Feasibility, safety, and impact of the RTS,S/AS01E malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi

Abstract

Background: The RTS,S/AS01_E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use.

Methods: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have 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 (IRRs) 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 outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-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. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission.

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 coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 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 in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury).

Interpretation: In the first 2 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 four doses of RTS,S.

Funding: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

Figure 1

Uptake of the RTS,S vaccine (A) Coverage of the first, second, and third doses of RTS,S among children aged 12–23 months in surveys done about 18 months after introduction of RTS,S. (B) Uptake of the primary three doses of RTS,S, in relation to use of LLINs, malaria transmission intensity, socioeconomic status, and sex. Vertical bars indicate 95% CIs. The percentage that slept under an LLIN the night before the survey was 67% in Ghana, 93% in Kenya, and 68% in Malawi. RTS,S uptake was documented from a home-based record (in 92% of children in Ghana, 88% in Kenya, and 91% in Malawi) or from caregiver recall for those without a record. Malaria prevalence was categorised according to tertiles of malaria prevalence among children aged 5–48 months. Wealth was categorised according to tertiles of principal component scores based on household assets. The prevalence ratios (and 95% CIs) in the proportion of children who had received the third dose of RTS,S between categories were 1·20 (1·05–1·38) in Ghana, 1·23 (1·01–1·50) in Kenya, and 1·20 (1·04–1·37) in Malawi for LLIN users compared with non-users; 1·04 (0·92–1·18), 1·00 (0·84–1·20), and 0·84 (0·69–1·02) for higher malaria prevalence compared with lower; 1·00 (0·88–1·13), 1·18 (1·04–1·35), and 1·04 (0·90–1·19) for upper wealth ranking compared with lower wealth ranking; and 1·06 (0·97–1·15), 1·01 (0·90–1·13), and 1·07 (0·99–1·16) for girls compared with boys. LLIN=long-lasting insecticide-treated net. RTS,S=RTS,S/AS01_E malaria vaccine.

Figure 2

Vaccination and vitamin A coverage, LLIN use, and health-care-seeking behaviour by country, area, and survey Indicators are within children aged 12–23 months at the time of the survey, except for LLIN use, which is within children aged 5–48 months. To assess whether vaccine introduction was associated with any change in coverage of other vaccines, coverage of LLIN use, care-seeking for fever, or use of vitamin A, the ratio of the prevalence in the midline survey to that at baseline was compared between implementing and comparison areas. The relative ratio (ratio of the prevalence ratio in implementing areas to that in comparison areas) is shown in the forest plots. *Ratio of prevalence ratio of pre-introduction and midline surveys. Equivalent numbers restricted to the sentinel areas are available in the appendix (p 59). †Vaccination coverages in Ghana are from HBR only in the baseline survey because vaccination status by recall was not captured; midline coverages presented are from HBR or recall; however, for comparability, the prevalence ratios for midline versus baseline surveys in Ghana use coverage by HBR only. ‡Full basic vaccination coverage refers to BCG at birth, three doses of OPV (excluding birth dose), three doses of the pentavalent vaccine, and one dose of the measles vaccine; children who received IPV at 14 weeks in place of the third dose of OPV were considered to be fully vaccinated for polio; IPV status was only available from recall in Malawi, only available from HBR in Ghana, and not available in Kenya by either method. §Vitamin A coverage was determined from HBR only in Ghana, recall only in Malawi, and both HBR and recall in Kenya. HBR=home-based record. LLIN=long-lasting insecticide treated-net. RTS,S=RTS,S/AS01_E malaria vaccine. OPV=oral poliovirus vaccine. IPV=inactivated poliovirus vaccine.

Figure 3

IRRs for safety outcomes in children eligible for at least one dose of RTS,S IRRs are presented for outcomes identified as safety signals in the phase 3 trial. Cerebral and severe malaria is shown for all cases and for the subset excluding cases that met the definition of suspected meningitis but for which meningitis status could not be determined (eg, due to a lumbar puncture not being done). Tracer conditions are those unlikely to be influenced by the RTS,S vaccine (admissions of any cause, excluding those with malaria, anaemia, or meningitis). IRR=incidence rate ratio. RTS,S=RTS,S/AS01_E malaria vaccine.

Figure 4

IRRs for impact outcomes in children eligible for three doses of RTS,S IRRs are presented comparing incidence between RTS,S implementation and comparison areas among children eligible to have received three doses of RTS,S. Severe malaria is shown for all cases and for the subset excluding cases that met the definition of suspected meningitis but for which meningitis status could not be determined (eg, due to a lumbar puncture not being done). Tracer conditions are those unlikely to be influenced by the RTS,S vaccine (admissions of any cause, excluding those with malaria, anaemia, or meningitis). IRR=incidence rate ratio. RTS,S=RTS,S/AS01_E malaria vaccine