MVC-2G

The challenge

The development of effective malaria vaccines was a major step forward in malaria control. They are now being used in more than 20 countries in sub-Saharan Africa to protect young children, alongside other control measures such as insecticide-impregnated bed nets.

However, the two currently licensed vaccines, RTS,S/AS01 and R21/Matrix-M, have moderate efficacy and only target the pre-erythrocytic (liver) stage of the parasite life cycle. There remains scope to improve their impact by also intervening at the blood stage, when parasites invade and multiply within red blood cells.

The project

Members of the MVC-2G project have focused on target antigens central to red blood cell invasion, and the potential to combine these antigens with R21/Matrix-M in a second-generation vaccine product. Since R21-induced immunity appears to be independent of natural blood-stage immunity, targeting both pathways in a single product should provide an additional layer of protection.

The RH5 protein is essential for red blood cell invasion and is highly conserved across Plasmodium falciparum malaria parasite strains. Studies in UK adults have shown that immunisation with RH5 reduces parasite growth rates. Safety and tolerability of RH5-based vaccines have been confirmed in Tanzania, while a Phase 2b study in Burkina Faso demonstrated significant efficacy against clinical malaria in young children.

In addition, structural analysis of the multi-protein complex critical to red blood cell invasion revealed another highly conserved structure that could be included in a vaccine. An antigen derived from this structure, known as R78C, strengthens the immune response induced by RH5.

Building on these promising findings, the MVC-2G project is extending clinical evaluation of blood-stage and multi-stage vaccine approaches in young children in Burkina Faso, including longer-term follow-up to further assess safety, immunogenicity and durability of protection, as well as additional evaluation of R78C and proof-of-concept combinations with R21 in a seasonal transmission setting. In parallel, the project is advancing clinical development through Phase 2b trials in children aged 5 to 17 months, comparing the safety and efficacy of a second-generation multi-stage vaccine candidate incorporating R21, RH5.1 and R78C with R21 alone, and optimising its delivery strategy for use in endemic settings. 

In addition, the project is exploring whether a simplified vaccination schedule could be adopted. Four doses of the R21/Matrix-M vaccine are currently administered at different ages during the first two years of life. This requires caregivers to make special visits to health facilities, outside the routine childhood immunisation schedule. The MVC-2G project is therefore conducting a study in Uganda to optimise dosing schedules, including alternative four-dose schedules better aligned with routine immunisation visits, to assess their safety and ability to elicit strong immune responses. 

A Phase 2b trial of an optimised schedule will then be run in Sierra Leone and Burkina Faso, representing different transmission settings, both perennial and seasonal. 

Ultimately, elimination of malaria will require vaccination of older children and adults, who typically acquire natural immunity and do not experience significant disease but are an important reservoir of malaria parasites. The MVC-2G project is thus also generating data to support the use of the vaccine in older age groups for elimination. A Phase 1b trial in Tanzania will first be conducted to optimise the vaccination schedule and downselect the most promising regimen. This selected regimen will then be evaluated in subsequent studies, including controlled human malaria infection (CHMI) studies in Kenya to assess safety and efficacy in adults, and an age-de-escalation study in Nigeria to assess safety and immunogenicity in older children. 

Impact

The MVC-2G project will generate critical data on a second-generation multi-stage malaria vaccine, building on the R21/Matrix-M vaccine. It will:

• Demonstrate whether the combination vaccine is more effective at preventing malaria in young children than R21/Matrix-M alone.
• Reveal whether more practical vaccination schedules in young children could offer good protection, which in turn could provide programmatic benefits.
• Generate data on multi-stage vaccines in older children, who are less susceptible to malaria disease but are a key reservoir of parasites driving transmission.
• Build capacity for malaria vaccine trials, including in Nigeria, which has not hosted such major trials before, despite having a very high malaria burden.

In summary, the MVC-2G project’s work will advance a second-generation multi-stage malaria vaccine with potentially higher efficacy and an easier-to-implement schedule, which could further reduce the burden of malaria and accelerate progress towards disease elimination.