Will monoclonal antibodies be a new weapon in the fight against malaria?

Monoclonal antibodies have revolutionized the treatment of cancer, autoimmune diseases, and inflammation in wealthier countries. But their role in treating and preventing infectious diseases was limited. Until COVID-19.

The emergence of SARS-CoV-2 heralded the first time that mAbs were mass produced — millions of doses were manufactured and administered in the U.S. alone — to combat any infectious disease. But, as our last IAVI Report article details, use of these antibodies was largely confined to the wealthiest countries, and their impact was short lived. The coronavirus’s rapid evolution quickly rendered these mAbs futile.

This experience, along with numerous challenges to developing, manufacturing, and delivering mAbs against much more complicated and variable pathogens such as HIV, is prompting some researchers to question just how large a role these proteins can, and should, play in response to infectious diseases.

For malaria, researchers are now facing this question head on. Several mAbs are in development to either prevent infection with Plasmodium falciparum, the deadliest malaria parasite and the most prevalent in Africa, or to protect against symptomatic disease, and some are showing great promise.

Recent results from a Phase 2 clinical trial show that a single subcutaneous injection of the engineered mAb L9LS was 77% effective in protecting against symptomatic malaria in children ages six to 10 years old, and 70% effective at protecting against P. falciparum infection overall during the six-month rainy season in Mali when malaria infections peak. L9LS was the second mAb developed and engineered to have a longer half-life by researchers at the Vaccine Research Center (VRC) at the U.S. National Institute of Allergy and Infectious Diseases (NIAID).

In a prior Phase 2 clinical trial with the first malaria mAb (CIS43LS), an intravenous infusion was either 88% or 75% effective at preventing infection in Malian adults from P. falciparum over a six-month malaria season when administered at a dose of either 40 or 10 milligrams respectively per kilogram of body weight. Together, these studies show that mAbs against malaria are highly effective at preventing seasonal malaria infection in two different age cohorts.

Now, researchers await results from an ongoing study of the L9LS mAb in infants and children ages five months to five years in Kenya, where malaria risk remains high year-round. They are also planning trials in younger infants (10-weeks old) and pregnant women, other groups at risk of increased morbidity and mortality from malaria. “This is what we envision as the next steps,” says Kassoum Kayentao, an epidemiologist at the Malaria Research and Training Center at the University of Bamako and lead author on the latest L9LS research paper.

Meanwhile, researchers at NIAID, funders, including the Gates Foundation and Unitaid, and product development partnerships, including the Medicines for Malaria Venture (MMV), are already considering how these malaria mAbs could fit into the bigger picture of malaria prevention, or even potential elimination. To do so they must contend with the high cost of developing and manufacturing these proteins and then delivering them in low- and middle-income countries that bear the highest malaria burden, something that hasn’t really been accomplished for any mAb product to date.

“I think the thing that most commonly comes up is just whether you really can get this to be cheap enough, and, if you can, then that’s the game,” says Robert Seder, Chief of the Cellular Immunology Section at the VRC at NIAID, who identified and developed both the CIS43LS and L9LS mAbs and is deeply involved in preparations for the potential introduction of malaria mAbs. “Ultimately it is going to be about cost.”

The high cost of mAbs is not a new issue. In 2020, IAVI and Wellcome published a call to action emphasizing the importance of investing in and applying new technologies to lower the costs of producing and developing mAbs, as well as other policy and advocacy efforts that could pave the way to broader mAb introduction and use in low- and middle-income countries. Then, earlier this year, IAVI, the Medicines Patent Pool, Unitaid, and Wellcome published a report based on a 2023 consultation focused on identifying novel business models to ensure mAb access.

Now, as data from clinical trials of malaria mAbs comes in, these ongoing discussions about cost, demand, and access are intensifying. How these issues get addressed for malaria could set the stage for the broader use of mAbs in populations that haven’t yet reaped their benefits. “Malaria may be the tip of the iceberg or the tip of the spear that could prove that you could make antibodies cheaply and get them into low- and middle-income countries,” says Seder.

The authors of this review article agree, saying, “mAbs for malaria are poised to become a paradigm-shifting intervention.” In some ways, they are already. “This is the first time that

studies show that a monoclonal antibody can prevent an infection of public health importance in Africa,” says Peter Crompton, Chief of the Malaria Infection Biology and Immunity section at NIAID, who is also helping to lead the clinical development of the L9LS mAb.

For Crompton, the conversations about mAb access echo earlier debates in global public health. “I was in medical school in the 90s, and I remember the debate about antiretroviral drugs for HIV. They became available here but were considered too expensive for Africa. I feel like this is the same kind of argument. Monoclonals are great, but they’re not for Africa. Well, I don’t buy that at all.”

