The future of topical vaccines

0:00This is Stanford Engineering's The Future of Everything, and I'm your host Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. and it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody.

0:37In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here and that you'll share it with your friends, family, neighbors, co-workers as well. I would never take my kids to the pediatrician to get six shots. There'd be some kind of mutiny, but your skin is a big organ and And I could ask them to rub one tab of cream behind their left ear for flu, their right ear for SARS-2, the left elbow for RSV, and so on. So I think this could be multiplexed more easily than other vaccines. And that could make, for example, one product that would cover you for the whole respiratory virus season.

1:22This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you're enjoying the Future of Everything podcast, please hit follow in whatever app you're listening to it right now so you never miss the future of anything. Today, Michael Fishback will tell us that the bacteria that live peacefully in our skin might be the source of new opportunities for vaccines that are delivered on your skin as a cream without any needles. Yes, you heard it right. Vaccines with no needles, they may become creams. It's the future of vaccines. Today, we are continuing our new feature, The Future in a Minute, where I'll ask the guest, Michael, a few quick questions and he'll give me some quick answers.

2:03We're going to do that at the end of our regular interview. Stay tuned. Before we get started, please remember to follow the Future of Everything podcast in whatever app you're listening to right now so you're always aware of new episodes.

2:22so when we think about vaccines we think about needles in our arms the general idea for vaccines is very straightforward you take a small piece of a pathogen a virus a bacteria maybe even a cancer a small piece not the whole thing you're not injecting something toxic into the body just a piece that the body can recognize. It can build up an immune response against that piece so that if you ever are exposed to that virus, that cancer, or that bacteria, your body, because it's seen that little piece, will see that little piece on the pathogen, attack it, kill it, and protect you from that disease.

3:00That's the basic idea of vaccines. But they come with some costs. There's a needle involved. There's some pain, swelling, and sometimes you really feel pretty bad for a couple of days, depending on what the vaccine is. Imagine if we could have vaccines delivered in a cream. Yes, as a cream. You just apply it to your skin, and then a few weeks or months later, you are immune to those pathogens, bacteria, viruses, and cancers. That sounds like science fiction, except we have found recently, and when I say we, the scientific community has found that bacteria that live on your skin, peacefully and normally, not causing any trouble, actually induce a big immune response right under the skin.

3:44We are very aware of these bacteria and we are watching them constantly. So if you can engineer those bacteria to have other little pieces that are from pathogens, the bacteria, the viruses, and the cancers, then maybe you can elicit a response and you can have that same protective response if you ever see those pathogens in the future. Well, Michael Fishback is a professor of bioengineering at Stanford University, and his lab has led in this line of reasoning with a series of stunning papers suggesting that maybe, this is still a maybe, we're going to have vaccines made out of bacteria that get applied as a cream.

4:24Michael, thanks so much for being here. You recently wrote a paper suggesting that vaccines may someday be creams and not needles, not shots. Where did that come from? Great. I have to take you back to the beginning. This was completely unintentional. It's a fun story and it came totally by surprise. So, the right place to frame this is to ask you that if I asked you, what do you think the immune system intends to do when it sees a pathogen, we could debate, you and I always do, but we would probably end up agreeing that it's trying to limit replication and dissemination so you don't die. Right.

5:02You want to contain it. It's like Michael Jordan. You might not be able to stop it, but you want to contain it. Exactly. But then if I asked you, what do you think the immune system is trying to do when it sees a microbial colonist that's living on the skin or in the gut? I don't think you would know. We certainly didn't. It's confusing. And I'll tell you why it's confusing. Because all this is work that happened before we got involved. People kept on making the same observation, which is that when you put certain organisms in the gut or on the skin of a mouse, you get a really weird immune response.

5:31If I were to tell you that the immune system doesn't see them at all because there's a barrier in the way, or it does see them somehow, but it realizes they're here to help us not to do any harm. So it gives a friendly wave and walks in the other direction. Just as a reminder, we have tons of bacteria that are normally colonizing our body and we live in harmony with them. And we don't get inflamed and we don't seem to be having a reaction. They just live on and in us and everything seems to be okay. That's right. And so it was a surprise when people began to see that, in fact, the immune system responds to them in a bizarre way.

