Tag: Escolano

A Q&A with Wistar’s Dr. Amelia Escolano

What got you interested in immunology?

My interest in immunology started in college. I took several immunology courses, and I was particularly attracted by antibody biology. One of these courses was Immunotechnology, and I remember being fascinated by the immense potential of antibodies for immunotherapy development. This interest further developed during my Ph.D. studies, which focused on macrophages, a type of immune cell. I investigated the role of calcineurin, a phosphatase enzyme, in macrophage polarization. In other words, I studied how calcineurin determined the specific pro- or anti-immune functions of macrophages and how this could impact the progression and outcomes of inflammatory processes.

The immune system is immensely complex. It is a very sophisticated and orchestrated network of immune mediators that interact and influence each other to provide protection against pathogenic threats. We have so much to learn about the many different immune cells and the cellular and molecular mechanisms involved in immune responses; the complexity and ingenious mechanisms of the immune system make it a very exciting area of study.

In addition to my interest in shedding light on some aspects of the immune response, the fact that the implications of immune system research are so clearly beneficial to human health makes this area of research very attractive to me and my team.

Now, in your lab, you investigate the mechanisms governing the immune responses to vaccines. Very broadly, can you tell us about that work?

Our research revolves around vaccine design; that’s the goal that informs our approach. We are interested in understanding how B cells and T cells respond to vaccination so that we can leverage this information to design better vaccines. In particular, we study the process of antibody affinity maturation.

Affinity maturation is the process by which antibodies are produced and refined to target a specific antigen, a component of a pathogen that activates the immune system. Antibody affinity maturation takes place in the germinal centers, which are anatomical sites where B cells work with a certain kind of T cell called T follicular helper (Tfh) cells to iteratively refine and test their B cell receptors — otherwise known as antibodies. This process allows the immune system to improve its antibody responses.

With this process in mind, we aim to understand how a vaccine should be designed so that the elicited antibody response can efficiently prevent infectious diseases for long periods of time.
In my lab, we study the immune response to sequential immunization in the context of HIV-1. Sequential immunization is a novel form of vaccination that requires multiple boost immunizations with different but related viral proteins. In the case of HIV-1, sequential immunization involves multiple boost immunizations with different versions of the envelope protein of HIV-1.

Sequential immunization takes advantage of the antibody affinity maturation process with the ultimate goal of getting the immune system to produce high-quality antibodies that can fight complex, highly variable viruses like HIV.

We analyze how B cell populations and their antibodies evolve in response to sequential immunization, and we’re testing strategies to make that antibody affinity maturation more efficient by focusing on both B cells and T follicular helper cells.

Why is sequential immunization necessary against HIV-1?

To vaccinate effectively against HIV, we need B cells to produce what we call a broadly neutralizing antibody, or bNAb. bNAbs are rare antibodies that can neutralize multiple different variants of HIV-1, and we expect a vaccine that elicits bNabs to protect effectively against HIV-1.

Our previous work showed that repeated immunization with the same HIV-1 envelope protein was not capable of inducing bNAbs. Instead, sequential immunization efficiently induced antibodies that potently neutralized a large number of different HIV-1 variants.

In a sequential immunization protocol, we start with an engineered HIV-1 envelope immunogen, which is a term that we use to describe an antigen we’re testing as a vaccine candidate. The role of this first immunogen is to activate a rare subset of B cells that have receptors with the capacity to be refined into bNAbs. These B cells respond to this first immunogen and increase their affinity for it.

That increase in affinity for the first immunogen is associated with an increase in affinity for a slightly more complex HIV-1 envelope immunogen, which is then used for a second immunization. Sequential immunization repeats this process multiple times as a way of gradually increasing the affinity of B cells for the unmodified wild-type, or naturally occurring, HIV-1 envelope protein. We nudge B cells along to make sure that they mature in a way where they get progressively better at reacting to different HIV-1 strains.

How are you able to tell that your sequential vaccination protocol has produced a broadly neutralizing antibody? What do you look for?

We test our sequential immunization protocols by looking at blood after vaccination and running what’s called a serum neutralization assay. This assay can determine whether the mix of antibodies in the blood, elicited upon vaccination, can neutralize different HIV-1 strains. The number of different HIV-1 strains that the serum antibodies can neutralize determines the breadth of these antibodies. This assay also informs us of the potency of the antibodies to neutralize each HIV-1 strain.

In addition to these neutralization assays, we analyze B cells from lymph node tissue to see which antibodies they’re expressing. We are then able to evaluate individual antibodies for their capacity to neutralize HIV-1. These evaluations help us refine our vaccine candidates and sequential immunization protocols by showing us what’s working and what isn’t.

For how long has this immunology work been your focus?

I’ve been working on this approach for HIV vaccine development since I started my postdoctoral studies in the Nussenzweig laboratory at The Rockefeller University in 2014. Now, at The Wistar Institute, where I established my independent lab two years ago in September of 2021, my lab is expanding this research.

