November 9, 2023 PAO-10-23-CL-07
David Dodd (DD): GeoVax Labs, Inc. is a clinical-stage bio-clinical company. We are focused on developing infectious disease vaccines and cancer therapies, and we currently have phase II programs in each of those areas.
In 2001, when the company was founded, the focus was solely on trying to develop a preventative vaccine for HIV. As you may know, there has yet to be a vaccine that prevents HIV. In 2014, we made a strategic decision to broaden our focus beyond HIV, and that has led us to this host of infectious disease programs. We have a next-generation COVID-19 vaccine in three phase II trials. We also have vaccines against hemorrhagic fever viruses, such as the Ebola virus, Marburg, and Lassa, as well as vaccines against Zika virus, and malaria, although these are not of a priority focus.
Another key area of priority and focus is oncology. We have an advanced head and neck cancer therapy in a phase I/II trial that is expected to soon be expanded into a phase II trial. This is being funded by the FDA under the Orphan Drugs Clinical Trials Program, again addressing people with advanced head and neck cancers.
DD: I have been associated with GeoVax since 2010, initially as an investor and a board member and later becoming Chairman of the Board. In September 2018, I added the role of Chief Executive Officer, becoming the company’s third CEO.
GeoVax has gone through recapitalization efforts over the years. In 2020, we successfully qualified to be listed on NASDAQ and moved forward to bring our products into the clinic. We acquired both of our clinical-stage products, the next-generation COVID-19 vaccine and Gedeptin targeted against advanced head and neck cancer, to jumpstart our presence in the clinic. It has been a very successful process, and we are very excited about what we’re developing now, as the company is well positioned to deliver some really important missions –– in one case a therapy, another a very important vaccine. Both are highly differentiated against competition, addressing critically unmet medical needs.
DD: That is an excellent question. We need next-generation COVID-19 vaccines because the current authorized vaccines are recognized as not sufficiently durable. This was outlined in an April White House announcement of Project NextGen. The current vaccines last maybe three to four months, and they have to be reconfigured every time there’s a new significant variant of concern. For example, we were talking about the Omicron XBB1.5 up until not quite a month ago when we started talking about the latest dominant subvariant EG.5 (Eris). Such variants will continue to emerge, and, as this occurs, it takes at least a month to reconfigure. By the time we finish a vaccine for one variant, we’re halfway to another variant evolving.
Another concern, as I mentioned, is the durability of the current vaccines. They require an extremely frozen state, which that we really can’t deliver and administer the vaccines the way we’d like to in some parts of the world.
Most importantly, the currently authorized vaccines are all focused on inducing a very strong antibody response, which is inadequate for many patients. Unfortunately, for 15 million people in the United States and approximately 250 million worldwide, their bodies do not respond appropriately to antibody stimulation, nor do the monoclonal antibodies work for these individuals. These people have depleted immune systems as a result of having certain medical conditions — they may have blood cancers, be HIV positive, have sickle cell anemia, or have renal disease, or they may be on suppressant drugs that inhibit the body’s ability to respond to antibody stimulation.
The GeoVax next-generation COVID-19 vaccine induces not only an antibody response but also a very strong T-cell response. We have achieved this by using more than just one component of the virus. The other vaccines focus on an element of the spike protein to induce that antibody response; we’re able to include multiple antigens, which is unique to our technology. You cannot do that with mRNA. You cannot do that with a protein and adjuvant, which is what Novavax has. Our GeoVax COVID-19 vaccine achieves a strong T-cell response by including a particular protein called the nucleocapsid. This minimizes how the virus escapes, and we have clinically tested it and shown potent protective immunity from the initial Wuhan strain and through delta and omicron/XBB1.5. We’re currently looking at the latest one, but so far, the data support that it does not require any reformulation. Such a COVID-19 vaccine is referred to as “variant agnostic.”
We also need more robust and durable vaccines in general that will provide longer-lasting protection. Our vaccine is showing durability over six months, which is more than twice what we’re seeing in the currently authorized vaccines. We are doing direct comparisons against the mRNA vaccines in two of our three Phase II clinical trials.
