Following years of reducing mortality, progress in malaria control has stalled. Around 400,000 people still die of malaria each year, most of them young children in sub-Saharan Africa.

Effective drugs exist for malaria, and a vaccine is undergoing pilot implementation studies in three countries. However, this is no time for complacency. The threat of drug resistance is very real, and vaccines offering greater efficacy are urgently required.

A portfolio approach is therefore essential. Progressing a range of products allows for the inevitability that some will not end up suitable for use, because of lack of efficacy or safety concerns. In addition, drugs and vaccines have to perform a range of functions in different populations, so products with different properties may be required.

The PAMAFRICA portfolio grant is progressing a portfolio of drug products managed by the Medicines for Malaria Venture (MMV). It is aiming to develop a single-dose cure for malaria, testing two compounds in development as well as a new formulation of existing drugs for young infants. It is also evaluating a new injectable form of cipargamin for severe malaria caused by drug-resistant parasites. Other emerging promising antimalarials will also be evaluated under this portfolio grant.

Novartis and MMV are partners in the WANECAM II project, a global collaboration coordinated from Mali, which is testing an antimalarial from an entirely new class, known as KAF156 or ganaplacide, to be used in combination with lumefantrine.

For vaccines, the MMVC project has the ambitious goal of developing a vaccine targeting all key stages of the malaria parasite life-cycle – pre-liver, liver, bloodstream and mosquito. A vaccine against the parasite forms found in the mosquito is also the goal of the PfTBV portfolio grant. The major advantage of this type of vaccine is that it would prevent completion of the parasite life-cycle in mosquitoes, blocking transmission.

Finally, the MIMVaC-Africa portfolio grant is bringing together a global consortium to assess five vaccine candidates in controlled human infection studies. The most promising will then be evaluated in a field efficacy trial.

WANECAM II is testing an antimalarial from an entirely new class to be used in combination with lumefantrine. Why is this antimalarial promising? How does the project connect to the WANECAM project funded under the first EDCTP programme?

The grant will support African trials of a novel antimalarial combination comprising ganaplacide (formerly KAF156) and a new once-daily formulation of lumefantrine. We are excited about ganaplacide because it has demonstrated the potential to treat resistant malaria and to be administered as a single dose.

The current project is built on the West African Network for Clinical Trials of Antimalarial Drugs (WANECAM 1) funded under the first EDCTP programme (EDCTP1). The network was expanded to include Niger and Gabon in Africa and The Netherlands in Europe, in addition to existing African member countries (Burkina Faso and Mali) and European countries (France, Germany, Sweden, and the UK). As well as the Medicines for Malaria Venture (MMV), we are also partnering with Novartis, which is the sponsor of the trials. The new trials will be conducted on the same sites developed with the funding from EDCTP1 and by the same teams trained during WANECAM 1.

What comes next?

The major and most important next steps for the project are the submission of the phase 2 trial protocols to ethics committees and regulatory authorities. With their approval, we can then start the trial. An investigator meeting will be organised in August/September 2020 prior to the start of the trial, hopefully in October 2020.

What progress was made in 2019?

The study teams have been recruited and governance bodies (i.e. the project board, independent scientific and operational advisory board, and the data safety and monitoring board) have been established. Long-term training of study staff and development of study procedures have begun. Drafting of clinical trial protocols and trial regulatory files is nearly complete and they will be submitted to ethics committees very soon. Community engagement and other site preparation activities have also been launched.

Malaria is a terrible scourge of communities, impairing their health and imperiling their economic prospects. A coordinated global effort has halved the burden of malaria since around 2005 but in recent years progress has stalled and reversed in some countries with the heaviest disease burden. New complementary tools and strategies are urgently needed to further drive down the disease burden and eliminate malaria. A malaria vaccine that averted the spread of infection would be a pivotal additional tool for malaria elimination.

Malaria transmission-blocking vaccines (PfTBV) halt parasite transmission to mosquitoes by targeting mosquito sexual-stage parasite antigens. The most advanced PfTBV (Pfs230D1M-EPA/AS01) induces high and durable high and long-lasting levels of antibodies in African adults, providing a benchmark for our partnership to rapidly identify the optimal candidate for phase 3 trials.

