The bite of an infected female Anopheles mosquito promotes entry Plasmodium sporozoites in the human bloodstream, marking the beginning of the parasite’s life cycle. The sporozoites then travel to the liver and multiply, after which they invade red blood cells, multiplying in numbers again. And in about a week or two, malaria, which is characterized by flu-like symptoms, which can be fatal if not diagnosed in time, occurs.
Usually one to 20 microns (millionths of a meter) in diameter, Plasmodium – a protozoa – in the human body, can cause significant blood loss and can clog blood vessels. In 2021, there were 247 million cases of malaria, with the disease endemic in sub-Saharan Africa among other regions, according to World malaria report 2022.
While global eradication of malaria is still something to be fought for, biotechs are working towards treatment measures and vector control strategies to drastically reduce the incidence of the disease. As we mark World Malaria Day on April 25, let’s take a look at some of the latest advances in malaria research.
Most 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 assistance to African countries that are badly affected by malaria.
Co-developed with the Serum Institute of India, the R21/Matrix-M vaccine, is a saponin-based Matrix-M adjuvant – a compound found in the bark of the soapbark tree. Considered a major advance in malaria research, the anti-sporozoite vaccine, which targets Plasmodium falciparum, surpassing the World Health Organization (WHO) goal of developing a malaria vaccine with at least a 75% efficacy rate. The vaccine, along with its booster dose, can yield positive results, as proven in clinical trials. The study found that the vaccine showed high levels of efficacy, including in children, for a three-dose regime, leading to the Food and Drugs Authority (FDA) in Ghana obtaining regulatory approval for R21/Matrix-M.
Another company with ambitions to control the spread of malaria is US-based Sanaria biotech. With an extensive pipeline currently in the preclinical and clinical stages, the company Plasmodium falciparum sporozoite (PfSPZ) vaccine aims to immunize the entire population in a certain area to get rid of malaria. With clinical trials already underway in four main regions, the US, Europe, Africa and Asia, 5.6 billion people have received live attenuated doses of the vaccine in 15 placebo-controlled trials.
Cultivating Plasmodium in vitro: a breakthrough in malaria research
In December 2022, Sanaria published encouraging research regarding its vaccine program. The company discovers the ability to culture Plasmodium without requiring mosquitoes as hosts, a breakthrough in malaria research. Currently, the company’s vaccine is produced on mosquitoes. Now, this advance could change the company’s advances in its vaccine technology. In addition, it paved the way for more cost-effective production of vaccines.
“By developing the capacity to produce infectious in vitro PfSPZ, meaning in culture vessels without the need for mosquitoes, we have made important breakthrough steps, firstly, to enable increased production to eventually meet the needs of hundreds of millions to billions of mosquitoes. people who will benefit from our PfSPZ vaccine,” said Stephen L Hoffman, chief executive of Sanaria.
Meanwhile, to envision the success of a genetically modified live parasite vaccine, a study led by physician and scientist Sean Murphy at the University of Washington School of Medicine shows potential. By erasing the P52, P36, and SAP1 genes on P. falciparum, research exploring whether the PfGAP3KO vaccine can protect against malaria by disarming the parasite. Individuals are vaccinated three or five times through 200 bites of PfGAP3KO-infected mosquitoes per immunization; results showed that half the people in the trial did not develop Plasmodium infection, and at the end of six months, some individuals remained partially protected. While further investigation of the vaccine’s efficacy is needed, the team has partnered with Sanaria to produce modified parasites for vaccine development.
In addition to Sanaria’s efforts to curb malaria transmission, Bill & Melinda Gates Foundation’s new monoclonal antibody (mAb) MAM01 is an engineered version of the human mAb generated following vaccination with UK-based Mosquirix GlaxoSmithKline, the first malaria vaccine to receive FDA approval. The Bill & Melinda Gates Medical Research Institute (Gates MRI) signed a licensing agreement with US-based clinical stage company Atreca for the development of MAM01, under which Gates MRI will acquire the 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 coating on sporozoites – and has shown protection from disease in animal studies.
