An estimated 229 million cases of malaria infection and 409,000 related deaths occurred in 2019 worldwide.  This has resulted in enormous suffering, economic burden, and regional social instability. Pregnant women, children and malaria-naïve travelers are at highest risk of being infected by the malaria-causing parasite, Plasmodium falciparum. Therefore, development of a malaria vaccine is a priority for the Department of Defense (DoD) as the disease remains a top threat to U.S. military forces deployed to endemic regions.

In an animal model study published in the journal npj Vaccines in the article “Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice,” scientists from the Walter Reed Army Institute of Research (WRAIR) and Naval Medical Research Center partner with researchers at the University of Pennsylvania and Acuitas Therapeutics to develop a new vaccine based on mRNA technology that protects against malaria.

A safe and effective malaria vaccine has long been an elusive target for scientists. The most advanced malaria vaccine is RTS,S, a first-generation product developed in partnership with WRAIR. RTS,S is based on the antigenic activity of the P. falciparum’s circumsporozoite protein (PfCSP)—an immunodominant coat protein expressed at the invasive stage of the malaria parasite.

Sterilizing immunity, a unique immune status and the ultimate goal in vaccine development, prevents parasitic infection in the host. While RTS,S provides some protection against malaria, field studies show limited duration of protection and sterile efficacy. These limitations associated with RTS,S and other first-generation malaria vaccines have led scientists to evaluate new platforms and second-generation approaches for malaria vaccines.

“Recent successes with vaccines against COVID-19 highlight the advantages of mRNA-based platforms—notably highly targeted design, flexible and rapid manufacturing and ability to promote strong immune responses in a manner not yet explored,” says Evelina Angov, PhD, researcher at WRAIR’s Malaria Biologics Branch and senior author on the paper. “Our goal is to translate those advances to a safe, effective vaccine against malaria.”

Like RTS,S, the new vaccine relies on P. falciparum’s circumsporozoite protein to generate an immune response. However, rather than administering a version of the protein directly, this approach uses mRNA to prompt cells to synthesize their own circumsporozoite protein that trigger a protective response against malaria.

“Our vaccine achieved high levels of protection against malaria infection in mice,” says Katherine Mallory, PhD, a WRAIR researcher at the time of the article’s submission and first author on the paper. “While more work remains before clinical testing, these results are an encouraging sign that an effective, mRNA-based malaria vaccine is achievable.”

The authors show that in vitro introduction of PfCSP mRNA into Chinese Hamster Ovary (CHO) cells results in a high-level of cell associated expression while in vivo introduction of the PfCSP mRNA packaged in lipid nanoparticle (LNP) in mice achieves sterile protection against infection with two P. berghei PfCSP transgenic parasite strains. The LNP delivery system protects and delivers the mRNA to the cell translation machinery and provides adjuvant activity that enhances immune response.

The authors note these findings that assess malaria infection at a stage before the parasite reaches red blood cells, shows that the PfCSP mRNA vaccine candidate results in sterile protection in mice, making it a compelling candidate for further investigation.

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