PROVIDENCE – A gaggle of Rhode Island leaders will gather on Monday morning, Sept. 25, to celebrate the groundbreaking of the new Wexford Innovation Complex, a milestone in the efforts to redevelop the former I-195 land on the edge of the former Jewelry District.

The list of notables includes: Gov. Gina Raimondo, Sen. Jack Reed, Sen. Sheldon Whitehouse, Rep. Jim Langevin, Rep. David Cicilline, House Speaker Nicholas Mattiello, Senate President Dominick Ruggerio, CommerceRI Secretary Stefan Pryor, and Brown University President Christina Paxson.

The dignitaries are to be joined at the podium by Jim Berins, president of Wexford Science and Technology, and Tim Rowe, CEO of Cambridge Innovation Center. [An equally impressive gaggle of reporters from most of the news media outlets in Rhode Island will no doubt be covering the groundbreaking.]

In many ways, the Wexford project owes a debt of gratitude to the pioneering work of Dr. Annie De Groot, the CEO and CSO of EpiVax, and her team of researchers and scientists, whose successes have demonstrated the potential for the biotech industry to grow and prosper in Rhode Island.

Founded in 1998 as one of the first start-up firms in the biotech industry cluster in Rhode Island, EpiVax has emerged two decades later as a world leader in the fields of immune engineering and vaccine design.

Today, screening tools that were developed by EpiVax have been employed by a global roster of companies in order to design and optimize therapeutic proteins and vaccines.

Proof of concept
Last week, the National Institutes for Health awarded a $5.8 million grant to engineer a vaccine to protect against bird flu [avian influenza A, H7N9] in a research consortium led by EpiVax.

The five-year program seeks to address pandemic preparedness, which is a pillar of the U.S. government’s National Strategy for Pandemic Influenza.

There is heightened concern about the potential of the H7N9 flu to become the next global pandemic, according the U.S. Centers for Disease Control and Prevention. H7N9 is “the influenza virus with the highest potential pandemic risk,” the CDC wrote recently in its journal, Morbidity and Mortality Weekly Report.

In people, H7N9 can cause a severe from of pneumonia and progress into septic shock and multi-organ failure. “We know of only a small number of people who presented with influenza-like symptoms and then recovered without medical attention,” the World Health Organization reported.

During the 2017 outbreak, the Chinese government reported 759 cases of H7N9, with 281 deaths, about a third of those infected. Although scientists say H7N9 has the potential to evolve into a global threat, right now it has one severe limitation that resists its potential to spread: the virus is not transmitted easily between people; about 90 percent of people catch the virus by handling poultry.

Since 2013, the team at EpiVax has been working to better understand the internal make up of the H7N9 flu virus.

“H7N9 is distantly related to seasonal influenza and presents a challenge for traditional flu vaccine approaches, which rely on prior exposure,” the news release about the NIH grant explained. Using state-of-the-art bioinformatics and structure modeling methods, the news release continued, the new collaborative research venture “aims to engineer the H7N9 hemagglutinin protein to resemble seasonal flu.”

The goal is to produce a vaccine that engages “immunological memory” and make conventional flu vaccines protective against the new, high-mortality avian influenza.

Collaborative research approach
Currently, EpiVax’s first-generation engineered H7N9 flu vaccine product is part of a clinical trial in Adelaide, Australia, managed by a team at Flinders University and Vaxine. “We are proud to be the first in the world to test in humans EpiVax’s innovative approach to modifying flu proteins to make them immunogenic,” said Nikolai Petrovsky, the research director at Vaxine, an Australian biotech firm focused on the development and commercialization of vaccines.

The five-year, $5.8 million NIH grant will be carried out by a collaborative group of researchers and scientists, with a wide range of expertise across immunology, structural biology, bioinformatics, animal infection models, and vaccine manufacture. The participating institutions include:

• EpiVax [Annie De Groot, William Martin, Lenny Moise

• UMass Medical School [Celia Schiffer]

• Protein Sciences, recently acquired by Sanofi Pasteur [Indresh Srivastava]

• University of Georgia [Ted Ross]

ConvergenceRI recently sat down with Lenny Moise, Ph.D., director of vaccine research at EpiVax, who was responsible for shepherding and securing the NIH grant. Moise, who has been with EpiVax since 2006, talked about the innovative approach being taken in developing the H7N9 vaccine as well as the maturation of EpiVax as a biotech company. Here is the interview:

ConvergenceRI: What is the role that EpiVax will play in the $5.8 million grant from NIH?
MOISE: We’re leading the consortium. It is a program that will involve scientists from different backgrounds and areas of expertise.

For instance, they include Dr. Ted Ross at the University of Georgia, who is an influenza vaccine and animal model expert.

He will be performing assays involving antibody analysis.

ConvergenceRI: Can you provide the context for the work being done, and the role that EpiVax has played over the past four years in developing an innovative approach to developing a vaccine for the H7N9 flu?
MOISE: As soon as sequences [for the H7N9 flu] became available publicly [in 2013], we jumped right in to design a vaccine against H7N9. In fact, one of the immuno-informatics experts at EpiVax, Matt Ardito, spent an entire weekend, clocking in 24 hours, performing an analysis, in order to come up with a [potential] vaccine design as fast as possible [that could contain] an outbreak of the new strain of flu in humans.