In addition to that, we need to be able to widely distribute and administer the vaccine, regardless of the location and conditions of a particular region. Our technology allows the vaccine to be freeze-dried or lyophilized, which doesn’t require the frozen state, so it is feasible for distribution and administration wherever needed.
We believe there is a significant need for such a vaccine worldwide. GeoVax is expanding one of our phase II trials now to even include sites outside the United States because there is such an interest in these populations and the medical community to address them. They’re underserved. They’re not even underserved — they’re not being served at all now; these people are still sequestered in their homes. We believe that what is needed is a more robust, more durable, and more easily administered vaccine related to COVID-19 or SARS-CoV-2.
DD: It’s based on Modified vaccinia Ankara (MVA), which is a weakened virus strain that was originally developed in the 1960s to make a vaccine against smallpox for people with compromised immune systems. It had to be extremely, exquisitely safe — especially for people with compromised immune systems. Importantly, MVA does not replicate in human cells.
With MVA, it is well known and validated that additional antigens can be incorporated into a vaccine construct using this technology. We’ve done up to five; we have three in our universal coronavirus candidate, which is preclinical status, and we have two antigens in the clinical-stage COVID-19 vaccine: the spike protein and the nucleocapsid.
The benefit of mRNA has always been the ability to produce so many doses at a large scale very quickly. Up until recently, you could not do that with MVA.I t was only produced using cells from chicken embryos, or eggs, through a very slow, cumbersome cell culture process.
With advances in continuous cell line manufacturing, however, we can eliminate what has been the primary shortcoming of MVA and make it possible to respond at the scale in the time needed to address to epidemics and pandemics. In the past year, GeoVax issued three press releases to showcase our achievements in this area, advancing a continuous avian cell line manufacturing process.
The initial press release outlined how we have validated the ability to utilize a continuous cell line process. Then, after evaluating various avian cell lines, we recently announced a license for ProBioGen’s avian cell line – AGE1. ProBioGen is a very well-known, highly respected company whose cell line has been in front of regulatory authorities before, so we are very excited. Additionally, we announced that we have engaged Advanced Bioscience Laboratories, Inc. (ABL), a very well-known MVA vaccine CDMO, to be our partner for manufacturing to translate into continuous manufacturing.
DD: Yes, that is exactly the idea, and we just presented this at the 2023 Keystone Symposia Annual Meeting in Atlanta, which happens to be where the GeoVax headquarters is located. Our team presented data on our MVA-VLP (MVA-virus-like particle) candidate, which has three antigens: the spike, the membrane, and the envelope. This vaccine is our candidate for a universal coronavirus vaccine, allowing us to get ahead of variants before they even emerge. This work is based on a project that was initially funded by the NIH (National Institutes of Health) and that we’ve continued to advance. As you might imagine, our priority is on the phase II stage COVID-19 vaccine. Still, the Keystone Symposia presentation and press release announcement outlined the great potential of MVA as a basis for a universal coronavirus vaccine.
DD: We have three phase II trials for our next-generation COVID-19 vaccine, referred to as GEO-CMO4S1. We think that these studies will demonstrate that our CMO4S1 vaccine provides a more robust, broader response, which will mean that not only will it not have to always be reconfigured for the next variant but be more durable, as well as be a longer-lasting type of booster vaccine that could be used for healthy individuals and people with compromised immune systems alike.
One of the trials is among healthy volunteers who were initially vaccinated with an mRNA vaccine; instead of boosting them with the mRNA vaccines, they’re receiving our GEO-CMO4S1 vaccine. That’s a 60-patient trial, and we announced several weeks ago that it is now fully enrolled. Those data will be coming out this year, and that will be a very important milestone.
