What are biotech companies doing to tackle malaria?

A single bite of a mosquito can release a microscopic but deadly parasite into the human bloodstream, Plasmodium sporozoites. This is the harsh reality of the infamous disease, malaria. The parasites 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. Biotech is making progress in malaria research and new treatment options are being explored.

Plasmodium, which is typically one to 20 microns (a millionth of a meter) in diameter, is particularly dangerous as it can cause severe blood loss and can clog blood vessels. As of 2022, there were 249 million cases of malaria, with the disease endemic to sub-Saharan Africa among other regions, according to the World malaria report 2023.

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 new treatments against malaria.

Fighting malaria through vaccination

R21/Matrix-M vaccine receives Ghana’s approval

A bit over a year ago, 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 to 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,the most dangerous species of the Plasmodium that affects humans, 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.

Culturing Plasmodium in vitro: the approach of Sanaria

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.

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 (CEO) of Sanaria.

The promise of genetically modified live parasite vaccines

Meanwhile, to envision the success of genetically modified live parasite vaccines, a study led by physician and scientist Sean Murphy at 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.

Bill & Melinda Gates Foundation’s MAM01 in malaria fight

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 U.S. Food and Drug Administration (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.

Unlocking new malaria treatments: Advances in RNA-protein research

Recent research at the University of California, Riverside, has significantly advanced our understanding of how RNA-dependent proteins can be targeted to combat malaria. This study utilized a novel lab technique known as R-DeeP to identify and characterize 898 RNA-dependent proteins in the deadliest human malaria parasite, Plasmodium falciparum. The approach revealed both known and previously uncharacterized proteins, some of which are specific to the parasite, and hence present new potential targets for therapeutic intervention.

The R-DeeP method involves treating parasite protein lysates with enzymes that degrade DNA and RNA, followed by detailed analysis using mass spectrometry and bioinformatics. This allows researchers to observe changes in protein behavior in response to RNA presence, providing insights into how these proteins interact with RNA within the parasite. Notably, the study identified a specific RNA-binding protein that interacts with Plasmodium transcripts involved in controlling virulence, making it a promising target for new malaria treatments.

This breakthrough not only deepens our understanding of the biological pathways essential for the malaria parasite’s survival but also highlights potential new strategies for developing drugs to prevent and treat malaria.

Weighing the outcomes of gene drives to combat malaria

Advancing malaria treatment through genetic biocontrol innovations

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 using CRISPR technology. The initiative aims to ensure that public health measures are in place, and provides training on gene drive biocontrols for stakeholders.

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. 

Revolutionizing malaria prevention with gene modification strategies

Another approach is to modify the mosquito’s gene, so that the malaria vector would not be able to transmit the disease.

“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 their ability to deliver therapies, chemically synthesized nanoparticles may affect other tissues. As a result, the method requires further research as an antimalarial treatment measure.

Challenges in malaria treatment efforts

In recent research published in Nature, scientists have identified a significant challenge in malaria treatment efforts in Ethiopia due to the emergence of malaria parasites that are resistant to both artemisinin-based treatments and standard diagnostic tests. These parasites have undergone genetic mutations and deletions that make them undetectable by rapid diagnostic tests, which traditionally identify specific parasite proteins. 

The studies conducted by researchers from Brown University, in collaboration with the Ethiopian Public Health Institute and the University of North Carolina, highlight the complex nature of these parasites. They’ve found that approximately 8.2% of the parasites not only resist artemisinin but also evade detection due to the absence of specific genes normally targeted by diagnostic tests. This dual resistance could lead to increased malaria transmission and higher mortality rates, complicating the Ethiopian government’s goal of eradicating malaria by 2030.

To address these challenges, the research underscores the urgent need for the development of new treatments against malaria. Additionally, it emphasizes the importance of genomic surveillance, a method that has significantly advanced over the last decade, to monitor and understand the spread and evolution of these resistant parasites. This approach is crucial for devising strategies that can effectively combat, and eventually eliminate malaria in Ethiopia and potentially other affected regions across Africa.

Improving our understanding of malaria through genomic surveillance

Genomic surveillance is the monitoring and analysis of genetic changes in organisms, particularly pathogens, to track their evolution and spread. This method uses technologies like DNA sequencing to identify and categorize genetic variations, which can inform public health responses, such as identifying drug-resistant strains or developing vaccines. It’s an essential tool in epidemiology, helping to predict outbreaks, understand disease transmission, and guide intervention strategies effectively.

Genomic surveillance is increasingly recognized as a pivotal tool in malaria control and elimination efforts, particularly as it pertains to tracking the spread of the disease and understanding the genetic makeup of malaria-causing parasites. 

Recent advances in genomic surveillance techniques have made it possible to identify and monitor genetic variations of the malaria parasite across various geographical locations. For instance, comprehensive mutation libraries have been developed that include mitochondrial markers to differentiate species of Plasmodium, which is essential for accurate diagnosis and treatment planning​​.

Moreover, projects like MalariaGEN have contributed significantly by creating extensive genetic data resources that support global efforts in malaria control by providing access to genetic and genomic data from parasites, mosquitoes, and human hosts involved in the transmission of the disease​​.

Genomic epidemiology, which combines genetic data with epidemiologic information, allows for more nuanced insights into the transmission dynamics of malaria. This approach is particularly useful in understanding how infections spread within and between populations, which can inform targeted interventions​​.

Moreover, the application of next-generation sequencing has enabled the tracking of malaria at an unprecedented level of detail, providing insights into the genomic epidemiology of malaria and supporting the profiling of co-infections and the identification of imported malaria parasites, which is critical for effective disease management and could lead to new treatment options​​.

However, despite these advances, there are still significant challenges in the widespread implementation of genomic surveillance, particularly in low-resource settings. In 2022, the WHO recognized these challenges and released a 10-year strategy aimed at enhancing the capacity for genomic surveillance globally. This strategy seeks to leverage existing capacities, address barriers, and strengthen the use of genomic surveillance across countries, acknowledging that many lacked this capability before the COVID-19 pandemic spurred broader adoption​.

As malaria 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.   

New technologies related to malaria treatment:

• Vaccines Against Malaria – Henry Jackson Foundation ⁠
• Novel Use of Senicapoc to Treat or Prevent Malaria – Boston Children’s Hospital ⁠
• Novel Antimalarial Therapeutics – University of South Florida ⁠
• High Affinity Ligands that Target Liver Cell Surface Receptor (CD81) and Prevent Malarial Invasion – The American University  in Cairo