6:09Bizarre, I would say, in three ways. First is that it's a really big response. Certain bugs, when you put them on the skin or in the gut of a mouse, give you a big adaptive immune response. Tons of a type of cell called the T cell show up on the other side of the barrier. The second thing that's odd is that this seems to happen in a way like if you ordinarily want to get an adaptive immune response, usually there's a breach in the barrier. There's an infection or a needle pokes through your skin if you're getting a vaccination. it's a five alarm fire and all of these immune cells rush in and there's a lot of inflammation and swelling and you might feel lousy and hopefully that immune response clears the pathogen but this process looks completely different you put a bug on one side of the barrier nothing happens it would seem for for seven to ten days that there's no inflammation if you look in the tissue it seems like nothing is happening at all it's just that about a week later a bunch of immune cells show up on the other side of the barrier and then perhaps most puzzlingly, they just seem to loiter there and do nothing.

7:11So this is puzzling because, as you and I know, the immune system doesn't trifle. When it acts, it has a purpose. And so why is the immune system mounting this big adaptive immune response that doesn't seem to have a purpose? And just to clarify, this is even for these kind of normal bacteria that we don't think of as causing disease generally? Absolutely. It seems to happen for every bacterium that's been studied. okay all right so so there we have it um how did you take that observation then and like what there must have been a couple of leaps that's right so erin chen in my lab was puzzled by this and felt that that something didn't add up and so she did an experiment i'll tell you what she did and then i'll tell you why she did it because it's backwards but it works better that way good she she wanted to know what are those cells there to do she didn't believe that they were there to do nothing.

8:04And so she had come up with a way of genetically engineering this very common skin colonist named Staph Epidermitus. This is a bug that lives on every square centimeter of skin on every human on the planet. This is a relative - Just to be clear, is this the staph that we talk about when we talk about a staph infection? This is a different staph. So the staph we talk about when we talk about a staph infection is staph aureus, and that's a more dangerous bug. This is its cousin, staph epidermidis, who is a friendly bug, colonizes every human. So Erin figured out a way to genetically engineer staph epidermidis, and she did something completely wild.

8:43She figured out a way to coat its surface in little pieces of a tumor, little antigens from a tumor. Why did she do that? Because she wanted to trick the immune system of the mouse into developing immune cells that the mouse thinks are specific for the bug, but we know could also recognize a tumor that's going to be somewhere else in the mouse. Why did she do that? Because she wanted to put these immune cells to a test. There are two completely diametrically opposed possibilities. One is that those immune cells could sit right under the skin like everybody else had seen them do and loiter and do nothing, which is I think what she thought they would do and probably everybody in the lab was expecting.

9:26The other possibility, of course, is that they could do what any self-respecting immune cells should do, which is to leave the site of colonization, go to the tumor, and kill tumor cells. So she wanted to distinguish between these two possibilities. Kind of made these bacteria look a little bit like tumor cells because of adding all of these tumor-like proteins on the outside of the bacteria. Precisely. And so she did the experiment, low expectations. The experiment's very simple. these mice have a tumor growing under the skin in their flank, so above their hip. And we don't prepare the mice in any way.

10:04These are normal mice, not genetically modified at all. We don't shave them or scrub them. All Aaron did was to dip a Q-tip in a bacterial culture and rub it gently on the head of the mouse. That's the whole experiment and just walk away. and uh i all the all the best data come through in a text message or a slack message and i remember this was a few days before christmas um seeing it was just a picture there are the mice that were in the control group and the mice that were in the treatment group and the mice that were in the control group had these giant tumors it's it looks gruesome the mice that were in the treatment group the tumors had disappeared wow okay so that means that those cells that were hanging out on the skin did indeed perceive what was going on on those bacteria.

