PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Good morning, and good afternoon to our call participants in Europe. Welcome to today's Chardan KOL call featuring Dr. Lauren Wood, clinical scientist, with over 30 years of experience researching immune therapies at NIH, and who currently serves as Chief Medical Officer of PDS Biotech. We'll be talking about applications of the Versamune platform for SARS-CoV-2 and other infectious disease vaccines. Thank you for joining us today, Dr. Wood. I'm Geulah Livshits, a biotech analyst at Chardan. As Dr. Wood is aware of, focus at Chardan and at -- is on identifying companies that can generate exceptionally high long-term investment returns by creating and sharing and value for the society. But during this call, we will not be discussing Chardan Research. Any discussion about Chardan Research should be coordinated between our participants and their respective salesperson at Chardan, and the recording of the call will be made available to clients after the call. Our compliance team has asked me to read this statement for the investor call. By participating in this call, our speaker attests that they made Chardan aware of any potential conflicts, and they will not discuss any material, nonpublic or confidential information that they're aware of that may breach their legal, regulatory or fiduciary responsibility to any parties. So in terms of format, this is a 45-minute to 1 hour long call, and participants have the opportunity to ask questions throughout the leadership call. To do so, please e-mail your questions to me [email protected]. So thank you again, Dr. Wood, for joining us today. To start off, would you please tell us about background in the oncology and infectious disease space to bring the conversation?

Yes. Thank you so much, Geulah, for having me this morning. As you highlighted, I have over 30 years of extensive clinical research experience at the NIH, both in the National Institute of Allergy and Infectious Diseases as well as National Cancer Institute. I was previously a clinical director of the vaccine branch at the Center for Cancer Research, where I oversaw translational development of immune-based therapies for both cancer as well as HIV infection, with a specific focus on immuno-oncology, checkpoint inhibitors and cancer vaccines at the time of my retirement from the NIH. My early career translational efforts actually focused on HIV and AIDS. Its infections as well as malignant complications as we know in that area, antiretroviral treatment has been transformative. My President and CEO, Dr. Frank Bedu-Addo, was able to talk me out of retirement to become PDS' Chief Medical Officer. I became aware of the Versamune platform technology, while I was still at the NIH. And I'm thrilled to have the opportunity to move this technology forward for both of the indications we're going to be discussing today.

Great. And so in terms of your experience, how does that play into your current role at PDS?

So I became aware of the Versamune platform technology at a World Vaccine Congress meeting, specifically addresses vaccines for both infectious disease as well as cancer. I have been working with personalized cellular therapies. We know how effective recent cellular therapies such as CAR T-cell therapies have been in the immuno-oncology space. My focus was on dendritic cell vaccines. And I was very impressed with the technology's ability to enhance and optimize the function of dendritic cells. Basically to deliver antigens to them, activate the dendritic cells and cause them to migrate to lymph nodes and stimulate T-cell responses, which is really the focus of cancer vaccines and specifically, dendritic cell vaccine. So the Versamune technology was appealing because it had and offered the potential for an off-the-shelf product that had the functional equivalent or maybe even superior to dendritic cell personalized products. So that's how I started. That started my scientific interest in Versamune, and I continue it both professionally as a PDS employee and Chief Medical Officer.

Great. And so speaking to the kind of the applications from the platform in both cancer vaccines and infectious disease. So how similar is developing a vaccine for something like cancer versus an infectious disease? Are there different properties? Or what do you see as the properties of a good cancer vaccine, to start off? And maybe I'll talk about the infections disease after.

So there are very important commonalities as well as distinctions between trying to develop vaccines for cancer as well as infectious disease. One thing I will highlight initially is the fact that both cancer as well as infectious disease pathogens undermine the normal immune defenses of the immune system to limit their effective eradication. So both cancer has mechanisms to keep the immune system from eliminating it, and infectious disease pathogens also have mechanisms that they utilize to keep the immune system from eliminating it. The key thing that's critical and that's in common for both diseases is that T-cells are critical to eradicating both of them. Again, like I highlighted, some mechanisms are shared in common. Others are unique. One of the things that's very challenging in developing cancer vaccines is that the antigens are from self-tumor tissue. So they tend to be tolerized. We don't recognize cancer antigens as foreign because it is cells, even though it's cells gone rogue and gone bad. And so that's one of the great challenges in developing cancer vaccines because these cells' antigens do not trigger innate immunity. And triggers of innate immunity are very important because the innate immune system is the first line of defense. So it's challenging to get and develop cancer vaccines that trigger innate immunity. This is where Versamune comes in because it is differentiating in that it's an adjuvant that we have documented that specifically triggers type 1 interferons. And type 1 interferons are those very important immune proteins that are triggered when the innate immune system is triggered. I mentioned that there are commonalities with infectious disease. Well, viruses and other pathogens oftentimes undermine the immune system's ability to trigger innate immunity and specifically, interferon signals. So it is another application for Versamune in the sense that Versamune is actually able to overcome the specific mechanisms that many viral pathogens and other infectious disease pathogens use to keep the immune system from responding to it.

