In a discussion with Malaria No More, Dr. Robert Seder and Dr. Peter Crompton, from the National Institutes of Health (NIH), talk about a new study that found that one dose of a monoclonal antibody medicine developed at NIH strongly protected adults from infection with the parasite that causes malaria during a six-month period and may have prevented malaria transmission to others. Based on these results, the findings indicate that antibody-based medication could eventually be used to help eliminate malaria from places where the disease regularly occurs.

Can you tell us about the study?

CROMPTON: The simple idea here is that we don’t yet have any tools that block the first stage of the malaria life cycle with high efficacy to completely prevent infection across all age groups. That’s when the mosquito injects the parasite when it first bites a human. And of course, a tool that could do that would have a dual benefit. One, it would prevent the subsequent development of blood stage parasites that cause disease and kill people. But two, it could also prevent the subsequent development of gametocytes that are taken up by mosquitoes and then transmitted to others. And so that is what we think is exciting about this report: for the first time we show that monoclonal antibodies that target sporozoites can do this.

SEDER: The Plasmodium falciparum parasite – the most prevalent and pathogenic malaria parasite – causes over 200 million cases of malaria and about 600,000 deaths, mostly in children in Africa, each year. We also know that malaria infection begins when mosquitoes inject a small number of parasites, called sporozoites, into the skin and blood. Those sporozoites then invade the liver and multiply before re-entering the bloodstream in large numbers as merozoites that cause disease, and gametocytes that are transmitted back to mosquitoes. But we’ve long believed that an intervention that completely blocks sporozoite infection would prevent disease and onward transmission to others. This study is exciting because it is basically showing that we now have a potential new tool that provides sterile protection that could prevent both disease and transmission to others.

How does it work?

CROMPTON: CIS43LS is a long-acting monoclonal antibody that targets sporozoites. A few years ago, we conducted a clinical trial in Mali, funded by the National Institute of Allergy and Infectious Diseases, and found that CIS43LS protected adults from P. falciparum infection during an intense 6-month malaria season, as detected by microscopic examination of blood smears. Although blood smears are typically used to detect malaria infection in studies of malaria drugs and vaccines, they aren’t sensitive enough to detect low-level infections that can be transmitted back to mosquitoes. So, we still didn’t know if CIS43LS could provide complete protection against infection.

To answer that question, we re-analyzed the trial, but with the most sensitive method available for detecting malaria infection—a RT-PCR test that is 2000 times more sensitive than blood smears—to determine if CIS43LS provided complete (sterile) protection against infection, and we found that a single dose of CIS43LS was up to 87.4% efficacious in blocking RT-PCR-detected infections over 6 months.

We then took the analysis a step further and used a highly sensitive RT-PCR test that specifically detects gametocytes and found that CIS43LS was highly efficacious in preventing new gametocyte infections during the 6-month study, suggesting that protected study participants would not transmit malaria back to mosquitoes. 

We concluded that long-acting anti-sporozoite monoclonal antibodies could eventually be used in mass administration campaigns, in combination with malaria drugs the clear pre-existing infections, as a new strategy to prevent malaria disease while simultaneously decreasing transmission to accelerate malaria elimination.

Of note, the recently approved RTS,S and R21 malaria vaccines offer protection against malaria disease in young children, and they are a much-needed addition to the anti-malaria armamentarium, that also includes chemoprevention and insecticides. Like CIS43LS, the RTS,S and R21 vaccines target sporozoites, but there is little evidence that they provide sterile protection against infection across all age groups that would prevent onward transmission.

But since dosing monoclonal antibodies is weight-based, anti-sporozoite monoclonal antibodies may prove cost-effective for disease prevention in infants and children before they become affordable for mass administration across all ages in elimination campaigns. However, based on the results of this study, we are optimistic that as more potent anti-sporozoite monoclonal antibodies are discovered, and the cost of producing monoclonal antibodies continues to fall, that anti-sporozoite monoclonal antibodies could complement other malaria countermeasures and prove to be a feasible and cost-effective malaria elimination strategy.

SEDER: What is also exciting is that this study shows that a single dose of the monoclonal antibody provided immediate, high-level sterile protection, which makes this approach optimal for malaria elimination campaigns since it only requires one contact, as opposed to vaccines that often require multiple doses over months to achieve protection. And these antibodies are super safe. The challenge, of course, is the cost. Right now, it is estimated that a single dose of monoclonal antibody would cost about $8 for an infant. But because it’s weight-based dosing, when you get into adults, it is more expensive. We hope this study will catalyze efforts to bring the cost down, because as the cost of production goes down, this could eventually be a tool that can be used in mass administration campaigns across all ages, including women of childbearing potential, to prevent disease in susceptible populations and to reduce transmission and accelerate elimination. So that’s truly exciting!

Dr. Bob Seder is Chief of the Cellular Immunology Section in the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, NIH, and Dr. Peter Crompton is Chief of the Malaria Infection Biology and Immunity Section in the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, NIH.