Similar to how wildfires start from a subtle spark then sweep through a forest, malaria-causing parasites—known as Plasmodium falciparum— multiply quietly in the liver before breaking free in the thousands to spread throughout the body. They infect and multiply again in red blood cells, which then burst open to release a new wave of parasites that invade fresh red blood cells. These vicious cycles of the ‘blood stage’ are what cause patients to feel malaria’s classic symptoms: fever, chills and fatigue.
Though there are WHO-recommended malaria vaccines today which work by targeting the ‘liver stage’ of malaria infection, their protection is partial and can wane over time, noted Laurent Rénia, a Senior Fellow and Principal Investigator at the A*STAR Infectious Diseases Labs (A*STAR IDL).
“This may be partly due to these vaccines targeting a single protein on the parasite and a single stage of its life cycle,” Rénia explained. “This is one reason why the field has been looking for more P. falciparum antigens, including from the blood stage, that could complement liver-stage vaccines and provide more protection.”
Together with Programme Lead and Senior Scientist Yun Shan Goh and other A*STAR IDL colleagues, Rénia and collaborators from Nihmegen Medical Centre, Netherlands, screened blood samples from 14 volunteers vaccinated against malaria, comparing them to a library of P. falciparum antigens. This library expanded on a previous version developed by the team by including 10 new hypothetical antigens: ones potentially linked to protection against the parasite, or expressed by its liver-stage form.
Through this screening, the team found that all nine malaria-protected individuals in the cohort had antibodies against PfVFT1, a hypothetical antigen with unknown function. Delving deeper, they noticed that PfVFT1 was present in P. falciparum throughout the blood stage. When the team removed the PfVFT1 gene from the parasite, it grew more slowly and took longer to complete blood-stage cycles.
“Our data suggests that PfVFT1 helps the parasite transition from one phase of blood-stage growth to the next,” said Goh. “Importantly, it also suggests that PfVFT1 can be a potential target for antibodies to fight the parasite during the blood stage.”
Next, the team vaccinated mice with PfVFT1 proteins and found that PfVFT1-targeting antibodies took a multi-pronged approach to infection protection. Not only did they block the parasites from invading fresh red blood cells, but they also triggered immune system components that punch holes in and destroy the parasites. Furthermore, PfVFT1-targeting antibodies marked parasites to be gobbled up by immune cells known as macrophages.
Additionally, the team analysed regional field isolates from Shoklo Malaria Research Unit, Thailand and global field isolates via publicly available sequences. “The PfVFT1 gene also appears to be highly conserved across parasite strains, suggesting that PfVFT1 as a vaccine target may offer good coverage,” added Goh.
The team plans to formulate a PfVFT1 vaccine using human-suitable components and confirm that the protective antibody responses seen in mice can be reproduced under clinical conditions. By combining a PfVFT1 vaccine with existing liver-stage vaccines, the researchers hope to create a multi-stage, multi-antigen vaccine that could ultimately offer more robust and durable protection than single-antigen approaches.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Infectious Diseases Labs (A*STAR IDL).
