Brandon Wilder, Ph.D., on the search for humans without malaria

Malaria is as old as humans; we have never lived without it. That is exactly what Brandon Wilder, Ph.D., is trying to change.

Wilder, assistant professor at the Vaccine and Gene Therapy Institute and Division of Pathobiology and Immunology, Oregon National Primate Research Center, splits his time between OHSU and U.S. Naval Medical Research Center 6 in Lima, Peru. NAMRU-6 is a biomedical research laboratory with a mission is to identify infectious disease threats and to develop and evaluate interventions to mitigate those threats. We sat down with him to talk about his background, his research and what’s next for his team.

Photo above: Mosquitoes raised, grown and infected in a carefully controlled research space created at the OHSU Vaccine and Gene Therapy Institute will aid in the search for new malaria drugs. (OHSU/Kristyna Wentz-Graff)

How did you become interested in science?

My mom was a medical technologist, and one day she permanently borrowed an old microscope from work. We lived in rural Florida, a place called Tangerine, and I’d go exploring and come home with pond scum to examine through the microscope. It opened my imagination to the microbial world.

What is the focus of your research?

Malaria is caused by the parasite Plasmodium, which has existed as long as humans have been a species. At this point it has evolved a lot of immunity-evading mechanisms, making developing a vaccine very challenging.

The complex lifecycle of the parasite brings complications to developing a vaccine, but also provides multiple points for therapeutic intervention. The parasites are spread to humans when a mosquito bites someone. They enter the blood stream and are carried to the liver, where they settle in to mature for about a week. Then, they leave the liver and return to the bloodstream, infecting the blood cells.

Our work has demonstrated, for the first time, that parasites can be successfully targeted by antibodies even while they hide inside the host liver cells. This goes against what has been the widely held view that antibodies only act against pathogens when they’re outside of cells. This is a major finding.

The two most promising vaccines are target the entire surface of the parasite as it leaves the mosquito. Antibodies bind to a targeted protein and block the parasite from moving into the blood and then the liver. Just this month, the first monoclonal antibody for malaria based on this concept demonstrated that high levels of protection against infection can be achieved over six months, providing an interesting alternative to a traditional vaccine.

The downside of just targeting the parasite en route from mosquito to liver is that, if a single parasite makes it to the liver, it will become a billion parasites in the blood and cause disease. Meanwhile, more than 625,000 deaths are caused by 240 million cases of malaria every year.

What’s ahead for your lab?

Brandon Wilder stands outside the OHSU Vaccine and Gene Therapy Institute. (OHSU/Christine Torres Hicks)

What the field needs is a different approach, one that can compensate for the complexity of the infection as well as the parasite’s immune-evasion strategies. We need a smarter vaccine that targets multiple proteins at multiple stages.

We’ve had significant breakthroughs in our first few years as a lab that are setting the foundation for our next steps, but work on malaria is complicated.

The parasite’s age, which helped it build such robust mechanisms for evading infection, also means it has evolved to infect everything from chickens and birds and lizards up to primates and humans. This means we have nice animal models but we must be careful, because it also means the parasites are very divergent. So the vaccine that works for Plasmodium falciparum does not protect at all against Plasmodium vivax—the second leading cause of malaria and a distant cousin to Plasmodium falciparum.

The mosquito life cycle also can’t be reproduced in vitro, which means we need mosquitos to complete the parasite life cycle in order to study interventions where the infection starts for humans. The VGTI insectarium is where we raise, grow and infect mosquitos. We then harvest the parasites that we can use in mouse models of malaria, but regular mice don’t get infected with the particular malaria found in humans. To get around this, we turn to mice modified to have human livers, known as “humanized liver chimeric mice.”

We’ve had exciting results following this path — our lab has successfully infected these mouse models with human malarial parasites and then use antibodies, including monoclonal antibodies, to study the best ways to block infection. Importantly, this model has predicted the performance of the first monoclonal antibodies in endemic areas, and we are currently working on developing and vetting the next generation of monoclonal antibody combinations that can provide higher protection for longer.

The World Health Organization estimated in 2021 that were more than 240 million cases that led to more than 625,000 deaths, primarily in children younger than five.

The finding that liver-stage parasites can be targeted by antibodies is an important finding — we killed 95% of intracellular parasites with antibodies. This is counter to what we have considered a known fact regarding antibodies. We’ve also found some interesting new ways that infected cells communicate their infection to the other “branch” of the immune system known as CD8 or killer T cells.

Using all of this information, we hope to identify a vaccination regimen that improves the durability and breadth of the human antibody and T cell response, both of which are critical for long-term protection. We feel strongly that antibodies or T cells targeting a single stage or even a single target will likely not protect against malaria at the levels needed for eradication.

“What the field needs is a different approach, one that can compensate for the complexity of the infection as well as the parasite’s immune-evasion strategies.”This is all possible because I have a great lab at OHSU and phenomenal collaborators both within VGTI and across the world. We are surrounded by people who know the science, work hard — the lab is successful because of everyone involved.

It also takes funding, and we are fortunate to have both private and federal funding.

I recently received the OHSU Faculty Excellence and Innovation Award, funded by the Silver Family Foundation, which has been really game-changing. To have an award that trusts promising investigators to do high-risk work lets scientists really take chances and try bold new ideas. And the fact that the funds are unrestricted is so important.

Of the many investments I’ve been able to make, investing in young scientists is perhaps the most important. Flexible funding allows me to pay them as much as possible and empower them to explore really cool ideas – with the chance to fail in ways that normal funding does not tolerate.

It is so easy to catalyze this kind of investment and I wish more funders had this kind of mentality— it changes the lab but applied at a larger scale would also advance science more generally.

Read more interviews with OHSU researchers and other Faculty Excellence and Innovation Award winners.

Links

OHSU investigators awarded $3 million for innovative, promising research

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