Extract from report of GACVS meeting of 15-16 May 2023, published in the WHO Weekly Epidemiological Record on 11 August 2023

RTS,S/AS01 vaccine

GACVS was provided with safety updates on the RTS,S/AS01 vaccine. The Malaria Vaccine Implementation Programme (MVIP) supported routine introduction of RTS,S/AS01 by ministries of health in selected areas of Ghana, Kenya and Malawi and evaluations of multiple domains, including vaccine safety in the context of routine use. GACVS previously reviewed safety data from the phase 1, 2 and 3 trials as well as data from the 24 months of MVIP pilot evaluations. A full evidence review of RTS,S/AS01, including all safety data and incorporating feedback from GACVS, was conducted by SAGE and the Malaria Policy Advisory Group (MPAG) in October 2021.

The SAGE/MPAG evidence review informed the WHO recommendation that RTS,S/AS01 vaccine be used for prevention of Plasmodium falciparum malaria in children living in regions with moderate to high transmission as defined by WHO. Since then, the safety profile has remained positive, with more than 4 million doses having been administered since the first roll-out in 2019. There has been no evidence of a causal relationship with any of the safety signals observed in the phase 3 trial (meningitis, cerebral malaria, and a gender-based imbalance in deaths), and no new safety signals have been identified.

The MVIP pilot phase was introduced sub-nationally and expanded to include MVIP comparator areas (initially non-vaccinating) after the WHO recommendation for use. Malaria vaccine has been introduced into routine Expanded Programmes on Immunization (EPIs). Sentinel hospital surveillance and community-based mortality surveillance have been integral in MVIP safety monitoring.

The African Advisory Committee on Vaccine Safety (AACVS) has additionally monitored the safety of the RTS,S/AS01 malaria vaccine and made recommendations to WHO Regional Office for African Region (AFRO) and stakeholders regarding the continued implementation of the MVIP and improvements to regional vaccine safety monitoring more broadly. AACVS concluded that MVIP safety evaluation data appeared robust, with the duration of the evaluation reasonable, and the sources of data appropriate and diverse. AACVS also noted that there were no new safety signals observed and no evidence of a causal relationship between RTS,S/AS01 and an increased risk of cerebral malaria, meningitis or any observed gender-based imbalance in mortality.

Data from the Malaria Vaccine Pilot Evaluation (MVPE) were also shared with GACVS. The objectives of the MVPE were to evaluate the extent to which the protection demonstrated in children aged 5–17 months in the phase 3 trial could be replicated in the context of routine health systems, particularly in view of the need for a 4 dose schedule; the extent to which RTS,S/A01 vaccination impacted all-cause mortality (including gender-specific mortality); and whether the excess cases of meningitis and cerebral malaria identified during the phase 3 trial were causally related to RTS,S/AS01 vaccination.

The most recent safety data further strengthen the positive assessment made in April 2021 by the MVPE, where the conclusion was that sufficient events had accrued to allow effects of the magnitude observed in the phase 3 trial to be detected with 90% power in pooled analyses of the data from the 3 MVIP countries. There was no evidence that the introduction of RTS,S/AS01 increased the incidence of hospital admission with either meningitis or cerebral malaria, nor any evidence that RTS,S/AS01 introduction was less effective against hospital admission with cerebral malaria than with other forms of severe malaria. The impact on mortality (about 10% reduction in all-cause deaths) was similar in girls and boys. Results were similar in all 3 countries. The evaluation will conclude at the end of 2023, with nested case control studies anticipated to be completed in mid-2024.

GACVS expressed interest in reviewing results regarding the fourth dose of RTS,S/AS01 when they are available, noting that coverage has been lower for this dose given the interval between administration of the third and fourth doses. Because of the steep decline in coverage, Ghana has changed its recommendations for fourth dose administration to 18 months.

R21/MatrixM vaccine

Presenters updated GACVS on the R21/MatrixM malaria vaccine, developed by the University of Oxford and manufactured by the Serum Institute of India, which will be the second malaria vaccine reviewed by WHO for a potential recommendation for use. Thus, WHO has requested that GACVS review the safety data of R21/MatrixM vaccine in the upcoming months.

The R21/MatrixM malaria vaccine is another preerythrocytic stage vaccine, indicated for reduction of clinical malaria in infants and children and is similar to RTS,S/AS01 in construct. Manufactured by Novavax, MatrixM adjuvant consists of a saponin extract (similar to AS01) and has been used in vaccines against COVID-19, respiratory syncytial virus and influenza.

