Extract from GACVS meeting of 1-3 December 2020, published in the WHO Weekly Epidemiological Record of 22 January 2021

In 2016, WHO recommended pilot introduction of the RTS,S/AS01 malaria vaccine in selected countries to answer outstanding questions, including the feasibility of reaching children with the recommended 4-dose schedule, the impact and safety signals observed in a phase-III trial for which causality has not been established, including higher relative risks for meningitis (10 times), cerebral malaria (2 times) and female deaths (2 times). The results will inform WHO recommendations on introducing the vaccine for routine use.

Three countries, Ghana, Kenya and Malawi, were selected for pilot implementation of a 4-dose schedule. In each country, 3–5 distinct subnational epidemiological settings were selected, representing moderate- to high-transmission settings in 2019. The malaria vaccine is given as a 3-dose initial series with a minimum interval between doses of 4 weeks, followed by a 4th dose 15–18 months after the 3rd dose. A policy decision on broader use of RTS,S/AS01 will be undertaken in April 2021 when data should be available for evaluation, according to the framework for policy decision endorsed by the Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee, if safety signals are resolved and trends on severe malaria and mortality are reduced in these countries. The pilot tests will continue until 2023 to determine the added incremental benefit of the 4th dose. A final decision on full use of the RTS,S/AS01 vaccine will be made in 2023.

The GACVS heard an update on evaluation of the safety component of the Malaria Vaccine Implementation Programme (MVIP) by four approaches: (i) routine spontaneous AEFI reporting of rare, unexpected AEFI; (ii) WHO-commissioned community mortality surveillance to measure impact, also by sex; (iii) WHO-commissioned in-patient surveillance of meningitis and cerebral malaria at sentinel hospitals; and (iv) a GSK phase-IV enrolled cohort with scheduled visits for AEFI, mortality by sex and in-patient surveillance for meningitis, cerebral malaria, AEFI and AESI. Safety data obtained in these evaluations is reviewed by a data and safety monitoring board that meets quarterly to review quality; outcomes of interest, including meningitis, cerebral malaria and deaths by sex; pharmacovigilance reports presented by NRAs; and GSK safety surveillance data from the phase-IV studies and recommends whether the MVIP should continue. The programme is overseen by a programme coordination group, a programme advisory group, GACVS and SAGE. The MVIP will update the African Advisory Committee on Vaccine Safety at their inaugural meeting in the first quarter of 2021.

GSK updated the GACVS on the activities described above, at baseline and after vaccine implementation, in vaccinated and unvaccinated children. No safety signals have been identified among the 53 459 study participants in the three countries.

WHO will request an interim analysis of data to inform the policy decision in 2021. Further analysis is planned in September 2023 and the final analysis in April 2026.

An update on routine surveillance of RTS,S /AS01 by the NRAs and the EPI in the three countries showed that AEFI reporting has improved in all countries since vaccination was implemented, for both RTS,S/AS01 and other vaccines. The data presented to the Committee did not reveal any unusual AEFIs or AESIs. It was observed, however, that AESI reporting had not kept pace with AEFI reporting. Challenges such as lack of funding and expertise resulted in delays in investigation of serious AEFI. Inadequate training, insufficient details in safety reports for efficient assessment of causality, difficulties in data validation and low reporting rates in some places due to inadequate sensitization of health care professionals and delays due to COVID-19 were observed.

Harmonization and capacity-building have been undertaken in the three countries through partner coordination meetings, focused refresher training programmes and root cause analysis. Innovative approaches such as shared line-lists, printing and distribution of AEFI/AESI reporting tools and manuals, comparison of data within and between countries and data quality checks have been implemented.

GACVS observed that no unusual or unexpected signals had been reported after use of the RTS,S/AS01 vaccine for over 1 year and welcomed the improved reporting of all AEFI that had been a by-product of strengthened AEFI reporting for RTS,S/AS01 in the three countries.

It was suggested that the baseline surveillance systems established in these countries could be used for detecting AESI associated with other vaccine introductions, such as for COVID-19. Lessons learnt from the MVIP could be applied in other countries as other novel vaccines are introduced.

