Industry-Academia collaborations to design next generation anti-malaria drugs

Partnership between academic research institutions and the biopharma industry has been essential for making breakthrough discoveries in disease research and translating those discoveries into therapies available in the clinic. A recent example is the collaboration between Serum Institute of India (SII), Oxford University and Novavax to deliver malaria vaccines to Africa on a large scale.

In the same spirit, we at Aganitha, have teamed up with scientists at the Centre for Cellular and Molecular Biology (CCMB) to apply our Generative AI solutions to predict, test, and optimize potential antimalarial compounds, against parasite drug targets identified and validated at CCMB. Using our Generative AI-powered Fragment-based drug discovery (FBDD) platform, our team has generated several lead compounds against a validated malaria drug target.

Deep science and Deep Tech are coming together to address the challenge of Malaria

The convergence of deep science and deep tech is an intersection that holds transformative potential for eradicating this ancient scourge. Advances in genomics, proteomics, and molecular biology have provided profound insights into the parasite’s biology, its interaction with the human host, and its transmission via Anopheles mosquitoes. High-throughput sequencing technologies have mapped the genomes of various Plasmodium species, revealing potential targets for new drugs and vaccines. For example, the Malaria Cell Atlas is an effort led by the Lawniczak lab to provide an interactive data resource of single-cell transcriptomic data across the full lifecycle of malaria parasites.  Similarly, PlasmoDB – the Plasmodium Informatics Resource offers a comprehensive database of the genome, phenome, and metabolic pathways of various Plasmodium species.

Understanding the biochemical pathways critical for parasite survival and replication has identified new drug targets and mechanisms of resistance. Studying how the parasite evades the human immune system has informed the development of more effective vaccines and immunotherapies. Building on all that we know today about the parasite and the disease pathology, Artificial Intelligence (AI) is playing an augmentative and innovative role in the fight against malaria, aiding in various aspects such as diagnosis, treatment, and prevention. A few examples are:

1. Diagnosis: Automated Blood Smear Analysis: AI-powered systems, like those developed by the startup Bluedot and Microsoft, use deep learning algorithms to analyze blood smears for the presence of malaria parasites. These systems can process images faster and with greater accuracy than traditional methods, reducing the workload on healthcare professionals and increasing diagnostic efficiency.
2. Predictive Modeling: Malaria Forecasting: AI models, such as those developed by IBM, analyze vast amounts of data, including weather patterns, population movements, and environmental factors to predict malaria outbreaks. This helps in the timely allocation of resources and implementation of preventive measures.
3. Drug Discovery: Identifying New Treatments: AI algorithms can screen millions of chemical compounds to identify potential new drugs for malaria treatment. For instance, platforms like Atomwise use AI to predict which compounds might effectively target the malaria parasite, speeding up the drug discovery process.
4. Disease Surveillance: Tracking and Reporting: AI-driven mobile apps and platforms, such as the ones developed by MalariaSpot, enable real-time tracking and reporting of malaria cases. These tools help health authorities monitor the spread of the disease and respond more quickly to outbreaks.
5. Host-Parasite biology and disease pathology: Understanding Parasite Resistance: AI is used to analyze genetic data from malaria parasites, helping researchers understand patterns of drug resistance. This information is crucial for developing new treatments and adjusting existing protocols to combat resistant strains.

Overall, human intelligence and Artificial intelligence working together can augment the accuracy, efficiency, and effectiveness of malaria control efforts, offering new avenues to reduce the disease’s global burden and eradicate this old disease from throughout the world.

Background on Malaria

Malaria’s history dates back to ancient times, with evidence of the disease found in Chinese writings from 2700 BCE and ancient Egyptian records from 1550 BCE. Today, with 249 million cases estimated globally in 2022, it is predominant in tropical and subtropical regions of the world, particularly in sub-Saharan Africa, South Asia, and parts of South America. In the recent past, however, malaria was widespread in parts of Europe and North America, with outbreaks occurring as far north as Russia and the United States. It was not until the 20th century, through improved sanitation, mosquito control efforts, and the use of antimalarial drugs, that malaria was largely eradicated from these regions. A few questions arise: Why is this ancient disease still relevant? Is this battle solely the concern of tropical nations? And finally, in this era of deep science and deep tech, are we more equipped than ever to combat this disease, once and for all? 

Why Every Corner of the World Should Care

Today when you think about malaria, you might imagine it as a distant problem confined to tropical regions. However, this wasn’t always the case, and it isn’t expected to be in the near future either. Even though the major disease burden today is shared by African and SouthEast Asian continents, with powerful forces such as globalization, frequent international travels, and climate change at play, the disease continues to make its presence across the world. In fact,  recent data from the U.K. Health Security Agency (UKHSA) shared on April 24, 2024, shows that malaria cases in England, Wales, and Northern Ireland rose to 2,004 reported cases in 2023, a 32% increase from 1,369 in 2022. Similarly, even though malaria was considered eliminated in the USA by 1951,  apart from the usual annual count of imported malaria cases, several homegrown cases were recorded in distinct geographical locations- Florida, and one each in Texas and Maryland in 2023.  This unusual pattern has been attributed to the resurgence of malaria in many countries and an increase in overseas travel. 

