The tenacity of the malaria parasite has all too often made it intractable to long-term therapeutic intervention. The development of parasite drug resistance is almost an inevitability, causing public health organizations to rethink treatment and prevention strategies. While vaccines would seem the most viable option toward long-term prevention and eradication, individual vaccines developed thus far have underperformed in larger populations tested.
Yet now, investigators at Imperial College London have begun testing whether using a combination of vaccines could provide greater protection from this deadly disease. Using two experimental antimalarial vaccines, which work in disparate manners, the researchers found they could dramatically reduce the number of malaria infections in animal studies.
Findings from the new study – published in eLife, in an article entitled “Synergy in Anti-Malarial Pre-Erythrocytic and Transmission-Blocking Antibodies Is Achieved by Reducing Parasite Density” – showed that the two vaccines, which independently achieve 48% and 68% reductions in malaria cases, can achieve a 91% reduction when combined. The study used genetically altered mouse parasites that express proteins expressed on the human version of the malaria parasite. The research was funded by the PATH Malaria Vaccine Initiative and the Medical Research Council (MRC), including researchers at Imperial’s MRC Centre for Outbreak Analysis and Modelling.
“This is the first direct evidence that combining vaccines of different types significantly improves their efficacy in terms of reducing malarial burden,” explained senior study investigator Andrew Blagborough, Ph.D., a research fellow in the department of life sciences at Imperial. “Reaching a potential 91% reduction in cases would have a huge impact on public health because the vaccines could be effective in areas where malaria is more prevalent.”
In 2016, there were an estimated 216 million cases of malaria, an increase of about 5 million cases over the previous year. The death toll from malaria soared to just under 500,000 – with drug resistance to first-line medicines such as artemisinin growing rapidly. Malaria is caused by a group of parasites that have a complex life cycle, spending time in the mosquito midgut and salivary glands, in the human liver, and circulating in human blood, where they cause the disease.
In the current study, the research team tested two types of vaccines: those that prevent mosquitoes from transferring the parasites, called transmission-blocking vaccines (TBVs), and those that prevent the parasite from infecting the liver, termed pre-erythrocytic vaccines (PEVs). RTS,S is the world’s first PEV malaria vaccine that has been shown to provide partial protection against malaria in young children by blocking infection of the liver. However, its maximum efficacy is under 50%. There are currently several types of TEVs in early trials, which are thought to reduce the number of parasites in the mosquito salivary glands. Their efficacy typically ranges from around 50% to 95%.
“It has been posited, but never demonstrated, that co-administering transmission-blocking vaccines (TBV) would enhance malaria control,” the authors wrote. “We hypothesized a mechanism that TBV could reduce parasite density in the mosquito salivary glands, thereby enhancing PEV efficacy.”
The researchers found that when a partially effective PEV was combined with the most effective transmission-blocking vaccine, the efficacy was around 91%. Moreover, the scientists showed that combining any of the two types of vaccines improved efficacy of the mixture more than might be expected from the single efficacy of each vaccine separately.
“While these findings are in the preliminary stages, they’re valuable as they shed light on optimizing strategies for preventing malaria,” noted MRC program manager for parasites and neglected tropical diseases Morven Roberts, Ph.D. “Learning that combining vaccines can dramatically boost efficacy in mice provides another potential tactic for controlling this disease. This is timely research as global health official work toward WHO targets to eliminate malaria by 2030.”
The research team would next study how combined vaccines could work in more complex situations. Dr. Blagborough remarked that “in the real world, the vaccine coverage we can achieve – how many people we can give it to – is important, as are the local levels of transmission and how prevalent malaria currently is in that area.
“We plan to use a combination of rodent experiments and computer modeling to help us estimate effectiveness requirements for future vaccines,” he concluded.