April 25, 2022
Malaria is one of the world’s most widespread and ancient infectious diseases, and controlling it remains a critical public health priority. This complex parasitic disease, transmitted from person to person by the bite of infected mosquitoes, threatens the lives and livelihoods of millions of people in tropical areas around the globe. Each year, on April 25, World Malaria Day provides an opportunity to reflect on recent advances in controlling this disease and the challenges that remain. Today, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), reaffirms our commitment to developing safe and effective medical tools against malaria, and, in the words of this year’s World Malaria Day theme, “Harnessing innovation to reducing the malaria disease burden and saving lives.”
Malaria infection, when uncomplicated, can lead to the disease’s hallmark symptoms of chills, intense fever, and sweating, all of which can be quite debilitating. Repeated bouts of malaria are not uncommon. If infection progresses to severe malaria, it can lead to coma, seizures, severe anemia, respiratory distress, organ failure, shock, and even death. Despite recent advances, malaria has remained a challenging disease to control, and particularly so during the COVID-19 pandemic. According to the World Health Organization, in 2020 alone 241 million people worldwide suffered from malaria, with 627,000 estimated deaths. In recent decades, children and pregnant women in Africa have been particularly affected.
Anopheles mosquitoes transmit the malaria parasite from person to person. Over the course of malaria parasites’ life cycle, they migrate through the bodies of mosquitoes that transmit them and the people they infect and undergo a series of dramatic changes. This life cycle complicates research and treatment because each life stage has different characteristics and vulnerabilities. Due to the complex nature of the parasite’s life cycle and despite decades of research on malaria, significant knowledge gaps remain. To address these unanswered questions, NIAID supports basic research into parasite-host interactions, from the genetics of the parasite to the processes that allow the parasite to invade human cells, where they replicate and further develop into different life cycle stages. Progress is being made, and an increased understanding of the biology of the malaria parasite is helping researchers develop new and improved drugs, important to address the inevitable development of drug resistance. In addition, such understanding can provide insights into how malaria parasites evade host immunologic defenses, and thus inform the development of better immune-based preventive and therapeutic interventions. NIAID also supports basic research into how the parasite develops over the course of its life cycle. The changes it undergoes allow it to be transmitted from humans to mosquitoes, to survive and develop in the mosquito, and to be transmitted from mosquitoes back into humans. Insights gained from these studies will help identify novel approaches to disrupt malaria transmission.
The lack of an effective malaria vaccine has severely hampered efforts to control malaria. In October 2021, the World Health Organization recommended the use of the Mosquirix malaria vaccine (also known as RTS,S/AS01), developed by GlaxoSmithKline, for children living in areas with moderate-to-high transmission of Plasmodium falciparum, the deadliest malaria parasite. While this significant achievement will save lives, the vaccine is only moderately effective, and a safe vaccine with greater and longer lasting efficacy is still urgently needed. To help in the search, NIAID conducts and funds research on a variety of vaccines that target different points in the parasite’s life cycle.
For example, NIAID has supported research on the PfSPZ vaccine, developed by biotechnology company Sanaria. The PfSPZ chemoprophylaxis vaccination approach induces immunity by introducing weakened live parasites into the body. One strategy involves weakening the parasites by radiation, thereby reducing their ability to progress in their life cycle while still eliciting protective immune responses. A second approach involves introducing live parasites in combination with either of two widely used antimalarial drugs, which kill the parasites once they have progressed to the liver or blood stage of their development. In June 2021, NIAID researchers published promising results from a clinical trial showing that this combination of live parasites and antimalarial drugs conferred high levels of durable protection when volunteers were later exposed to disease-causing malaria parasites. A larger Phase 2 trial has also evaluated the regimen in adults in Mali.
Various antimalarial drug regimens can effectively treat and control the disease. However, as certain strains of malaria parasites develop resistance to existing drugs, new treatments are urgently needed. Scientists at NIAID’s Vaccine Research Center isolated an antibody from the blood of a volunteer who had received an investigational malaria vaccine and cloned it in the laboratory to develop a monoclonal antibody (mAb) for malaria. The researchers evaluated the mAb, known as CIS43LS, in a clinical trial and found that it safely prevented malaria for up to nine months in people who were exposed to malaria parasites. A Phase 2 trial with CIS43LS in Mali has been completed. The results of this study, which assessed the safety and efficacy against natural malaria infection during the rainy season, will be submitted for publication soon.
To enhance protection and reduce cost, a new and more potent a monoclonal antibody known as L9 was recently isolated. In mice, L9 can neutralize the liver stage of the malaria parasite, according to research by NIAID scientists and colleagues. An updated version of L9 (L9LS) which has a longer half-life in the circulation, has completed Phase 1 clinical trials for safety and efficacy following controlled malaria infection; two Phase 2 studies will be performed this year in Mali and Kenya in infants and young children to assess safety and efficacy.
Improved diagnostics for malaria, especially for severe forms of the disease, continue to be an important goal of NIAID research. Currently, most malaria diagnostics rely on a blood sample; however, NIAID is supporting research into noninvasive tests. Auto Detection Software for Plasmodium Infection in Retinal Exams, or ASPIRE, is currently under development with NIAID support. Potentially, it could improve the diagnosis of cerebral malaria by observing the back of the retina to check for the presence of malaria parasites in blood vessels . Cerebral malaria can lead to brain damage, long-term neurological deficits and death, and researchers hope that the software could significantly reduce inaccurate diagnoses.
More precise diagnostics, which are designed to reveal the genetics of a malaria parasite, are also under investigation. These assays rely on CRISPR to detect certain genes in the malaria parasites found in a patient’s blood sample—including genes that grant the parasite resistance to antimalarial drugs. These tests could someday tell a healthcare provider which treatment to provide, without the risk of prescribing antimalarial drugs to which the parasite is resistant.
New, transformational technologies also can dramatically speed up processes that once took years. In this regard, NIAID supports research that relies on artificial intelligence and machine learning to identify promising leads for vaccines and drugs, speeding up the early-stage processes. Intensive data analysis has allowed researchers to glean insights from longitudinal studies on the role of asymptomatic infection in sustaining malaria transmission within a community, and to identify vulnerable populations that may need targeted malaria prevention measures.
Malaria currently impacts nearly half of the world’s population, and clinical trial networks have become instrumental in conducting the large-scale studies that have transformed malaria research in recent years. The NIAID-supported International Centers of Excellence for Malaria Research (ICEMR) program supports epidemiologic and field research at more than 50 field sites in 17 countries where malaria is endemic. The multidisciplinary research infrastructure at ICEMR sites has also allowed ICEMR investigators to support large-cluster randomized trials to produce data on new and established malaria interventions. Ongoing studies are evaluating new kinds of bed nets, targeted mass drug administration in high-risk areas, and whether a broader age range of children can benefit from being given anti-malarial drugs during seasons when there is a high risk of malaria. Recent research from the ICEMR program has identified previously unknown groups that contribute to malaria transmission, including school-age children and people with chronic asymptomatic malaria infection. Researchers hope these findings may help inform new malaria control strategies.
Despite the new challenges posed by the COVID-19 pandemic, NIAID researchers continue to make progress in easing the global burden of malaria. On this World Malaria Day, NIAID reaffirms its dedication to pushing back against this evolving disease, using cutting-edge technologies, and novel approaches to old challenges, to accelerate progress in malaria research.
B.F. “Lee” Hall, M.D., Ph.D., is chief of the Parasitology and International Programs Branch in the NIAID Division of Microbiology and Infectious Diseases. Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, Maryland.