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The bite of an infected female Anopheles mosquito abets the entry of Plasmodium sporozoites into 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.
As of 2023, there were an estimated 263 million malaria cases and 597,000 malaria deaths in 83 countries, according to the World Health Organization (WHO). While a WHO report revealed that 2.2 billion cases of malaria and 12.7 million deaths have been averted since 2000, the disease remains a serious global health threat, particularly in the WHO African Region, which comprises 47 member states.
The global eradication of malaria is still something to strive for, and biotechs are working towards treatment measures to drastically reduce the incidence of the disease, amid recent foreign aid funding cuts.
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Closing treatment gaps: Coartem Baby approved for infants
The most notable win of late is the approval of Coartem Baby, the world’s first medicine to treat babies infected with malaria, by Swiss regulators. Although Coartem has long been approved by regulators across the world, it was limited to adults and children who weigh 5 kgs and more. Babies were being treated with the version for older children, which presented a risk of overdose. The new formulation bridges a significant treatment gap for infants below 5 kgs, who make up a critical neglected group.
Developed by Swiss giant Novartis and the non-profit Medicines for Malaria Venture (MMV), Coartem Baby is a new formulation of Coartem, which is made up of artemether and lumefantrine. Artemether becomes active once it enters the body, and it works by inhibiting the process of protein synthesis required for the parasite to live and multiply in the host. However, artemether clears out of the body quickly, so combining it with lumefantrine, which provides sustained antimalarial activity, improves the efficacy.
Coartem Baby is designed to dissolve in liquids, including breast milk, and has a sweet cherry flavor, making it easier to be administered.
The treatment will be introduced on a “largely not-for-profit basis to increase access in areas where malaria is endemic,” according to a press release.
Vas Narasimhan, chief executive officer (CEO) of Novartis said: “For more than three decades, we have stayed the course in the fight against malaria, working relentlessly to deliver scientific breakthroughs where they are needed most.”
Bringing affordable vaccines to the public: can MMV, Eyam Biotech, and GSK keep their promises?
As malaria is one of the deadliest diseases, particularly among children, affordable ways to eradicate the infection are pressing. The MMV has teamed up with Canadian biotech Eyam Biotech to deliver $1 treatment shots against malaria.
“The approach to develop affordable monoclonal antibodies with longer dosing intervals could be truly transformative for improving delivery and efficacy of broad-scale preventive malaria campaigns, including potential use in mass administration campaigns to accelerate malaria elimination,” said Brice Campo, senior director of MMV, in a press release.
The plan is to develop monoclonal antibodies to prevent malaria. They will employ Eyam’s platform technologies, the Jennerator, an artificial intelligence (AI) engine for designing the antibodies, and Gemini, a delivery system that can carry multiple therapies in a single shot. Gemini is what will make the dosing cheaper, potentially putting monoclonal antibodies at the forefront of infectious disease therapeutics, as they are typically known to have a higher cost of production.
Meanwhile, in a bid to bring more affordable antimalaria measures to the table, pharma giant GSK and India-based Bharat Biotech have vowed to bring Mosquirix, the world’s first malaria vaccine that has already been approved in several countries, to children in 12 countries in Africa where malaria is endemic. Prices will be slashed by half to less than $5 by 2028.
Mosquirix also goes by the name RTS,S, and is the first of its kind to be recommended by WHO in 2021. It is designed to limit the ability of Plasmodium to infect and multiply in the liver. Mosquirix boosts the production of antibodies that work against proteins found in the parasite.
This new endeavor will promote the rollout of an otherwise expensive vaccine in countries affected by the disease.
“Any lower-cost vaccine means children in the most affected communities in endemic countries can be protected. Sustained affordability is essential to ensuring that the progress we’ve made in malaria control is not only maintained but accelerated,” said Kwaku Poku Asante, director of the Kintampo Health Research Centre in Ghana.
Can gene-deleted parasites make for a good vaccine?
Meanwhile, biotechs are on a quest to widen treatment options across patient populations. One company ambitious about controlling the spread of malaria is U.S.-based Sanaria. In hopes of achieving higher efficacy and lowering the disease burden compared to available malaria vaccines, Sanaria’s PfSPZ-LARC2 is in the clinic in Burkina Faso.
The one-dose vaccine contains the genetically engineered Plasmodium parasite, which has been weakened by deleting two critical genes that cause the parasite to disintegrate after initial replication in the liver, without progressing to disease-causing blood-stage malaria infection.
Results from an ongoing trial revealed that the vaccine was safe and caused no malarial infections in adults. The next phase of the trial will see the candidate tested in children aged between 11 and 19 and six and 10 years old.
“The PfSPZ-LARC2 vaccine is uniquely positioned to meet WHO’s ambitious goal of achieving over 90% protection against malaria infection, a milestone no current vaccine has ever matched. This will be unprecedented,” Sodiomon Bienvenu Sirima, the trial’s principal investigator, said in a press release.
Engineered antibody MAM01 combats malaria in clinic
While the MMV has big dreams to bring affordable medicines to people in regions plagued by malarial infections, so do other non-profits. The Bill & Melinda Gates Foundation is involved in the making of the monoclonal antibody MAM01 along with the University of Maryland School of Medicine in the U.S.