If and when the vaccine is introduced on a larger scale in other countries, targeted training and support for staff at health facilities will be important to improve reporting, in addition to training and supporting peripheral heath workers. Countries cannot expect that their own spontaneous (passive) safety surveillance systems will identify other events of interest unless they are strengthened through a specific, targeted approach. In certain circumstances, cohort event monitoring through parents and guardians of beneficiaries would be a better approach.

Full report of GACVS meeting of 1-3 December 2020, published in the WHO Weekly Epidemiological Record of 22 January 2021

Following a joint review convened by the African Vaccine Regulatory Forum (AVAREF), the national regulatory authorities of Ghana, Kenya and Malawi granted special authorization in May 2018 for use of the RTS,S malaria vaccine in the planned pilot implementation programme. It is anticipated that introduction will commence later this year. GACVS has assessed the safety profile of RTS,S throughout its development and clinical trials and will continue to assess safety data arising from the pilot implementation.³ Safety data will be derived from: (i) post-marketing monitoring of cohort events by the manufacturer GlaxoSmithKline (GSK), with detailed active follow-up; (ii) surveillance of mortality throughout the pilot area and surveillance of meningitis and cerebral malaria in sentinel hospitals in both control and RTS,S areas; (iii) active surveillance of adverse events of special interest (AESI); and (iv) pharmacovigilance through passive reports of adverse events following immunization (AEFI) with all vaccines from each country. A communications strategy and mechanisms for sharing these data during implementation are being developed to ensure that data flow between and within each country (as part of the pilot study and as part of national pharmacovigilance) and from GSK to the African Regional Safety Committee and the coordinators of the pilot implementation study, AVAREF and GACVS.

In June 2017, GACVS endorsed criteria to ensure that each country had a functioning system for reporting and assessing AEFI in time for introduction of the pilot project.⁴ The criteria are: (i) a minimum of 10 AEFI reports per 100 000 surviving infants; (ii) a functioning AEFI committee that meets regularly; (iii) trained, resourced AEFI investigation teams; (iv) safety communications plans evaluated and tested; (v) an identified focal person in each country’s expanded programme on immunization to oversee and ensure optimal reporting and training; and (vi) methods for active surveillance of AESI developed and data collection initiated.

Each country reported progress at the GACVS meeting in December 2017 and have now provided further updates. Ghana is meeting all the criteria. Regular training is provided to health care workers in reporting AEFI, and further training is planned for both the AEFI committee and the investigation teams. Reporting targets are shared with regions, and job aids have been developed. A communications plan is ready to be tested. In Malawi, although the reporting rates for 2017 are on target, more training is required in the pilot areas to sensitize health care workers and for investigation teams to assess AEFI and to use the reporting tools. Communications plans have been developed and have been pilot-tested, and training is planned. In Kenya, although the reporting rate is below 10 per 100 000, sensitization projects were begun in May 2018, and a second round of sensitization is planned just before introduction of RTS,S. Electronic reporting is being pilot-tested in one county. A communications plan is being drafted and members of the national AEFI committee appointed. Training for AEFI investigation teams is planned.

GACVS encouraged each country to ensure training of investigation teams and sensitization for reporting as soon as possible, so that AEFI surveillance would be functioning when pilot implementation began. It also stressed the importance of ensuring the timely availability of individual data on AEFI in order that the levels and quality of reporting can be monitored regularly throughout the pilot project and any improvements made when necessary. GACVS also noted that barriers to reporting, such as the belief of health care workers that a report indicates an error on their part, should be addressed in training.

For criterion (vi), on active surveillance, a working group with representatives from each country, WHO and the Centers for Disease Control and Prevention (Atlanta, GA, USA) has produced a manual that can be adapted in each country to its protocols for AESI surveillance. The manual, which covers 11 adverse events with both Brighton case definitions and simplified working case definitions, was presented for comment to GACVS. Surveillance would be limited to the duration of the pilot implementation project and to the target age group in both the control areas and those receiving RTS,S. Each country will identify which health care workers and health care facilities are to be responsible for active surveillance. Cases will be identified by regular review and extraction of case details at the facilities on reporting forms. The data will then be entered into a dedicated AESI database. GACVS agreed that development of country protocols, training and testing should proceed as soon as possible, and these activities are planned for the third quarter of 2018. GACVS noted that, if pilot implementation of RTS,S starts later in 2018, AESI surveillance may not be fully in place. Surveillance is an important component of the safety evaluation that allows comparison of control areas with those in which RTS,S is implemented and should be initiated as soon as possible.