I came to The Wistar Institute with a vision of what I wanted my science to be, and Wistar has helped make that vision a reality. Here, I have found great colleagues, I have established fantastic collaborations both at Wistar and UPenn and I have seen my program grow exponentially. I’ve also found great opportunities to explore other research areas that have strengthened my program’s approach.

I find it hard to believe that two years have gone by already; the time has been both positive and productive. The welcome and support I’ve had at Wistar make me feel like a real part of a community. I can tell that all my Wistar colleagues — across the labs, across the departments — have an investment in seeing our science succeed.

Scientists developed COVID-19 vaccines in record time — less than a year after the genome of the virus was sequenced, countries started authorizing use of multiple vaccines. But the virus is rapidly changing, and new variants have been emerging that are more likely to overcome the protective barrier from vaccination.

Amelia Escolano, Ph.D., who became an assistant professor at The Wistar Institute in September, wants to help science regain the advantage. During her postdoctoral studies at The Rockefeller University, she pioneered a new form of vaccination against HIV. She proved that this type of vaccination regimen involving sequential immunization would be necessary to induce broad protection against HIV. At The Wistar Institute, one of her first research goals will be wielding what she learned in her postdoctoral work to develop universal vaccines against HIV-1, other viruses — including cancer-associated-viruses, and tumor neoantigens.

Branching Out

For Amelia, everything clicked about being at Wistar. “It is exactly the kind of place I was looking for,” she said. She thinks the size of the institute is just right for sparking discussion and collaboration. Amelia is already feeling the support of her new colleagues, and excited about all the disciplines she will be exposed to through interactions with scientists at neighboring academic institutions, such as the University of Pennsylvania.

Although her postdoctoral project at The Rockefeller University centered largely around HIV, Amelia looks forward to casting a wide net in her own lab. “The fact that the Cancer Center is here is going to open up new avenues of research and synergies,” Amelia said. She is already brainstorming with several new colleagues at Wistar about how they could collaborate to design vaccination strategies against cancer–associated viruses and tumor neo-antigens.

A Scientist is Born

Amelia cannot think of a time when she did not want to be a scientist. Both of Amelia’s parents were chemists so it would seem to be in her blood.

Amelia’s first hands-on experience happened when she was only about four years old and she received a little microscope as a gift. She dashed outside to collect bugs and puddle water from the backyard of her home in a small village in northern Spain and then sprawled out on the floor to study the specimens using her new equipment. Amelia’s decision to focus on biology was also a no-brainer as soon as she started learning about the cell in school. “I was actually fascinated by the cell and the size of molecules, and how such tiny things could have such interesting functions,” Amelia said.

Amelia had some setbacks in her career and sometimes muses about why she has stuck it out in science. “I must really love it” is the only answer she can provide. “The satisfaction you feel when things finally work makes you forget all the failure the months before,” Amelia said. It is the thrill of knowing that “you had this important question and then your experiment gave an answer and nobody else at the moment knows it,” she explained.

Next Steps

At the heart of the strategy to make a universal HIV-1 vaccine is injecting a series of different versions of a viral component, in this case part of the HIV-1 envelope protein. This strategy is believed to be necessary to induce a broadly protective immune response against HIV-1. Amelia showed during her postdoctoral studies that the first of these injections had to be with a highly engineered envelope protein and that using more natural versions of this component for subsequent injections helped achieve the desired result: broadly neutralizing antibodies that can protect against many different strains of HIV-1. She will continue animal studies at Wistar to optimize sequential immunization approaches.

When Amelia started hearing about COVID-19, she immediately thought that SARS-CoV-2 which causes COVID-19, could be a target for sequential immunization. She suspects this virus will be an easier target than HIV-1 because of the lower mutation rates. She thinks a series of injections with natural versions of spike from a range of newly emerging SARS-CoV-2 strains may lead to broad protection from multiple variants. Amelia sees no limit to the applications of this approach to viruses and bacteria. “The same approach can be translated for all types of pathogens in general that mutate over time,” she said.

Building a Platform

Amelia expected some challenges at the time of recruiting personnel as an early-stage investigator, however, she has been pleasantly surprised. “People are interested in the projects,” Amelia said. “My previous work on vaccine design was well-timed so that I can now join the current research workforce aiming to develop new vaccines”.

As a Finalist in the prestigious Blavatnik Regional Awards for Young Scientists in 2020, Amelia has been more motivated than ever to use her special platform to push for the advancement of women in science and all STEM fields. In addition to trying to support and inspire the many female scientists she has mentored, Amelia speaks out to increase representation of women in different scientific environments. She hopes to continue these efforts taking advantage of her new position at The Wistar Institute.

As she grows her research program, Amelia has no shortage of hobbies to help take her mind off science’s many roadblocks. She loves running and just about all outdoor activities. She also disconnects from work by drawing cartoons of characters that live in her imagination. Amelia has even entertained the idea of illustrating books to promote science to help give the next generation of scientists the excitement she had as a young kid.

Written by, Carina Storrs, Ph.D.