Safety of R21/Matrix-M Malaria vaccine

Extract from GACVS meeting of 13-15 November 2023, published in the WHO Weekly Epidemiological Record of 1 March 2024

Presenters updated GACVS on the R21/Matrix-M malaria vaccine, developed by the University of Oxford and manufactured by the Serum Institute of India. The evidence-review process of the vaccine included the Strategic Advisory Group of Experts in Immunization (SAGE)/Malaria Policy Advisory Group (MPAG) Working Group on Malaria Vaccines, the R21/Matrix-M Safety Working Group, the African Advisory Committee on Vaccine Safety, and GACVS. WHO Prequalification process of the vaccine was also ongoing at the time of the meeting[1].

Previously WHO R21/Matrix-M Safety Working Group presented their review outcomes on the updated safety data of the multi-centre phase 3 trial which began in January 2021 to evaluate the efficacy of 5 µg R21 / 50 µg Matrix M at the July GACVS ad hoc meeting. Presenters addressed the remaining questions from the July GACVS meeting and provided updates on SAGE and MPAG recommendations on two malaria vaccines (RTS,S/AS01 and R21/Matrix-M).  

In the ongoing Phase 3 clinical trial of R21/Matrix-M, there are two different administration strategies, seasonal and age-based. The vaccine is given in 4 doses, a 3 dose primary series with the first dose given to children between five and 36 months of age, followed by a 4th dose 12 months after dose 3. When given using a seasonal strategy in areas of highly seasonal malaria transmission, the vaccine has high efficacy (75%) against all episode of clinical malaria during 12 months follow-up.  Vaccine efficacy is maintained during six months after the fourth dose is given. When given in an age-based strategy, in areas of low and moderate transmission, vaccine efficacy is around 66% during 12 months follow-up, and is maintained during the 6 months after the fourth dose is given. In total, 142 serious adverse events (SAEs) were reported, and were balanced between the R21/Matrix-M arm and the control arm (rabies vaccine). Of those, six were considered related, and were all febrile convulsions. There was no difference in SAEs by gender. In children randomized to receive R21/Matrix-M, there was a slightly higher frequency of local solicited adverse events, typically injection site pain, and systemic solicited events, manifested as a higher frequency of fever.

At the July GACVS ad hoc meeting, the committee recommended closely monitoring Adverse Events of Special Interest (AESIs), including deaths, which were not considered related to vaccination, and seizures, febrile convulsions within seven days, and severe fever (which can lead to febrile convulsions), especially if the vaccine is co-administered with other vaccines. Special attention should be given to understanding the attributable risks of serious adverse events by conducting timely causality assessment and analysis including the analysis of gender difference and nutritional status in fatal outcomes. According to the data presented to the committee, the attributable risk of febrile convulsions was found to be in the range of other vaccines and all febrile convulsions resolved without sequalae.

An imbalance of deaths was noted between the two study arms, with a higher number of deaths in the R21/Matrix-M group versus the Rabies vaccine (control) group (2:1 randomization) although the difference was not statistically significant, recognizing the limited study power for this outcome. Presenters explained the details of the fatal cases, drawing attention to the total where there were 15 deaths in the vaccine arm and 4 in the control arm giving a frequency of 0.5, and 0.2, respectively. When deaths due to injury are removed, the totals are 12 (R21/Matix-M) and 3 (control), for a frequency of 0.4 and 0.2, respectively. There was no clustering, or pattern in terms of vaccination timing or cause. There was no imbalance in severe malaria, which occurred at a frequency of 0.77 for the R21/Matrix-M arm and 0.98 for the control arm, though it was noted the study was not powered to evaluate severe malaria.  Additional safety data were compiled, including a line listing which showed no pattern and no relationship to the vaccine. There was no imbalance in use of seasonal malaria chemoprevention, use of insecticide treated bed nets, nor nutritional status at enrollment. The vaccine was efficacious in underweight children. Therefore, there were no confounders found to explain the imbalance in deaths. 

SAGE recommendations were presented which emphasized priority areas of monitoring and evaluation research to be pursued, including completing the ongoing co-administer studies with other relevant infant vaccines; observational studies on the occurrence of febrile seizures; post-licensure studies on vaccine-effectiveness; and monitoring for malaria rebound and impact on severe malaria through the ongoing Phase 3 trial, which includes four years of follow up (already planned by the developer). Post-licensure monitoring in infants and young children, including for febrile seizures should occur, as should evaluations of vaccine efficiency against severe malaria, and of impact on mortality using available systems. Finally, interchangeability studies on heterologous schedules with RTS,S/AS01 and R21/Matrix-M are recommended. SAGE and MPAG recommend GMP and IVB prioritize, coordinate, and monitor identified high priority research activities, and support the development of generic protocols, as needed, to guide study designs. MPAG plans to follow-up on the status of these recommended research priorities annually.

 Approaches to respond to these recommendations were explored by the Committee. One approach would be through the strengthening of routine surveillance. This option may face challenges, as the countries where the vaccine will be disbursed are lower- and middle-income countries where capacity is limited for capturing data, conducting investigations, and completing causality assessments, which are minimum necessities for cases to be captured through routine surveillance. Another approach could be through active surveillance through utilizing existing networks of sentinel sites or other methods, such as cohort event monitoring. Specifically, to be monitored for post-authorization: rebound malaria and mortality, co-administration with other vaccines and febrile seizures, high fever within seven days of administration, and other AESIs identified through GACVS guidance. Regarding risk management, there is a need for collaboration with Prequalification (PQ) team to provide information of the status of the Risk Management Plan (RMP) shared by the manufacturer. The RMP follow up is based on Prequalification team recommendations, and any update of the RMP that might be submitted by manufacturer. There is a need for growing partnerships with other organizations to leverage expertise and maximize efforts as there are regional initiatives to monitor safety data jointly for post-marketing surveillance.

GACVS recommended to have a highly coordinated approach to monitoring throughout the rollout of the vaccine for a number of outcomes, including febrile seizures, mortality, and severe malaria, among others. There was a suggestion for the safety experts to join and coordinate in the efforts of MPAG to follow up with all of these issues and other priority research areas and other suggestions from the RMP after roll out. The committee emphasized the importance of education to the community on febrile seizures. The committee sees the importance of having effective post-marketing surveillance and agreed on the importance of pharmacovigilance planning. Also, it recognizes the need for system strengthening and capacity building, specifically for routine surveillance as well as other essential pharmacovigilance activities, such as the consideration of active surveillance activities.

Full report of WHO GACVS and WHO ACSoMP 13–15 November 2023, published on 1st March 2024