Got it. That makes sense. And so are the -- so that -- just as some of the commonalities and the differences in vaccine development, do you see any other specific challenges for either cancer vaccine development or infectious disease vaccine development that need to be overcome other than the one that you've just alluded to?

Yes. Another very, very important one is the ability of the immune system to actually see the antigen of interest that we want the immune system to respond to, to recognize, effectively target and then eradicate and eliminate. Both cancers as well as infectious disease pathogens often down-regulate immune system proteins that are on the surface of cells that are necessary for antigen recognition. These surface proteins are called the major histocompatibility complex, MHC. It's basically your tissue type. But every single antigen has to be presented in the context of these major histocompatibility proteins. There are 2 pathways, the Class 1 pathway triggers fighting killer T-cells, whereas the Class 2 pathway triggers helper CD4 T-cells that also lead to the development of antibodies. And what cancers as well as infectious disease pathogens do is they often down modulate and down regulate the expression of these surface proteins.So the problem is your immune system can't respond to an antigen that it can't see. Again, this is also where Versamune is really differentiating in both the cancer and the infectious disease space. In the context of this Type 1 triggering of interferons, we also see that there's excellent presentation of antigens, by both the Class I and the Class II pathway. And so as a consequence of that, you see the development of very potent, very broad and long-lived T-cell responses as well as antibody responses. Another important commonality to be addressed in both spaces.

Got it. Got it. And so then in terms of thinking about the properties of an optimal response for either -- optimal vaccine rather for either cancer or infection disease. So how would those factors fit into the properties that you would be looking for?

So again, for both cancer and infectious disease vaccines, what you don't have is the right kind of immune response. We know, very importantly, that for eradication of cancers, T-cells are critical to getting rid of cancers and controlling cancers. We also know that they're important in infectious diseases, but it's also dependent upon the pathogen. Antibodies are very good for both bacteria as well as viruses, but we also know that T-cells are critically required for viruses. So what's necessary for both vaccines and vaccine approaches is to induce not only the right quantity of T-cells, but also the right quality of T-cells. You can induce a lot of T-cells, but if those T-cells are shooting blanks, they're not really killing the targets, then they're not doing you any good. So you've got to induce not only the right quantity and high levels of T-cells, but you've got to induce T-cells that have the right quality. They have to be potent, and they have to be able to get the job done and actually kill the tumor cell or eradicate and kill the virus infected cell. The other thing that's really critically important is, in addition to having T-cells that do the job, you also want T-cells that remember what the enemy looks like. You don't want to fight a hard fight, get rid of the enemy. And then if the enemy returns, you don't recognize what they look like. So T-cells are also very important for memory and remembering what either a tumor antigen associated with the cancer looks like or an antigen associated with an infectious disease pathogen looks like so that if your immune system encounters it again, it's able to rapidly respond and eradicate it. Memory is key.

Got it. That makes sense. And so to what extent do different pathogens present unique challenges with respect to vaccine design and development? You just mentioned virus and bacteria. Within the space of different viruses, to what extent are there unique challenges that are presented?

