Update on safety of malaria vaccines
WHO recommends 2 vaccines – RTS,S and R21/Matrix-M – for the prevention of P. falciparum malaria in children in malaria-endemic areas. Both vaccines are currently used throughout Africa. As of 13 November 2024, 15 countries have introduced malaria vaccination: 8 have introduced RTS,S, 8 R21/Matrix-M and 1 country both vaccines. A summary of safety findings on RST,S was presented by the WHO unit on Immunization, Vaccines and Biologicals, including data from 2 recent clinical trials and from 46 months of implementation of the malaria vaccine implementation programme (MVIP), which ended in December 2023. Data from the MVIP showed no evidence of safety signals in the 2009–2013 phase 3 trial,1 including no excess cases of meningitis or cerebral malaria, no evidence that the impact on severe malaria differed for cerebral malaria and for other forms of severe malaria and no difference in vaccine impact on mortality by sex.
Findings from the more recent phase-3 trial of RTS,S and seasonal malaria chemoprevention2, 3 showed that the local and systemic adverse event profiles were similar to that of control vaccines; there was no association between RTS,S and meningitis, cerebral malaria or sex-specific mortality; and the incidence of febrile seizures after vaccination with RTS,S was 1 in 4500 doses (less than the rate in the previous phase 3 clinical trial: 2.2–2.5 in 1000 doses). The phase 2 RTS,S fractional dose trial4 also raised no safety concerns. Several clinical trials are being conducted to investigate the safety and efficacy of R21/Matrix-M. VAC078 is a randomized controlled trial (RCT) conducted in partnership with the Serum Institute of India (SII) and the University of Oxford, England.5 Safety data were presented that had been collected up to 1 August 2024 on the first 3 doses and the first 2 booster doses. The most common AEFIs in the vaccinated group were fever and injection site pain. There were 6 serious adverse events that were possibly, probably or definitively related to receipt of the vaccine (5 in the R21/Matrix-M group and one in the control group, all febrile convulsions). There was no statistically significant difference in serious AEFIs according to sex, and no deaths were assessed as being related to vaccination. The trial data and safety monitoring board reviewed the safety data and expressed no serious concern. Safety data from 2 other RCTs of R21/Matrix-M, VAC088 (NCT05155579) and VAC092 (NCT05385510), sponsored by the University of Oxford were also briefly presented. No serious AEFIs related to vaccination and no febrile convulsions have been reported to date. A representative of the marketing authorization holder, SII, was invited to present the updates on their RMP, including the implementation status of post-approval safety studies. These include the R21-PMS-01 case– control study which was described in detail. A representative of the WHO Regional Office for Africa provided an overview of data collected during routine pharmacovigilance and pilot safety studies in 12 African countries in which vaccination with RTS,S and/or R21/ Matrix-M has been implemented. Between August 2023 and October 2024, relatively few AEFIs were reported. Seven serious AEFIs were classified as vaccine-related after investigation and causality assessments: 4 reports of fever and convulsions (from Kenya), one report of fever (from Ghana) and one report of systemic inflammatory response syndrome and one of dark urine (both from Cameroon). Several challenges experienced during routine monitoring of malaria vaccine AEFI were described, including low reporting rates, non-uniform reporting, the low quality of many reports and several issues in case investigation and resourcing. The Committees welcomed the updated information on use of 2 WHO-prequalified malaria vaccines to vaccinate more than 4 million children. The Committees commended the post-market surveillance in a number of the countries in which the vaccines are used and strongly recommended that all relevant partners, including governments and the manufacturer, allocate resources to post-market surveillance, case investigation, causality assessment and support for reporting and timely sharing of data as part of health system strengthening. The Committees stressed the importance of calculating AEFI rates and collecting and reporting information on issues such as programmatic errors, which have not been included in the data presented to date. The Committees requested the company to continue reporting detailed safety outcome data from the ongoing VAC078 study, including imbalances (e.g. deaths), even if not statistically significant. The Committees also requested that the company continue to provide data from clinical studies in extended populations, including children as young as 6 weeks of age and women of childbearing age. With respect to the planned R21-PMS-01 case–control study on R21/Matrix-M, the Committees emphasized that the study be very carefully designed to ensure robust findings. In particular, GACVS strongly encouraged the manufacturer to work with local authorities and all participants to obtain documented vaccination histories.1RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015;386(9988):31–45. https://doi.org/10.1016/S0140-6736(15)60721-8.
2Chandramohan D et al. Seasonal malaria vaccination with or without seasonal malaria chemoprevention. N Engl J Med, 2021;385:1005–17. https://doi. org/10.1056/NEJMoa2026330.
3Dicko O et al. Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind randomised, controlled, phase 3 trial. Lancet Infect Dis. 2023;24(1):75–86. https://doi.org/10.1016/S1473-3099(23)00368-7.