In addition, Manus Bio aspires to stop the spread of mosquito-borne diseases. After receiving $2 million in funding from the Bill & Melinda Gates Foundation, the US-based biotech focused on the antimalarial component artemisinin – derived from the wormwood plant, Artemisia year. Its cell engineering platform, BioAssemblyLine, will assist in the production of artemisinin – obtained by fermentation.
Considering the results of activating genes to fight malaria
Moreover, in fighting malaria, biotech companies are not alone. An initiative by the Foundation for the National Institutes of Health in the US called GeneConvene Global Collaborative coordinates research in the area of genetic biocontrol, a well-established method for managing pests and pathogens. Genetic biocontrol is the release of organisms into an area to prevent populations of invasive species.
But how can this technique be used to prevent malaria in the first place?
The collaboration, working with researchers and policy makers for the potential use of gene driving mosquitoes, could even be developed from CRISPR technology. This initiative aims to ensure that public health measures are in place, and provide training on gene drive biocontrol for stakeholders.
Since living organisms inherit two different copies of a gene, one set from the female parent and the other from the male parent, the chances of the genes displaying the gene drive being passed on to the next generation, are higher, thereby influencing the inheritance of certain 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 of the genetic biocontrol methods applied to prevent dengue fever is to irradiate male mosquitoes to make them sterile. After that, they are released into the wild where they mate with females.
“And if you do enough of this, you reduce the population a lot,” said Santos, who stated that it had not yet been studied for fighting malaria.
“One of the things that, I think, is interesting about genetic biocontrol, is that it’s very species-specific,” he said.
“So this is different from going into a pond and killing the larvae… You are trying to kill the mosquito that transmits malaria by putting the larvicide in the pond, but you may also be affecting other species. Whereas these genetic approaches are very specific, because they operate through mating, they only directly affect members of other species or species complexes that can mate and produce offspring.”
However, some researchers doubt this method for fighting malaria, because mosquitoes are pollinators, and are an integral part of the ecosystem. Killing a species can cause a series of reactions that can affect populations of other species.
Another approach is to modify the mosquito’s genes, whereby the vector will not be able to transmit malaria.
“So it’s not that mosquitoes don’t have offspring, but mosquitoes do have offspring, but offspring bring change,” said Santos.
Santos explained that because evolution tries to get mosquitoes fit, a gene-drive approach could help drive population change.
“This gene-driver approach has several properties that make it very attractive… One of them is – because a mosquito would be spreading genetic changes in the environment, it would not require a change in behavior at the individual level.”
Santos believes that from a health equity perspective, this will protect everyone in a given area. “No one needs to go to get vaccinated or go to be tested and treated,” he added.
“It also has the potential to establish and survive in conflict zones, or refugee settings or other settings, where it has traditionally been very difficult to deliver some other health interventions,” said Santos, who praised the technology’s potential cost-cutting benefits.
The scope of nanotechnology in malaria prevention
Like the gene drive concept currently being tested in laboratories, another approach that can be applied to fight pathogens is nanotechnology. As parasites develop drug resistance to treatments such as chemotherapy, the challenge is being examined to overcome this limitation with the use of nanotechnology. Studies have shown that compounds such as lipids, proteins, and metal nanoparticles (NPs) and even plant extracts have successfully combatted malaria through effective drug delivery, with plant-based particles such as leaves, roots and latex, providing an increased response to the disease. . With the aim of targeting Plasmodium directly, metal nanoparticles have been effective in controlling various Plasmodium species.
While nanotechnological strategies could be a potential alternative approach with nanomaterials demonstrating their ability to deliver therapeutics, chemically synthesized nanoparticles may affect other tissues. As a result, this method requires further research as an antimalarial treatment.
Because this disease affects millions of lives in 87 countries, eradicating this disease will not be easy. And while interventions such as genetic biocontrol and new vaccine candidates look promising, there is an urgency for rigorous research and development in the malaria area. But as the prevalence of diseases such as smallpox is now obsolete thanks to collaborative global vaccination programmes, the hope that malaria can be eradicated remains a possibility.