That's a really excellent question, Geulah. And my first response is it is really the nature of the pathogen itself that kind of determines what the challenges are going to be in terms of developing an effective immune response to it. An example is HIV. It's a virus, but it's a retrovirus, which means that it's an RNA virus, but it infect cells and then it transcribes its RNA into DNA, which is then transcribed again into RNA and then it makes its viral infectious proteins. We understand this life cycle very well because it is a retrovirus. It can become latent because it can kind of stop copying itself in the DNA state. And so that's a challenge because you've got an immune response that needs to not only eradicate HIV, but also potentially eradicate cells in which the HIV DNA is hiding in the cells and is quiescent. It's very challenging. And it's why after 35 years, we still yet don't have an HIV vaccine, even though we understand this virus very well scientifically. In contrast, we've got flu. Everybody understands about the flu. It's something that we all have to deal with every year. Influenza viruses are RNA viruses, but they represent different challenges for the immune system because of their immutability. They have outer coat proteins that the immune system rapidly responds to, generates an immune response, able to eradicate the influenza virus, and you get over the flu, even if you feel really bad for several days. But the problem is with these influenza viruses is that they change these proteins that are on the outer coat rapidly. And so it's why we all have to go through year after year, getting influenza vaccines because the flu viruses that are circulating have changed these outer coat proteins. So it's like the immune system has to start from scratch all over again. Again, those are just some of the challenges and a highlight of how different pathogens can require challenges in terms of immune responses that control them. One thing that isn't common though is that T-cell responses are key to ultimately controlling both of those viral infections, both influenza as well as HIV.

Got it. Great. And so I think you may have alluded to this already, but to what extent can learning from the cancer vaccine design space translate to vaccine development for the infectious disease and vice versa?

So like we discussed, the critical, critical element is to be able to trigger that our immune system's first-line of defense, which is innate immunity, okay? Type 1 interferons. When you trigger Type 1 interferons and innate immunity, it sends messages to the entire immune system to really induce immunoresponses that are rapid, broad and potent. We also need to induce immunoresponses safely and that lack toxicity. We don't want to deliver vaccines, either therapeutic vaccines for cancer or preventative vaccines for the flu or other infectious pathogens that make us feel as if we have the disease, like we're so sick we're run over by a truck and so forth. And that's another differentiating feature is the ability to induce immunity and immune activation that's specific for the pathogen, but doesn't give you lots of nonspecific systemic inflammation. Because that's what causes people to feel bad, they feel achy and feel like they have the flu. So those qualities are very, very, very important. It's also important to differentiate that there are always going to be differentiating challenges between developing vaccines for cancer versus vaccines for infectious disease. Generally, when we talk about developing cancer vaccines, we're talking about therapeutic vaccines, trying to harness the immune system in a patient that's already resisting cancer. As opposed to infectious disease vaccines, where we're really talking about prevention of disease. It is important for everyone to know that we have successfully developed at least one preventative cancer vaccine, and that is the vaccines targeting human papillomavirus.

All right. Of course. That makes sense. And so as you mentioned, in the infectious disease space, there tends to be a lot of discussion about the antibody responses. But as we just discussed, T-cells are clearly important as well. Can you talk a little bit more about the importance of the CD4 and CD8 T-cells? And whether it's to what extent the induction of at cell response can factor into parameters like the duration of protection from infection delivered by a vaccine?

Okay. That's a great question. And there are, again, important differences. Currently, most of the infectious disease vaccines that are designed to prevent infection can induce T-cells. The focus is on antibody production. And antibodies, again, are very important in preventing and potentially controlling infection. They're particularly effective in controlling bacterial infection because bacteria kind of tend to float around in the body or be on the surface of tissues and cells and tissues. In contrast, viruses are actually parasites. They have to go inside cells to be able to take advantage of the whole cellular machinery to replicate and then spread. So they actually, in addition to antibodies, absolutely require T-cells in order to control that viral replication, spread and ultimately, eradication of the virus from the body. An exception in the contrast that I just highlighted is TB. Tuberculosis is a bacteria, but it really kind of behaves a little bit more like a virus in that it's an intracellular pathogen. And it lives inside cells, replicates very slowly. Hence, the challenges that we have in eradicating TB. Versamune's ability to really induce high levels of T-cells are critically important. One, because it can happen rapidly, and it needs to happen rapidly, so you can get over the infection and start feeling better. But more importantly, the induction of these T-cells allows immune memory to be generated. And while we know that the levels of antibody responses and T-cell responses all tend to fall off after you've gotten over an infection, we generally know that T-cell responses tend to be more long-lived than antibody responses. That varies according to the pathogen. But another reason why T-cell responses and inducing them are very important for the control of viral infections and can contribute to efficacy.

Got it. That makes sense. So from that standpoint, there's going to be a longer duration for responses when T-cells are involved in a vaccine. It's actually...