4Westercamp N et al. Could less be more? Accounting for fractional-dose regimens and different number of vaccine doses when measuring the impact of the RTS,S/ASo1E malaria vaccine. J Infect Dis. 230(2):e486–95. https://doi.org/10.1093/infdis/jiae75.
5Datoo MS et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet. 2024;403(10426):533–44. https://doi.org/10.1016/S0140-6736(23)02511-4.
Successes and challenges in safety monitoring and country experiences in countries that implemented the RTS,S/AS01 vaccines
Extract from GACVS meeting of 10 August 2021, published in the WHO Weekly Epidemiological Record of 11 March 2022
One element of the success of the MVIP is the good
quality of the household survey data that have been
collected, despite the very challenging setting of the
COVID-19 pandemic.
Overall reporting from routine surveillance systems
The focal points of national regulatory agencies share their country safety information for pooled analysis and reported the summary at the quarterly DSMB meetings. They meet with WHO regional focal points to review safety data and discuss the recommendations made by DSMB, following the DSMB meetings, which they attend. Following RTS,S/AS01 vaccination, 2496 AEFIs and AESIs, were reported in all 3 countries of which 603 were serious and 93 were fatal. Almost 90% were reporting through the phase 4 study with others through routine surveillance systems and MVPE sentinel hospitals. Among the 7318 AEFIs reported to the routine surveillance systems, 150 (2.05%) were following RTS,S/ AS01 vaccination. Among the 334 serious AEFIs, 9 were following RTS,S/AS01 vaccination. So far, no safety signals for previously-unknown rare events have been reported. The limitations of these passive surveillance systems include the low reporting rate and the limited resources for monitoring, data analysis and follow-up for the serious AEFIs. The current COVID-19 pandemic contributes to the limited resources available for causality assessments.
Country-specific AEFI reporting
Ghana and Malawi provided data for 26 months, from May 2019 to June 2021 and Kenya for 21 months, from October 2019 to June 2021. In Ghana 299/2058 (14.5%) AEFIs following RTS,S/AS01 were serious, compared with 98/201 (48.8%) and 206/237 (86.9%) in Malawi and Kenya, respectively. The majority of the events were reported via the phase IV study. In Ghana causality assessment has been done for all 33 serious AEFIs reported via routine passive surveillance and MVPE sentinel hospitals, but no information is available for the 266 events in the phase IV trial. In Malawi causality assessment for the 4 serious AEFIs reported via routine passive surveillance has not been done, but it has been done by GSK for the 94 events reported in the phase IV study. In Kenya causality assessment has not been done for the 83 serious AEFIs reported via routine passive surveillance but 135 and 44 of the serious AEFIs reported in the phase IV study have undergone causality assessment by GSK and the national expert committee, respectively. In Ghana, 11/22 fatal AEFIs occurred 11 to 30 days after vaccination, in Malawi, 16/36 fatal AEFIs occurred 151 to 480 days after vaccination, and in Kenya 495/841 (58,9%) 14/33 fatal AEFIs occurred 151 to 360 days after vaccination. The conclusions from all 3 countries are that there are no safety concerns or unknown rare events have been identified since the initiation of RTS,S/AS01 vaccination. Reporting via the routine passive surveillance system is low and the future challenge will be to improve reporting rates and also to have sufficient resources to perform investigations and causality assessments in a timely manner.
MVIP DSMB recommendationsDSMB recommended continuation of MVIP and congratulated the MVIP on their progress made on this ambitious program and for reaching this important 24-month primary analysis. They said that the number of events accrued was adequate to provide sufficient statistical power to exclude associations between RTS,S/ AS01 and meningitis, cerebral malaria, and higher mortality in females of a similar magnitude to those observed in the phase 3 trial, after accounting for observed levels of vaccine coverage and contamination on population-level effects. The DSMB noted limitations in diagnosing cerebral malaria and challenges with meningitis surveillance but any uncertainty does not alter their conclusions regarding safety concerns. They concluded that the pilot evaluation results pooled from all 3 countries demonstrate effectiveness of RTS,S/AS01 against severe malaria, with both broad or strict definitions of severe malaria. As expected, there is not sufficient power yet to detect any impact on mortality. The DSMB agreed with the sponsors’ conclusion that the phase 4 ad hoc analysis was not interpretable due to incomplete or missing data. However, no safety signals were seen when reasonable assumptions were made about missing data. The DSMB noted that the planned interim analysis is expected in late 2023. Based on data reviewed from the national routine passive surveillance systems, the DSMB did not find evidence of new conditions that warrant closer safety tracking. They noted that collecting and investigating AEFIs remains a challenge for the national systems and that most of the reports were via the phase 4 or the MVPE sentinel hospitals and that very few serious events or deaths have been investigated. The DSMB encourages ongoing efforts to strengthen these important systems.