Novel class of anti-malaria antibodies could lead to next-generation interventions

A novel class of antibodies that binds to a previously untargeted portion of the malaria parasite could lead to new prevention methods, according to a study by researchers at the National Institutes of Health (NIH) published today in Science.

The most potent of the new antibodies was found to provide protection against malaria parasites in an animal model. The researchers say antibodies in this class are particularly promising because they bind to regions of the malaria parasite not included in current malaria vaccines, providing a potential new tool for fighting this dangerous disease.

Malaria is a life-threatening disease caused by Plasmodium parasites, which are spread through the bites of infected mosquitoes. Although malaria is not common in the United States, its global impact is devastating, with 263 million cases and 597,000 deaths estimated by the World Health Organization in 2023.

Of the five species of Plasmodium that cause malaria, Plasmodium falciparum is the most common in African countries where the burden of malaria is largest and where young children account for the majority of malaria deaths. Safe and effective countermeasures are critical for reducing the immense burden of this disease.

In recent years, new interventions have been developed against malaria, including vaccines that are currently being rolled out for young children in regions where the disease is prevalent. Anti-malarial monoclonal antibodies (mAbs) are another promising new tool that has been shown to be safe and efficacious against infection with P. falciparum in adults and children in early clinical trials.

The anti-malarial mAbs evaluated in trials in malaria-endemic regions target the P. falciparum sporozoite—the life stage of the parasite that is transmitted from mosquitoes to people. By binding to and neutralizing the sporozoite, the mAbs prevent sporozoites from infecting the liver, where they otherwise develop into blood-stage parasites that infect blood cells and cause disease and death.

The most promising anti-malarial mAbs tested in humans to date bind to a protein on the sporozoite surface called the circumsporozoite protein (PfCSP) at locations near to or containing amino acid repeats in a region called the central repeat region. This portion of PfCSP is also included in the two available malaria vaccines. The researchers in the current study aimed to find mAbs that target new sites on the sporozoite surface.

Led by scientists at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), the research team used a novel approach to find new portions—or epitopes—on the sporozoite surface where antibodies bind. They isolated human mAbs produced in response to whole sporozoites, rather than to specific parts of the parasite, and then tested the mAbs to see if they could neutralize sporozoites in a mouse model of malaria. One mAb, named MAD21-101, was found to be the most potent, providing protection against P. falciparum infection in mice.

This new mAb binds to an epitope on PfCSP outside of the central repeat region that is conserved—or similar—between different strains of P. falciparum. Notably, the epitope, called pGlu-CSP, is exposed only after a specific step in the development of the sporozoite, but it is widely accessible on the sporozoite surface—a scenario that the researchers say could mean pGlu-CSP would be effective at eliciting a protective immune response if used in a vaccine.

As pGlu-CSP is not included in currently used malaria vaccines, mAbs targeting this epitope are unlikely to interfere with the efficacy of these vaccines if the vaccines and mAbs are co-administered. According to the scientists, this could provide an advantage because this new class of antibodies may be suitable to prevent malaria in at-risk infants who have not yet received a malaria vaccine, but may receive one in the future.

Findings from the study will inform future strategies for the prevention of malaria and may facilitate the development of new antibodies and vaccines against the disease, the researchers indicate. The scientists also note that more research is needed to examine the activity and effectiveness of the newly identified antibody class and epitope, according to their paper. The approach used in this study could also aid the development of a new generation of countermeasures against other pathogens, in addition to malaria.

A novel class of antibodies that binds to a previously untargeted portion of the malaria parasite could lead to new prevention methods, according to a study by researchers at the National Institutes of Health (NIH) published today in Science.

The most potent of the new antibodies was found to provide protection against malaria parasites in an animal model. The researchers say antibodies in this class are particularly promising because they bind to regions of the malaria parasite not included in current malaria vaccines, providing a potential new tool for fighting this dangerous disease.

Malaria is a life-threatening disease caused by Plasmodium parasites, which are spread through the bites of infected mosquitoes. Although malaria is not common in the United States, its global impact is devastating, with 263 million cases and 597,000 deaths estimated by the World Health Organization in 2023.

Of the five species of Plasmodium that cause malaria, Plasmodium falciparum is the most common in African countries where the burden of malaria is largest and where young children account for the majority of malaria deaths. Safe and effective countermeasures are critical for reducing the immense burden of this disease.

In recent years, new interventions have been developed against malaria, including vaccines that are currently being rolled out for young children in regions where the disease is prevalent. Anti-malarial monoclonal antibodies (mAbs) are another promising new tool that has been shown to be safe and efficacious against infection with P. falciparum in adults and children in early clinical trials.

The anti-malarial mAbs evaluated in trials in malaria-endemic regions target the P. falciparum sporozoite—the life stage of the parasite that is transmitted from mosquitoes to people. By binding to and neutralizing the sporozoite, the mAbs prevent sporozoites from infecting the liver, where they otherwise develop into blood-stage parasites that infect blood cells and cause disease and death.

The most promising anti-malarial mAbs tested in humans to date bind to a protein on the sporozoite surface called the circumsporozoite protein (PfCSP) at locations near to or containing amino acid repeats in a region called the central repeat region. This portion of PfCSP is also included in the two available malaria vaccines. The researchers in the current study aimed to find mAbs that target new sites on the sporozoite surface.

Led by scientists at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), the research team used a novel approach to find new portions—or epitopes—on the sporozoite surface where antibodies bind. They isolated human mAbs produced in response to whole sporozoites, rather than to specific parts of the parasite, and then tested the mAbs to see if they could neutralize sporozoites in a mouse model of malaria. One mAb, named MAD21-101, was found to be the most potent, providing protection against P. falciparum infection in mice.

This new mAb binds to an epitope on PfCSP outside of the central repeat region that is conserved—or similar—between different strains of P. falciparum. Notably, the epitope, called pGlu-CSP, is exposed only after a specific step in the development of the sporozoite, but it is widely accessible on the sporozoite surface—a scenario that the researchers say could mean pGlu-CSP would be effective at eliciting a protective immune response if used in a vaccine.

As pGlu-CSP is not included in currently used malaria vaccines, mAbs targeting this epitope are unlikely to interfere with the efficacy of these vaccines if the vaccines and mAbs are co-administered. According to the scientists, this could provide an advantage because this new class of antibodies may be suitable to prevent malaria in at-risk infants who have not yet received a malaria vaccine, but may receive one in the future.

Findings from the study will inform future strategies for the prevention of malaria and may facilitate the development of new antibodies and vaccines against the disease, the researchers indicate. The scientists also note that more research is needed to examine the activity and effectiveness of the newly identified antibody class and epitope, according to their paper. The approach used in this study could also aid the development of a new generation of countermeasures against other pathogens, in addition to malaria.