A multi-centre phase 3 trial began in January 2021 to evaluate the efficacy of 5 µg R21 / 50 µg MatrixM. A total of 4800 children aged 5–36 months were included with 2 : 1 randomization (R21/MatrixM vs rabies vaccine). The phase 3 trial is evaluating 2 administration strategies. The first strategy is seasonal administration in areas of highly seasonal transmission (2400 participants at 2 sites in Mali and Burkina Faso), where a 3-dose primary series is given just prior to the malaria season (April/May–June/July) followed by dose 4 given annually in June/July the following year. The second strategy is a standard (age-based) administration (2400 participants aged 5–36 months of age) including a 3-dose primary series given at 0, 1, and 2 months starting at 5 months of age and dose 4 given 12 months after dose 3. This is being trialed at 3 sites: Dande, Burkina Faso (highly seasonal–low/moderate transmission setting), and in low transmission areas of Kilifi, Kenya, and Bagamoyo, United Republic of Tanzania.

The SAGE/MPAG Working Group on Malaria Vaccines is currently reviewing the evidence for a potential WHO recommendation for use of R21/MatrixM vaccine under the current WHO malaria vaccine policy. Evidence includes data from 12-months follow-up post dose 3 in sites evaluating age-based administration and 18-months follow-up post-dose 3 in sites evaluating seasonal administration. The Working Group will then provide recommendations to SAGE and MPAG, who will jointly determine whether R21/MatrixM can be recommended for use or if further data are required before a decision can be made.

The SAGE/MPAG Working Group has asked GACVS to review the R21/MatrixM data and has provided GACVS with its initial observations of the safety data. Firstly, the Working Group acknowledged that, although the number of deaths in the phase 3 trial was small, there was an imbalance in deaths between the vaccine and control group. The safety data on mortality, and malaria-related deaths in particular, were difficult to interpret and required further scrutiny. The Working Group has requested case reports and suggested GACVS review cause of death by study arm and sex. Finally, it also stressed the importance of reviewing safety data for MatrixM in infants and young children, as there is limited data on the use of this adjuvant in younger age groups. To assist the GACVS review, the SAGE/MPAG Working Group has requested clarifications and additional data regarding the number and rate of severe adverse events, AESI, and deaths from the University of Oxford and the Serum Institute of India.

The R21 Safety Working Group presented the outcomes of the safety data review of R21/MatrixM vaccine at the GACVS ad-hoc meeting on 30 June 2023.

Following a positive scientific opinion of the RTS,S/AS01 malaria vaccine by the European Medicines Agency,³ and the 2016 WHO recommendation for pilot implementation,⁴  the MVIP was set up to support routine introduction of the RTS,S/ AS01 vaccine by the ministries of health and to evaluate the feasibility, safety and impact of the vaccine when deployed through routine immunization programmes in selected areas of 3 pilot countries (Ghana, Kenya and Malawi). At the recommendation of the Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria policy advisory group (MPAG), the safety evaluation is focused on potential safety signals identified in the large multisite RTS,S/AS01 Phase III trial, i.e., an excess of meningitis cases and cerebral malaria cases, and a post-hoc finding of an imbalance in deaths among girls who received the RTS,S/AS01 vaccine compared with those who did not.

In each country areas of moderate-to high-transmission settings were selected by the respective Ministries of Health in 2019 for RTS,S/AS01 pilot introduction. Within the pilot region in each country, districts or similar areas were randomly assigned to introduce the vaccine in 2019 (vaccinating areas), or to delay introduction until a decision is reached about safety and effectiveness in routine use (comparison areas). A total of 158 areas were randomized, i.e., 66 districts in Ghana, 46 sub-counties in western Kenya, and 46 groups of immunization clinics and their associated catchment areas, in Malawi. Each area has a total population of about 100000 and an expected birth cohort of about 4000 per year. Household surveys were conducted in the vaccinating and comparison areas before vaccine introduction in each country. The primary objective of the midline household survey was to estimate the percentage of ageeligible children who had received 3 doses of RTS,S/AS01 by 12 months of age. The secondary objectives were to evaluate the impact of RTS,S/AS01 introduction on:

• the uptake of the other EPI vaccines
• other malaria preventive interventions (insecticide treated bed net use)
• health-seeking behaviour for febrile children The end line household surveys to estimate the percentage of age-eligible children who had received 4 doses by 27 months of age, and similar secondary objectives, will be carried out in 2022.

