The bite of an infected female Anopheles mosquito abets the entry of Plasmodium sporozoites in the bloodstream of humans, marking the beginning of the parasite’s life cycle. The sporozoites then travel to the liver and multiply, following which they invade red blood cells, proliferating in numbers yet again. And in about a week or two, malaria, characterized by flu-like symptoms, which can be fatal when not diagnosed in time, occurs.
Typically one to 20 microns (a millionth of a meter) in diameter, Plasmodium – a protozoan – in the human body, can cause severe blood loss and can clog blood vessels. As of 2021, there were 247 million cases of malaria, with the disease endemic to sub-Saharan Africa among other regions, according to the World malaria report 2022.
While the global eradication of malaria is still something to strive for, biotechs are working towards treatment measures and vector control strategies to drastically reduce the incidence of the disease. As we observe World Malaria Day on April 25, let’s take a look at some of the latest progress in malaria research.
Recently, in April, Ghana, where there is a prevalence of nearly 5.9 million cases, became the first country to approve the University of Oxford’s malaria vaccine. Hundreds of millions of doses of the vaccine will be able to provide help for African nations that are severely affected by malaria.
Co-developed with the Serum Institute of India, the vaccine R21/Matrix-M, is a saponin-based Matrix-M adjuvant – a compound present in the bark of the soapbark tree. Regarded as a major advancement in malaria research, the anti-sporozoite vaccine, which targets Plasmodium falciparum, surpassed the World Health Organization’s (WHO) goal of developing a malaria vaccine with at least a 75% efficacy rate. The vaccine, along with its booster dose, could reap positive results, as proven in clinical trials. The study found that the vaccine demonstrated high levels of efficacy, including in children, for a three-dose regime, leading to the Food and Drugs Authority (FDA) in Ghana authorizing regulatory clearance for R21/Matrix-M.
Another company ambitious about controlling the spread of malaria is the U.S. based biotech Sanaria. With a vast pipeline currently in preclinical and clinical stages, the company’s Plasmodium falciparum sporozoite (PfSPZ) vaccines aim to immunize entire populations in specific regions to eliminate malaria. With clinical trials having been conducted in predominantly four regions, the U.S., Europe, Africa and Asia, 5.6 billion people have received doses of the live attenuated vaccines across 15 placebo-controlled trials.
Culturing Plasmodium in vitro: a breakthrough in malaria research
In December 2022, Sanaria published encouraging research regarding its vaccine program. The company discovered the ability to culture Plasmodium without the need for mosquitoes as hosts, breaking ground in malaria research. Currently, the company’s vaccines are manufactured in mosquitoes. Now, this advancement could transform how the company progresses in its vaccine technology. Besides, this paves the way for the production of more cost-effective vaccines.
“By developing the capacity to produce infectious PfSPZ in vitro, meaning in culture vessels without the need for mosquitoes, we have made the critical, first, breakthrough steps for enabling manufacturing scale up to eventually meet the needs of the hundreds of millions to billions of people who would benefit from our PfSPZ vaccines,” said Stephen L Hoffman, chief executive officer of Sanaria.
Meanwhile, to envision the success of genetically modified live parasite vaccines, a study led by physician and scientist Sean Murphy at the the University of Washington School of Medicine demonstrated potential. With the deletion of the P52, P36, and SAP1 genes in P. falciparum, the research explored whether the vaccine PfGAP3KO could protect against malaria by disarming the parasite. Individuals were administered the vaccine three or five times via 200 PfGAP3KO-infected mosquito bites per immunization; results showed that half the people in the trial did not develop Plasmodium infection, and at the end of six months, some of the individuals remained partially protected. While further investigation into the vaccine’s efficacy is warranted, the team has partnered with Sanaria to produce the modified parasites for vaccine development.
In addition to Sanaria’s efforts to curb malaria transmission, the Bill & Melinda Gates Foundation’s novel monoclonal antibody (mAb) MAM01 is an engineered version of a human mAb that is generated upon vaccination with U.K.-based GlaxoSmithKline’s Mosquirix, the first ever malaria vaccine to receive approval from the FDA. The Bill & Melinda Gates Medical Research Institute (Gates MRI) entered into a licensing agreement with U.S.-based clinical stage company Atreca for the development of MAM01, for which Gates MRI will obtain commercial rights to the antibody in low- and middle-income countries where malaria is rampant.
