NIAID Marks World Malaria Day

April 25, 2023

Statement of Hugh Auchincloss, M.D., B.F. “Lee” Hall, M.D., Ph.D., and Robert Seder, M.D.
National Institute of Allergy and Infectious Diseases
National Institutes of Health
 

Colorized electron micrograph showing malaria parasite (right, blue) attaching to a human red blood cell. The inset shows a detail of the attachment point at higher magnification.

Credit: NIAID

Malaria, a parasitic disease transmitted by mosquitoes, has ravaged humankind since ancient times and still imposes a heavy burden on the world’s most vulnerable. Fully half of the global population is at risk of infection, and repeated bouts of illness are not uncommon. According to the World Health Organization, an estimated 247 million new malaria cases occurred in 2021, the second straight year that number rose after 20 years of decline. Uncomplicated malaria cases are characterized by debilitating cycles of high fever, intense chills, fatigue and sweating. Severe malaria can lead to organ failure, shock, severe anemia, coma and—all too often—death. In 2021, malaria claimed the lives of an estimated 619,000 people, most of whom were children under age five.

World Malaria Day is an opportunity to reflect on continuing challenges posed by malaria and reaffirm a commitment to overcoming them. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, joins with the global health community in recognizing this year’s theme of “Time to Deliver on Zero Malaria: Invest, Innovate, Implement.”

One very promising innovation for malaria prevention involves administering monoclonal antibodies (mAbs) that rapidly neutralize parasites just after they enter the bloodstream and before they can reach the liver to initiate disease. With further clinical development, these mAbs could be a powerful tool for seasonal malaria control in infants and children. They also could help prevent malaria during pregnancy, which, if left untreated, can cause pregnancy loss, stillbirth and low birth weight. CIS43LS, the first mAb to be tested as a malaria preventative, was developed by scientists at the NIAID Vaccine Research Center (VRC). An NIAID-sponsored trial of CIS43LS conducted in Mali during the annual six-month period of intense malaria transmission found that a single, intravenous dose was up to 88% effective at preventing infection in non-pregnant adults over a period of 24 weeks. This trial was the first time a mAb was shown to prevent infection in a malaria-endemic setting.

A second VRC-developed mAb, L9LS, was found to be safe and highly protective when tested in an NIAID-sponsored Phase 1 trial in U.S. adults. L9LS is more potent than CIS43LS and can be administered at lower doses via subcutaneous injection, a more cost-effective and logistically feasible route than intravenous infusion. NIAID-sponsored Phase 2 trials in Mali and Kenya are now evaluating if mAb L9LS can prevent malaria in infants and children.

MAbs for malaria prevention are safe and well-tolerated and can be used in all age groups including pregnant women. Unlike vaccines, which may require multiple doses and take time to have a protective effect, mAbs begin to work immediately after a single dose. Also, the VRC-developed mAbs target a part of the parasite that varies very little from strain to strain. As such, they likely will be effective against most circulating parasite strains. Ongoing and future trials could establish the promise of mAbs as a new intervention for prevention of malaria across several age groups and clinical uses.

Earlier this month, health authorities in Ghana and Nigeria approved a malaria vaccine called R21 for use in young children. Developed by Oxford University scientists and manufactured by Serum Institute of India, R21 is the world’s second malaria vaccine to be approved by regulatory bodies following the 2021 World Health Organization recommendation of Mosquirix malaria vaccine (also known as RTS,S/AS01) for children. These first vaccines are welcomed as an important way to save lives, but there remains a need for additional malaria vaccines with greater and longer lasting efficacy. NIAID conducts and supports many research projects aimed at this goal.

For example, scientists in NIAID’s Laboratory of Malaria Immunology and Vaccinology (LMIV) develop and clinically evaluate a variety of prototype malaria vaccines. Among these are transmission-blocking vaccines (TBV), which do not directly protect vaccinated persons from infection. Instead, TBVs kill malaria parasites when they enter mosquitoes as the insects take a blood meal from a vaccinated person. Using these vaccines, the chain of infection would be broken because uninfected mosquitoes no longer transmit parasites from person to person. The LMIV’s leading TBV candidate is being tested in Phase 2 trials in Mali and additional trials are planned in other West African countries.

