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Antibodies targeting Achilles heel of parasite provide roadmap for better malaria vaccine

Brandon Sack, PhD

Posted on Mar 23rd, 2018

Malaria is an extremely complex parasite that has been evolving to evade our immune system since the dawn of humankind. It is also by far the most complex organism we’ve tried to fight with a vaccine. Today, it continues to infect over 200 million people every single year.

This week we co-authored two separate papers highlighting breakthroughs that put us one step closer to an effective malaria vaccine. We identified a new class of antibodies which can bind the malaria parasite as it comes out of the mosquito and completely prevent the parasite from establishing infection. This indicates that for a malaria vaccine to be improved, we need to make a vaccine that forces the body to produce these new antibodies rather than the type produced by current vaccine candidates. Thus, this is a turning point that will significantly shift the field toward incorporating this finding in the next generation of malaria vaccines.

Understanding Antibodies and Vaccines

All vaccines we have to date are based on getting you to produce antibodies against a pathogen. Antibodies are proteins that are produced by immune cells (B cells) which circulate throughout your entire body and can bind to and neutralize a pathogen. However, antibodies are very, very specific—only recognizing a very small piece of a single protein. This makes them very potent in fighting off dangerous pathogens without accidentally binding to one of our own similar-looking cells and destroying it. But it also makes them tricky because this small, unique piece of a protein that is bound also needs to be a site of vulnerability for the pathogen so that antibody binding lead to its inactivation or death. Making antibodies which bind to a small, functional portion of a pathogen that looks nothing like one of our body’s own tens of thousands of proteins may seem like long odds. But fortunately for us, the body can make over 1 trillion unique antibodies, meaning that the immune system can recognize pretty much any new pathogen that comes along.

But at the same time the pathogens are evolving with us and learn the tricks of our immune system. The proteins of pathogens can evolve to be inaccessible, revealed for only a short time, or can just be really hard to make antibodies against. This problem has stymied HIV vaccine work since the virus has evolved, such that proteins critical for virus infection are extremely difficult for us to make antibodies against. The malaria parasite has also evolved a mechanism whereby once bound by antibodies, they can shed their entire surface with the antibodies like a snakeskin (see picture).

Picture caption: Above, a malaria parasite is shown coated in these novel antibodies (shown in red). The parasite has shed its outer coat to try avoid these antibodies (tail-like structure, toward bottom right), but the remainder of the sporozoite remains bound.

So, if you want to make the best vaccine possible, your vaccine needs to focus your immune response to produce primarily highly functional and sometimes rare antibodies to jump ahead of this evolutionary game. This approach is often called “rational vaccine design”.

Past Malaria Research

The most advanced malaria vaccine to date, called “RTS,S”, forces your body to make antibodies against the protein that coats the entire surface of the malaria parasite as it comes out of the mosquito and is injected into your skin. This protein is called “circumpsporozoite protein” or “CSP”. Unfortunately, the RTS,S vaccine only protects 30-50% of people in large clinical trials conducted sub-Saharan Africa. Part of the problem is that the antibody levels in vaccinated people decrease over time, and the remaining antibodies aren’t able to stop infection. So to improve RTS,S, you either need your vaccine to make tons more of the same antibodies or make more potent antibodies that can provide protection with less of them around.

And while there are many others are looking for antibody-based vaccines against malaria, progress has been slow, in part, because antibodies which stop human malaria infection are extremely difficult to study in the lab. The first place a malaria parasite goes after being injected into the skin is the liver. If you stop the parasite from making it to the liver, you stop infection. Typically, we would use mouse models of malaria to test the ability of antibodies to stop the parasite from making it from the skin to the liver. However, human and mouse malaria species are different enough that antibodies against the human parasites don’t work against the mouse ones. And infecting mice with the human malaria species is not possible, as the human malaria parasites don’t recognize the mouse liver. Quite the conundrum.

What we found, how we did it, and what now?

We got around this problem by using “humanized liver mice”. These mice have had their mouse liver cells replaced with human liver cells through a combination of genetic engineering and cell transplantation. The end result is a mouse with a normal-looking liver that is actually full of human liver cells.

This is a huge step forward for us since we’ve now got mice we can infect with human malaria. Even better, we can inject these mice with specific antibodies to mimic vaccination and see what kinds of antibodies are best for preventing infection. For these two papers, we took antibodies isolated from volunteers vaccinated with live yet weakened malaria parasites that infect but don’t cause disease. Going in we knew that all these antibodies recognized CSP, which at first wasn’t very exciting since the RTS,S vaccine is based on CSP and didn’t have great results. Yet after extensive testing, we found that only a subset of these CSP-specific antibodies was highly effective at preventing infection of humanized liver mice. Importantly, these antibodies protected about 70% of mice from infection even when we injected low levels of antibody which mimic what you can achieve with a vaccine for over two years. For reference, the RTS,S vaccine only gives about 30% protection.

Even more, together with our collaborators—from as close as down the street to as far as Switzerland and Tanzania—we figured out that these antibodies were binding to a part of CSP that wasn’t included in the RTS,S vaccine. Thus, if we can shift the focus of RTS,S to make these new types of antibodies, we can make a more efficient vaccine capable of generating more effective antibodies that are highly functional at low levels for years, not months. It may even be possible to inject these antibodies directly into travelers and protect them for as long as 6-12 months, similar to what is being tested for preventative HIV vaccines. For now, we’ve got a new road map to an effective malaria vaccine, and the race is on to actually produce such a vaccine and better understand how we can cajole the immune system into making these antibodies.

About the Author

Brandon is a Postdoctoral fellow in the Kappe Lab. Brandon received his PhD in 2012 from the University of Florida where he studied how to modulate the immune system to enhance liver-directed gene therapy for hemophilia. Brandon joined the Kappe lab in 2012 with the goal of using immunology to improve malaria vaccines. Since joining the lab, Brandon has helped discover how the malaria parasite is first sensed by the immune system in the liver and how this can impact the effectiveness of a genetically attenuated parasite vaccine. He has also developed in vivo models, including a human-liver chimeric mouse model, to test how antibodies can function to protect against malaria by preventing the sporozoite from reaching the liver. Brandon is also currently involved in projects which aim to advance malaria vaccines by identifying novel malaria vaccine targets and how we can best direct the immune system to these targets. Outside of the lab, Brandon spends most of his time outdoors either backpacking or running ultra-marathons in the mountains of the Pacific Northwest or surfing and shivering in the chilly waters of the Washington and Oregon coasts.

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