With global climate warming, the risk is increasing as hotter, more humid conditions extend the mosquito breeding season and boost their populations. And as the summers continue to get hotter, the likelihood of malaria re-emerging in temperate regions like the USA and Europe increases (Figure 1). The complexity of the parasites, which is not yet fully understood, could be another factor at play. With parasites gaining resistance to recommended drugs and mosquitoes gaining resistance to known insecticides, malaria resurgence may not be as distant as it may seem today. It has the potential to become more  frequent and widespread, and hence worth watching out for.

While the future of malaria in these regions remains uncertain, if there is one thing that the COVID pandemic has taught the world, it’s that preparation is crucial. Climate change isn’t going away, and neither is the threat of malaria. While globalization on the one hand could cause the spread of malaria, at the same time it promotes global collaborations and mobilization of resources to tackle malaria in any part of the world. 

Malaria is a global health security concern that requires coordinated, multi-national, and multi-sector efforts to effectively combat the disease.

Malaria research goes beyond addressing this singular disease; it encompasses the development of methodologies and tools to combat a range of mosquito-borne illnesses including Zika, dengue, and others. The healthcare professionals trained in malaria diagnosis and treatment are well-equipped to manage other ailments and respond promptly to emerging outbreaks. Surveillance and response systems tailored for malaria can play a crucial role in monitoring and controlling the spread of various infectious diseases. Swift diagnostics and enhanced treatments are imperative in tackling the escalating resistance to antimalarial medications and insecticides. Gaining deeper insights into the spread of these mosquitoes could pave the way for targeted interventions, such as the application of larvicides in specific habitats, offering a safer and more efficient alternative to widespread spraying. Expanding our horizon to the basic science  research efforts against malaria,  insights into the complexity of malaria pathogenesis could help advance our understanding of other diseases such as dengue and chikungunya. Broader implications include a better understanding of host-pathogen interactions, immune evasion tactics of the pathogens, drug resistance mechanisms, and vector biology.

Challenges for Malaria Eradication

Challenges in malaria eradication are multifaceted. Some of the key obstacles are:

• Drug Resistance: The emergence of drug-resistant strains of the malaria parasite undermines the effectiveness of recommended antimalarial medications, complicating treatment efforts.
• Lack of a vaccine: This lays more burden on curative measures. To date, the most advanced vaccine candidate is RTS,S/AS01 (Mosquirix), which targets the pre-erythrocytic stage of Plasmodium falciparum. While Mosquirix represents a significant breakthrough, its efficacy is modest, providing partial protection. Clinical trials have shown that it can reduce the risk of malaria by about 40% in young children, which is far from the near-total protection offered by vaccines for other infectious diseases like measles or polio. Additionally, the immunity conferred by Mosquirix wanes over time, necessitating booster doses to maintain its protective effects.
• Insecticide Resistance: Mosquitoes, the vectors of malaria, develop resistance to insecticides used in mosquito control measures, reducing the efficacy of spraying campaigns and bed nets.
• Limited Access to Healthcare: In many malaria-endemic regions, access to healthcare services, including diagnostic testing and treatment, is limited, leading to undiagnosed and untreated cases.
• Poverty and Socioeconomic Factors: Poverty and socioeconomic disparities exacerbate the burden of malaria, as marginalized communities often lack access to preventive measures and proper healthcare.
• Climate Change: Changes in temperature and rainfall patterns influence mosquito breeding habitats and malaria transmission dynamics, potentially expanding the geographic range of the disease.

Malaria is preventable and treatable, provided timely diagnosis and the administration of appropriate medications. Therapeutics and interventions play critical roles in the comprehensive management and control of malaria, addressing both the treatment of individuals diagnosed with the disease and the broader efforts to prevent its transmission and impact on communities. Let’s look into the current landscape of therapeutics and some of the global public and private efforts against malaria.

Uniting All Efforts For a Malaria-free Future

Public and Private sectors coming together

Medicines for Malaria Venture (MMV) plays a crucial role in the global fight against malaria. A public-private partnership, it’s dedicated to discovering, developing, and delivering effective and affordable antimalarial drugs. One of MMV’s most significant initiatives is its collaboration with the Roll Back Malaria (RBM) Partnership to End Malaria. This global framework aims to reduce the incidence of malaria and, ultimately, eliminate it as a public health problem. MMV’s efforts have led to the development of next-generation antimalarials that address drug resistance and reduce transmission rates. Their approach includes partnering with pharmaceutical companies, academic institutions, and other stakeholders to ensure that new treatments are accessible to those who need them most.

Even though Artemisinin-based Combination Therapies (ACTs) remain the first-line treatment for uncomplicated malaria, emerging resistance to artemisinins and its derivatives presses the need to identify novel drugs and drug targets.  Pharmaceutical giants like Novartis and GlaxoSmithKline (GSK), along with MMV have been instrumental in laying the groundwork for screening large numbers of compounds for antimalarial activity, until recently available as MMV Open Box. Novartis, for example, has been a leader in providing artemisinin-based combination therapies (ACTs), which are currently the gold standard in malaria treatment. GSK has made significant contributions with the development of RTS,S, Mosquirix, the world’s first malaria vaccine. This vaccine has undergone extensive trials and is now being rolled out in pilot programs across several African countries.Other pharmaceutical companies like Sanofi, Merck, and BioNTcech are also making strides. For instance, Sanofi has developed ASAQ, a fixed-dose combination therapy that simplifies malaria treatment and improves patient adherence. These efforts highlight the importance of pharmaceutical innovation in the ongoing battle against malaria.