BIO from the BAYOU: Build Your Biotech Network with Key Opinion Leaders and Investors
30 Sept 2023 · 17 min
0:00
In this Bio from the Bayou episode, hosts Dr. Elaine Hamm and James R. Zanewicz interview Tulane faculty Dr. Elizabeth Norton and Dr. Jay Kolls about their novel pneumonia vaccine, CladeVax. The conversation begins with the scientists’ personal motivations—Norton’s early fascination with infectious disease sparked by reading The Hot Zone and a CDC internship, and Kolls’s clinical exposure to HIV‑related pneumonia during his training in New Orleans. They discuss the shortcomings of current pneumococcal vaccines, which target polysaccharide capsular antigens and require multiple doses, and the growing threat of multidrug‑resistant Gram‑negative bacteria such as Klebsiella pneumoniae and Acinetobacter baumannii. CladeVax is presented as an intranasal, inactivated vaccine that uses a proprietary adjuvant (developed in Norton’s lab) to elicit strong mucosal CD4⁺ T‑cell responses and IgA antibodies, providing protection that is less dependent on surface polysaccharides. The vaccine’s antigen set centers on conserved outer‑membrane proteins, beginning with OmpX, with plans for a quadrivalent formulation covering additional prevalent proteins. The hosts explore the collaborative synergy between Norton’s adjuvant expertise and Kolls’s clinical‑immunology perspective, highlighting complementary strengths in immunology, regulatory knowledge, and manufacturing. Value propositions include safety for immunocompromised populations (as an inactivated nasal vaccine), broad‑spectrum coverage of MDR pathogens, and a delivery platform that could be adapted for other vaccines. Preclinical data in small‑animal models show robust T‑cell and IgA responses; the team is transitioning to a human‑compatible spray device and aims for a Phase 1 trial in early 2026, contingent on milestone achievements. They note the need for partners for Phase 2/3 trials, large‑scale manufacturing, and distribution. The discussion concludes with broader industry trends toward rational, combination, and mucosal vaccines, and mentions related projects such as an oral fentanyl vaccine and the potential to repurpose vaccine‑elicited T cells as CAR‑T immunotherapy for immunocompromised patients. The episode ends with contact information and a call to engage with the Gulf Coast biotech ecosystem.
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You're listening to Bio from the Bayou, featuring stories and industry insights from experts in the bustling biotech scene in New Orleans.
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I'm James Zanewicz, the Chief Business Officer for the Tulane School of Medicine.
And I'm Dr. Elaine Hamm, the Executive in Residence for the Tulane School of Medicine.
And this is Bio from the Bayou.
Welcome back to Bio from the Bayou. I'm your host, Dr. Elaine Hamm, the executive resident at Tulane University School of Medicine. And today's guests are Dr. Elizabeth Norton and Dr. Jay Coles. Dr. Norton is an associate professor of microbiology and immunology, and Dr. Coles is a professor of medicine and pediatrics. both at Tulane University School of Medicine, and they have been working on a new pneumonia vaccine called CladeVax, and that's what we're going to chat about today. Welcome to the show, you guys.
Thank you for having us.
Well, to kick things off, I love asking scientists, what drives you and what led you to work in infectious disease specifically? And Elizabeth, we'll start with you.
I think what drives me is curiosity about the immune system and the problems the immune system encounters, such as infectious disease or other kind of external and internal threats. And then what led me to work in infectious diseases and immunity and vaccines was I'm the daughter of a librarian, so I read a lot of books growing up, including The Hot Zone and Michael Crichton books, and that just stimulated my imagination. And then as an undergraduate, I was lucky enough to work at the Centers for Disease Control in Atlanta, Georgia, and that just continued my interest in it.
I myself have a dog-eared copy of The Hot Zone that I read when I was in high school, which led me to be a microbiologist. So, I love the commonality. Well, Dr. Coles, what about you?