But the questions of who will buy them and at what price still linger. What remains abundantly clear, however, are the devastating consequences of this parasitic disease. In 2022, there were 294 million cases of malaria — 94% of which occurred in Africa, according to the World Health Organization (WHO). Malaria claimed more than 600,000 lives that year; 95% of those deaths occurred in Africa, and 76% of them occurred in children under the age of five. One in five childhood deaths in sub-Saharan Africa from all causes are due to malaria, according to the Jenner Institute at Oxford University.

Yet progress in battling malaria, a disease that has afflicted humans for millennia, is sluggish, at best. According to a statement issued by the WHO on April 25 in commemoration of this year’s World Malaria Day: “Progress in reducing malaria has ground to a standstill.” This standstill is occurring despite several available preventive and therapeutic options: insecticide-treated bed nets, early diagnosis and treatment with anti-malarial combination therapies, chemoprevention for those at highest risk of developing severe disease, including infants, children, and pregnant women, as well as the recent authorization of two malaria vaccines, GSK’s RTS,S/AS01 and the Jenner Institute’s R21/Matrix-M.

More than 2 million children in Ghana, Kenya, and Malawi have already received the RTS,S/AS01 vaccine through the Malaria Vaccine Implementation Program, supported and coordinated by the WHO, Gavi, the Vaccine Alliance, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and Unitaid. More countries are planning to launch vaccination programs with RTS,S and R21 soon, according to the WHO.

Kayentao says Mali may be one of the countries introducing malaria vaccines next year. He is eager to see the vaccines get introduced, yet he still thinks the L9LS mAb has several advantages. “First of all, it’s easy to administer. It’s only one subcutaneous injection,” he says. And that single shot provides immediate protection for six months, whereas the RTS,S vaccine requires three injections in the primary series followed by a booster dose.

“In addition to the four contacts with the medical system that are required for the existing vaccines, there is also the need to administer seasonal malaria chemoprevention four times during the six-month rainy season each year in countries in the Sahel region,” Kayentao explains. “So, in terms of deployment, it [the mAb] makes sense to me.”

The authors of the recent study on the L9LS mAb say that a proposed strategy of combining seasonal malaria chemoprevention with an annual vaccine booster would require over 20 healthcare contacts for children by the time they reach five years of age.

“The real unmet public health need is a highly effective prevention tool that can be given in a single healthcare contact. That would solve a lot of problems,” says Crompton. “There are 50 million or so kids in sub-Saharan Africa that every month for four to five months out of the year are eligible to receive a three-day course of anti-malarial drugs, and although this is a critically important program, you can imagine that it’s a challenge to implement,” he explains. “Adherence can also be a challenge. The first dose is directly observed, but typically subsequent doses are left with the caregiver, who may or may not complete the course. If you couple that with the threat of drug resistance, we think the idea of swapping that out with a single injection of a mAb before the rainy season has obvious advantages.”

For several years, public health agencies have warned against the spread of malaria parasites in several areas of Africa that are resistant to some of the most common drugs. A potential advantage of the mAb, which targets a specific and highly conserved region on the sporozoite transmitted by the mosquito into humans, is that the development of resistance may be less likely. Unlike viruses, including SARS-CoV-2, that replicate and can mutate to escape antibodies, the sporozoites transmitted from mosquitos to humans don’t initially replicate. “They only replicate when they get into the liver. There isn’t really any biologically plausible mechanism by which the sporozoite could escape in vivo under the pressure of a monoclonal as happens with viral infections,” explains Crompton. “The mosquito injects about 100 sporozoites into the skin and blood, and within minutes to hours, these sporozoites have invaded hepatocytes so it’s also a very brief window where they are actually exposed to the monoclonal.”

So far, according to Seder, they have only detected a single mutation in one parasite out of 30,000 in Africa that could render the L9LS mAb less effective, so it is not something researchers are too worried about.

What they are worried about is the cost of manufacturing antibodies. When manufactured at scale, small molecule drugs and vaccines can be made cheaply. Even mRNA vaccines, which were the linchpin of the response to the COVID-19 pandemic in wealthier countries, are expected to be manufactured more widely and at a much lower cost in the near future.

But the infrastructure required to manufacture antibodies is more complicated and more expensive. “It requires a much bigger footprint,” says Seder. “And the question is who has the capacity to do it for minimal profit?” Seder says generic manufacturers, including the Serum Institute of India which has made an enormous business out of mass-producing vaccines and selling them at low prices in low- and middle-income countries, have not made antibodies to the same scale as vaccines.

And unlike the mAbs for respiratory syncytial virus that were recently developed by AstraZeneca/Sanofi and Pfizer, there isn’t as much demand for malaria antibodies outside of areas where there is seasonal or year-round transmission. “This would be a wonderful tool for travelers to avoid chemoprophylaxis, which is effective but has a number of challenges, but it’s not like COVID or HIV where there is a large dual market,” says Crompton.

