PfVIMT

The challenge

Malaria vaccines are one of the most significant public health advances of the past decade and are being rolled out across multiple countries in sub-Saharan Africa. The two licensed malaria vaccines, RTS,S and R21, have the potential to save hundreds of thousands of children’s lives every year.

However, these vaccines are of moderate efficacy, and work continues on next-generation products. Malaria parasites have a complex life cycle, and vaccines could potentially target different stages of parasite development. RTS,S and R21, for example, both interfere with parasite invasion of liver cells, which provide a safe haven for the initiation of parasite multiplication. 

But there is also interest in targeting a later stage – the gametocytes that are taken up by mosquitoes and develop into the form that can reinfect people. This strategy – known as transmission blocking – does not directly prevent infection or illness in vaccinated individuals but reduces parasite circulation and the total malaria burden in a community.

The project

The PfVIMT project team has been working on a highly promising transmission-blocking malaria vaccine, Pfs230D1. Field studies supported by EDCTP2 and U.S. NIH have shown that it is highly effective at reducing parasite transmission in school-age children and adults – groups that typically experience less severe disease but are an important reservoir of parasites that sustain transmission within communities.

In the Global Health EDCTP3-funded PfVIMT project, the team is combining Pfs230D1 with the existing vaccine R21 to develop a product with both disease-prevention and transmission-blocking activity. 

Initially, a phase II study is planned in Mali, in which various formulations and doses of Pfs230D1 combined with R21 and will be tested in school children and adults. This study will assess the transmission-blocking effects of the vaccine using a ‘direct skin feeding assay’, through which laboratory-bred mosquitoes are allowed to feed on naturally infected participants and are then dissected to determine whether they contain malaria parasites (and how many). Prior vaccination with a Pfs230D1-containing vaccine should reduce both the number of mosquitoes that take up parasites and the parasite load in infected mosquitoes. Once the new combination has been shown to be safe, studies will begin enrolling younger children, down to 5 years of age.

The phase II study of the combination vaccine will establish the efficacy to block mosquito transmission. The safety and efficacy will then be confirmed in a multi-country phase III trial involving participants of all ages 5 years and older, again using the direct skin feeding assay to assess its impact on transmission. Based on the observed effects on mosquitoes, the team will use modelling to estimate the likely impact on the malaria disease burden when entire communities receive the vaccine.

The key advantage of the direct skin feeding assay is that results are available very quickly, supporting regulatory submissions through accelerated approval mechanisms. Actual impacts on disease incidence and malaria burden can be determined in post-licensing phase IV studies.

Impact

The PfVIMT project will advance the development of a combination malaria vaccine that could provide additional public health benefits. It will:

• Establish the safety and efficacy of a Pfs230D1+ R21 combination vaccine.
• Generate the evidence needed to support an application for regulatory approval.

If the promise of Pfs230D1+R21 is confirmed, a combination vaccine could be used across a much wider age group than is currently vaccinated, significantly reducing both symptomatic and asymptomatic infections and further reducing the burden of this critical disease.