Improving Malaria Vaccine Could Hinge On Carbohydrates

Carbohydrates on the surface of malaria parasites play a critical role in malaria’s ability to infect mosquito and human hosts, an international research team has shown for the first time.

The finding suggests steps that may improve the only malaria vaccine approved to protect people against Plasmodium falciparum malaria – the most deadly form of the disease.

Dr Justin Boddey, who co-led the research, said:

“Malaria parasites have a complex lifecycle that involves constant shapeshifting to evade detection and infect humans and subsequently mosquitoes. We found that the parasite’s ability to ‘tag’ key proteins with carbohydrates is important for two stages of the malaria lifecycle. It is critical for the the earliest stages of human infection, when the parasite migrates through the body and invades in the liver, and later when it is transmitted back to the mosquito from an infected human, enabling the parasite to be spread between people.

Interfering with the parasite’s ability to attach these carbohydrates to its proteins hinders liver infection and transmission to the mosquito, and weakens the parasite to the point that it cannot survive in the host.”

Improving Malaria Vaccine Design

The first malaria vaccine approved for human use – RTS,S/AS01 – was approved by European regulators in July 2015 but has not been as successful as hoped, with marginal efficacy that wanes over time.

Ethan Goddard-Borger

Dr. Justin Boddey (left) and Dr. Ethan Goddard-Borger looking at mosquitoes in the Walter and Eliza Hall Institute insectary.
Credit: Walter and Eliza Hall Institute

Also leading the team was Dr Ethan Goddard-Borger, Mr Sash Lopaticki and Ms Annie Yang at the Walter and Eliza Hall Institute, with support from Professor Norman Kneteman at the Univeristy of Alberta, Canada.

Dr Goddard-Borger said the research had attracted a lot of interest because of the implications it has for improving malaria vaccine design:

“The protein used in the RTS,S vaccine mimics one of the proteins we’ve been studying on the surface of the malaria parasite that is readily recognised by the immune system. It was hoped that the vaccine would generate a good antibody response that protected against the parasite, however it has unfortunately not been as effective at evoking protective immunity as hoped.

With this study, we’ve shown that the parasite protein is tagged with carbohydrates, making it slightly different to the vaccine, so the antibodies produced may not be optimal for recognising target parasites.”

Carbohydrates In Vaccines

Dr Goddard-Borger said there were many documented cases where attaching carbohydrates to a protein improved its efficacy as a vaccine.

“It may be that a version of RTS,S with added carbohydrates will perform better than the current vaccine,” he said. “Now that we know how important these carbohydrates are to the parasite, we can be confident that the malaria parasite cannot ‘escape’ vaccination pressure by doing away with its carbohydrates.”

Dr Boddey said the Institute’s insectary, opened in 2012, was critical to the discovery:

“Carbohydrates have long been considered unimportant to malaria parasites. This discovery reveals that carbohydrates are very important, and in two completely different lifecycle stages. This is exciting because to ultimately eradicate malaria we need combined approaches that attack different stages of the parasite at once.”

The work was supported by the Australian National Health and Medical Research Council, Human Frontiers Science Program, Ramaciotti Foundation Establishment Grants, and the University of Melbourne Early Career Researcher Grant.

Sash Lopaticki, Annie S. P. Yang, Alan John, Nichollas E. Scott, James P. Lingford, Matthew T. O’Neill, Sara M. Erickson, Nicole C. McKenzie, Charlie Jennison, Lachlan W. Whitehead, Donna N. Douglas, Norman M. Kneteman, Ethan D. Goddard-Borger & Justin A. Boddey
Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts
Nature Communications 8, Article number: 561 (2017) doi:10.1038/s41467-017-00571-y

Top Image: A malaria parasite (yellow) invading liver cells (pink/red). Credit: WEHI.TV/Walter and Eliza Hall Institute of Medical