“It's about enabling research of the future.”

Aleksandar Antanasijevic is a new Tenure Track Assistant Professor at EPFL’s School of Life Sciences (Global Health Institute - GHI). In his research, he develops novel electron microscopy-based methods to analyze immune responses, aiming to create antibodies and vaccines against emerging viral pathogens, and even antivenoms for snake bites. His lab also uses advanced structural and computational biology tools to understand antibody-mediated immunity and develop algorithms capable of accurately predicting it.

How did you get into science?

That story started in Serbia, my home country! I was a really good student in middle school and high school. I used to compete at, national-level championships in physics and math; those were my strengths. But I also really liked medicine, so when I finished high school, I applied to a college of medicine. Except, that summer we played a little bit too much football and basketball, and I didn’t prepare as much I should have. And so, a straight A’s student with a lot of diplomas from high school just failed the qualifying exams! It was devastating at the time.

But then I thought, “I can either try again next year, or I can consider an alternative.” And since I had a good background in physics, math, and chemistry, I applied as a second option to a college of physical chemistry at the University of Belgrade.

I got in, and loved it from day one. I enjoyed the lectures and was introduced to a research-driven mindset. I also appreciated the fact that you can apply that knowledge and training on biomedical research, bridging two of my main science interests. I gradually shifted into biophysics and biochemistry, and a couple of years later I was working on antibodies and vaccines!

How did you start working on vaccines?

Towards the end of my PhD in Chicago, I began being interested in cryo-electron microscopy (cryoEM). Around 2016, the great “resolution revolution” had happened, starting with several major technological breakthroughs and ultimately leading to the Nobel Prize for Chemistry awarded in 2017 to, among other people, Jacques Dubochet at UNIL.

I got excited about the application of cryoEM to viruses, therapeutic and vaccine research, so I joined Andrew Ward’s lab at the Scripps Institute. There, I learned how to use cryoEM to characterize different vaccine candidates, evaluate their performance in various animal models, and apply that information to improve their potency.

What does your research focus on now?

We have several different projects, most of which are related to antibody-mediated immunity and vaccine design. The main pathogens studied in the lab are human immunodeficiency virus (HIV), enteroviruses, and flaviviruses.

We are developing novel electron microscopy methods to rapidly evaluate how antibodies interact with vaccines and pathogens at high resolution. This information is used to identify the most essential components of immune response capable of conferring protection against future encounters with the pathogen. We then translate these findings to vaccine design with the main idea of maximizing the induction of “preferred” types of antibodies and reducing all “off-target” responses.

We also use the structural data to ask more general questions; for example, what makes the most targeted sites on the surface of the antigen special? Are there any molecular patterns that are particularly attractive for antibodies? We're asking this because we want to develop computational methods for modeling immunity. If the initial rounds of vaccine evaluation can be completed using a computer, then we would further accelerate vaccine design process and reduce the number of animals needed for preclinical research to what's absolutely necessary.

We are also applying electron microscopy to evaluate if the tests that are currently being done for studying antibody-mediated immune response – which are based largely on blood – are actually the best tests. For a lot of viruses, including COVID, the entry points are the nasal or oral cavities. And the replication sites for some viruses are oftentimes in the gut, while for respiratory viruses they're often in the upper respiratory tract.

This means that the local immune response in those cavities is also the primary immune response against the pathogen. But vaccines are oftentimes administered through injection, which is one reason people shy away from them. That can be improved by making vaccines a little easier to administer – for example as a nasal spray or orally – which would be more convenient and might also provide better immune support at the right place in the body.

So right now, we are analyzing antibody responses using samples from local tissues, like nasal swabs and saliva. We hope to get a more complete picture on what makes up protective immunity and try to mimic that through vaccination.

Are you running any non-vaccine projects?

We are working with antivenoms against snakebites. It is actually one of my favorite projects. Snake venom is a neglected tropical disease that causes around 150,000 deaths per year globally. Additionally, there is a much larger number of people that end up with life-altering sequelae.

Snake venom is composed of diverse toxin proteins that can induce an immune response, but the problem is that the toxins can actually kill you before you mount that immune response. So antivenoms kind of mimic our own antibody response, but given the diversity of toxins, antivenoms are usually effective only against a narrow range of snakes. If you actually get bitten by one, the species needs to be identified so you can receive the right treatment.

So we are isolating antibodies that can broadly neutralize a range of toxins found in venom, with the goal of developing universal antivenoms, meaning you wouldn't have to identify the snake; you would just carry a solution of antibodies in your backpack and take them if you get bit.

What techniques do you use in the lab?

The main one is electron microscopy. We rely on mainly two different inputs for samples. Antigens, viruses or virus-like particles are produced in the lab. On the other hand, specific antibodies are isolated from patients or animal models, depending on the study.

Electron microscopy imaging is performed at the Dubochet Center or at CIME, and we spend a lot of time processing and analyzing the structural data. The rest depends on the specific project. For example, we use computational tools to study the distribution of antibody epitopes in different viruses/vaccines and engineer new antigens based on that data. We also apply in vitro functional assays to assess how potent and broad are the antibodies that we produce.

What are your plans for the future?

Right now, it's all about setting up the lab. We’ve acquired equipment, starting the research, and we are actively engaging different collaborators in the area, obtaining permits and authorizations to work with real-patient samples – which is the goal: to improve human health. We are looking forward to establishing a large collaboration network, bridging hospitals, other academic researchers in the region, and pharmaceutical companies. I'm excited about building that network.

By combining efforts, we get to do things that go beyond what we can achieve by ourselves as a group, while also accelerating the research timeline to actually contribute to human health in our own lifetime. That's my hope and vision for my lab.

What do you think about EPFL?

EPFL is this environment of engineers, people that are really into building new technology, new tools, new methods. And I really resonate with that. It’s not only that we propose to investigate a certain biological phenomenon, but rather we seek to build a tool that will allow us to study this biological phenomenon in a way that hasn't been possible before. And then other people can adapt it, potentially leading to many new discoveries. It's about enabling research of the future. And that's what I respect about EPFL and why I enjoy working here.

Antanasijevic Lab – Virology and Structural Immunology