Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up

Abstract

Background Following a 30-year development process, RTS,S/AS01E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01E through active participant follow-up in the context of its real-life implementation. Methods EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. Conclusion GSK’s post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01E’s benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa. Graphic abstract

Introductory Chapter: Malaria in 2022 – Promises and Unmet Needs

“…This new strategy is leading to reduced new malaria cases worldwide [ 9 ]. Recent study on the vaccination campaign impact reports that in a population of children from 5 months age, who received all four doses of malaria vaccine, in a follow-up time of 4 years, they observed a reduction in both clinical and severe malaria cases of 39% and 29%, respectively [ 10 ].…”

Perception and awareness towards malaria vaccine policy implementation in Nigeria by health policy actors

“…The development of an anti-malarial vaccine is important for regional malaria elimination and future eradication efforts. Malaria vaccine policy is a global effort, and the vaccine has already been applied to a large number of children in Ghana, Kenya, and Malawi [ 13 – 15 ].…”

“…There have been efforts to evaluate the effectiveness, cost-effectiveness, efficacy and safety impact of malaria vaccines implemented in the three regions of Ghana, Kenya, and Malawi [ 15 , 16 ]. The pilot programme coordinated by the WHO indicates that the vaccine is successful in terms of safety and feasibility [ 18 ].…”

Five decades of clinical assessment of whole-sporozoite malaria vaccines

“…Results from a large Phase III clinical study have shown that 4 doses of the vaccine present relatively modest and rapidly waning 25.9% and 17.3% effectiveness against clinical and severe malaria, respectively, in newborns aged 6–12 weeks, and 36.3% and 32.2% efficiency against clinical and severe malaria, respectively, in children aged 5–17 months [( 3 ) and reviewed in ( 4 )]. A post-approval plan comprising 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S in the context of its real-life implementation will support the ongoing evaluation of the vaccine’s benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa ( 5 ). Moreover, RTS,S is not expected to protect against the other human malaria parasites, namely P. vivax (Pv), P. ovale , P. malariae , and the zoonotic P. knowlesi ( 6 ).…”