Researchers gear up for preclinical testing of coronavirus vaccine

Immunologist Natasa Strbo and her team have put aside their work on HIV, malaria, and Zika to develop a vaccine for COVID-19.

When Natasa Strbo was investigating perforins for her Ph.D. dissertation at the University of Rijeka in Croatia, she received an unexpected invitation to work with Echkard Podack, the scientist who had discovered the family of antibacterial proteins that helps our immune systems kill infectious invaders.

But when Strbo arrived in Podack’s lab at the University of Miami’s Miller School of Medicine in January 2000 to complete her dissertation, she learned that he had other ideas. The legendary chairman of the Department of Immunology and Microbiology, who died in 2015, was looking for help advancing the live-cell vaccine he developed for lung cancer using heat shock protein gp96, a member of the family of proteins that our cells naturally produce in response to stress. It was a subject she knew little about.

Today, Strbo is a world expert on gp96, a “fascinating little molecule” that has put her in the worldwide hunt for a vaccine against COVID-19, the novel coronavirus that has infected 10 million people around the world and killed more than a half million of them. Backed by Heat Biologics—the company Podack co-founded in 2008 to use the gp96 vaccine platform to stimulate immune responses against a variety of cancers, viral infections, and other diseases—Strbo’s unique COVID-19 vaccine is on track to begin manufacturing for preclinical-testing next month.

With more than 125 other teams around the world working on a vaccine for the coronavirus that emerged in China late last year, the field is crowded. Many teams are farther along in what could prove to be an astonishingly quick race to the finish line. Dr. Anthony Fauci, the nation’s top infectious disease expert, said that a vaccine could be available in the United States by the end of this year.

But Strbo—who has, for now, put her work developing vaccines for HIV, malaria, and the Zika virus on hold—is undaunted. Like Fauci, the assistant professor of immunology and microbiology believes the world will need multiple COVID-19 vaccines to fill both the worldwide demand and address the different needs of different populations.

Nor does she consider the hunt a competition, but rather a privilege—to carry on Podack’s work and to learn more about both the novel virus that brought the world to a standstill and the fascinating little molecule that she has dedicated her life’s work to understanding.

Strbo, who wears a gold charm with an uncanny resemblance to the round, spikey novel coronavirus—it’s actually a traditional Croatian costume decoration originating in the 11th century that she inherited from her grandmother—addressed both in the following interview.

What exactly does gp96 do, and how can it be employed in the fight against so many deadly diseases—from lung cancer to the novel coronavirus?

Our vaccine works by harnessing heat shock protein gp96, a powerful immune system activator. When a cell dies and the contents of that cell spill out, which happens during infections, gp96 alerts the immune system that something bad just happened. So, our vaccine platform uses this signaling mechanism to activate the immune system against different infectious diseases or tumor cells. Over the past two decades, we have developed an exciting and avant-garde reagent: a heat shock protein, chaperone gp96, that generates effective anti-tumor and anti-infectious immunity. So far, we have used this approach to develop potential HIV, malaria, and Zika vaccines. In addition, our gp96-based vaccines for the treatment of non-small cell lung cancer are currently being tested in clinical studies.

What makes your approach for a COVID-19 vaccine so different, especially from traditional approaches that rely on weakened strains of the disease to trigger an immune response?

Since our own cells naturally express gp96, we reprogrammed a human cell line to continually secrete gp96 along with one of the most immunogenic COVID-19 proteins. This complex activates a robust, long-term immune system response. So, unlike a traditional vaccine, we are not injecting an attenuated or weakened version of the virus, which in essence is designed to induce our natural gp96 to trigger the immune response. Instead, we are hijacking the core principle behind the induction of the immune system without applying the actual virus. That’s very crucial. We’re not using anything from the virus that would cause replication of the virus.

How does your vaccine train the immune system to recognize COVID-19 and mount its defense?

While we’re not using the whole virus, we are using the COVID-19 spike proteins—which are expressed in those little spikes you see on the outside of that now-familiar ball of the coronavirus. The inner core of the ball contains the RNA, the genetic information for the virus. The outer ball is encased in a membrane, which is made of this protein with those little spikes, and they are basically the keys that unlock our cells and deliver the genetic material inside. And of course, the genetic material has all these components needed to make a new virus, which is how it replicates. That’s how you have one copy of the virus coming into the cell and thousands coming out. So what we are doing with our vaccine is mimicking—not delivering—the virus. We are mimicking the infection in such a way that we are teaching the immune system to recognize these viral proteins so, when the true virus comes in, our immune cells already recognize the outside envelope of COVID, and they attack it.

When you say “we,” who are you referring to and how has your team managed to create the vaccine during the University’s lockdown?

There are no words to describe my silent COVID-19 warriors who have been working in the lab since day one of the stay-at-home order. My two research associates, Eva Fisher and Laura Padula, are my right hand and my left hand. They created the DNA that incorporates the coronavirus genes—the spike—and combined them with the gp96 to create the vaccine cell line. It’s a really tedious process that takes a lot of TLC, especially in this time of social distancing and isolation.

What do you think the chances are that the U.S. will have a vaccine for COVID-19 by the end of this year?

That’s the million-dollar question and I only know two things for sure. It won’t be like the Hollywood movie, “Outbreak,” in which Dustin Hoffman develops a vaccine within hours of a virus’s discovery that’s 100 percent effective. Neither will we follow the classical timeline for the development of vaccines, which has multiple phases that take an average of 20 years. Look at Ebola. It took 27 years from the initial outbreak to the phase 1 clinical trial and then an additional 20 years from the clinical trial to get the licensed vaccine in December 2019. Another extreme example is dengue. It took over 75 years to go from the first clinical trial to the licensed vaccine, which comes with major restrictions regarding age, as well as previous dengue infection. What we’re seeing with COVID-19 is a completely new paradigm, where the phases for vaccine development overlap. Now the manufacturing is happening side by side with the safety studies. That was completely unheard of before COVID-19, but then we have a tremendous, urgent, worldwide need. And money is flowing to fund it. Scientifically that’s okay. We can overlap these phases to save the time.

Are there drawbacks to your COVID-19 vaccine?

Since the gp96 vaccine is cell-based, it can’t be manufactured on a large scale. But we are not aiming for large distribution where everybody would get it. We’re going for the vulnerable populations, particularly the elderly and the immunosuppressed. The immune response in the elderly is definitely different than other age groups. And we think this approach, where we activate the natural immune response without the actual virus, could work well in people over 65. But the good thing about what is happening now is that we are all learning from each other. The whole world is a big laboratory; and now more than ever, it’s important that we share information as soon as possible so we can adapt the vaccine when needed. It’s a new virus and we don’t know much about it. So how are we going to fight it if we don’t know what it does? 

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