Absolutely. We know that there are not only memory T-cells, but also memory B-cells. These memory cells of the immune system do just that. They remember what the enemy looks like, what the invading pathogen looks like, what the invading tumor cell looks like. And when they see it again, they're able to rapidly ramp up and amplify so that then they can arm these killer T-cells to get rid of the pathogen or turn into antibody factories and generate tons of antibodies, again, also to neutralize and get rid of the pathogens. So memory responses are critical. If you don't get good memory responses with a vaccination, it's why you have to keep getting repeated vaccinations or why you might need 3 vaccinations to induce protective immunity as opposed to a single vaccination. So these memory responses are really important to the quality of any vaccine that you're delivering.

Great. And so as you mentioned at PDS, you guys are using the Versamune platform to develop both therapeutic and prophylactic vaccines for cancers as well as infectious diseases, respectively. So can you tell us a little bit more about the platform and the specific characteristics? I know you mentioned the type 1 interferon induction. Is there any other characteristics that make the platform suitable for both of these applications?

So as you highlighted, we've talked about Versamune's immune's ability to trigger Type 1 interferons, to also significantly enhance antigen presentation by both pathways, so the immune system is actually able to see antigens. But another unique property about Versamune is how it is engineered for simplicity. It is a synthetic lipid that is positively charged. And it's actually sized to be the same size approximately as virus-like particles. So because this adjuvant is sized to look like virus-like particles, the dendritic cells of the immune system basically love to gobble it up because it basically mimics in size and shape viruses. So it looks like a virus, but it's not a virus, but the immune system cells take it up as well as any antigen that is co-delivered with it. The other thing is, is that because it's positively charged, it naturally fuses with our immune system cells, the dendritic cells, because our -- the cell membranes are negatively charged. And we know that positive and negative charges come together. And so it's another way in addition to being sized like a virus and wanting to be taken up, that it actually ensures that not only the particles, but the antigens get inside these antigen presenting cells. The other thing that appears to really be differentiating about Versamune is that once the antigens are inside the cells, it's important that they get processed. The antigens have to actually be broken down in and digested, in a sense, into smaller pieces so that then they can be presented, either along the Class I pathway or the Class II pathway. So if you don't have antigen uptake in the first place, or if you have antigen uptake, but you don't have antigen processing, again, the immune system will not see the pieces of that either tumor antigen tumor cell or that invading pathogen that it needs to see to really respond to. So those are some other unique differentiating properties of Versamune that indeed make it unique. Finally, the other thing that I'd like to highlight is that all of the activities of Versamune and its ability to stimulate the immune system and all of the properties that I've described actually occur locally. It occurs in the skin when we deliver the vaccine, and there is uptake of Versamune nanoparticles along with whatever tumor or infectious disease antigens are co-delivered with it. And those dendritic cells mature, but then they migrate to the lymph nodes. And the lymph nodes are basically the community center for the immune system. Everything is there, T-cells, B-cells waiting to see what they need to respond to. And we know that Versamune causes dendritic cells to migrate to the lymph nodes, stay there for up to a week after a single vaccine and basically, sits there in the lymph node community center and tells all the T-cells and the B-cells, what they need to respond to. And as a consequence, you see very significant amplification, lots of T-cell responses, you see great quality T-cell responses that are potent. But importantly, you don't see any of the systemic inflammation that generally causes people to feel bad oftentimes when they get immune-based therapies, fevers, chills, aching because things are localized in the lymph nodes. So it also makes it a very safe intervention.

Great. And so can you summarize the key clinical and preclinical data that you've seen or generated in oncology to date?

So the key data that we've seen in oncology to date is that we documented the triggering of Type 1 interferons. This potent induction of cytolytic T-cells associated with HPV tumor regression in a preclinical mouse model, after a single dose of vaccine. Importantly, we also verified that there was immune memory, and mice that were cured of these tumors were protected from tumor rechallenge. So that importantly reinforced all of the critical elements that we wanted to see. We also confirmed this in a Phase I trial where we saw induction of high levels of these potent virus-specific CD8 killer T-cells within 2 weeks of a single vaccination. We also saw that these T-cells were able to regress virus-mediated lesions that the Versamune and the tumor antigens that were delivered with it actually viral antigens to human papillomavirus, which we know causes cancer. We're very well tolerated across a range of doses tested and associated with self-limited local injection site reactions that resolve within several days and no dose-limiting or significant systemic toxicity. So that's very important that we kind of confirmed in humans, the same things that we were able to observe in our mouse model. A combination of these strong T-cell responses, coupled with a very well-tolerated safety profile, minimal adverse events, we believe, really has implications for highly effective protection potentially in the infectious disease space as well as cancer.

