Shape of Key Malaria Protein Could Help Improve Vaccine Efficacy

Understanding the shape of a key protein that the malaria-causing parasite Plasmodium falciparumuses to infect humans could aid in the development of a more effective vaccine to guard against the mosquito-borne disease, according to researchers at NIAID.

Shape of Key Malaria Protein Could Help Improve Vaccine Efficacy

Colorized scanning electron micrograph of red blood cell infected with malaria parasites, which are shown in blue. The infected cell is in the center of the image area. To the left are uninfected cells with a smooth red surface.
Credit: NIAID

Background

More than 40 percent of the world’s population lives in areas where there is a risk of contracting malaria. In 2013, about 584,000 people died of malaria, mostly African children. The development of a safe and effective malaria vaccine is critical to control malaria globally, especially given that the parasitePlasmodium falciparum, one of the species of Plasmodiumthat causes malaria in humans, has developed resistance to current antimalarial drugs.

So far, the most advanced vaccine is RTS,S, also known as Mosquirix, which has been tested in more than 15,000 infants and children in clinical trials in Africa. The vaccine was approved for use in African children by European regulators in July 2015 and is the first licensed malaria vaccine. In clinical trials, it was shown to protect 30 to 50 percent of vaccinated children against malaria disease for roughly a year.

The RTS,S vaccine works by targeting an extended, rod-like protein, called the circumsporozoite protein (CSP), which is secreted by the malaria parasite. CSP is composed of three regions, or domains, but only two of these domains are targeted by the RTS,S vaccine. Protein domains are distinct areas in a protein that are typically responsible for a particular function or interaction.

Results of Study

In a recent study in the journal Infection and Immunity, NIAID scientists and collaborators found that in mosquitoes CSP collapses into a crumpled formation once the sporozoites reach the mosquito’s salivary glands, masking two of these protein domains, including the domain not targeted by the RTS,S vaccine. When a mosquito bites a person, the insect then injects the parasite with its saliva and releases sporozoites into the skin. During this phase, CSP remains in its collapsed conformation following entry into the skin and reverts to an open conformation once it reaches the liver cells.

The scientists demonstrate that native CSP has two different conformations and that the “collapsed” conformation is the one accessible to the human immune system the majority of the time. “Stabilizing CSP in this conformation might improve the efficacy of a next-generation vaccine,” said Krishan Kumar, co-first author on the study and associate research scientist at The Barnett Institute at Northeastern University.

Significance

Because the current RTS,S vaccine provides limited protection against malaria disease, researchers are interested in figuring out how to make a more effective CSP-based vaccine. These new findings show the importance of understanding the biology behind this conformational change, possibly due to a mechanical or molecular signal, and may aid in the development of a second-generation malaria vaccine.

Next Steps

Researchers would need to test a vaccine candidate in animals that preserves this collapsed CSP conformation in order to evaluate its level of protection.

Reference

Herrera R et al. Reversible conformational change in the Plasmodium falciparum circumsporozoite protein masks its adhesion domains. Infection and Immunity. DOI: 10.1128/IAI.02676-14