COVID-19 Vaccine Development Update: An Interview With Novavax

In this critical time, a key question continues to emerge: When will a coronavirus (CV) vaccine be ready?

The clinical-stage biotechnology company Novavax recently announced their efforts in working towards the development of a vaccine to tackle the SARS-CoV-2 outbreak.

The company is in the process of developing and analyzing several candidates that adopt the Novavax proprietary nanoparticle technology, some of which have been "in the freezer" following the SARS-CoV epidemic that occurred several years ago.

Currently testing their candidates in animal models, Novavax told Technology Networks that they are expecting to progress to human clinical trials in May or June of this year.

We spoke with Gregory Glenn, MD., President of Research and Development at Novavax, to learn more about the vaccine candidates, the progress that has been made in clinical testing and how Novavax is working to shorten the typical time-frame for vaccine development in this emergency situation.

MC: You previously said that a SARS vaccine could have altered the impact of the novel coronavirus (CV) outbreak. Can you expand on what you meant by this, and what factors prevented a SARS vaccine from being licensed?

Gregory Glenn: Seasonal influenza, respiratory syncytial virus, SARS, SARS-Cov-2 and MERS all have a molecular mechanism by which they infect a host cell. They have to bind to a receptor on the surface and they have a protein that possesses a fusion function, which you can think of as a syringe, which injects the viral genetic material into a human cell, taking over the cell machinery. Now the host cell replicates the virus rather than producing human proteins. The cells usually lyse, break and cause inflammation.

Across these viruses, the syringe can look different. It can be orange, purple, green, long or small; but it has to have a plunger. These proteins have a lot of homology. If you look at the 3D structure of the beta CVs, externally they look similar, but they mutate. They mutate like crazy. If you have a CV infection you have several hundred versions of it floating around in your body. The mutations that matter are the ones that help the virus survive and become the most "fit" virus that can spread. This happens with flu.

Flu, like SARS, operates via proteins with a cell binding function and a fusion function. We have developed a vaccine for seasonal flu for which we're just about to unblind a Phase III trial. Our thesis is that we don't need another flu vaccine, we need a better flu vaccine. The way we make our vaccine is by displaying the whole protein in such a way that the conserved parts are also seen by the immune system, so you get an immune response not just to the variable region but also to the conserved region. The result is broad cross protection.

Our particular vaccine technology is a full length, recombinant protein from the surface of the virus that is inserted into a nanoparticle and gives you an immune response to the conserved portion of the protein. It's therefore somewhat "immune" to the effect of mutations. We already know there are mutations in SARS-CoV-2, but this should not impact the effectiveness of our vaccine.

In 2012 we generated a spike protein that was 100% effective and a very good neutralizing antibody. This was in the freezer, and when the current SARS-CoV-2 popped up we brought it out and conducted animal studies. We (and others) have evidence that immunity to SARS could neutralize the virus in SARS-CoV-2.

Returning to your question, in my opinion, had there been a mechanism back in 2012 to fund this sort of work, the vaccine could have been taken to licensure and stockpiled. Then, when this outbreak originally occurred, we would have had everything we needed to respond and potentially have the crisis covered. That's how you can be prepared for a pandemic.

The lesson that I have learnt is that we need to have a mechanism to fully develop the SARS-CoV-2 vaccine through licensure and stockpile. Another CV will come in the future.

MC: Do you think the factors that prevented the vaccine from being licensed in 2012 are now being addressed?

GG: I do, and I'm encouraged. The governments across the globe have discussed "preparedness", but I'm not sure that in the last 10 years there has been much progress in the setting of vaccine development. There wasn't a long view of how to be prepared for a pandemic from a vaccine standpoint. As a result, there hasn't been any funding to support such efforts. However, philanthropists, the Gates Foundation and the Wellcome Trust, funded an initiative known as Coalition for Epidemic Preparedness Innovations, or CEPI, and have been mining away at the topic, funding early vaccine development. We recently received funding from CEPI. The process of vaccine development is extremely expensive.

From a business perspective, I'm faced with the challenge of: do I take my team away from other projects that they're working on? Will this be detrimental to business survival? We're a company and we can't work on things that do not have a market and won't make a return on investment.

In the context of emerging infectious diseases, we estimate that we've already spent $100 million so far with no return. We created a really good Ebola vaccine, arguably the best Ebola vaccine, and we spent a lot of money. We've been reluctant to engage with CEPI to-date, but now I think that not only will they support early development as well as late development, but also with COVID-19, there are fundamental changes to the underlying social contract.

My view is that the governments need to "step up" with a program where they create a market for vaccines with reliable suppliers. This has to happen or we're going to live in a society where there's lots of interchange, thereby viruses will mutate and jump again, and we will be facing a similar battle. Through licensure, there's some possibility that, should another CV move from animals to humans, and humans are not immune to that particular strain, the vaccine we produce today has enough cross-reactivity to be relevant or highly relevant to a new outbreak.

MC: Are we potentially talking about a "universal" vaccine here?