It is an engineered version of a human monoclonal antibody that is generated upon vaccination with Mosquirix. It was licensed to the Bill & Melinda Gates Foundation by now-acquired antibody developer Atreca in 2021 for commercial rights in low- and middle-income countries where malaria is rampant.
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. Now, in clinical trials, MAM01 is being evaluated for its safety and effectiveness in healthy participants who will either receive it through an IV or a shot under the skin.
The foundation has other antimalaria programs up its sleeve. It funded Massachusetts-based Manus Bio’s fermentation-based approach for making dihydroartemisinic acid (DHAA), a natural precursor of the antimalarial compound artemisinin. Artemether, present in Coartem and Coartem Baby, is a derivative of artemisinin.
The two have had a long-standing relationship to advance malaria treatments, with the American biotech bagging three awards from the Bill & Melinda Gates Foundation over the years. Manus Bio has now stepped up its involvement in the space. It raked in $32.4 million from the Department of Health and Human Services to develop critical medicines, which include anti-malarial therapies, in November last year.
Moreover, in the fight against Plasmodium falciparum, German vaccine developer Sumaya Biotech has a unique approach. It aims at alerting the immune system towards two crucial stages of the parasite’s infectious cycle, the liver and the blood stage. Its vaccine SUM-101 targets a protein called MSP1, which is exposed on the surface of merozoites, the infectious form of the parasite that invades the blood cells.
Hoping to beat RTS,S’ efficacy, SUM-101 is in the phase 1 stage, and trials in Germany and Tanzania have proven its safety. Studies in Burkina Faso and Tanzania will be launched soon.
Challenges in malaria treatment efforts
However, as with many treatments for infectious diseases, overcoming resistance is a major challenge. Scientists have identified strains in Ethiopia that are resistant to artemisinin-based treatments and capable of evading detection. These parasites have undergone genetic mutations and deletions that make them undetectable by rapid diagnostic tests, which traditionally identify specific parasite proteins.
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, there is a need to better understand the biology of these parasites. 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.
Unlocking new malaria treatments: advances in RNA-protein research
Perhaps that’s where RNA research comes in. The University of California, Riverside, is looking into how proteins and RNA interact inside the parasite. With the help of its lab technique known as R-DeeP, it identified and characterized 898 RNA-dependent proteins in the malaria parasite. 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 the 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
Meanwhile, an initiative by the Foundation for the National Institutes of Health (FNIH) 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.
“Part of the decision process for countries to approve field studies of genetically modified mosquitoes is an assessment of environmental risk. This includes potential effects on human and animal health as well as ecosystem effects, including ecosystem services like pollination.”
Genetic biocontrol approaches have the potential to prevent the transmission of malaria by reducing the numbers of malaria vector mosquitoes or making them unable to pass the malaria parasite from one person to the next, according to Michael Santos, senior vice president of Science Partnerships, chief population health science officer at the FNIH, and director of the GeneConvene Global Collaborative. The organization has banded together with the African Union Development Agency-NEPAD to provide training to biosafety regulators on good governance for genetic biocontrol approaches.
But how can this technique be used to nip malaria in the bud?
“This is achieved by genetically engineering mosquitoes in a laboratory to possess the desired trait, like decreased fertility or resistance to the malaria parasite), then breeding those mosquitoes in a lab to raise more mosquitoes with that trait,” said Santos. “If those mosquitoes were introduced into the wild, and they work as intended, they could reduce malaria transmission. Depending on the genetic approach, that reduction could be designed to be temporary or long-lasting.”
This has previously been implemented to prevent dengue by irradiating male mosquitoes to make them sterile. Following this, they are released into the wild, where they mate with females.
Both approaches – reducing the numbers of malaria vector mosquitoes and making them unable to pass the malaria parasite from one person to the next – have been demonstrated in laboratory studies with mosquitoes in cages, explained Santos. Moreover, an initial field study in Djibouti of reducing the numbers of invasive Anopheles stephensi mosquitoes was conducted.
“In the coming years, there may be more field studies of genetically modified mosquitoes to prevent malaria transmission, including both genetically sterile mosquitoes and mosquitoes engineered to pass on their modifications to future generations. These field studies would evaluate how genetically modified mosquitoes perform in the wild, and whether there are any environmental safety concerns,” said Santos.
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.
But Santos pointed out that the mosquito species responsible for transmitting malaria are “not important pollinators” and research has previously supported this idea.
“Part of the decision process for countries to approve field studies of genetically modified mosquitoes is an assessment of environmental risk. This includes potential effects on human and animal health as well as ecosystem effects, including ecosystem services like pollination. There are thousands of species of mosquitoes, and many pollinator species besides mosquitoes,” said Santos.
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.
By modifying the mosquito’s gene, 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, they don’t require any individual level behavior change.”
“It also has the potential to establish and persist in conflict zones or refugee settings, where it’s traditionally really difficult to deliver some other health interventions,” said Santos.
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.
Advancements in antimalarial drug discovery and development