We didn’t know how virulent it may be; we didn’t know how far it may spread. There was a lot of nervous energy around it.

ConvergenceRI: Many people believe that H7N9 flu is the next big threat for a pandemic. Is that accurate?
MOISE: According to the CDC’s influenza risk assessment tool, it is the avian influenza with the highest pandemic potential today.

ConvergenceRI: One of the problems with developing a vaccine for the H7N9 flu is that it has been described as a kind of “stealth” virus, because it can camouflage itself from the body’s normal immune responses. Is that accurate?
MOISE: That’s right. This is a stealth virus in the sense that it takes humans longer to develop a protective response than we would against seasonal flu. It takes approximately 21 days to develop antibodies that will neutralize seasonal flu virus; in people who have survived a H7N9 infection, those effective antibodies come up later, at least a week later.

ConvergenceRI: Does the new grant by NIH to invest in developing a recombinant vaccine to combat H7N9 flu represent a switch in policy? Hadn’t BARDA been the primary funder of such research?
MOISE: Since 2013, BARDA has been leading the way to develop a vaccine that will be manufactured and stockpiled for the nightmare scenario if this virus adapts for sustained human-to-human transmission.

NIAID [the National Institute of Allergy and Infectious Diseases] has also been significantly funding H7N9 vaccine research. In fact, we have a different SBIR grant from NIAID for a different H7N9 vaccine program; that is one example of NIH’s commitment to developing H7N9 vaccines.

But those vaccines would be further back in the pipeline than what BARDA funds; BARDA funds research and development that is at a more advanced state.

NIH is supportive, and it has contracted resources that are valuable to investigators [to pursue] research in small animal models and vaccine manufacturing and even clinical trials, which we have been trying to access.

We have independently developed an improved H7N9 vaccine [compared to] the classic vanilla vaccine.

ConvergenceRI: What happened next?
MOISE: Rather than make the vanilla vaccine, we have taken a close look at the sequence of this H7N9 hemagglutinin molecule, which is the critical antigen for developing an immune response.

We found that the molecule, in our predictive analysis, is poorly immunogenic, and in fact, contains an epitope that would stimulate a part of the immune system that shuts down effective antibody responses.

With that information in hand, we [believed] that we needed to do something different in [manufacturing a vaccine] than we do every time a new type of flu is discovered.

So, we designed an alternative to the natural sequence that circulates, and discovered that it is more immunogenic than the native sequence. We conducted a number of pre-clinical studies and then partnered with Protein Sciences, which produced this optimized vaccine.

We then partnered with Nik Petrovsky in Adelaide, Australia, who is now conducting a Phase 1 clinical trial with that optimized vaccine. That trial is recruiting now, and hopefully we will have data by the end of the year or the first quarter of next year, which will help to inform the work that we are doing in this new NIH H7N9 program to improve on the vaccine design.

ConvergenceRI: What is the strategy to do that?
MOISE: We think we can improve the vaccine by introducing more immune memory that we have from the seasonal flu, in order to make a more effective vaccine against the bird flu.

You and I are not often exposed to bird flu; hopefully, we will never be exposed. We don’t have contact with poultry like people in some other countries.

Nearly the entire world has not developed immune memory to bird flu. Contrast that with seasonal flu. We have all been exposed or vaccinated at some point, and the vaccine we receive once a year, or should receive once a year, relies on immune memory to drive an effective antibody response. That's why only one dose is needed. Without the benefit of [immune] memory to develop an effective response to H7N9, a new kind of vaccine strategy is needed.

Our strategy is to engineer an H7N9 vaccine that draws on memory of seasonal flu.

ConvergenceRI: When the work is completed on the NIH grant, five years down the road, what is the outcome you are seeking?
MOISE: At the end of this five-year program, we expect to have a fully optimized recombinant H7N9 hemagglutinin vaccine that will go on for further pre-clinical development to reach a clinical trial.

ConvergenceRI: Is there a chance that timetable would be speeded up if for some reason that there was increased human-to-human bird flu transmission coming out of China?
MOISE: Yes. I believe that if we have data that demonstrates better immune responses to the new vaccine designs we will generate over the course of this program, better than what we have seen up until now with the vaccine that is now in clinical trial, then should there be increased concern about the spread of H7N9 among humans, then [I expect] that there will be an interest in moving forward with one of those designs.

This is one grant, it is a research grant, and NIH is practical in the sense that they want to see significant development toward a clinical trial. But, it is still a research grant where we have an opportunity to test multiple designs and to do that in a systematic way.

We will be testing the vaccine in animal models in mice. We will be doing something that’s novel in the flu research community, which is to pre-infect mice with seasonal influenza, so that they develop the immune memory that we have. Then we will vaccinate the mice with our H7N9 vaccine to see if we can harness the immune memory like we would want to see in a clinical trial in humans. Does that make sense?