Malaria vaccine development has been slowed by the stepwise approach of assessing one protein in the clinic at a time, thereby delaying evaluations and diverting resources from other targets. We circumvent these challenges by directly comparing lead vaccine candidates, delivery platforms and adjuvants, providing definitive down-selection of optimal candidates for later efficacy trials. The resulting PfTBV could be used alongside RTS,S, or “anti-infection” vaccine components. Multi-stage vaccines would directly protect and halt onward parasite transmission.

The PfTBV consortium consists of four African countries (Burkina Faso, Guinea, Mali and Liberia), two European countries (Denmark and The Netherlands), and one US institution (PATH), which liaises with the US National Institutes of Health as a third party.

The primary consortium objective is to compare three well-characterised sexual-stage vaccine candidates in humans: Pfs48/45 (first-in-human testing), Pfs230 (clinical benchmark), and a Pfs230-Pfs48/45 chimeric antigen.

What comes next?

A booster dose vaccination is planned for the current ongoing Mali TBV study.

Starting later in 2020 or early 2021, observational studies will launch in Liberia, Guinea and Burkina Faso to prepare those sites for malaria transmission-blocking vaccine trials. These studies will identify the specific age group and location of malaria parasite carriers in the community for both asexual and sexual parasites, as well as the level of parasite transmission through mosquitoes.

In the second half of 2021, trials will be launched to compare Pfs230- and Pfs48/45-based vaccines, with different adjuvants, to identify the most promising candidate for a large-scale trial.

These trials will also establish bioassays and endpoints for future phase 2 and 3 efficacy trials.

In 2022, a multi-country (Burkina, Guinea, Mali and Liberia) phase 2 community-based malaria transmission-blocking vaccine study will be undertaken, using the most promising TBV antigen and adjuvant.

What progress was made in 2019?

A phase 2 study of the safety, immunogenicity and vaccine efficacy of Pfs230D1M-EPA/AS01 in Doneguebougou village, Mali and surrounding villages started in April 2019 and was completed in March 2020. This study is evaluating safety and vaccine activity (reducing parasite transmission to mosquitoes) in the context of naturally occurring infection.

After a pilot age de-escalation phase that demonstrated safety in children as young as 5 years, subjects 5 years and older received vaccinations on a 0, 28 and 56 day schedule. First vaccinations were completed in 1,101 volunteers, with 1,078 (97.9%) subjects receiving all three vaccinations.

We were able to meet our sample size requirement estimates in the 2019 malaria season for tests of vaccine activity. This will allow us to determine vaccine activity within a year.

We have also decided to give a booster dose and to assess vaccine activity during a second season, to see if the vaccine retains a lower level of activity over 2 years. These results will inform the design of the 2-year multi-country trial planned for years 4-5 of the EDCTP project.

Training, site preparations and protocol submissions or approvals have been completed in three other African countries, where additional project studies will launch later in 2020 or 2021.

The PfTBV consortium is accelerating the development of vaccines that interfere with the transmission of malaria via mosquitoes. Why is this approach important?

The MIMVaC portfolio grant is bringing together a global consortium to assess five vaccine candidates in controlled human infection studies. How does this approach work and why is it important?

Our ambitious programme aims to downselect candidate vaccines for field trials in malaria-endemic countries using controlled human infection studies. This involves (1) immunising study participants with candidate vaccines and (2) assessing the efficacy of the candidate vaccine by deliberately infecting participants with malaria parasites either by mosquito bite or by direct injection of sporozoites or parasitised erythrocytes. The resulting blood-stage infection will be curtailed by the administration of antimalarial drug

The most promising vaccines will be selected to progress into field trials in Africa. This approach is important as it minimises costs, shortens the vaccine development plan, and maximises the likelihood that vaccine candidates will reach the field in endemic countries.

What is the (short- and long-term) expected impact of this project?

We have an extensive programme of cross-fertilisation and capacity building through MSc and PhD training programmes, exchanges visits and so on. We believe that sites will come out stronger from this exciting and challenging collaboration.

We expect that this project will make major contributions in advancing the development of promising malaria vaccine candidate and that we will be able to deliver one or two promising candidates for pivotal phase 3 trials. An effective malaria vaccine is a crucial aspect of the malaria community’s commitment to malaria elimination. We hope that our consortium’s work will be a valuable contribution towards that goal.