Malaria Gamechangers, Part 8: Monoclonal Antibodies

Part 8 of our Malaria Gamechangers series (check out Episodes 1-7) highlights the development of monoclonal antibodies for malaria prevention. Many associate monoclonal antibody drugs with the COVID-19 pandemic. These man-made proteins, which act like human antibodies and offer passive immunity, hold tremendous potential well beyond COVID-19. In recent years, antibody candidates have emerged for cancer, autoimmune diseases, and other diseases – including malaria. The National Institute of Allergy and Infectious Diseases (NIAID) has developed a malaria antibody drug – CIS43LS – that has shown to be 88% effective at preventing malaria infection among adults throughout the six-month peak malaria season in Mali, Africa.

Unlike a vaccine, which relies on a strong immune response and takes time to develop protective antibodies, a monoclonal antibody protects almost immediately after injection and can work even in people with weakened immune systems. In addition, this monoclonal antibody drug requires just one dose, unlike the pioneering malaria vaccines which require multiple doses.

As with all antibody drugs, a key consideration is cost and scalability. Monoclonal antibodies are relatively expensive to produce and distribute. Therefore, as NIAID and its partners continue to conduct CIS43LS clinical trials, they have also developed a more potent antibody – L9LS – that can be administered in a smaller dose and thus be more cost-effective. NIAID is currently conducting L9LS trials in Mali and Kenya focused on children and women of childbearing potential, with the goal of showing high levels of safety and efficacy across all age groups, in areas of both seasonal and year-round transmission.

I recently interviewed the lead researcher, Dr. Robert Seder, who is the Chief of the Cellular Immunology Section in the NIAID’s Vaccine Research Center. You can watch the film and read the full interview below.

Emile Dawisha: Why are monoclonal antibodies a gamechanger in the fight against malaria?

Dr. Seder: So the Vaccine Research Center develop monoclonal antibodies to prevent malaria by neutralizing the parasite during the pre-erythrocytic stage, before it reaches the liver. The ability of antibodies to mediate high level protection by preventing infection, completely preventing infection, would also prevent onward clinical malaria and transmission. So we’re aiming to get it at the earliest bottleneck, where the parasites following infection are relatively low and they’re not replicating and they’re not variant. So it’s the ideal place to to attack and limit the initiation of the infection.

The potential advantages of using antibodies for passive prevention of malaria are many. First, monoclonal antibodies have an outstanding safety profile with minimal off target effects. Unlike vaccines that require multiple doses and take time to have a protective effect, monoclonal antibodies are effective shortly, usually as early as seven days following administration of a single dose. And they, at least so far, can remain highly protective for six months against intense seasonal transmission.

Also, unlike vaccines, antibodies don’t depend on the host immune system for generating an immune response to the vaccine; so as a result, the antibody concentrations that we give should be predictable across all ages.

Finally, monoclonal antibodies mediate protection by a single mechanism; and that can be quantitatively determined, and that really facilitates modeling of protection across all age groups. They can only work by one mechanism.

Additional advantages, specific to monoclonal antibodies, that we’ve developed at the Vaccine Center include: They would protect against all circulating strains of Plasmodium falciparum in Africa, which has the largest morbidity and mortality, especially in children under the age of five. And they target a conserved region on the sporozoite, which is, I mentioned before,  where the mosquito begins its infection. So the mosquito is transmitting infection by the sporozoites.

We think that one of the potential advantages of an antibody over vaccines in preventing malaria is that it’s just done with a single dose; and in the data so far, which is adults and children in Africa, it’s been very safe. We will be testing the monoclonal antibodies in women this year in Mali of childbearing potential, and hopefully next year, actually do a study in pregnant women.

So I think overall, a major advantage of the antibodies is it can be used essentially from birth to adults and in pregnant women.

Mr. Dawisha: So will the initial focus of monoclonal antibodies be on seasonal transmission areas?

Dr. Seder: The initial data we have now is, we have very good data at six months. One of the issues with monoclonal antibodies is that it’s a protein. And so when you give it, it actually has a defined half life, and so it will dissipate over time. And so we’ve made changes to the antibody that are well known that make the antibody last longer. But as far as we know, right now, it lasts for six months. And we’re testing it now in Kenya whether a single dose could last an entire year. And so you would have a way to prevent perennial transmission, which occurs in East Africa and other sites, as well as seasonal transmission which is found in West Africa and in the Sahel region.

I might add that in my comments I had compared some of the advantages of a monoclonal antibodies compared to vaccines. Of course the major advantage of vaccines is immune memory. And so when the immune system… when you give a vaccine, you’re teaching our own B cells to be able to produce antibodies, and those B cells can produce antibodies over the course of a lifetime. So of course that’s why many of our vaccines work over the course of a lifetime – because they have memory. The issue with malaria is that, with vaccines, you need to give several vaccinations to achieve a very high titer of antibody so it can prevent a clinical infection over a long period of time. And that has required the vaccines to be… you need at least for immunizations, and possibly yearly boosting So there are defined, I think, advantages of antibodies and there’s also, you know, obviously defined advantages of vaccines.