10:51And they did act. In fact, they went ahead and attacked the tumor that shared the same kind of markers, so to speak, that she had put on the bacteria. The tumor also had, and they went after the tumor. Am I following? We found that they left the skin, went through the bloodstream, entered the tumor and killed tumor cells, which is, so there's a few things here. I think the most important for me to say is that this was a big surprise to us. The stories we'd been telling each other, not just within my lab, but among people who study this in the field of microbiome research, especially people who are interested in immunology, we had all come to think that the immune response against friendly bugs was, the words we used were homeostatic.

11:38It was sort of there to keep the peace gentle, neutered. And so seeing an immune response that was set off by a friendly skin colonist kill a very difficult tumor was a huge surprise to us. Also physically separate. I mean, you said you put the bacteria on the head, but that the cancer was, I think you said, somewhere on the leg, which means these guys are not just sitting there. There's some kind of communication going on. That's right. There's some kind of communication. And moreover, this is not an immune response that's just localized to the site of colonization. This is a systemic immune response.

12:11And we hadn't realized that before. Was there redness? So this is a kind of a crazy, random question. But on the scalp, where you had put these cancer-looking bacteria, was there redness and inflammation? Because they couldn't tell the difference between the real cancer and the bacterial cancer. So they just said, let's attack everything. or how did they, or did they distinguish? This is a really important question. There's no redness at all. We've looked very carefully that this is a peculiar case, and I'm going to come back to this later, in which you get a potent adaptive immune response, but the mouse doesn't feel lousy in the same way that you would if I vaccinated you.

12:53Okay. All right. So this is huge. How do you follow this up? Of course, as a scientist, whenever you get an unbelievable result. You have to become a skeptic. You have to doubt that everything was done correctly, you know, because this is a big deal. So, so how does this story unfold? For sure. And now it gets stranger. So there, uh, Aaron, uh, Aaron Chen, who led that work in my lab, um, was, was working alongside a newer member of my lab, Jeanette Buspin. So Jeanette, uh, is a, she's an immunologist by training and a very skeptical person. Um, I think Jeanette saw all of this firsthand and thought that something doesn't add up here.

13:32There's more than we had realized. And so ordinarily, and this is Jeanette's reasoning, when the adaptive immune system really goes after something, both of its arms are engaged, not just the cancer-killing T cells, which we just talked about, but also the B cell, which makes antibodies. Antibodies, yes. And so Jeanette was wondering, is it possible that there is an antibody response against this skin colonists. Now, I have to say in my own defense that that's an absurd question because the skin is in the way, plus the bug is not here to do any harm. So what business would the immune system have mounting an antibody response against a bug that's living in a friendly manner on the other side of the skin?

14:18You also said that it's all over all of our skin, which would mean it It would be a huge resource allocation for an organism to mount a big response against something that's literally everywhere on the body. It would be a huge investment of energy and resources in a bug that you don't really think is going to attack. Correct. It seems, you know, like worthless and far-fetched. So, of course, you did the experiment anyway.

14:50again, our hopes were not high. She did the same thing that Erin had done. She took a Q-tip, dipped it in a bacterial culture, and just rubbed it gently on the head of the mouse. And then she tracked the level of antibody in the bloodstream of the mouse. Now, here, I got to remind you of what data look like when you're looking at antibodies in the bloodstream. Ordinarily, you and I would have seen graphs like this during the pandemic, looking at antibody in the bloodstream following vaccination, you would get your first shot and there'd be a spike of antibody and then it would come back down and you would wait three or four weeks and you get a booster and it'd go up a little further.

15:25So this is, yeah. Kind of multiple exposures to get the body used to seeing it and kind of kick it into action in terms of building a response. Exactly. And so in this experiment, Jeanette just started colonizing the head of the mouse as Aaron had done. And we saw two things that were a big surprise. One is that the level of antibody in the bloodstream just kept on going up and up and up. We couldn't believe this until we reached about six weeks where it topped off at a level that we would have been shocked to see even if we had vaccinated the mice, even if we had used an mRNA vaccine, for example, we got more antibody just from having colonized the mice.