I went to University of Maryland Medical School and then had the— as a medical student, you know, you have an opportunity to work at different hospitals in your senior year to figure out where you want to train. So, I did a month at Charity Hospital in the intensive care unit in 1984, and obviously the HIV epidemic was raging in New Orleans at the time. So, I decided to train here because it was such an urgent medical problem at the time. And obviously a lot of these patients were developing pneumonia, so that taught us that T cells were important. in the lung, and I had the opportunity to go into a laboratory that was focused on how T cells work in the lung, Dr. Judge Shelton's lab at LSU. And during my course of training, we got better control of HIV, but pneumonia still actually then became the number one killer of children in the world. It surpassed diarrheal disease. So, my lab has been really focused on pneumonia, both in pediatric cases, but also in patients that have compromised immune systems.
Great. More about pneumonia. Pneumonia is an infection of one or both of the lungs, and it It can be caused by bacteria or viruses or fungi. And most people with pneumonia can respond well to treatment, but pneumonia can be very serious and even deadly. And several months back, I myself got an upper respiratory virus. And while I eventually got rid of that, it slowly but surely turned into a bacterial infection that became multidrug-resistant pneumonia. And I was quite sick for quite some time. And drug resistance is this huge problem that continues to get worse and worse. So there really is a need for new and better ways to combat this disease. And so, Jay, why don't you start us off and explain how your pneumonia vaccine, CladeVac, works and what it specifically targets?
Yeah, well, as you know, most current pneumonia vaccines for bacterial pneumonia target what's called the surface sugars or the surface polysaccharide. And so, you know, there's Prevnar 7, which was actually really focused on the type of bacteria that causes meningitis, and so the 7 strains that were put in that vaccine were largely the strains that cause meningitis, and they expanded that to 13, right, to cover more of the strains of bacteria that cause pneumonia, and they just recently released the 20. But yeah, there's 100 serotypes, 100 different strains of that bacteria.
Right.
So I think our current technology is a little bit like whack-a-mole technology, and what we thought was with CladeVax is why don't we take advantage of the cells that are already in the respiratory tract, these T helper cells, they're marked by a molecule called CD4, And those are the ones that are actually depleted in AIDS, right? So that was evidence that they're pretty important in the lung. And so fortunately enough, I had the pleasure of working with Dr. Norton, who had a longstanding history of adjuvants, and one of her adjuvants was very strong at inducing these types of CD4 responses. And then what we did was we chose antigens from multidrug-resistant gram-negative bacteria called Klebsiella. And it turns out that the way we prioritized our antigens, we were looking for antigens that one, were immunogenic, but two, broadly reactive across multiple, not just Klebsiella, but other related bacteria that are multidrug-resistant, including Acinetobacter baumannii, which is a big problem in our military population. Coupled these antigens with the adjuvant that the Norton Lab had developed, and compared to other adjuvants we had tested, it was one of the strongest stimulators of these T cells. And we showed that these T cells have this cross-reactivity, so they can provide not only protection independent of the sugar that's on the surface of bacteria, but also additional members of related bacteria.
I think that's such an interesting point. When we think of pneumonia, it's a lot of different things, but the vaccines currently really focus on pneumococcal pneumonia. And so the ability to hit a variety of different types of causes of pneumonia, I think, is such a key piece of this. Well, and it sounds like, well, both of you had an interest in the immune system, and that led you to this work. It's a great way to approach infectious disease. Resistance is a challenge, and this is an interesting approach. So, what led you specifically to team up? Is it the shared interest in the immune system, or what else was it?
Well, I think my lab focus, at least half of it, is on adjuvants, which are ways to improve vaccines. The root word is from a Latin word, adiudare, which means to help. So, it's different, and specifically, the adjuvants I work on allow for mucosal delivery, So, in this case, Cladevax is an intranasal vaccination. So, we're always looking for partners, and Jay and I just happen to have this happy marriage where the adjuvant that I'm working on works really well with the antigens that he's talking about, these outer membrane proteins that help prevent the Klebsiella pneumoniae that Cladevax targets.
I would add on that the Norton Lab is also— I'm trained as an immunologist, and obviously I clinically see patients with pneumonia, so I think about the clinical development plan. Dr. Norton's lab is also expert on, you know, some of the regulatory issues about manufacturing and how you produce things. So I think we have a lot of complementary expertise for the CLADEVAX program.
