In a discussion with Malaria No More, Dr. Robert Seder, Chief of the Cellular Immunology Section in the Vaccine Research Center in the National Institute of Allergy and Infectious Diseases, NIH, talks about his latest malaria research, including vaccine development and testing.

How did you get started working on malaria?

SEDER: I started nearly 15 years ago, when I began working with tropical disease researcher, Dr. Stephen Hoffman, on developing a malaria vaccine. My primary interest, at the time, was T cell biology, which was being looked at to provide immunity to malaria. Essentially, T cells would kill the parasites in the liver, before they get into the bloodstream and cause clinical infection. Dr. Hoffman asked if I could conduct preclinical animal studies measuring the T cell responses to help guide clinical trials.

As a result, we were able to show that in non-human primates, if you gave the vaccine intravenously, you would be able to get higher frequency T cells in the liver. Whereas, if you gave it intradermal, or under the skin, there were very few T cells. That showed us that the route of vaccination could have a dramatic effect on getting T cells to the key site to destroy the parasite before it can reach the blood to cause malaria. That led to nearly ten years of research – and giving the trial vaccine intravenously in the U.S. and in field trials in Africa where the work is ongoing.

One of our key takeaways was that when you’re testing in the United States, these are typically adults with no prior history of malaria exposure. So, when we're vaccinating them, their immune responses and their protection might be dramatically different than what would happen when you go to Africa, where they've lived with malaria their whole life. And that makes a huge difference in how they respond to a vaccine based on their level of previous exposure.

That led us to realizing that prior malaria exposure could have a dramatic effect on vaccine efficacy. Thus, we did a study in infants in Kenya during their first year of life with the hypothesis that they would have a very low level of malaria and would have more of a “unprimed’ Immune response which occurs over time and can affect the immunity and protection by the vaccine. Surprisingly, we found that the immune responses and protection in infants with the vaccine was very low.  So, then you start to look at tools or interventions where you don’t need to induce an immune response from the host and prior exposure to malaria isn’t a factor.

Was there something about malaria that particularly struck your interest?

SEDER: If you look at what we call the “Big Three” for causing deaths worldwide, it is HIV, TB and malaria. So, I have gravitated toward working on vaccines against these diseases that have major, global health impacts, and malaria clearly fit that.

Also, based on my longstanding scientific interest in T cells and vaccines, malaria fit well with my longstanding work and expertise. But applying that can also be super challenging.

Then going to Kenya, I got to see firsthand what it was like for a mother who had one or more children – and the burden of malaria for her and her family. I started to really understand the profound need and the potential impact.

If you asked, what keeps me going and working? It’s that mother and her child in those resource poor areas in Africa. I often say, if malaria came to the United States and it was clear to people that their newborns or infants could risk dying from a mosquito bite, we would understand how it could impact all of us. So, just going to another area of the world where there are far fewer resources has deeply influenced how I now think about the research we are doing today.

What are you working on now?

SEDER: So, the good thing about being at The Vaccine Research Center at the NIH is that we have outstanding scientific and clinical investigators.

We work in large teams comprised of colleagues at the NIH, CDC investigators in Mali and in Kenya, to leverage everybody’s expertise.

For example, in April, my colleague, Dr. Peter Crompton, an outstanding physician-scientist in the NIAID in collaboration with Kassoum Kayentou a renowned researcher in Mali, published a seminal study that looked at giving a single dose of a monoclonal antibody to six- to 10-year-olds before the season started.  The data showed that it induced high level protection against malaria.  This was a very exciting result because when the rain comes, people typically get infected many times for a period of 6 months. So, a single dose of the antibody at one visit prior to the rainy season becomes very efficient for the health care provider, as well as for the children since they don’t need frequent medication given monthly to prevent malaria during the season. Plus, healthcare workers don't have to go out in the field to provide the monthly medication. So, I think that was a breakthrough study in showing that with one dose, we can offer a potentially cost effective and yet highly effective tool against seasonal transmission.

So, I think all those studies are very exciting, because the data demonstrating safety and high-level protection following a single dose of a monoclonal antibody for 6 months can potentially allow this new intervention to be deployed in children or pregnant women and extended to travelers, military personnel, and healthcare workers.

Are there more new tools and technologies coming up that you're personally excited about?

SEDER: Yes, on the vaccine side, we have two approved malaria vaccines now: R21 and RTSS. We expect both will be very impactful on lowering the number of malaria cases in infants and young children under the age of 5.  But I think we can likely improve upon the existing vaccines. So, the major question is whether we can enhance the efficacy and durability of the vaccines. The current plans are to make a multi-stage vaccine to combine the current R21 vaccine with a blood stage vaccine and potentially a transmission blocking vaccine. One important issue will be whether the vaccinees can be used outside the current recommended age groups of 5-30 months. Data exists that the immune responses outside of these ages are lower with RTSS and R21 vaccines.

In terms of using new technologies, mRNA vaccines may be considered but it will be important to demonstrate that immune responses following these vaccines are durable.

And of course, there's ongoing development of drugs or perhaps long-acting drugs, even though I’m not personally in that space. And then, there’s gene drive, which is a technique used to try to eliminate mosquitoes. But I think all of those go together. So, between bed nets, spraying, antibodies, vaccines and early diagnosis, combined with greater access to drug treatment, we can hopefully shore up gaps.

As for the malaria fight, how would you describe which chapter we’re in?

SEDER: We're not at the beginning anymore for sure, because we have a massive amount of experience across public health measures, drug treatment, vaccines and mechanisms by which malaria is causing infection.  

Monoclonal antibodies are in the early phase of development. We hope to integrate this intervention with other modalities or in some cases replace the standard of care. As monoclonal antibodies work very quickly for up to 6 months and are safe across all ages, they are a very flexible tool for use to control malaria.

But as we look at new tools and technologies, all of this comes with a cost. What I’ve learned over the last years is that anything we do has to be cost effective because there is limited funding available. So, you have to have something that either replaces something that exists – and saves money … or has something that's just really cheap.

So, a lot of focus now is on getting a monoclonal antibody – and delivering that for just 5-10 bucks for infants and children. Ultimately if we can continue to iterate and make more potent antibodies then the cost will go down. The critical issue at this point is who will produce the monoclonal antibody at low cost.

Is ending malaria achievable in our lifetime?

SEDER: I grew up in Chicago rooting for the Cubs. This was a lesson in hope, disappointment and patience. So, for the Cubs to win the World Series, I realized that with good management, a great group of individuals working as a team, they could ultimately accomplish the goal. Thus, as a vaccinologist working my life to develop a vaccine against HIV, malaria TB or cancer, I am focused and play the long game. By nature, I am extremely optimistic we’ll get there.

###