Great. That's really helpful. And so in infectious diseases and in cancer as well, but in infectious diseases, there's a variety of vaccine platforms that are in development. As you're aware, for example, there's many different platforms that are already being deployed in the COVID-19 pandemic, including inactive or attenuated viruses, non-replicating vectors, RNA, DNA as well as adjuvant in protein or peptide. So thinking within that context, do you think that there are particular parameters that make some of these platforms better or less well-suited to use in the COVID-19 or, say, influenza?

So you've raised some really critically important points as it relates to vaccine development for infectious disease. And that is there are a variety of ways to deliver your antigen of interest, whether it's nucleic assets like mRNA, DNA or recombinant subunit proteins or viral vectors. And each approach can be associated with both strengths and weaknesses in terms of the ability to scale up, their effectiveness and the types of immune responses that they induce. Typically, recombinant subunit proteins have incredible safety. There are no issues with preexisting or the development of immunity that sometimes is a concern with viral vectors or attenuated or non-replicating vectors. Genetic materials like mRNA, DNA, they can be rapidly generated once the sequence is known. The challenge is often getting sufficient amounts of that genetic material into cells so that they, in turn, express the protein of interest and induce the immune response that's wanted. I do think that whatever approach is utilized, ultimately, it's going to need to rapidly induce both potent T-cell responses as well as antibody responses and have a need for those T-cell responses to be long lived. The other thing that I do want to highlight right now, it's a perfect opportunity to point out that there's incredibility with the Versamune adjuvant technology in that it can be co-formulated and delivered with mRNA, DNA, proteins, peptides, even viral vectors that are engineered to express protein. So there's incredible versatility in the platform and being combined with many different approaches to deliver antigens.

Got it. That brings me to my next point about kind of where does the Versamune platform fit into that broader context, both in terms of the platform applications or potential co-formulations as well as specific vaccine products that PDS might be developing?

So I think the key differentiator is that the Versamune platform, the focus has been on generating high-quality, high-quantity, potent antigen-specific pathogen-specific T-cells, which we have shown that we can do. It's important because in viral infections, T-cells are important to immediate control of the infection, like I said previously, eradicating that infection but also with long-term memory. Antibody smart responses are also needed and need to be developed for short-term protection. It's important that we see both of those responses because what you'd like is an immune response that is as broad as possible, as potent as possible and as long-lasting as possible. I'd like to say that an immune memory response is the gift that keeps on giving because if you get a very potent response, that is then leads to long-lived, long-term immunity. That is the best gift that you could have because it then provides ongoing protection from rechallenge from either your cancer or from an infectious disease pathogen.

Yes. That makes sense. And so within that landscape, how do parameters like cost factor in? And where would something like Versamune fall within that spectrum?

So cost is a very important issue, particularly when you're talking about a pandemic vaccine, like we're seeking to generate for COVID-19, where you're going to have to manufacture hundreds of millions of doses quickly, efficiently and cost effectively. One thing that I had previously highlighted was the fact that Versamune is composed of one entity. It is a single synthetic positively-charged liquid. So that means that it is rapidly scalable to dramatic quantities very cost effectively because there's not a lot of complexity in its manufacturing. We have chosen to use and pursue a recombinant subunit vaccine. Those subunit protein vaccines have been appealing because of their safety. Historically, there have been challenges because protein subunit vaccines were limited in their potency in terms of their immunogenicity and their ability to actually induce protein immune responses. And one of the things that we've confirmed is that Versamune delivered with proteins or with peptides, which are pieces of proteins, can generate very, very potent immune responses, even with low and very small doses of antigen. That's also very important. If you're able to deliver a technology that allows you to have dose sparing of antigen, that means that you can make your antigen go farther in terms of making more doses of your vaccine to be able to deliver to people. So it's important to have that technology that induces all of the things we've previously discussed: rapid onset of immunoresponses, T-cell responses that are high-quality and high quantity, antibody responses, T-cell responses that are associated with immune memory as well as a technology that is simple, safe and rapidly scalable. And we think that, that positions Versamune very well and uniquely in the COVID-19 space.

And then what about the logistics of storage or administration? Again, the different platforms have different characteristics with respect to those parameters.