NIAID has also long supported research on PfSPZ malaria vaccine candidates. These vaccines contain live parasites (in the sporozoite, or SPZ, stage of their lifecycle) that have been weakened by radiation so that they cannot cause serious infection but can still prompt a protective immune response. Among the studies and trials of various PfSPZ vaccine candidates tested by NIAID-supported researchers was one that exposed vaccinated volunteers to either the same strain of parasite as contained in the vaccine or a strain that differed genetically. Overall vaccine efficacy compared to placebo was 78%, regardless of the challenge strain used. Another NIAID-funded investigator led a Phase 1 trial of a PfSPZ vaccine candidate in adults in Burkina Faso, Africa. The trial found that a series of three vaccine doses, rather than a five-injection regimen previously tested in a Malian trial, was safe and stimulated production of antibodies against malaria parasites.

NIAID also supports research on improved PfSPZ vaccines, including a product that contains sporozoites weakened through removal of specific genes. In human malaria challenge studies using mosquito bites to deliver vaccine, one such genetically attenuated PfSPZ vaccine was shown to be more potent and required lower doses than earlier candidate PfSPZ candidates. This new PfSPZ vaccine candidate may enter a Phase 1 trial soon.

The conventional way of obtaining parasites for malaria vaccine research and production is extremely laborious and difficult to standardize or scale up. It requires secure insectaries where mosquito larvae are raised until the sporozoites mature inside the adult mosquito salivary glands. Lab personnel must then manually remove the parasite-filled glands from each insect before they can be processed for vaccine or other research uses. In 2022, NIAID-funded researchers made a very significant advance when they succeeded in growing sporozoites in lab-grown cells (in vitro) without the need for mosquitoes. These mosquito-free sporozoites can invade lab-grown liver cells where they mature into the form that creates disease in humans. The innovation of in vitro grown sporozoites that can be produced at large scale will open new avenues for research on parasite biology and will allow novel sporozoite vaccines to be produced more efficiently.

NIAID also supports research to develop improved malaria diagnostics. For example, NIAID-funded investigators are developing a point-of-care malaria diagnostic that detects hemozoin, a by-product of malaria-infected red blood cells. Such a hemozoin-based test could be an improvement over currently available tests that are based on detecting a parasite protein called histidine-rich protein 2 (HRP2). Because some malaria parasites have mutations in the HRP2 gene they cannot be identified using available rapid diagnostic tests. NIAID also recently solicited proposals to develop CRISPR-based malaria diagnostics. This approach offers several advantages including high programmability and compatibility with low cost and ease-of-use and would be appropriate for use in resource-constrained settings.

In 2010, NIAID established the International Centers of Excellence for Malaria Research (ICEMR) program. This global network of independent research centers comprising more than 50 field sites in 17 malaria-endemic countries works to provide basic knowledge, interventions and evidence-based strategies needed to understand, control and ultimately prevent malaria. The multidisciplinary research infrastructure at ICEMR sites allows for large-scale randomized trials that efficiently generate data about the efficacy of both new and established malaria interventions.

Some of the numerous accomplishments of ICEMR-funded researchers were detailed in a recent report published in the American Journal of Tropical Medicine and Hygiene. Among these was the finding, in a setting of high malaria in Uganda, that repeated indoor residual spraying with effective insecticides resulted in almost complete elimination of clinical malaria cases within five years. Previously, children in this region typically suffered three to five cases of malaria each year.

Research by ICEMR scientists has also shed light on various aspects of mosquito ecology and behavior, yielding new knowledge that might be applied to the control of these disease-spreading insect vectors. For example, ICEMR-conducted investigations in Africa, Latin America and Asia detected a shift in the biting behavior of mosquitoes, with more mosquitoes biting outdoors and earlier in the evening than previously observed. This change in vector behavior could mean that standard mosquito controls, such as insecticide-treated bed nets and indoor residual insecticide spraying, may become less effective than in the past. Other vector research by ICEMR investigators is aimed at finding new, sustainable ways to reduce human-mosquito contact outdoors. One promising approach, studied in Mali, involved developing traps containing toxic sugars to lure mosquitoes. Further research is ongoing on this vector control tool, which may be best suited to dry environments where sugar-containing vegetation is sparse.

The challenges of controlling malaria are formidable, but innovation, investment and implementation efforts exemplified here show that they can be overcome. On this World Malaria Day, NIAID recognizes the dedication of the world’s scientists and all those who are working to end malaria.     

Hugh Auchincloss, M.D., is Acting Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. 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. Robert Seder, M.D., is Chief of the Cellular Immunology Section and Acting Chief, Vaccine Immunology Program, in the NIAID Vaccine Research Center.

Image shows: Colorized electron micrograph showing malaria parasite (right, blue) attaching to a human red blood cell. The inset shows a detail of the attachment point at higher magnification.
Credit: NIAID

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