ConvergenceRI: Yes.
MOISE: For the longest time, people have studied flu vaccines in “naïve” mice. But humans are not naive. In fact, the seasonal flu vaccine that we all receive is effective with only one dose, because of immune memory.

That is exactly what we are trying to harness, so we’re not going to immunize naïve mice, we’re going to develop a model of immune memory formed before vaccination, in order to model the human response as best we can.

ConvergenceRI: Will you partner with Protein Sciences to produce the vaccine?
MOISE: We are partnering with Protein Sciences for production of the vaccines. They are the world experts in making recombinant hemagglutinin. They have an FDA-licensed product for seasonal flu [Flublok], and we’ve been collaborating with them for a number of years.

ConvergenceRI: Has there been any feedback, now that Sanofi Pasteur has acquired Protein Sciences, about the new research program?
MOISE: Day-to-day operations will not involve Sanofi; we will work with Manon Cox, the CEO of Protein Sciences, and her team.

We will interact with Sanofi when it comes to publishing data; any publication has to go through an approval process. It is our understanding with our collaborators at Protein Sciences that Sanofi is supportive of Protein Sciences being involved with the new research program, and that is something we’re very happy about.

ConvergenceRI: Is there a validation that comes with the NIH grant for EpiVax’s efforts to push for a new approach to vaccine development as well as biologics, where EpiVax is no longer on the outside looking in, but part of the road map? Does that question make sense?
MOISE: I understand your question, because I’ve been here for many years and I’ve seen the evolution of the field toward greater acceptance of the integration of immuno informatics tools into vaccine design.

This is our finest example of a vaccine that requires some enhanced [signal] to elicit an effective immune response. There are groups that usie adjuvants; that is like pouring gasoline on a fire, as Annie likes to say, because you don’t know how to control it. It could work well; it could also get out of control. We know adjuvants have had their safety issues, and the FDA is very concerned about that.

We are attempting to do something novel, which is to think about what T-cell responses are activated in the course of vaccination. We want to engineer vaccine antigens that elicit those T-cell mechanisms that will contribute to a protective response and avoid the ones that inhibit that response.

ConvergenceRI: Does the NIH grant represent a sea change in vaccine strategy?
MOISE: I think you’re accurately describing it. We feel very gratified that NIH recognizes the importance of this thinking and this kind of vaccine design strategy that has been lacking in the field, rather than making the vanilla vaccine.

We need to make more effective vaccines. The seasonal flu vaccine is a great example of sometimes making a vaccine [with older technologies] that is not is not sufficiently effective.

Rather than do what we’ve always done, we are doing something different – and that is now gaining greater acceptance.

ConvergenceRI: Will the grant enable you to expand your workforce at EpiVax even more?
MOISE: There is room to hire in this grant budget.

There is significant personnel support provided [in the grant], and it is truly needed, because it is a very large research program, larger than the typical R01 grant from NIH [the original and historically oldest grant mechanism used by NIH to support investigator initiated, health-related research and development based on the mission of NIH].

One partner I didn’t mention who is part of the consortium is an investigator at UMass Medical School, Celia Schiffer, who is a structural biologist and who will help guide the selections of the novel vaccines we design, so that changes we make to improve the T-cell response will not significantly disturb the structure of the hemagglutinin molecule. This is important because we need to manufacture the protein, and we need a protein that will maintain the critical structures that antibodies recognize on the natural H7N9 virus.

ConvergnceRI: Is there a problem with the talent pipeline, in finding workers to join EpiVax? Is there a lot of competition because of the proximity to Boston?
MOISE: We are hiring now. You can see on our website the job postings page that there are opportunities. We have a tough time finding individuals who have the type of experience that we need, particularly, from where I sit, we are looking for people with t-cell immunology backgrounds.

Those are harder to find, because we are competing not just with others in Rhode Island but also in the region. It’s a very, very exciting time in biotech, which means that there are many openings and [there are lots of] companies that are hiring people with these skills.

I’d like to see the biotech industry grow here so that we do have a larger pool of people to draw upon.

ConvergenceRI: Is the biotech industry cluster gaining more traction here in Rhode Island, from EpiVax’s perspective, given that you are something of a senior citizen?
MOISE: [laughing] We’re not even 20 yet. Maybe in the Rhode Island biotech sector that is old. But, we feel very young. We feel like we’re taking off, definitely not slowing down, by any stretch. We are only getting busier.

You’ve read about the exciting cancer neo-epitope vaccine subsidiary that’s spinning out of EpiVax. This is a very exciting time for us.

ConvergenceRI: Does it feel like there is more traction?
MOISE: Yes. We have products; we do not have FDA-approved products. But we do have our immuno-informatics protein immunogenicity screening and vaccine design toolkits. They are [strong] products in the marketplace, gaining traction.

They may not generate the kind of buzz that a drug approved by the FDA does; I understand that. But we are maturing. We are moving forward. We are in Phase One clinical trials in Australia, which is huge for us.

There is a level of maturity that the company has achieved. And, there is room for greater growth.

We’ve grown significantly over the last couple of years. I think it’s been a healthy growth process, not too sudden, not just in one area. As we grow, I think, we’re only going to get stronger.