And those are very, very important. Investors and you, I know, Geulah, are aware of the term cold chain as it relates to the delivery of vaccines. Our therapeutic cancer vaccine, PDS0101, as well as the COVID-19 vaccine program that we're pursuing, does require refrigeration. And we work on formulations to maximize the duration of stability of the products. Most vaccine products do require some form of cold chain storage, whether they have to be frozen until they're delivered or whether or not they could be stored in a refrigerator before they're delivered. And so ultimately, elimination of cold chain is one of the research priorities that PDS as well as many other companies have. Right now in COVID-19, the urgency is to get vaccines using platforms that have been tested previously in humans rapidly into clinical trials, so we can assess their immunogenicity and see if we can generate some immune responses that are potent, hopefully, long-lived, and then also simultaneously work on further optimizing the product so that cold chain delivery is eliminated.

Right. Got it. That makes sense. So maybe turning to some of the specific programs that PDS has been working on. Can you walk us through the data that you or your collaborators have generated and that you can disclose for the flu vaccine? And then we'll turn to COVID.

Okay. So in collaboration with Professor Jerry Woodward at the University of Kentucky and the scientists in this laboratory, we've had long-standing collaborations in terms of investigating the impact of co-delivering Versamune with different types of infectious disease antigens. And one of the experiments that we did was to codeliver Versamune with Fluzone. And so those viewing by web and who have access to actually via their computers, see the slide that's currently on the screen. The thing that's really important is that when we deliver blue -- Versamune with Fluzone, which is a commercially available, annually generated flu vaccine that everybody gets immunized with. We delivered Fluzone alone or Fluzone with Versamune. And like most influenza vaccines, there are 3 different titers or types of influenza viruses that are present usually, 3, sometimes 4 in our annual flu vaccines. And importantly, we saw that there was a dramatic increase, a 40-fold increase actually in terms of the number of neutralizing antibody titers that we saw when Fluzone was given with Versamune. That's on the right-hand side, reflected by the kind of dark black blue bars that are on the far right. And that's the standard dose of Fluzone delivered with Versamune. Importantly, the other aspect that we saw associated with Versamune delivering being delivered with Fluzone was that we could give 5-fold lower doses of Fluzone antigen and still see dramatic enhancement of antibody titers, which is the green bars across all 3 types of influenza viruses. And the takeaway message is that Versamune plus Fluzone, whether delivered with a regular dose or even a fivefold lower dose of Fluzone generated dramatically higher antibody responses than Fluzone alone, which are the yellow bars present across the slide. So in the context of a pandemic, again, I highlighted how we want to be able to induce antibody responses rapidly. So to be able to induce 20-fold or 30-fold or 40-fold higher antibody responses than what you might see with the antigen alone is critically important. And what's equally important is, if you're able to do it with less antigen, that allows for dose sparing, and it allows you to manufacture more vaccines that can be delivered to more people who are in need of it. So that is the Fluzone did in.

Great. That makes sense. And so in terms of potential application for a universal flu vaccine, can you talk a little bit about what that pathway looks like?