The MVIP has 4 approaches for the evaluation of the safety of RTS,S/AS01 in routine, (real-world) use. These are (i) routine pharmacovigilance by the ministries of health for spontaneous adverse event following immunization (AEFI) reporting of rare, unexpected AEFIs; (ii) WHO-commissioned community mortality surveillance to measure the impact of vaccination and also sexspecific mortality rates; (iii) WHO-commissioned hospital surveillance of meningitis and cerebral malaria at sentinel hospitals; and (iv) a GSK phase-IV cohort study with scheduled visits for AEFIs, sex-specific mortality and in-patient surveillance for meningitis, cerebral malaria, AEFIs and adverse events of special interest (AESIs). A 2-step approach for analysis has been planned with the aim of ensuring that a recommendation can be made as soon as the benefit-risk ratio of the vaccine is established so that the vaccine will not be unnecessarily withheld from countries in need. The first planned analysis in 2021, after 2 years aimed to confirm if the safety signals had been satisfactorily resolved for meningitis and cerebral malaria and sex related mortality, and if the data available for effectiveness for the reduction of severe malaria and mortality were consistent with a beneficial impact of the vaccine. On the basis of these data, and other new evidence on the vaccine since the recommendation for pilots in 2015, a decision will be made by WHO to recommend a broader use of RTS,S/AS01. The second analysis is planned in 2023 to assess the value of the fourth dose and the vaccine’s effectiveness to reduce mortality. On the basis of these final results, WHO may adjust its recommendation.

The malaria vaccine is given as a 3-dose initial series with a minimum 4-week interval between doses, followed by a fourth dose 15 to 18 months after the third dose delivered by the national immunization programme in each country. Since the pilot programme started, over 2.1 million doses of RTS,S/AS01 have been administered and more than 740 000 children have received at least one dose. The vaccination coverage for one dose was 88%, 71% and 69% in Malawi, Ghana and Kenya, respectively, in 2020 and 92%, 76% and 81%, respectively, for April to June 2021. Vaccination coverage for 3 doses was 80%, 74% and 72%, respectively, for April to June 2021. Safety data obtained in these evaluations is reviewed by a data safety monitoring board (DSMB) meets quarterly to review data quality; outcomes of interest, including meningitis, cerebral malaria and deaths by sex; pharmacovigilance reports presented by the regulatory authorities; and GSK safety surveillance data from the phase-IV studies. Based on their evaluation the DSMB recommends if the MVIP should continue or not. The programme is overseen by a programme coordination group, a programme advisory group, GACVS and SAGE and MPAG. An extraordinary meeting of the GACVS was held on 10 August 2021 to review the conclusions and recommendations about the primary safety analysis at 2 years (data cut off April 2021) made by the DSMB and the African Advisory Committee on Vaccine Safety (AACVS). GACVS provided recommendations on what post authorization safety monitoring system should be in place should the vaccine be recommended for broader use in sub-Saharan Africa by SAGE and MPAG in October 2021.

¹European Medicines Agency assessment: Mosquirix: Opinion on medicine for use outside EU (accessed 10 August 2021).

Full report of GACVS meeting of 10 August 2021, published in the WHO Weekly Epidemiological Record on 11 March 2022

The primary objective of the midline survey was to estimate the percentage of children aged 5 to 48 months old who had received 3 doses of RTS,S/AS01 by 12 months of age, assessed using their vaccine card or by recall. The secondary objectives were to assess the impact of RTS,S/AS01 introduction under real-world conditions on the coverage with other EPI vaccines, the use of other insecticide-treated bed nets and the healthseeking behaviour for children with febrile episodes, in comparison with the baseline results. Data were available from Ghana (collected November 2020) and Malawi (collected March to April 2021). The results showed that the malaria vaccine coverage was comparable with the coverage reported from routine administrative data, although the point estimates were lower in Malawi and higher in Ghana. There was no negative impact on the uptake of routine vaccines, use of bed nets or health-seeking behaviour, following the introduction of the malaria vaccine. Vaccine uptake was equitable, with similar uptake across wealth rankings, based on household assets, and by gender, and was similar among children in relation to use of insecticide-treated nets.