An international research team led by Australia's Walter and Elizabeth Hall Institute of Medical Research (WEHI) has shown for the first time that carbohydrates on the surface of malaria parasites play a key role in infecting their mosquito and human hosts, which may lead to the development of improved new vaccines.
That discovery suggests a means of improving the only malaria vaccine to date approved for Plasmodium falciparum malaria, the most deadly form of the disease, which infects more than 200 million people worldwide and kills around 650,000 each year.
Malaria eradication requires the development of new therapeutics, particularly an effective vaccine. The first vaccine approved for human use, RTS,S/AS01 (Mosquirix, Glaxosmithkline plc), was approved in Europe in July 2015 but has marginal efficacy that decreases over time.
In a recent large phase III trial in African children, for example, vaccine efficacy in infants ages 6 weeks to 12 weeks declined from 27 percent to 18.3 percent over 48 months.
Although the safety and efficacy of Mosquirix has been demonstrated in small numbers of African and North American adults, the vaccine has yet to be approved by the U.S. FDA.
Thus, there is an unmet need, "as the present vaccine is not effective enough to eradicate malaria, for which improved vaccines are urgently needed," Justin Boddey, an associate professor and laboratory head at WEHI in Melbourne, told BioWorld Asia.
Published in the Sept. 15, 2017, online edition of Nature Communications, the new study was led by Boddey and Ethan Goddard-Borger, laboratory head of the Division of Chemical Biology at WEHI.
The study showed the malaria parasite "tags" its proteins with carbohydrates in order to stabilize and transport them, and that this process is important in completing the parasite's lifecycle.
"Malaria parasites have a complex lifecycle involving constant shape-shifting to evade detection and infect humans and subsequently mosquitoes," Boddey said.
"The malaria parasite displays proteins on its surface that allow it to move around the human and mosquito hosts. This enables them to evade the immune system," he explained.
"Our study shows that some of these key surface proteins are stabilized by attachment of carbohydrates, without which they are unstable and are degraded inside the parasite's cells. This blocking interferes with the parasite's ability to move around the host and invade liver cells, so it cannot complete its life cycle."
"The protein used in the RTS,S vaccine mimics one of the carbohydrate-tagged proteins we've been studying on the malaria parasite's surface," said Goddard-Borger.
That has important implications for improved vaccine design. "It was hoped that the existing vaccine would generate a good protective antibody response against the parasite, but it has not been as effective at evoking protective immunity as was hoped," he said.
"We've shown that when the parasite protein is tagged with carbohydrates, making it slightly different to the vaccine, antibodies produced against the vaccine may not be optimal for recognizing malarial parasites," Goddard-Borger added, noting there were other cases where attaching carbohydrates to a protein improved vaccine efficacy.
"A version of RTS,S with added carbohydrates may perform better than the current vaccine. And now that we know how important these carbohydrates are to the parasite, we are confident the malaria parasite cannot escape vaccination pressure by simply doing away with its carbohydrates," Goddard-Borger said.
"Carbohydrates have been considered unimportant to malaria parasites [but we have now shown] that they are very important, and in two completely different lifecycle stages," said Boddey.
"These principles have led to the development of experimental vaccines, for example against Streptococcus, with an optimal mix of protein and carbohydrates that are 50 to 100 times more potent than existing vaccines," Goddard-Borger said.
"This is an exciting development, because to eradicate malaria we need combined approaches that attack different stages of the parasite ... which may one day save lives," he noted.
"Vaccines are essential for eradicating diseases, but creating malaria vaccines is difficult, because there are many different forms of the parasite throughout its life cycle and around the world. The parasite also rapidly adapts to selection pressures to become resistant to therapeutics," said Goddard-Borger. "Despite its disappointing efficacy, the RTS,S/AS01 vaccine is the first to protect against any parasite, let alone malaria. That work began in the late 1980s, so it has taken nearly 30 years to reach this point.
"Next-generation vaccines would arguably take less time to develop and evaluate in clinical trials, although the process will still take 10 years or more to get approval, depending on funding, research collaborations and luck.
"The next stage will be to generate vaccines with and without the carbohydrate tags and evaluate them in preclinical models of malaria and for their ability to identify protective antibodies in humans," Goddard-Borger concluded.
"Our ultimate goal is to progress such improved vaccines to the clinic, which will require close co-operation with the pharmaceutical industry and clinicians in the field."