We also recently announced a trial to evaluate immunocompromised patients, specifically those with chronic lymphocytic leukemia (CLL), which is a blood cancer disease in which both the disease and the treatment inhibit the body’s ability to respond to antibody stimulation. In this clinical trial, 80 patients are enrolled, all of whom initially received an mRNA vaccine. The study evaluates a booster, randomized, so 40 will receive our GEO-CMO4S1 vaccine and 40 will receive the Pfizer vaccine. This trial is moving along very well, and we should reach the interim point for analysis this quarter.
The third phase II trial is for immunocompromised stem cell transplant patients. This population is recognized by the medical community as having the highest risk for severe disease, hospitalization, and death. We recently published the results from the safety lead-in doing a direct comparison as a primary vaccine against mRNA vaccines in the peer-reviewed journal Vaccines. We recently issued a press release covering this. We showed the far superior immune response of our CMO4S1 vaccine versus the mRNA vaccine, largely driven by the T cell response that you just don’t receive that with the mRNA. More recently, we’ve announced the initiation of site expansions in the U.S. related to this trial.
We have significant interest in having a COVID-19 vaccine addressing the needs of immunocompromised patients because they don’t adequately respond to the mRNA vaccine. Such patients benefit from the T cell response from our vaccine; that is why we are expanding this clinical trial to multiple sites, both outside the United States. It is a rather large program with almost 260 patients, and it’s randomized, with half receiving our CMO4S1 vaccine and half receiving a mRNA vaccine. We’re following all the patients for at least a year, so we can track them and show the comparative results.
DD: Absolutely. A lot of people will ask why we need vaccines for diseases that we don’t have here in the United States. Well, we closed down the world for coronavirus, which had a 1.5–2.5% fatality rate. Meanwhile, at the very top of the list in biodefense or potential bioterrorism are these hemorrhagic fever viruses —the Ebola family, meaning Ebola Zaire and Ebola Sudan, the Marburg virus, and the Lassa virus — and these types of viruses have a 50–90% percent fatality rate. We need vaccines for these not because we think there might be an outbreak necessarily in the U.S., but because the U.S. government and other free societies recognize that there are unfriendly states out there that have this at the top of their list to try and develop and release such viruses as weapons.
To help prepare for this type of situation, we have developed different vaccines. The NIH and the U.S. military have supported our developments in these areas. To date, we have completed non-human primate studies, and the data from the Ebola Sudan and Marburg studies will be presented on our behalf by Dr. Jason Comer from the University of Texas Medical Branch at the World Vaccine Congress annual meeting at the end of November. Previously, we showed 100% protection in a single dose through non-human primates with Ebola Zaire. More recently, we’ve demonstrated approximately 80% protection with two doses against Ebola Sudan, and similar results with Marburg. We don’t intend to advance these products into clinical, but we’re in discussions with companies who have biodefense as part of their core business. While our focus will remain on cancer therapy area and coronaviruses, we anticipate that our biodefense developments will advance through such partnerships, addressing critically important needs against potential bioterrorism threats.
Mark Newman (MN): As David mentioned, GeoVax was founded on an HIV vaccine platform, but after establishing that technology, we began applying it to other targets. Our HIV program was based on VLPs. VLPs are very immunogenic, and they can mimic the actual virus that you’re being infected with.
To target cancer, we played a little trick: we used the inside of the VLP and replaced the outside with a cancer antigen, so it’s an engineered hybrid product. Our lead product uses MUC1 (mucin 1), which is a well-documented, well-established tumor-associated antigen that is highly expressed in many cancers.
However, when overexpressed, the normal glycosylation patterns are not intact, in terms of both numbers and complexity, so it looks more like a foreign antigen. That signals the immune system that there’s something wrong, which results in an immune response. In the cancer epidemiology world, it’s been demonstrated that patients will sometimes initiate T cell or B cell responses to altered mucins, just as a function of having the cancer. Typically, those patients will do a little better ––there’s a higher prognostic value. So, there’s a nice observational pathway supporting the use of this target.
Our MUC1 cancer vaccine is the mucin gene delivered with an Ebola product at the core of the VLP to help make it into a virus, specifically a modified MVA. It infects the cell, driving a high level of expression of MUC1. Because it’s expressed at such a high level, you get the aberrant glycosylation pathway invoked and errors induced, just like you would in a normal cancer. So, there should then be an immune response.