Still in preclinical development, MAM01 targets the malaria circumsporozoite protein – a surface protein that forms a dense coat on the sporozoites – and has displayed protection from the disease in animal studies.
Additionally, Manus Bio aspires to halt the spread of the mosquito-borne disease. Having been awarded $2 million in funding from the Bill & Melinda Gates Foundation, the U.S.-based biotech focuses on the antimalarial component artemisinin – derived from the wormwood plant, Artemisia annua. Its cell engineering platform BioAssemblyLine will aid in artemisinin production – obtained through fermentation.
Weighing the outcomes of gene drives to combat malaria
Moreover, in the fight against malaria, biotech companies are not alone. An initiative by the Foundation for the National Institutes of Health in the U.S. called the GeneConvene Global Collaborative is coordinating research in the field of genetic biocontrol, an established method to manage pests and pathogens. Genetic biocontrol is the release of organisms into an area to prevent an invasive species from populating.
But how can this technique be used to nip malaria in the bud?
The collaborative, works with researchers and policymakers for the potential use of gene drive mosquitoes, which can even be developed from CRISPR technology. The initiative aims to ensure that public health measures are in place, and provides training on gene drive biocontrols for stakeholders.
As living organisms inherit two different copies of their genes, one set from the female parent and the other from the male parent, the probability for a gene that displays gene drive for it to be passed on to the next generation, is higher, thereby influencing the inheritance of specific genes.
According to Michael Santos, vice president of Science at the Foundation for the National Institutes of Health and director of the GeneConvene Global Collaborative, one method in genetic biocontrol, implemented to prevent dengue, is to irradiate male mosquitoes to make them sterile. Following this, they are released into the wild where they mate with females.
“And if you do this enough, you reduce the population a lot,” said Santos, who expressed that this is yet to be studied against malaria.
“One of the things that is, I think, exciting about genetic bio control, is that it is very species specific,” he said.
“So it’s different than going out to a pond and larviciding… You’re trying to kill the mosquitoes that transmit malaria by putting larvicide in the pond, but you’re probably affecting other species too. Whereas these genetic approaches are very specific, because they operate through mating, they only directly affect the other members of the species or the species complex that can mate and produce offspring.”
However, some researchers are skeptical about this method to combat malaria, as mosquitoes are pollinators, and an integral member of the ecosystem. Knocking out the species could result in a cascade of repercussions that could affect other species populations.
Another approach is to modify the mosquito’s gene, where the vector would not be able to transmit malaria.
“So instead of the mosquitoes having no offspring, the mosquitoes have offspring, but the offspring carry the change,” said Santos.
Santos explained that because evolution tries to make the mosquitoes as fit as they can be, gene drive approaches can help induce the change in the population.
“These gene drive approaches have some properties that make them really exciting… One is that – because the mosquitoes would propagate the genetic change in the environment, it doesn’t require any individual level behavior change.”
Santos believes that from a health equity perspective, this would provide protection to everybody in a specific area. “No one needs to go to get vaccinated or go to get tested and treated,” he added.
“It also has the potential to establish and persist in conflict zones, or refugee settings or other settings, where it’s traditionally really difficult to deliver some other health interventions,” said Santos, who lauded the technology’s potential cost-cutting benefits.
Scope for nanotechnology in malaria prevention
Like the concept of gene drives that are being tested in labs at present, another approach that could be applied to counter the pathogen is nanotechnology. As the parasite develops drug resistance against treatments like chemotherapy, the challenge is being examined to overcome this limitation with the use of nanotechnology. Research has shown that compounds like lipids, proteins, and metallic nanoparticles (NPs) and even plant extracts have been successful in battling malaria through effective drug delivery, with plant-based particles like leaves, roots and latex, delivering an elevated response against the disease. With an aim to directly target Plasmodium, metallic nanoparticles have been effective in controlling various Plasmodium species.
While nanotechnology strategies could be a potential alternative approach with nanomaterials depicting its ability in delivering therapies, chemically synthesized nanoparticles may affect other tissues. As a result, the method requires further research as an antimalarial treatment measure.
As the disease plagues millions of lives in 87 countries, wiping out the disease is no small feat. And while interventions like genetic biocontrol as well as novel vaccine candidates seem promising, there is an urgency for rigorous research and development in the malaria field. But as the prevalence of diseases like smallpox is now no more owing to a collaborative global vaccination program, the hope that malaria could be eradicated remains a possibility.