It's been really fun because Jay has fantastic ideas about immunology and stimulating the immune system. And then on my side, I have kind of the ho-hum, very kind of methodical how you get to a vaccine maybe the types of things that you need to move it forward. And the combination's been great for, I think, CladeVax and also for our collaboration.
Yeah, I mean, to be honest, I wasn't even aware of— my lab has traditionally been funded by what are called these R01 grants that you submit and get reviewed. And I wasn't even familiar with these types of contracts that the Norton Lab was quite familiar with. So I learned a lot from this whole experience to date, so, and continuing to learn, so.
That's a great marriage of thinking about the clinic, but also some of the really important things that really get a drug to market. Manufacturing may be boring to some, But it's such a key part of what would actually get something from bench to bedside. Kind of diving a little bit more into that, we've talked a little bit of some of the value proposition of CladeVax. We've talked about the spectrum of activity. We've talked a little bit about the mucosal immunity. Let's dig into that just a little bit more of what are some of the key sort of value propositions of CladeVax specifically, whether it's, you know, talking about mucosal immunity a little bit more, manufacturing, that type of thing.
The product brings a few value properties that are distinct. The first and easiest one is by using this adjuvant, we have a technology to have an inactivated vaccine. The only other nasal vaccine currently in the market is a live attenuated vaccine, which means if it's a live vaccine, you can't use it in certain immunocompromised populations, pregnant women, very young, older individuals, transplant patients. So, just getting that technology out there would be a huge advance for the field because then it opens it up for potentially other vaccines to be used that way. And then the second value is that CladeVax targets something that there's no other vaccine on the market is trying to target or has successfully targeted. And so, this is important both in the US and also globally.
Klebsiella pneumoniae is one of the most common causes of community-acquired pneumonia Yeah, obviously, we're targeting bacteria that fight with a lot of multidrug-resistant issues. I think the other thing that we need to learn from this type of technology is duration of protection.
Yeah.
We have a lot of experience with vaccines that elicit antibodies. We have less data on vaccines that elicit these types of T-cell responses. But, you know, I think this pathogen lives in contaminated drinking water, so presumably there's ongoing environmental exposure in endemic areas, and we actually think that the that that would actually allow our vaccine a better duration of efficacy because essentially you're getting kind of periodically boosted with just natural exposure to the pathogen.
That's super interesting. Yeah, so with the current pneumococcal vaccines, how often do they have to be given for them to be effective?
In healthy patients, you know, typically one series is sufficient, but in, like, patients with sickle cell disease that have— obviously don't have a functioning spleen, for example, it's recommended they get vaccinated every 5 years. Other immunocompromised patients also recommended to get boosted.
Yeah, that duration can be incredibly important. Well, let's talk a little bit about what your recent studies have shown you. You guys want to talk a little bit about some new data with us?
Well, so our initial data was just done with one antigen, right? This outer membrane protein X, it's called OmpX. And the reason why we chose that is it's highly prevalent in almost all strains of Klebsiella that have been sequenced. The Department of Defense has actually sequenced over 3,000 strains of clinical Klebsiella, and it's in every one of them. But obviously, a single antigen would run the risk of escape resistance, right? So we're envisioning a quadrivalent vaccine, and so part of the work we're doing under the CLAVAX contract is validating those components, those 3 other components in addition to OmpEx, and what's called down-selection, to validate that these are prevalent in clinical strains, but also immunogenic in our preclinical models.
And just to add to that, I think the second kind of exciting thing that we're moving towards is practical delivery in humans. You know, when we do these studies, we typically do them in small animal models to make sure that the vaccine's working, that it's safe, and it's protective. And we do that by just directly what we call pipetting, which is just putting the volume straight into the nares or the nose of the animal. But for humans, we're going to use this spray device. So it's going to be like a mist straight into the nose. So we're working on kind of changing out the formulation so that it can be this nice spray.
Great. Well, and so then how close are you guys to the clinic?
We plan to go into early 2026, but of course there's a few things, milestones that we have to reach in order to make that target.
So along those lines, then, are you looking for partners or collaborations?