In the cancer field, everything is really an add-on at this stage of the game, so we look to work with the standard of care and then take the next step. The cancer vaccine would be used in conjunction with other drugs or treatments, most notably checkpoint inhibitors. If you want to induce an immune response, especially in a tumor where the microenvironment is typically immune suppressive, you need to override those checkpoints. So, this would be an add-on to a checkpoint inhibitor, like Keytruda or Opdivo. The homerun here is if we can make immune responses to the types of tumors that don’t normally respond to Opdivo or Keytruda, which are mostly solid tumors –– adenocarcinomas and things like that.
MN: It’s a combination of an unmet need and more practical considerations. This is an injectable product; so you need to be able to see and target the tumor, and head and neck fit the bill. In terms of the need, head and neck tumors are pretty barbaric –– they can be disfiguring and impact your ability to swallow, speak, and breathe. Initially, we’re positioning this as palliative care. That means that the patients have gone through their normal treatments and had different levels of success or failure. We’re trying to provide comfort for the final six weeks to a year, whatever it might be, and shrink their tumors.
When you start killing tumors, neoantigens are released. This is what gives you personalized cancer vaccines in which you identify neoantigens in a patient's body based on the tumor they have and make a specific vaccine targeting it.
If we can attack the tumor directly and let the tumor release the antigen, then the tumor itself is the personalized vaccine –– it is now inducing an immune response. As you destroy the tumor, you downregulate the immunosuppressive effects. If you have a patient on Opdivo or Keytruda –– a checkpoint inhibitor –– the tumor destruction itself will ideally induce an immune response. This will help control the tumor, in conjunction with the checkpoint inhibitor. This happens in radiation therapy: you use focused photon radiation or something similar to destroy the tumor, and then you can detect immune responses that come into the tumor in some patients.
MN: Absolutely. With imaging technologies being what they are today, you can put a needle pretty much anywhere. I think breast cancer would be a nice next step –– it’s readily imaged, so you can follow the needle right where you want to put it. And the nice thing is, as I said before, it’s an add-on, so we’re not looking at replacing or competing with anything. We’re looking at making the whole situation better: destroying a tumor actively, along with an individualized vaccine that would be used in conjunction with current drugs.
MN: Gedeptin is currently in phase II for head and neck cancer. That’s a small, FDA-supported trial, primarily to document safety, but so we’re also looking at anti-tumor effects. By the end of the year, we’ll decide on whether we have our answer. We are manufacturing a new batch of material with a new technology; so that’ll be available next year as well to support phase III testing or an expanded phase II. The regulatory pathway is still under discussion, but it’s based on results. With good results, we would theoretically get approval in the head and neck cancer area with an additional 20–30 patients. That’ll be a discussion with the FDA.
We’re already talking to cancer experts about expanding into other patient types. For this, we are working with academic medical centers –– that’s where you can get research products tested best. We’re looking at a potential breast cancer expansion with Emory University, which is also in Atlanta. Theoretically, this could be approved after an expanded phase II, which would make it a phase III, and then we would do a phase IV, following the approved product to make sure that the effect is what you want.
Once we get past the first step, we can start moving into earlier stages of cancer. In theory, we may be able to get to the point where you may have been just diagnosed yesterday, so you’re going to get radiation and chemotherapy, but this could be added to that treatment. You do radiation and/or chemo, and as soon as that’s done, you would start with this product. That’s kind of the standard pathway: you go into the highest-risk, greatest-need patients and then work backward into larger and larger patient populations.
The MUC1 vaccine is still in the preclinical setting, being investigated in humanized mice. We’re working with the University of North Carolina, who are experts in that. The humanized mouse is a mouse that expresses the human MUC1 gene, which is a nightmare in some ways because it’s a mouse; it’s not a human. There are all sorts of breeding issues and things you have to deal with. But with this transgenic mouse, we are testing different types of implanted tumors. Three out of the four are pancreatic cancer tumors, which is the most aggressive, and the final one is more of a colon cancer tumor. Those studies are ongoing.