GG: Well, the definition of universal would mean that we have one spike protein vaccine that covers every single CV out there. Rather, I would say that we are talking about a broadly cross-reactive vaccine; this would be the better term. People talk about the development of a universal flu vaccine. Maybe it's possible, but first things first, it would be really great if we can create a vaccine that works. What happens at present is that, in the case of flu, we select certain strains and we develop vaccines to protect against those strains. But what we're seeing in the U.S. is that the efficacy for certain strains is abysmal. Over the last several years, flu has been one of the major causes of morbidity and mortality. The vaccines just work very poorly. So, we want a markedly improved vaccine first – that would be a big achievement.

MC: What is the added value of utilizing the Matrix-M™ adjuvant with the vaccine?

GG: Matrix-M™ is essential. It boosts the magnitude of the immune response, which means that you get both a longer response and a higher quality response. Some of that quality relates to manufacturing antibodies to the conserved regions of the virus.

When you immunise you need to have a specific signal, such as the 3-D structure of the spike protein, but you also need a danger signal that says 'hey, this is dangerous' so you need to have an immune response to this. The Matrix-M™ adjuvant has gone through a lot of rigorous testing so that it's dialled in the right qualities to be both safe and to provide a strong adjuvant effect needed to make an immune response to these highly purified and highly characterized recombinant proteins.

MC: Let's talk preclinical testing. Can you expand on the positive results Novavax have had and what the next steps are?

GG: Here is what I can tell you. In a vaccine program, what you do (which is really helpful), is to develop a certain level of immunity by vaccinating mice and other animals.

The nice thing about immunity is that you're not just looking at the levels of the functional antibody. The spike protein on the surface of the virus engages with a receptor binding protein called ACE2. This binding could be compared to the docking of a spaceship, if you will. In SARS-CoV-2, this interaction is likable to super glue. It's very specific and there is extremely high affinity. I've never seen anything like it.

The goal, therefore, is to create a vaccine that blocks that interaction. We have taken the SARS-CoV-2 gene sequence published via the internet and inserted it into a cabbage worm cell (this is a long-adopted method in vaccine development) so that the protein is produced in the cell. We then have a lot of work to do to make sure that this exercise has produced the protein in the right content figuration. Does it bind to the human receptor? We create recombinant versions of the human receptor to test that.

We put the spike protein on a chip, send in the vaccine and, if everything's right, it should bind to the spike protein because of this "super glue-like" affinity, it should dock to the receptor and stop the interaction, and it does. It's a critical step forward.

As time goes on, we will have more data available. We may have to make the decision to deploy the vaccine based on animal studies showing that it works. This happened with previous infectious diseases and it was effective. Sometimes in these emergency situations you may have to make a decision based on the quality and breadth of animal and in vitro data that you have available. You can get really nice quantitative data from these studies that indicate how well the vaccine works.

We are at a place where I think we have a good candidate and we're cruising as fast as we can towards starting a clinical trial. I think we're looking towards starting clinical trials in May or June, to provide a rough timeframe.

MC: We know that vaccine development can take between eight to ten years in some situations. What measures are in place to attempt to shorten this time frame in this situation? How are the Food and Drug Administration (FDA) and public health authorities collaborating with Novavax here?

GG: I think the eight to ten years is a "typical" timeframe. The Ebola vaccine development took four years, but there was no immediate rush at this time. Under normal circumstances the development of a vaccine takes place via a well-structured schedule with set timelines for meetings with the FDA. In this context, the FDA are really collaborating with us to shorten the typical timeframes for certain conversations. We're hoping to have clinical trial data towards the end of summer that indicates the vaccine is safe and that it triggers a functional immune response.

We normally do things in series, so in this context we are taking risks. Frankly, I feel like I'm driving on a racecourse that I've driven 500 miles on before, so I know every turn; I know what risks we can or cannot take. There are certain things you can stack up to be in parallel and certain things you must do in series, and that's going to be part of the negotiations with the FDA: what is it that we can stack up? This is a crisis and so the FDA are eager to contribute.

MC: What do we know about the novel coronavirus' ability to mutate? How are Novavax taking this into consideration?

GG: We know that it mutates, and I believe that there is even a website dedicated to tracking the mutations. I think the reason SARS-CoV-2 has spread the way it has is because the receptor binding activity is stunningly efficient, making the virus super infectious.

Think of this as a subway. When a subway is packed, you can just see the heads of people on board. This is kind of the same for the spike proteins – the immune system can see the head. The viruses that mutate in this "head" section may avoid immunity that we develop to other types of CV and may not be seen by the immune system in this crowded environment.

With our vaccine, the process is more comparable to an empty waiting room. There's a few of the proteins on the surface of a nanoparticle, so the protein is naked to the immune system; it can see everything, particularly the conserved region of the protein. We believe that this will help create a more immunogenic response with broader coverage.

Dr Gregory Glenn, President of Research and Development, Novavax, was speaking to Molly Campbell, Science Writer, Technology Networks.