Well, the nice thing about this contract was it specifically was to support everything to a Phase 1 in healthy volunteers. And assuming that we hit all our milestones, that we have the budget to support Phase one, but obviously, if the phase one looks promising in terms of, and one of the things we're going to look at is not only a T cell response, but also this antibody response that's unique to mucosal tissues called IgA. The circulating antibodies are mostly what are called IgG, and actually, we know from COVID vaccinations that those IgG molecules are really important in protecting the distal lung. You know, where your air exchanges are occurring. You know where the alveoli are, but they're not very good at protecting your nose. And this is why you. see these breakthrough infections because you don't get great mucosal immunity from these intramuscular mRNA vaccines. So that's one of the things we're going to be looking at, and I think if that looks positive, then obviously we'll need partners to go to a phase 2 and a definitive phase 3 study.
Yeah, and distribution of the vaccine, mass production of the vaccination, that is nothing that we would be prepared to handle ourselves, so we would absolutely need partners to do that.
Well, that's what's great about infectious disease clinical development is that even though your phase 1 will be in healthy volunteers, you'll be able to get an indication of how well it's working just by those measurements that you were talking about, Jake. That's interesting. Well, just to kind of wrap things up, where do you think the vaccine industry is headed in, in general? And also, what are some projects that you are excited about? Elizabeth, we'll start with you.
I think the vaccine industry is pushing forward for more rational vaccine design, more combination vaccines, more attempts at things like Cladevax, where it's a mucosal delivery so that you hopefully are blocking transmission or carriage just as much as blocking severe disease in the individual. That's been one of the problems with past vaccinations is if you do an intramuscular vaccine, which is the most common platform, you get great systemic antibodies, but those don't always help with blocking transmission to other populations that maybe the vaccine's not working in. And I think the other projects that I might be excited about is, you know, for our adjuvants, what has become really apparent to me is that they allow the intricacy of the immune induction of the route to really take center stage. So, Allowing you to do an intranasal vaccine helps provide nasal and respiratory immunity. And we also work on oral vaccines and the same gastrointestinal mucosal protection. But what's fun is we have a project on fentanyl, and what I've been learning in that project, protecting against a substance abuse drug, is that some of these mucosal routes can also really help, it seems like, create an immunity. Kind of protection helmet around the brain. And so that's been an interesting project for me that's distinct from CladeVax.
Sounds super cool and probably a future podcast episode as well.
Great.
All right, Jay?
So, you know, I mentioned that Klebsiella is endemic in Asia, but in the United States, it's a complication of immunocompromise. And particularly when I was at the University of Pittsburgh, it was a real big complication in patients receiving solid organ transplantation. So, The CLADEVAX-elicited T cells that we see, at least in our preclinical models, seem to be resistant to some of the drugs we use for transplant immunosuppression, suggesting that we could potentially test efficacy in a higher-risk population like solid organ transplant recipients. But also, we showed that the T cells elicited by the vaccine, we can actually use them almost like CAR T cell therapy, as immunotherapy. And so Janet McCombs in our centers is looking at making Klebsiella-specific CAR T cells And if permissible, I'll give a plug to Dr. Bruce Blaser. He's a world-class transplant immunologist. He's actually going to give our Medicine Grand Rounds on March 13th. And one of his topics is going to be these issues of CAR T cells for non-oncological indications. And so I think that's another interesting approach. You know, we always think about CAR T cells for cancer, but I think CAR T cells for infections in immunocompromised hosts are another interesting area.
Very cool. And much needed as we're— the issue and the second pandemic of multidrug-resistant bacteria is looming. It's good to know that we have other options beyond the sort of standard antibiotics, that there's other things in the works. So, well, guys, thank you so much for your time, and we look forward to hearing about your work in the future.
Thank you for having us.
Yeah, thanks, Dr. Horton.
As always, we'll have Dr. Norton's and Dr. Cole's contact information and informational links posted in our show notes. Make sure you check them out to learn more.
Thanks for joining us for Bio from the Bayou, and we hope you'll join us If you'd like to learn more about the emerging biotech scene in New Orleans and the Gulf Coast region, visit us at biofromthebayou.com, where we have more info on who we are, how to get involved and connected in biotech in New Orleans, and the industry events we'll be hosting where you can meet with us in person.
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