We consider them to be IND-enabling in that if they work, there is a National Cancer Institute (NCI) network that is interested in this type of thing. NIC has identified MUC1 as the number two antigen of interest. It’s a nice target, and we could move into clinical trials fairly quickly. A year or so after we pull the trigger, we have to manufacture it, determine safety, and get the products all released. But, again, this would be an add-on product. One additional advantage of the MUC1 story is that there is a long history with that protein and a lot of different vaccines have been tested. We’re evaluating adjuvants and other vaccines that have already been in the clinic showed some promise and have documented safety. So, we would be able to conduct clinical trials with multiple products.
Right now, we’re looking at working with a peptide adjuvant that has been in multiple cancer clinical trials. There are different flavors of this peptide, but the one we’re working with comes from the University of Pittsburgh. We will immunize with the peptide and follow up with the MVA or immunize with the MVA and follow up with the peptide. We believe that will allow us to direct the immune response to where we want –– either preferentially antibodies or preferentially T cells –– and then boost it. We don’t know what we need; we might need both. You can’t get both if you just have a peptide. You can get both with a vector, but there are limitations. Putting it all together is the approach we’re taking.
MN: The MVA-VLP story is very flexible. We have identified two or three other antigens. Again, we’re not going to swim upstream. We’re going to look at what the NCI thinks is a good tumor antigen, and we could make VLP express a type of MVA with those. Two tumor types we have our eye on are Wilms tumor and melanoma. Melanoma has been investigated for vaccines in the past. Melanomas tend to be fairly immunogenic. They respond to checkpoint inhibitors, which indicates that there is an immune response. There are multiple melanoma targets.
MUC1 could theoretically make or help make checkpoint inhibitors function in adenocarcinomas, which is huge. Adenocarcinomas are the most common human tumor type, and they are very aggressive. So, the MUC1 is the focus. If everything goes right, we could have products and be ready to start clinical testing in approximately a year-and-a-half to two years. I just need a couple of really good mouse studies.
MN: The way that we work is that our internal core team, which is the molecular virology side, puts together the new vectors. We have a very innovative immunologist who can help with defining all the studies that we need to do. And we have a preclinical expert, someone who can help organize and drive all of the animal tests and so on.
We investigate our animal models and so forth either with contract research organizations or with academic experts who have animal models that allow us to get at mechanisms. We have what we need internally to make the products but work with experts and their models to test them, and that’s ultimately how it would be handled in the clinic as well.
MN: Yes, because the technologies are based on the same platform. With the MVA-VLP or anything with MVA, there’s a lot of synergy between the cancer programs and infectious diseases. Of course, we have different experts that we identify and work with for the models. Gedeptin is its product. That stands alone. The only overlap there is that it’s viral vector-based.
MN: I would also like to highlight our flexibility. We think that we will be able to move into a single dose for a lot of our products. We’re going to be evaluating products for self-administration –– skin patches that you could put on your skin and let sit for 30 minutes, and you’ll be vaccinated. This is very important if you’re going into resource-limited areas to attack a pandemic like monkeypox in the Congo. Something that could be self-administered or administered without WHO medical staff, but just nurses and things like that, would be advantageous. We are looking at technologies to enable that. These are very flexible programs that we can modify or adapt to different uses. And they fit with a lot of other people’s programs, so it’s just a matter of finding the right combination.
Mr. Dodd joined the GeoVax Board of Directors in March 2010 and was elected Chairman in January 2011. Effective September 2018, he began serving also as the President, CEO. Mr. Dodd has led GeoVax through a significant transformation, including a corporate recapitalization and up-listing to Nasdaq (September 2020), followed by the Company acquiring the exclusive worldwide rights to two phase II-status products. Mr. Dodd holds Bachelor of Science and Master of Science degrees from Georgia State University and completed the Harvard Business School of Advanced Management Program.