The WHO Malaria Vaccine Implementation Program: clarifying misconceptions
Dear Editor,
We strongly disagree with the assertion that the Malaria Vaccine Implementation Programme (MVIP) is at odds with international ethical standards. The systematic evaluation of programmatic implementation of a newly approved product is considered good practice - not medical or scientific experimentation.
The RTS,S/AS01 malaria vaccine has been authorized for use in the pilot areas by the National Regulatory Authorities of Ghana, Kenya and Malawi and has received a positive scientific opinion from the European Medicines Agency; it is not an experimental vaccine. 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 has been shown to significantly reduce malaria, including life threatening severe malaria. Modeling suggests that, if introduced broadly, the vaccine could save tens of thousands of lives per year [1]. Given the 228 million malaria episodes suffered every year, and the 405,0000 premature deaths attributed to malaria every year, it is important to take all steps to tackle this disease.
The imbalance in female mortality in the Phase 3 trial was identified by a post-hoc analysis and was considered by the national regulators and the 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. Accordingly, mortality is being carefully monitored and action will be taken should the need arise.
The vaccine is now being provided to children through the routine immunization services of the Ghana, Kenya, and Malawi Ministries of Health as part of childhood vaccination programmes. The consent process used for administration of RTS,S is the same as that used for all vaccines provided through these programmes – an “opt-out” approach that is otherwise 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 programmes in the three countries have used a variety of communication approaches to inform the communities about the pilot introductions, the reasons for the pilots, and the risks and benefits of vaccination with RTS,S.
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.
Independent of the vaccine implementation by the EPI programme, groups of researchers in each country are conducting observational studies to evaluate the routine use of the vaccine – specifically to evaluate the impact and feasibility of delivering the four vaccine doses and to consolidate 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]. Such registration is considered good practice and 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 MoH of Malawi, Ghana, and Kenya. The evaluation of the pilot implementation is being conducted in accordance with established and recognized national and international ethical standards and with respect to human subjects regulations. The evaluation protocols have been reviewed and approved by four ethical review boards. The information gained from the evaluations will help to inform the broader use of the RTS,S vaccine, 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/...
[3] ClinicalTrials.gov. Protocol Registration Data Element Definitions for Interventional and Observational Studies. Available at https://prsinfo.clinicaltrials.gov/definitions.html#StudyType
Competing interests:
WHO provides scientific and technical leadership to the MVIP.
02 March 2020
Soumya Swaminathan
Chief Scientific Officer
Kate O'Brien, Director, IVB, WHO; Pedro Alonso, Director, GMP, WHO
Rapid Response:
The WHO Malaria Vaccine Implementation Program: clarifying misconceptions
Dear Editor,
We strongly disagree with the assertion that the Malaria Vaccine Implementation Programme (MVIP) is at odds with international ethical standards. The systematic evaluation of programmatic implementation of a newly approved product is considered good practice - not medical or scientific experimentation.
The RTS,S/AS01 malaria vaccine has been authorized for use in the pilot areas by the National Regulatory Authorities of Ghana, Kenya and Malawi and has received a positive scientific opinion from the European Medicines Agency; it is not an experimental vaccine. 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 has been shown to significantly reduce malaria, including life threatening severe malaria. Modeling suggests that, if introduced broadly, the vaccine could save tens of thousands of lives per year [1]. Given the 228 million malaria episodes suffered every year, and the 405,0000 premature deaths attributed to malaria every year, it is important to take all steps to tackle this disease.
The imbalance in female mortality in the Phase 3 trial was identified by a post-hoc analysis and was considered by the national regulators and the 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. Accordingly, mortality is being carefully monitored and action will be taken should the need arise.
The vaccine is now being provided to children through the routine immunization services of the Ghana, Kenya, and Malawi Ministries of Health as part of childhood vaccination programmes. The consent process used for administration of RTS,S is the same as that used for all vaccines provided through these programmes – an “opt-out” approach that is otherwise 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 programmes in the three countries have used a variety of communication approaches to inform the communities about the pilot introductions, the reasons for the pilots, and the risks and benefits of vaccination with RTS,S.
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.
Independent of the vaccine implementation by the EPI programme, groups of researchers in each country are conducting observational studies to evaluate the routine use of the vaccine – specifically to evaluate the impact and feasibility of delivering the four vaccine doses and to consolidate 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]. Such registration is considered good practice and 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 MoH of Malawi, Ghana, and Kenya. The evaluation of the pilot implementation is being conducted in accordance with established and recognized national and international ethical standards and with respect to human subjects regulations. The evaluation protocols have been reviewed and approved by four ethical review boards. The information gained from the evaluations will help to inform the broader use of the RTS,S vaccine, 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/...
[3] ClinicalTrials.gov. Protocol Registration Data Element Definitions for Interventional and Observational Studies. Available at https://prsinfo.clinicaltrials.gov/definitions.html#StudyType
Competing interests: WHO provides scientific and technical leadership to the MVIP.