³ See No. 28, 2017, pp. 393–396.

⁴ See No. 3, 2018, pp. 17–19.

Full report of GACVS meeting of 6-7 June 2018, published in the WHO Weekly Epidemiological Record of 20 July 2018

The pilot implementation plans for the RTS,S malaria vaccines in Kenya, Malawi and Ghana have continued to develop since the GACVS meeting in June 2017.³ In particular a tripartite agreement between PATH, GSK and WHO, in terms of roles and responsibilities, and a funding agreement with GAVI, UNITAID and the Global Fund to Fight AIDS, Tuberculosis and Malaria were signed. Plans for a joint regulatory review in the implementing countries for restricted use in pilots have also been devised. In addition, a programme advisory group has been established. It is anticipated that pilot introduction will start mid- to late-2018.

At the June 2017 meeting, GACVS endorsed 6 key indicators of readiness for vaccine pharmacovigilance (PV) for the implementing countries – to be in place 6 months prior to vaccine administration. These were i) a minimum of 10 AEFI reports per 100 000 surviving infants; ii) a functioning AEFI committee that meets regularly; iii) trained and resourced AEFI investigation teams; iv) safety communication plans evaluated and tested; v) an identified person within the Expanded Programme on Immunization (EPI) to oversee and ensure optimal reporting and training; and vi) methods for active surveillance of adverse events of special interest (AESIs) developed and data collection initiated.⁴ GACVS received progress updates from each country on PV readiness, as well as the results of meetings between the countries on establishing the scope and their methodology to monitor AESI.

In Kenya, reporting rates are close to the target, with plans in place for education sessions and guidance for health-care providers to achieve the target. Work is in progress to establish a national AEFI committee and implement training at the national level. One officer in the EPI programme will oversee safety; communication plans are currently being developed.

In Malawi, a national AEFI committee has been constituted and a reporting system developed. Training has led to an increase in reporting of AEFIs, and also covered causality assessment for national experts. Plans are in place to use the VigiFlow reporting software for adverse events developed by the WHO Programme for International Drug Monitoring as the national database and for vaccine safety data sharing in early 2018.

In Ghana, AEFI reporting rates have increased and initiatives are in place to further increase not only the rates, but also timeliness, so that reporting levels will be achieved in all regions of the country. Additional activities include sharing revised reporting forms, educational lectures and the development of job aids. A national AEFI committee is in place, and additional training is being planned for AEFI investigation. A communication plan is also being developed.

Joint meetings of the 3 countries have occurred through a web-based work group platform to help establish the AESI to be monitored. A total of 10 events have been selected and a surveillance manual is being prepared with appropriate reporting forms and assessment tools. Training will need to be conducted to enable surveillance to begin.

GACVS welcomed the progress achieved, but also recognized the challenges remaining in reaching PV readiness prior to RTS,S introduction, and in AESI surveillance, given how soon vaccinations will begin. GACVS emphasized the importance of each country continuing to rapidly progress PV readiness according to the indicators, in view of target introduction later in 2018. Although the target of AESI reporting starting 6 months prior to vaccine introduction may not be feasible, nonetheless, this should occur as soon as possible to allow comparisons between pilot areas randomized to receive RTS,S and corresponding control areas. Ascertainment of vaccination history of AESIs was also identified as an area that could be challenging. However, GACVS learned that additional resource will be available to register vaccination status in RTS,S pilot areas.

³ See No. 8, 2017, pp. 393–396.

⁴ See No. 28, 2017, pp. 393–396.

Full report of GACVS meeting of 6-7 December 2017, published in the WHO Weekly Epidemiological Record of 19 January 2018