The Malaria Vaccine Implementation Programme in Africa: clarifying misperceptions
Extensive testing in clinical trials has confirmed that the malaria vaccine, RTS,S/AS01, reduces malaria significantly, including life-threatening severe malaria. Modeling studies suggests that, if introduced widely, the vaccine could save tens of thousands of lives per year.1
The Malaria Vaccine Implementation Programme (MVIP) is now underway to (i) support the pilot implementation of RTS,S/AS01 by routine health systems, and (ii) evaluate the routine use of the vaccine. In recent days, it has become clear that the distinction between these 2 sets of activities is not always recognized, and this has caused some confusion. Here we aim to clarify these – and some related – key points.
An estimated 228 million malaria episodes, and more than 400 000 premature deaths, are attributed to malaria every year. It is clearly urgent to take extra steps to tackle this disease.
RTS,S/AS01 has been authorized for use in pilot areas of Ghana, Kenya and Malawi by the respective national regulatory authorities (NRAs) and has received a positive scientific opinion from the European Medicines Agency (EMA). These regulators concur in their assessment that the vaccine has an acceptable safety profile and that the benefits of the vaccine outweigh the risks.
The vaccine is now being provided to children through the routine immunization services of the Ministries of Health of Ghana, Kenya and Malawi as part of childhood vaccination programmes.
Separate from vaccine introduction, independent evaluation teams are conducting surveys and surveillance to understand how best to introduce the vaccine into routine systems, the effect of the vaccine on child survival, and the vaccine’s safety profile when used routinely. The systematic evaluation of the programmatic implementation of a newly approved product is considered good practice – not medical or scientific experimentation.
Vaccine administration by the Expanded Programme on Immunization
The consent process for administration of RTS,S/AS01 is the same as that used for all vaccines provided through the Expanded Programme on Immunization (EPI) – an “opt-out” approach that is sometimes referred to as “implied consent”.2 This means that parents receive information about the vaccine from the ministry of health and can decide to present for, or to opt-out of, any or all vaccinations. The EPI in the 3 countries have used a variety of communication approaches to inform communities about the pilot introductions, the reasons for the pilots, and the risks and benefits of vaccination with RTS,S/AS01.
The decision to allocate the vaccine to randomly selected communities in each country was taken in conjunction with national authorities as a fair way to allocate limited vaccine doses in the first part of a phased, sub-national introduction. This has the added benefit of strengthening the robustness of the programme evaluation.
As with other new vaccines, and in line with national and international regulations, the safety profile of RTS,S/AS01 will continue to be monitored during its phased introduction. In particular, the safety signals that arose during the clinical testing of the vaccine are being carefully monitored during its introduction. Additional information is presented here.
In brief, during the Phase 3 trial of RTS,S/AS01, more cases of meningitis were identified in children who received the vaccine than in those who did not.
The phase 3 trial showed that the vaccine reduces severe malaria by 29%. However, among those children who did develop severe malaria, there were more cases of cerebral malaria, one type of severe malaria.
Finally, a post-hoc analysis identified an imbalance in female mortality in the phase 3 trial. This was considered by the national regulators and by the European Medicines Agency (EMA). The EMA concluded that there is insufficient information to classify the finding as a “potential risk” (a formal EMA classification) and that this was likely to be a chance finding, but one that should be monitored during vaccine introduction.
No causal link to the vaccine has been established for the meningitis, cerebral malaria or female mortality findings in the phase 3 trial. These concerns are being monitored carefully and regularly during the pilot implementation: prompt action can and will be taken should the need arise.
Independent from the vaccine’s introduction, groups of researchers in each country are conducting observational studies to evaluate the routine use of the vaccine. This involves evaluation of the impact and feasibility of delivering the 4 recommended doses of the vaccine, and consolidation of its safety profile. Written informed consent is sought from all participants in the observational studies for activities that are beyond routine care.
The programme evaluation protocols were submitted for full ethical review and received approval both at WHO and from the national ethics review boards in the participating countries. The evaluation has been registered on clinicaltrials.gov as an observational study, defined as a study “in human beings in which biomedical and/or health outcomes are assessed in pre-defined groups of individuals. Participants in the study may receive diagnostic, therapeutic, or other interventions, but the investigator does not assign specific interventions to the study participants. This includes when participants receive interventions as part of routine medical care, and a researcher studies the effect of the intervention”.3
Study registration is considered good practice; nearly 69 000 (21%) of the studies registered on clinicaltrials.gov are observational studies.
In summary, the RTS,S vaccine is undergoing phased introduction by the Ministries of Health of Malawi, Ghana and Kenya. The evaluation of the pilot implementation is being conducted in accordance with recognized national and international ethical standards and with respect to human subjects regulations. Information gained from the evaluations will help inform decisions around the broader use of RTS,S/AS01 both within the countries piloting the vaccine and across Africa, as part of the global effort to reduce suffering and deaths from malaria.
1 Penny M, Verity R, Bever C, et al. Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models. Lancet 2016; 387: 367–75
2 WHO, 2014. Considerations regarding consent in vaccinating children and adolescents between 6 and 17 years old. Available at https://www.who.int/immunization/programmes_systems/policies_strategies/consent_note/en/
3 ClinicalTrials.gov. Protocol Registration Data Element Definitions for Interventional and Observational Studies. Available at https://prsinfo.clinicaltrials.gov/definitions.html#StudyType