A sponsored satellite symposium focused on lessons to be learned from the pilot implementation programme for RTS,S/AS01, the first effective malaria vaccine.

The world has long sought an effective malaria vaccine. The RTS,S/AS01 vaccine, developed by GlaxoSmithKline, finally achieved this ambition, providing moderate efficacy but with the potential for significant public health impact.

In a sponsored satellite symposium organised by PATH and chaired by Professor Evelyn Ansah, Director of the Centre for Malaria Research, University of Health and Allied Sciences, Ghana, a range of presenters examined why it took so long between scientific validation of the vaccine and its introduction into malaria-endemic countries.

Background to the pilot implementation of the RTS,S malaria vaccine

As summarised by Dr Mary Hamel of WHO, following positive phase III trial data, RTS,S/AS01 received a positive scientific opinion from the European Medicines Agency (EMA) in 2015. In theory, this should have led to rapid regulatory approvals and introductions. However, safety signals and concerns about the feasibility of a fourth dose led the WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) to recommend a pilot implementation project to gather further data on these issues.

The Malaria Vaccine Implementation Programme (MVIP) took place in Ghana, Kenya and Malawi. The latest data have shown that RTS,S/AS01 has delivered a 13% reduction in all-cause mortality and a 22% reduction in hospitalisation for severe malaria. No safety concerns have arisen and introduction of the vaccine has not disrupted other malaria control measures such as use of insecticide-treated bed nets.  

Outside the MVIP countries, implementation of RTS,S/AS01 is likely to begin in 2024. This is nine years after the initial EMA decision. The assessment process that was established after efficacy data had been obtained delayed introductions substantially; however, it also reduced many uncertainties and arguably increased trust in malaria vaccination given the careful attention that was given to potential safety concerns. The lessons learned have been used to establish a more streamlined approach for the second effective malaria vaccine, R21/Matrix-M.

Learning by doing: Pilot implementation of the malaria vaccine in Kenya

Rose Jalang’o of the National Vaccines and Immunizations Programme in Kenya discussed how the assessment process had played out at a country level.

In Kenya, the pilot implementation was carried out as a cluster randomised trial in eight counties. Rollout was achieved successfully, with coverage of RTS,S/AS01 comparable to that of Penta3 in year 1 and measles second-dose vaccination in year 2.

In October 2022, the Kenyan National Immunisation Technical Advisory Committee (NITAG) recommended national introduction of RTS,S/AS01 and an application was submitted to Gavi for financial support. Overall, the vaccine has delivered public health benefits and has catalysed greater collaboration between the national immunization programme and the malaria control programme. Although the delay in introduction may have left children unprotected during the assessment period, the delay did provide time for the country to make preparations for vaccine use and ensure a successful implementation.

Nesting the phase IV in the pilot implementation: Challenges and opportunities

Dr Miloje Savic, Global Health Vaccines and Adjuvants, GSK Vaccines (Belgium), noted that the post-phase III appraisal process had presented major challenges to GSK as the vaccine’s developer.

GSK’s clinical development plan included a phase IV post-licensing study to collect additional data on safety and effectiveness. These plans had to be modified as the appraisal process evolved – seven protocol amendments had to be made, each involving substantial amounts of work. The phase IV study was eventually integrated within the MVIP.

Another critical challenge was manufacturing. Given uncertainties about WHO recommendations and regulatory approvals, manufacturing was paused. A long-term halt to manufacturing would have led to major supply shortages once a positive decision was made, as start-up of manufacturing would take some time. Ultimately an innovative financing agreement was agreed with Gavi and MedAcess, so that manufacturing could continue.

When to Invest? The impact of market uncertainty on malaria vaccine manufacturing

Jonathan Hutchin of MedAccess (United Kingdom) provided more details of the financial discussions and the eventual mechanisms agreed to ensure that manufacturing could continue.

The key challenge was risk management: the manufacturers, GSK, faced the possibility of major financial losses if manufacturing continued but the product was not recommended or Gavi chose not to purchase it; conversely, Gavi faced the risk that, to ensure availability, it would need to purchase a vaccine in advance of a recommendation for use.

MedAccess, a body backed by the UK Government, was engaged to identify a solution to this conundrum, to create a bridge between the two parties involved. It brokered an agreement which, in effect, provided Gavi with the assurance that its funds would not be depleted if it purchased vaccine in advance, so that GSK could continue manufacturing. MedAccess charged a flat fee, to support its sustainability, to arrange this agreement.