So I think the real focus would be, in addition to examining these antibody responses, would be to characterize and examine the T-cell responses that would be associated with flu antigens. We haven't specifically done it with flu antigens, but we've done it with other recombinant protein antigens. And we can tell you that we see induction not only of antibody responses, but also of CD8 and CD4 T-cell responses, which happens very rapidly. And actually, that's a natural segue into some preliminary data that literally is hot off the press as it relates to codelivery of Versamune with a SARS-CoV-2 antigen, the full-length recombinant S protein antigen. Can we pull up that slide? This is excellent. Thank you so very much. This is early preclinical data, but it is, again, proof of principal data that documents that we can deliver very, very high neutralizing antibody responses, equivalent to those that have been observed in patients who are recovering from COVID-19 that are hospitalized. Here, you see the neutralizing antibody response at day 14. Again, within 2 weeks of vaccination. And you can see on the left-hand side, control mice have no response. Those where we delivered just the receptor binding domain, which is a small component of the spike protein or the full-length spike protein in and of itself, you can see very minimal induction of antibody responses that is dramatically enhanced when you deliver either the spike receptor binding domain or the full-length protein with Versamune. Importantly, the crossed boxes represent the neutralizing activity. It's very high with the antibody titers delivered with Versamune, and that's very, very important. On the right-hand side, you can see that we actually continue the experiments out to an additional 30 days. We see even greater strengthening of the antibody responses. So what we wanted was rapid injection of antibody responses for near-term protection, and we want those antibody responses to be functional and have neutralizing activity, which they do. The next slide highlights the fact that we're actually also able to induce T-cell responses. Again, wanting to document this rapidly following vaccination and document the fact that we can see induction of these T-cell responses. And I've highlighted throughout my talk, not only the importance of the quantity of T-cell responses, but also the quality of T-cell responses. So on the left-hand side, we see this day 14 T-cell response, and we see, again, very high quantities in the green bar and the blue bar, whether you deliver the Versamune with just 1 type of spike recombinant protein versus a full-length spike protein, a piece, you see dramatic induction of these T-cell responses. But what's really reflected on the right-hand side of the slide is the fact that we see induction of potent responses, responses where the T-cells secrete both multiple cytokines, what we call polyfunctional T-cells. These dual positive T-cells are represented by the darkest navy blue bars. They are expressing both interferon gamma as well as another very important immune protein called TNF alpha. So many vaccine products are able to generate T-cells that produce 1 cytokine interferon gamma or TNF alpha or IL-2. But it's really critically important that we see induction of T-cells that generate and are able to have multiple cytokines, and we see that as well. So those are preliminary data, we are going to be confirming that with additional experiments. But it's important for us to know that we are able to, when we deliver Versamune with a full-length protein from SARS-CoV-2, the spike protein that is a common antigen in many of the platforms that have moved forward and progressed into clinical trials that we can see the rapid induction of these neutralizing antibody responses as well as these T-cell responses. The studies are ongoing so that we can assess how long-term the memory is and also the ability of these responses to protect the animals from challenge with SARS-CoV-2. Those are ongoing.

Right. Right. Yes. So in terms of steps to get into the clinic, does that entail looking at the protection from infection?

So like many of the other vaccines that have preceded, we are planning to do challenge studies. Fortunately, it's been made clear by both the FDA and the EMA as well as the WHO consortium that toxicology data, safety and immunogenicity data is necessary to go into human trials. And preclinical challenge studies can be conducted in parallel to getting into human clinical trials, and that's what we're planning on doing.

Got it. And so looking at the data, just one question on it. I feel that this is after 2 doses in mice. Do you think that there's potential to get protection after a single dose, again, coming back to the potential for dose sparing and things like that?

Yes. And so that is our next round and a set of experiments. Scientists always anticipate the next steps, and that is exactly what we're planning. We wanted to -- we know that as we proceed with translation into first in human trials, we're going to be delivering 2 doses of vaccine, which is why these experiments were done with 2 doses of vaccine, but we are planning on repeating the experiments and also characterizing these same parameters after a single dose of vaccine. We know that for the WHO's target product profiles for COVID-19 vaccine that ideally, they would like a vaccine that is effective across a broad population, okay, which really includes individuals who are younger as well as those individuals who are older because we know that sometimes in individuals who are older, vaccines are not as immunogenic or their protection doesn't last as long. So the goal is to ultimately have a vaccine that works well for everyone and ideally is -- works after a single dose. Whether or not that will be possible, we'll have to see. But again, we're hoping that the potency of immune responses and the quality of immune response and the quality of immune response that is delivered with Versamune will allow potentially that dose sparing. Not only the amount of antigen that's actually in the vaccine dose, but dose sparing in the sense that you get the bang for the buck that's necessary with a single dose of vaccine as opposed to 2 doses of vaccine. But that really still has to be investigated, and it's something that's ongoing.

Right. Right. So with the extremely crowded COVID-19 or SARS-CoV-2 vaccine landscape and a handful of programs moving quickly through clinical trials, what do you see as the potential path for smaller players with programs that are not yet in the clinic?

Well, I think the potential path for players that are not in the clinic is really going to be informed by what we continue to learn about the natural de novo immune responses to SARS-CoV-2 infection. Part of engineering a vaccine to prevent and protect against any pathogen is actually understanding the body's own natural immune response to the pathogen. And one of the things that's recently emerging literally, the data changes day-to-day and week-to-week, but one of the things that's emerging about SARS-CoV-2 is 2 important things. It seems like the potency and the strength of immune responses to the virus is really dependent upon the severity of illness. So immune responses have been documented to be stronger and more potent in those patients who are hospitalized with COVID-19 infection as opposed to individuals who are asymptomatic and have minimal symptoms. So that's the first implication. If it doesn't kill you while you're in the hospital, you're really going to have strong immune responses to it. The second issue is it appears that, unlike SARS, a related beta coronavirus where we had a pandemic that was thankfully, it interrupted in 2003, as well as MERS, another coronavirus, the antibodies to SARS-CoV-2 do not appear to last for a long time. And it appears that they can drop off very dramatically after weeks to just months. So if this is really confirmed in terms of multiple studies that native infection gives you antibody responses, but those antibody responses are short-lived, that is really going to put the onus on all of us in the vaccine field. One, to develop antibody responses that are potent neutralizing, but also long-lasting, that last longer than what we see with de novo responses. But I think it also then amplifies the critical importance of T-cell responses in controlling the virus and also providing long-term protection.

