MVIP provides an opportunity for case control studies to be conducted to address additional questions about vaccine impact, that cannot be answered directly through the cluster-randomized design. Additionally, new data bring into question the importance of the 4th dose in the recommended schedule. The MVIP Programme Advisory Group recommended case-control studies, as a priority, to address these questions to inform policy. We propose to embed case-control studies into the Malaria Vaccine Pilot Evaluation (MVPE), to strengthen the evaluation of safety and effectiveness (including the incremental effectiveness of a 4-dose vs 3-dose regimen), and to develop tools that can be used by national immunization and malaria control programmes to monitor vaccine effectiveness following introduction.

The case-control studies will take advantage of the community-based mortality surveillance and hospital-based disease surveillance systems that have been established as part of the MVPE. We will estimate excess risk of meningitis and cerebral malaria, and of mortality in girls, associated with RTS,S vaccination, three safety signals observed in the phase-3 trial, and will estimate vaccine effectiveness in preventing malaria in children, the importance of rebound effects, and the incremental benefit of receiving a 4th dose. The project will make important contributions to policy recommendations about wider use of the RTS,S malaria vaccine at global and country-level and help maximize acceptability, uptake and impact, if recommended for use. The project also aims to promote the use of case-control approaches by EPI and malaria control programmes in high-burden countries, strengthening their capacity to monitor the effectiveness of the malaria vaccine. A strong dissemination and communication plan is proposed to maximise potential impact of this study.

Mvpe-cc's utilization of technology or innovation

Incidence-density case-control designs will be used with community controls recruited concurrently with cases, matched on date of birth and neighbourhood. This type of design allows the incidence rate ratio associated with the exposure (RTS,S vaccination) to be estimated. The same methods will be used in each country, and the studies are powered for pooled analyses across the three countries.

Goals of the project

IncidencResults from the case-control studies within the broad Malaria Vaccine Pilot Evaluation will help to inform global vaccine recommendation decision on the potential use of the malaria vaccine in sub-Saharan Africa. The studies will estimate excess risk of meningitis and cerebral malaria, and of mortality in girls, associated with RTS,S vaccination. In addition to these safety signals observed as part of the phase-3 trial, the studies will estimate vaccine effectiveness in preventing malaria in children, the importance of rebound effects, and the incremental benefit of receiving a 4th dose. The project also aims to promote the use of case-control approaches by the Expanded Programme of Immunization (EPI) and malaria control programmes in high-burden countries, strengthening their capacity to monitor safety and effectiveness of malaria vaccines.