Malaghan visiting researcher: Dr Lauren Holz

“Malaria is a problem that isn’t going away, and we’re increasingly seeing that what we’re doing isn’t enough,” says Dr Holz.

“We need better tools to control it. The key is a long-lasting, efficacious vaccine, and that comes from understanding both immune biology and the parasite’s lifecycle.”

During infection, malaria-causing Plasmodium parasites briefly enter the bloodstream through a mosquito bite. Within a matter of hours, the parasite lodges within the liver where it replicates extensively for up to a week, before egressing into the bloodstream to cause disease in the form of blood-stage malaria. It is during this liver stage that vaccine-induced T-cells have their best chance to intervene, killing infected cells before the parasite can spread further.

Dr Holz’s team found that several known vaccine targets are only present on Plasmodium at certain points during the infection cycle in the liver. While TRAP, a classic malaria antigen, appears early in the liver-stage, proteins discovered by Holz and colleagues such as RPL6 and SERA1 appear at different times within the liver stage . Vaccinating against either antigen alone gave only modest protection. Combining both, however, allowed T-cells to target infected cells across the entire liver stage, sharply improving efficacy.

“Understanding when these targets appear has changed how we think about designing an effective vaccine,” says Dr Holz.

In 2020, her lab pivoted to mRNA vaccine technology, developing the first tissue-targeted mRNA vaccine in collaboration with researchers at the Malaghan and Ferrier Institutes. Dr Holz notes that standard mRNA vaccines are surprisingly poor at generating the liver-resident T cells, a challenge her lab has overcome through their trans-Tasman collaboration.

Dr Holz’s visit builds on an ongoing collaboration with the Hermans Lab, whose postdoctoral researcher Jordan Minnell has been designing next-generation mRNA vaccines for malaria within the RNA development platform for testing in more sophisticated models. The partnership is set to continue, with the team using mathematical modelling and mass spectrometry to identify further antigen targets. Their ultimate goal is to feed these discoveries into a vaccine platform capable of driving optimal immune responses, bringing this tissue-targeted approach a step closer to real-world use.