Identification of the proteins in Plasmodium vivax provide new targets for a malaria vaccine

July 31, 2017

3 Bullets:

  • Scientists from ISB and the Center for Infectious Disease Research led an international collaboration to identify proteins in the malaria parasite Plasmodium vivax.
  • P. vivax and P. falciparum cause the majority of malaria cases, but P. vivax is far less-studied, in part because it cannot be grown in the lab.
  • The research aims to provide new targets for a malaria vaccine.

By Kristian Swearingen, PhD

The disease malaria is caused by parasites of the genus Plasmodium. These parasites are transmitted to humans in the bite of infected mosquitoes. The parasites invade the liver where they multiply and then emerge to infect the blood, at which point they cause the clinical symptoms of malaria. Mosquitoes that feed on infected blood are themselves infected and can spread the disease to others. According to the WHO World Malaria Report, there were 212 million new infections and 429,000 deaths from malaria in 2016. Over half of these deaths were children under five years of age. Among the reasons malaria remains such a formidable disease is the lack of an effective, approved vaccine.

The majority of human malaria cases are caused by P. falciparum and P. vivax. While P. vivax affects more people across a wider global range, most malaria research efforts focus on P. falciparum. This disparity is due in part to the fact that the symptoms are more severe and the mortality is higher from falciparum malaria, especially among children in sub-Saharan Africa. At the same time, P. vivax is more challenging to study: there are several strains of P. falciparum that can be easily grown and experimented on in the laboratory, whereas no such strains exist for P. vivax, meaning that all experiments must be done with parasites obtained directly from infected patients. While vivax malaria is often not as severe as falciparum malaria, it is still a debilitating disease that causes fevers, severe anemia, and respiratory distress that is fatal more often than has previously been appreciated. Furthermore, with a single bite from a P. vivax-infected mosquito, a person can suffer not just a single bout of malaria, but recurring malaria episodes that can last for months if left untreated. These recurring infections are due the unique ability of P. vivax parasites to lie dormant in the liver and reactivate weeks to months or even years later. Another unique challenge of P. vivax is that, unlike P. falciparum, it can invade the blood and transmit to mosquitoes before causing the symptoms of malaria in the infected person, meaning that by the time a sick individual presents to a doctor, they have likely already spread the disease.

These factors are the motivation for developing vaccines that could stop mosquito-delivered malaria parasites from ever reaching the liver. However, no such vaccine currently exists. The most advanced malaria vaccine candidate to-date contained a portion of a protein that is found on the surface of P. falciparum sporozoites, the form of the parasite that is transmitted from mosquitoes to humans. Exposing the immune system to this protein trains the body to recognize and fight sporozoites when they arrive. This vaccine showed approximately 50% efficacy in phase-III clinical trials. While these results are encouraging, a better vaccine is needed if malaria eradication is to be achieved. This vaccine is also specific to P. falciparum and would not recognize P. vivax parasites. It is thought that the power of this type of vaccine could be boosted if it were combined with several other sporozoite surface proteins to create a multivalent vaccine.

Members of the team that recently identified new targets for a malaria vaccine on the surface of P. falciparum sporozoites (https://www.systemsbiology.org/research/scratching-surface-malaria-parasite/) have now turned their attention to P. vivax. We performed the most comprehensive analysis to-date of the proteins present in P. vivax sporozoites, the parasites that are transmitted to humans in the bite of infected mosquitos. The parasites were obtained from patients who presented with malaria at health centers in Thailand and who volunteered to provide blood samples. The blood was fed to mosquitoes, and after the parasites had matured, the mosquitoes were dissected and parasites were extracted from the mosquito salivary glands. Some of the samples were used to profile the total complement of sporozoite proteins, while others were treated with a compound that attached a chemical tag only to proteins on the parasite surface, enabling us to isolate surface proteins from the rest of the parasite material. The proteins were identified using the state-of-the-art mass spectrometry equipment in the lab of Professor Robert Moritz at ISB.

Our work identified nearly 2000 proteins present in P. vivax sporozoites and found evidence for dozens that are located on the sporozoite surface. We compared these proteins with previous work on P. falciparum sporozoites and found a high degree of similarity in the types and abundances of proteins found in the two species. Importantly, we also identified key differences. For example, because the two species evolved from a common ancestor, most of their genes are similar and encode proteins that have the same function. However, we identified many proteins in P. vivax for which there is no correlate in P. falciaparum. One of these even turned out to be located on the surface of P. vivax sporozoites, representing a potential target for a P. vivax-specific vaccine. Additionally, our previous work with P. falciparum had shown for the first time that two important sporozoite surface proteins are decorated with sugar molecules, a modification that changes the way the proteins are recognized by antibodies. Our new work has now shown that these proteins are also modified by sugars in P. vivax sporozoites, but in a different pattern than that seen in P. falciparum.

This study, the first of its kinds performed on P. vivax sporozoites, provides valuable new information to malaria researchers by lending new insight into the biology of the parasite as well as providing critical information for vaccine design.

Title: Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites
Journal: PLOS Neglected Tropical Diseases
Authors: Kristian E. Swearingen, Scott E. Lindner, Erika L. Flannery, Ashley M. Vaughan, Robert D. Morrison, Rapatbhorn Patrapuvich, Cristian Koepfli, Ivo Muller, Aaron Jex, Robert L. Moritz, Stefan H. I. Kappe, Jetsumon Sattabongkot, Sebastian A. Mikolajczak
Pub. Date: July 31, 2017
DOI: http://doi.org/10.1371/journal.pntd.0005791