Got it. And so those type of parameters, and those things that might frame the target profile of SARS-CoV-2 vaccines that we could see a few years down the road versus what we might see now?

Yes, because it may be that in order for this particular pandemic virus, it may be that T-cell responses are more critical or long-term protection. And not only critical, maybe even essential to long term protection. One of the things that we've learned is that with both SARS-CoV and MERS, antibody responses would persist at least for 1 year and then start to drop off at 18 months to 2 years, and were still detectable, even up to 6 years in patients who had recovered from SARS. In contrast, T-cell responses in patients who had recovered from SARS were detected up to 11 years after resolution of their infection. So SARS-CoV-2 really appears to be and is emerging to be somewhat distinct from its related family virus members and that its antibodies don't seem to last as long as either SARS-CoV or MERS. We know that T-cell responses have been documented in patients who have recovered from SARS-CoV-2. And again, I think that there's going to be literature that continues to suggest that T-cells may have an increasingly more important role in terms of protection of disease.

Got it. And then with respect to vaccine design, I think some of the initial concerns for SARS-CoV-2 vaccines were around the potential for toxicity around antibody dependent enhancement of infection or Th2-driven immune toxicity that had been previously reported in other preclinical experiments for prior coronaviruses like SARS or MERS. Is that something that you've seen signals of either in the literature or your programs in the Versamune studies?

So we have not seen that with Versamune studies. But again, we have not yet proceeded into the challenge studies in immunized mice to see whether or not there is this enhancement. So what you refer to is a very, very important, at least theoretical concern. I'm not aware yet that it has been reported specifically in SARS-CoV-2. But the phenomenon that you described of antibody-dependent enhancement, for those who are listening, is where the immune system makes antibodies to a protein associated with the pathogen. But some of those antibodies, instead of neutralizing the virus, actually allow the virus to get into cells more efficiently and allow the virus to replicate, thereby causing disease enhancement. It is a concern really for any antibody platform that induces either exclusively antibodies or predominantly antibodies because that is what we call a Th2-biased response that is solely focused on antibodies. We believe that vaccine platforms that induce a cellular response or T-cell response, what we call Th1-biased response, provide a greater balance and minimize the risk of this antibody-dependent enhancement because you have both T-cells as well as antibodies to the viral pathogen, and the T-cells are there, and we know are critically important from the beginning to controlling the replication, the spread and getting rid of the virus. So again, the issue that you raised is one of significant importance. And it's also why all of the vaccine trials for SARS-CoV-2, we'll be monitoring patients who have received vaccines to ensure that we don't actually see evidence of this antibody-dependent enhancement of infection. But to date, I'm not aware that it's been specifically reported in humans with SARS-CoV-2.

Great. That's helpful. All right. And so to be sensitive to time, I see we're just about at the hour. So are there any final thoughts that you'd like to emphasize before we wrap up?

So I would leave individuals with the critical parameters that are necessary for a SARS-CoV-2 vaccine as well as for a cancer vaccine, and that is to induce immune responses that are broad, potent, rapidly induce them and using a technology that is simple, that is safe, and also scalable so that it can rapidly be ramped up and also cost effectively be delivered to as many people as can potentially benefit either from protection or from its activity. Versamune is really unique in the aspect of what it's able to do in terms of triggering the immune system by triggering type 1 interferons as well as presenting both tumor and virus antigens to induce those kinds of broad potent responses that involve antibodies for short-term protection, near-term protection as well as T-cells for longer-term memory protection. So those, I think, are the key takeaways.

Fantastic. Great. So I'd like to thank you again, Dr. Wood, for the great discussion and for joining us today, and thank you for listening.

Yes. Thank you for having me. I appreciate it greatly. I hope everyone continues to stay healthy and well. Thank you, again.

Okay. Great.