Mr. Dawisha: Where our monoclonal antibodies currently being piloted and what are the next steps, assuming the product continues to show strong efficacy?

Dr. Seder: So right now we’re studying the antibody during periods of intense seasonal transmission in Mali over six months and perennial transmission in Kenya. We’ve recently reported results from clinical trials in adults in Mali and have ongoing trials to see if it’s safe and effective in children six to ten years of age in Mali and infants in children five months to 59 months in Kenya. We hope to have that data probably in the next twelve months.

So that is where we are with those critical use cases, which are obviously children under the age of five and even children between six and ten years of age. I would note that it’s really the older children that are the reservoir of malaria, that have the greatest contribution to transmission. So while the majority of the mortality occurs under the age of five, there is still a lot of morbidity in older children and they also are, as I said, a reservoir of being able to transmit, so I think we need to think about kids, at least probably through ten years of age.

There are several immediate steps that we’re taking to continue to develop this tool to make sure that it’s broadly accessible. So one is that we need to prioritize how we use it and where to use it – what’s the best use cases. So there are many different use cases, but the initial focus will be to achieve the greatest impact to limit morbidity and mortality in those highest risk groups, and ultimately use it for elimination when the resources become available.

So we envision that if we are to get to a phase 3 trial, we would use the antibody for seasonal malaria protection in areas that don’t have year-round transmission in children under the age of five. That would be our primary use case because we think we can achieve high level protection at six months, and children under the age of five are the ones that bear the largest burden of morbidity and mortality. As we get more data whether a single dose of an antibiotic can mediate protection for one year, we would then extend studies to kids under the age of five in areas where there’s perennial transmission.

A major use case is that infants and young children that are hospitalized [with] malaria and have severe anemia, or are severely malnourished, have very high mortality upon discharge. And so we think that giving a monoclonal antibody prior to discharge would hopefully limit mortality over a period of six months. So that is a major use case in prioritization based on the high mortality in those participants.

As I mentioned before, we’d also like to use the antibody to protect pregnant women and their unborn babies. Recognizing that because they are adults, and pregnant women weigh more, they would require more antibody and that actually you know would be more expensive per person. But due to the burden of malaria on both the mother and the baby, this is a really important use case.

The antibody also has potential to be an incredibly useful tool in emergency situations and in areas with ongoing displacement where we might only have one chance to engage with people at risk of malaria before they move to a new location. So for example, malaria outbreaks are seen four to eight weeks following flooding in malaria endemic regions. People who’ve been displaced from their homes due to the disaster could benefit from a tool that would protect them with just one interaction with the health system. You can imagine antibodies could be used in refugee camps; you can imagine antibodies could have been used when you have lockdown from COVID, where they might have been limited in terms of their access to health care. So we think that a tool that could really prevent malaria over a period of six months could have dramatic effects in those use cases.

Importantly, we continue to iterate and make more potent antibodies. So we generated initial data with our first antibody and now we’re already testing our second antibody. And we continue to iterate because the more potent the antibody is, the the lower cost it will be. And so we anticipate that we’ll probably ultimately have a new generation antibody that would work at a lower dose and allow cost reduction.

Finally, a really important step in getting antibodies out to those who need it is to identify who will manufacture the antibody for the phase 3 trials and then the long term, And we believe we’re gonna need somebody in the long term that can really produce antibodies at large scale. I think the first goal is to show that antibodies can work in a phase three trial; and at the same time be working really hard that, in anticipation of success of the trial, we would have antibodies available immediately upon licensure for people to use.

Ideally, my goal in the long term is to find a manufacturer in a malaria endemic country who can produce this once it’s on the market, and it would mean that it’s being produced where it’s being used. And I think that’s ultimately allowing people in the endemic areas to control their own production and cost. And I think that this would be important not only for malaria antibodies, but for antibodies for other infections like RSV, for potentially future pandemics; as well as use those type of manufacturing facilities to make antibodies for autoimmune disease or cancer, which are widely used in, certainly our country and countries around the world that are much too expensive to be used in places like Africa. And so I think that if we can build infrastructure within the endemic areas to make antibodies, they could be used for many things.

Mr. Dawisha: Could you please expand a bit on the results of the recent trials? What kind of efficacy levels are monoclonal antibodies producing in these trials?

Dr. Seder: Our first study in adults, where the antibiotics were given intravenously once, at the higher dose of the antibody [efficacy] was close to 90 % protection. And at the lower dose it was 75 % protection, and so that was with an IV infusion.

And so, I think [the World Health Organization’s] goal was somewhere around 75 or 80 % protection for three months, so we think we’re really shooting for, kind of, 75 % protection for six months. I think that would be, with a single dose, really transformative. Of course, we would like to have higher level protection and that indeed might come with more potent antibodies.

The other thing I should mention in terms of distribution, is that I do think that we like to see the antibodies used in areas such as the the the Democratic Republic of Congo where there’s an enormous amount of malaria but access to health care may be relatively limited. And if you are really seeing people potentially just once a year, would this be a useful tool in places like the DRC to control malaria.