Lowering costs will therefore be critical to making mAbs affordable and available in low- and middle-income countries. One way to make mAbs cheaper is to make them more potent. More potent antibodies require lower doses, and lower doses mean lower overall costs. This approach was highlighted in an editorial by Trevor Mundel, President of Global Health at the Gates Foundation, which accompanied the latest results on the L9LS mAb in the New England Journal of Medicine. “Further improvements in both potency and pharmacokinetics are likely to be needed in order for monoclonal antibodies to have a broad effect in reducing the malaria burden,” he wrote.

Work is already underway to further improve L9LS’s potency and researchers at NIAID are confident this can be achieved. “I think we are close with what we have now, but if we can make something two- or three-fold better that lasts long, that’s probably all we need,” says Seder. “I do think we can get there.”

Crompton says the goal is to be able to produce the antibody at a cost of approximately U.S.$50 a gram. For infants, one of the groups that stands to benefit the most from a malaria mAb, a single dose could be around 150 milligrams, or approximately $8 a dose. Right now, seasonal chemoprevention costs about $5 per child per year. “So that’s getting in the range of being competitive with seasonal malaria chemoprevention. And if it [the mAb] means better compliance, less risk of drug resistance, and easier implementation, then it’s kind of hard to ignore that,” he adds.

Further studies will also help delineate the best uses for malaria mAbs either in conjunction with or instead of existing interventions. There are several circumstances in which the type of high-level, immediate protection offered by a mAb would be useful in helping to lower malaria morbidity and mortality. One of these circumstances is protecting infants. The two existing malaria vaccines are only approved for infants older than five months of age and it takes three dose to establish immunity, so if a mAb could help protect infants through their first year of life, that would be one clear use case.

Another situation where mAbs could be useful is for children who are being discharged after being hospitalized with severe anemia or malaria. These children are often malnourished, and, as a result, they have a 30% increased risk of dying upon discharge, according to Seder. Current guidelines are to provide these children with oral malaria chemoprevention every month for three months after hospitalization to reduce this risk, but Seder and Crompton foresee an opportunity to replace this with a single dose of mAb before hospital discharge that could protect the children for six months, thereby eliminating the need for compliance to the anti-malarial drugs.

A third scenario is to administer the mAb to women at risk of malaria before or shortly after they become pregnant. Here again, though, cost will be the major issue as adults weigh more and will require much larger doses of antibody than children or infants.

Yet another role for the mAb would be in school-age children who are not eligible for vaccination with the current vaccines and who are less likely to receive chemoprevention during the malaria season, yet still suffer a high burden of malaria. The disease isn’t as deadly in these children, but it still makes them quite sick.

Ultimately, cost may be the biggest factor in determining if or how these antibodies are used. Which is why researchers are continuing to optimize the L9LS antibody and others in development. “We feel our role as a government research institute is to keep moving this along the clinical development pathway and to essentially de-risk it,” says Crompton. “I’m optimistic that there will be a path to making it available and we feel like we can maximize the probability of that if we continue to advance the clinical development.”

In addition to the clinical development, there are also plans to advance viable business models that could enable an affordable and sustainable supply of mAbs. Unitaid recently closed a call for proposals to fund work that seeks to identify and demonstrate the feasibility of different strategies for equitable access to mAbs for major public health challenges in low- and middle-income countries, as well as for future pandemics and emerging threats. The goal is to identify models for reducing the cost of producing and delivering mAbs, addressing regional priorities, and engaging with communities who stand to benefit from their use.

“It’s important to highlight that this call for proposals was disease and product agnostic,” says Anne-Isabelle Cameron, a technical officer on the strategy team at Unitaid. “We’re looking at mAbs for infectious diseases broadly and trying to answer some of the critical questions about how supply models could work to meet potential demand from low- and middle-income countries. We need to anticipate and remove potential access barriers now, both for demand and supply, for mAbs in resource-limited settings.”

The Gates Foundation is also investing in technologies to increase the likelihood that mAbs will become more widely available for malaria, and other infectious and non-infectious diseases as well. In an interview on malaria mAbs on the Foundation’s website, Jacqueline Kirchner, who leads the foundation’s grantmaking for biologics, said: “I’m very optimistic that monoclonal antibodies and other biologics will be democratized and will be made available at a much lower cost than they are right now. This may not happen through any one technology. It will likely be through multiple approaches.”

Although malaria antibodies are rapidly advancing, everyone agrees that the goal is to develop strategies that will apply far beyond this single disease. “We need to be thinking about this holistically and focus generically on the need to get mAbs into Africa whether it’s for infectious diseases, future pandemics, or wider use of anti -cancer or autoimmune mAbs,” says Seder. “And I think this will happen.”