Feasibility, Safety, and Impact of the RTS,S/AS01 _E Malaria Vaccine When Implemented Through National Immunisation Programmes: Evaluation of Cluster-Randomized Introduction of the Vaccine in Ghana, Kenya, and Malawi

Abstract

Background: RTS,S/AS01_E malaria vaccine (RTS,S) was introduced by national immunization programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. Prospective evaluations were conducted to address questions about feasibility and effectiveness, and to assess safety signals that had been observed in the phase 3 trial, before recommending wider use. One-hundred-fifty-eight clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunization clinic catchment areas in Malawi) were randomized to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 and 9 months and a fourth dose at approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury, hospital admission with severe malaria, and, with respect to safety, hospital admission with meningitis or cerebral malaria, and deaths in girls compared to boys, and, for feasibility, vaccination coverage. Preliminary findings contributed to the World Health Organisation’s recommendation in 2021 for widespread use of RTS,S in areas of moderate to high malaria transmission.

Methods: Mortality surveillance was undertaken in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in 8 sentinel hospitals in Ghana, 6 in Kenya, and 4 in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. Sufficient data had accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRR’s) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact), to that in non-eligible age groups, between implementation and comparison areas. To determine if there was evidence of a difference between girls and boys in the vaccine’s impact on mortality, the female: male mortality ratio in age groups eligible to receive the vaccine relative to the ratio in non-eligible children was compared between implementation and comparison areas.

Findings: By April 30 2021, 652,673 children had received at least one dose of RTS,S and 494,745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and of the third dose, 66%, 62% and 62%, respectively. A total of 26,285 children aged 1-59 months were admitted to sentinel hospitals and 13,198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases (IRR (implementation:comparison areas) for hospital admission with meningitis was 0·63, 95% CI 0·22,1·79 and with cerebral malaria 1·03, 95% CI 0·61,1·74), and the impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·04, 95% CI 0·90,1·21). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% (95% CI 5%, 51%) reduction in hospital admission with severe malaria, and a 9% (95% CI 0%, 18%) reduction in all-cause mortality excluding injury.

Interpretation: In the first two years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes, there was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of 4 doses of RTSS.

Trial Registration: The evaluation is registered on ClinicalTrials.gov (NCT03806465) as an observational study.

Funding: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis, and Malaria; and Unitaid. SA was supported at the initiation of the pilots by the Initiative to Develop African Research Leaders (IDeAL) Wellcome Trust award (# 107769). Funding to Mike English supported the establishment of the Clinical Information Network (CIN) -Senior Wellcome Fellow (# 097170). We acknowledge the support of the Wellcome Trust to the Kenya Africa Asia Programme (#092654 and # 203077) that provides core support to CIN. Support to RWS as part of his Wellcome Trust Principal Fellowship (# 212176). KAM was supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (Grant Number APP1160936).

Declaration of Interest:

Ethical Approval: Consent of parent/guardian was sought for data collection following approval by the institutional review boards of the evaluation partners’ institutions and WHO (SS6). Sentinel surveillance in Kenya used an established routine system and parental consent was only obtained for CSF storage. An independent data safety monitoring board, and the MVIP Programme Advisory Group, provided oversight.

Keywords: Malaria vaccine, RTS, S/AS01E, RTS, S/AS01E evaluation, Malaria vaccine implementation programme, Malaria vaccine programme evaluation, MVPE, MVIP, Malaria, Vaccine, Implementation research