I recently met with Doctors Without Borders about trying to potentially do studies in areas like the DRC, and they also raised the idea of of using antibodies potentially in areas of  displacement where often they see people once and they have to administer multiple vaccines in health care during that single visit. And one potential advantage of an antibody is it really likely would not interfere with ongoing vaccines to many other things. So it’s a nice tool to have that, you know, could be administered in the context of other health care and it probably wouldn’t have any interference. They leave and they don’t see them again, so if they’re traveling and they’re going to a malaria-endemic area, if they also could give them an antibody that might protect them for four to six months, that would be useful.

Mr. Dawisha: And that’s an advantage that monoclonal antibodies have over, say, the new malaria vaccines, which require multiple doses.

Dr. Seder: So let me let me defend the vaccines here, as a vaccinologist. So yes, the current plan is at least four doses with RTS,S and R21. And then the recent data from Brian Greenwood shows that if you actually boost with RTS,S every year in a seasonal setting and during that season give kids four monthly treatments with drugs, you really limit the morbidity and mortality from malaria. So that is a wonderful intervention. But if you count up the number of visits that you might see – you count every visit for a vaccine and then the multiple visits with the drug – we’re trying to simplify the process. If in fact just a single dose of an antibody works for six months against seasonal malaria – we’re talking about giving one dose at year one, one dose at year two, three, four, and five – so that’s just one visit compared to the multiple visits that you would need for the vaccine and the drug treatment. But I might add that the vaccines – now R21 – presumably will be made in a very cost effective manner. And the drugs are very cheap.

So I think that we’re now in an area where we have real solutions to affect malaria. And now the question is how do we best use the tool. And what I like to do is just get the data and then look at what the data says where the tools can be used best.

I think our goal is to just show that we have high level protection in kids under the age of five in seasonal settings with one dose, and we compare that with the current standard of care, which would be four doses of drug treatment. Now we might need to at some point compare –  how does the antibody compared to the vaccine? And you wanna look over five to seven years, what is in fact the best intervention for protection and the easiest on the health care system? And I think that’s possibly something we’re gonna need to do.

And so I would say the antibody could immediately used in, in areas where they’re actually deploying vaccine, and then you’re gonna have kind of two different interventions in the same, you know, age group, right? And you have to figure out what might be best to use. And then the question always is, might they be used together in different ways? And that’s kind of a question that will leave for another day for now, but I do, think that there’s likely to be a study that’s gonna have to understand how antibodies would compare to vaccines in those age groups.

I would add that the vaccines are approved at least right now only for five to 17 months of age. It’s possible maybe they would work a little longer. But RTS,S was shown not to work as well between six and twelve weeks of age, whereas an antibody probably could be given at four weeks of age and work immediately and antibodies could be used across any age. There’s very little data on RTS,S in older age groups. And so if you’re gonna start to use this for older age groups, they’re gonna have to show that the vaccine works in those age groups.

So I think a potential advantage is the ability to use the antibody, like I said, from birth to adults and in pregnant women. So that’s where this might be… we get all the data and we might have different use cases for how vaccines are used and antibodies are used, which I think is a good thing, right? As long as it’s predicated on data, right? That we all do the studies and we, together, make decisions on what is best in terms of protection and then what is best for health care delivery and cost. And if antibodies become too expensive, then, you know, that might be a major advantage for vaccines. But I think we’re early in the game now, and we need to just get the data to make those decisions later on.

Mr. Dawisha: What’s the long-term goal with monoclonal antibodies and what are the potential roadblocks along the way?

Dr. Seder: The long term goal in my mind, is ensure access and equity. That is my goal, that people in Africa have the right to whatever is the best that they can get for for health care intervention. And so that’s really what we wanted to do, and we think that something that is safe and highly effective at blocking infection and onward transmission with only one interaction with the health system per year is very attractive.

So I think the long term goal obviously is to use this tool for elimination. If you think how you eliminate something, if you’re eliminating something with a vaccine, elimination is predicated on coverage. And so you can imagine that the best thing to do for elimination is, if you had to, you really likely only have one time to see an entire population. You have one interaction, and so you could give them a drug to get rid of parasites that they have, and we envision you give them at the same time an antibody. When you’ve eliminated things like smallpox, those are done where you have vaccines that are basically a 100% protective with one dose. So I don’t think we’re close to that with malaria. So we think that this really could be an ideal tool for elimination.

Then finally, in terms of the roadblocks, this is all about cost, cost and scalability. So that’s really what I’m spending a lot of time on now, to make the most potent antibodies that we can, find cell lines that produce them as high as possible. And then finding manufacturing facilities that will do this in the most cost-efficient manner.

And so that’s kind of the end piece. And does the world have the will to create capacity for something like this, where it’s primarily gonna be used in Africa, it’s primarily gonna be used in kids and pregnant women. Do we have the capacity to to drive the cost down and produce a lot of it? That’s really the the billion dollar question.

Stay tuned as we highlight our next Malaria Gamechanger, monoclonal antibodies, in the coming weeks.