NIAID Now | April 24, 2020
Today NIAID marks World Malaria Day, acknowledging the profound impact of this ancient, mosquito-borne parasitic disease, which in 2018 sickened 228 million people and killed approximately 405,000 worldwide. This year, the observance comes amid a pandemic caused by a new disease, COVID-19, that is straining global health systems, complicating malaria control programs, and threatening the progress toward malaria elimination that has been made since 2000. At this critical juncture, NIAID officials are working with counterparts in the World Health Organization (WHO) and other governmental and non-governmental organizations to maintain and tailor malaria interventions in the context of COVID-19 response.
The World Malaria Day theme, “Zero malaria starts with me,” encourages governments, academic institutions, philanthropies, and others to prioritize research, mobilize resources, and empower communities affected by malaria. Selected examples of recent advances by NIAID investigators and NIAID-supported scientists featured below illustrate how the Institute is working to reach “zero malaria” through research projects that include discovery, development, and evaluation of new or improved diagnostics, treatments, and mosquito control interventions, as well as the development and testing of vaccine candidates.
A search of the malaria parasite Plasmodium falciparum (P. falciparum) genome by NIAID scientists identified a key source of its ability to elude human immune responses. The investigators examined parasite transcription factors—proteins that regulate activity of other genes—and determined that altering a single nucleotide in one transcription factor gene severely hampered the parasite’s ability to withstand immune system responses. Because this transcription factor regulates the activity of 46 different genes, any number of those genes may play a role in making Plasmodium more visible to the immune system. The researchers say further exploration of those genes may help uncover targets for experimental therapeutics or a preventative vaccine.
Controlling malaria requires controlling the mosquitoes that carry and transmit the parasite. NIAID-supported researchers and their collaborators in Burkina Faso developed a novel form of mosquito control using Metarhizium pingshaense, a fungus that is harmless to people, but deadly for mosquitoes. In a semi-field trial, the team exposed insecticide-resistant mosquitoes to a hybrid strain of fungus and determined that fungus-infected mosquitoes had significantly shorter life spans than non-exposed mosquitoes and produced fewer viable eggs. Metarhizium biopesticides have previously been used in some African countries to control agricultural pests with no negative effects on the environment or non-target insect populations.
Overcoming Antimalarial Drug Resistance
Resistance to the malaria drugs chloroquine and piperaquine is associated with distinct sets of mutations in the Plasmodium falciparum chloroquine-resistance transporter (PfCRT) protein, which spans a membrane inside the parasite and helps it overcome drug effects. Efforts to design new antimalarials to counteract drug resistance have been stymied by lack of information about the structure and function of PfCRT. NIAID-supported investigators broke the impasse by revealing the atomic-level structure of PfCRT and determining how changes at specific locations allow it to resist malaria drugs. This new structural and functional information can now be applied to design next-generation antimalarials.
Target Drug Discovery
Recent annual World Malaria Reports from the WHO suggest that progress toward malaria elimination has slowed or stalled in some regions. Regaining momentum requires new tools and interventions, including long-acting drugs that can inhibit malaria parasites in more than one of their life-stages. Such drugs could play a critical role in reducing circulating parasite numbers in endemic regions and would aid in elimination campaigns. An international team of scientists, including NIAID-funded investigators, screened nearly 30,000 compounds and identified potent inhibitors of a family of parasite proteins called Pf CLK3. Inhibiting PfCLK3 slowed activity in more than 400 genes known to be essential for parasite survival. Moreover, PfCLK3 inhibitors acted against sexual and asexual stages of parasite development in multiple parasite species. The researchers concluded that PFCLK3 is a potential target for new preventative and therapeutic drugs as well as a target to block the transmission of parasites from host to host.
Human Immune Response
People who live where malaria is common gradually develop the ability to control parasites and typically experience milder cases of disease as they age. A detailed picture of the underlying molecular mechanisms of infection-induced host immune responses would greatly aid the design and evaluation of new malaria interventions, including vaccines. NIAID scientists and NIAID-supported researchers developed such a picture by collecting blood samples from Malian children over three years (thus covering multiple malaria seasons.) The team found that a child’s first parasite infection resulted in one of three reactions: infection without symptoms; infection and delayed fever; or concurrent infection and fever. They then compared a suite of immune responses among the groups and discovered a strong association between the presence of a set of specific human immune responses and the ability to control both parasite replication and fever. Insight into which immune reactions are linked to parasite and symptom control will assist vaccine designers to make products that elicit similar responses.
Research on Vaccines and Related Immunologic Interventions
NIAID supports the development of numerous candidate malaria vaccines. The Institute has conducted and supported multiple early-stage clinical trials of PfSPZ, a candidate malaria vaccine made of weakened malaria parasites. It is intended to prevent malaria infection and is now being evaluated in multiple clinical trials in malaria-endemic regions, including in infants and children.
NIAID researchers also are working on a candidate vaccine designed to block transmission of the malaria parasite from infected humans to mosquitoes. Although a transmission-blocking vaccine would not prevent malaria infection, by limiting further spread it could reduce new malaria infections in communities over time. A clinical trial of the investigational vaccine in Mali returned promising results and planning for a phase 2 clinical trial testing its efficacy is underway.
Scientists from NIAID’s Vaccine Research Center are continuing to advance the development of a monoclonal antibody, CIS43LS, that could be used for seasonal control and targeted elimination efforts as well as by tourists, health care workers, and military personnel to prevent malaria infection. A trial evaluating the antibody’s safety and efficacy against a controlled human malaria infection began earlier this year. NIAID experts also are collaborating with Malian scientists to discover additional broadly protective monoclonal antibodies.
The malaria vaccine MosquirixTM(RTS,S/AS01) is the furthest along in human efficacy trials, but in a Phase 3 trial it was found to be only moderately successful at preventing infection and the durability of protection was less than desired. NIAID-funded scientists performed immunological analyses on clinical samples from children and infants who had been vaccinated with RTS,S and who live in areas with differing levels of malaria in the community. They found that the quality of vaccine-elicited antibodies (the avidity with which they bound to their targets) mattered more than antibody quantity as a predictor of how well RTS,S would perform. This improved understanding of markers associated with RTS,S vaccine protection will guide future vaccine design improvements.
In research published this week, NIAID-supported investigators described a human antibody that causes malaria parasites inside red blood cells to self-destruct before they can multiply. The new research builds on information gathered by NIAID scientists during a multi-year study of Tanzanian children, which revealed that some children were naturally more resistant to severe malaria than others. The new study offers one reason for the difference: malaria resistance is tied to higher levels of an antibody that acts against the parasite protein PfGARP. The team developed experimental vaccines designed to deliver PfGARP (thus stimulating anti-PfGARP antibody production) and tested them in nonhuman primates. Results of those experiments are promising, the scientists say, raising the possibility of developing similar vaccines for humans in the future.
In this pandemic year, the goals of malaria control and eradication may appear to be in retreat. But there is reason to remain optimistic. A new WHO report weighs various threats to malaria eradication, including threats posed by epidemics of other diseases. The report concludes that while epidemics may cause short-term setbacks, malaria eradication is still a worthwhile goal and should remain the long-term vision. Progress toward that vision requires commitment and on this World Malaria Day NIAID reaffirms its commitment to continue supporting robust research aimed at achieving a world free of malaria.