16:04And this is almost needless to say, but these mice must be in some way special that they hadn't seen this bacteria before. That's correct. They had a new exposure. It's a new exposure. Having said that, this also happens against the bacteria that live naturally on the skin of the mice. And so we would learn that later. The second thing we learned that was even more surprising is that the antibody response never goes away. Jeanette, a couple of weeks ago, sent me a data point from an experiment like this, but where she had let it go for nine months and the antibody level is exactly the same as it was at six weeks.

16:42And she hadn't touched the mice in the interim. Right. So it's been nine months, but without swabbing the head every day. This is just, the last one was nine months ago. So it would seem that the process of colonizing the skin of the mice with staph epidermidis was making them immune in some way against this skin cause. Gotcha. Okay. So this is so far very interesting. We have an unexplained immune response. And you said there are two arms to the immune system and both arms are kind of activated by this exposure. Right. And so there's a couple of things that Jeanette did. The first is that, and I'll just leave this as a little island because we're following up on this now, but this is all we know.

17:27She wondered, is there any chance this is happening in humans as well? And so the experiment she wanted to do would have been that she would have come to you, swabbed your skin, isolated your staph epidermidis, and then drawn your blood to ask, are there antibodies in your bloodstream against your own? Yeah. Right. But we were in a rush. And so, she did an experiment that was almost as good where she went to the Stanford Blood Bank and got 10 blood samples and then asked whether there are antibodies in those blood samples against the staph epidermidis strains that we had in the freezer. So they're not a perfect match, but close enough.

18:05Let's just have a look. These are humans and we do expect them to be colonized by this bacteria, just like all of us are. And so let's see what they show. That's right. And every human we looked at, every human we've looked at since, has extraordinarily high levels of antibodies against staph epidermis. It is as though you'd been, even if you'd been vaccinated recently, we would have been impressed to see levels this high. And of course, this is a bug that nobody's been vaccinated against. So that doesn't guarantee that what we're about to talk about is also happening in humans, but I think it makes it more likely than it would have been.

18:42Right, right. Because you have this one correlation point between mice and humans that at least keeps hope alive that this is a general phenomenon. That's right. So, okay. So then what Jeanette did that kind of captured everybody's attention is it starts with, she was asking an innocent question. What exactly are the antibodies targeting on the bug? What structure are they seeing and binding to? And through a series of clever experiments, she figured out that they're binding to this giant tree-like protein that sits on the surface of the book. It has a trunk that sticks straight up through the Kevlar-like meshwork that surrounds the bacterial cell.

19:23And to display a domain that sits above the arbor, as it were, whose function we don't understand at all. This big tree-like protein is getting bound by these antibodies. Great. I mean, that actually, some people who have followed COVID have heard about the spike protein. And it's not the same, but we've learned that these organisms, viruses, and bacteria sometimes just have these things poking out that we sometimes understand and sometimes we need to understand. That's right. And in this setting, the similarity between this giant protein whose name is AAP and the spike protein on COVID or the big protein called HA on flu is that they're a major target for antibodies.

20:07Right, right. And so Jeanette had an idea. She figured if colonizing mice with staph epidermis leads to antibodies against this tree-like protein, she wondered, what if we put something into the tree-like protein? What if we engineered something into the tree-like protein that we want antibodies against? Yep. She chose tetanus toxin and wondered - Certainly wanted antibodies against tetanus. That's right, because we've all been vaccinated against tetanus. And so she wondered if she splices tetanus toxin into this tree-like protein above the arbor, could she, by colonizing mice with an engineered bacterium displaying tetanus toxin on its surface, could she trick the immune system of the mouse into making antibodies against tetanus?

20:55Yes. Now, I just want to be really clear. We are not turning this bacteria into the tetanus bacteria. It only has a small piece of tetanus that it's that's been, as you said, engineered in. So the antibody, if it works, might recognize this little piece, but we're in no way putting the mice at risk of getting tetanus. That's correct. And this little piece that we've taken from tetanus toxin is non-toxic. It's completely harmless. And so this is a piece that you would find in a vaccine. Got you.

21:53and that it would - Without mucking it up. So she tried anyway. A few of the things she tried did not work. And one she tried worked amazingly well. We could see that it was on the surface and we were kind of surprised. And so same experiment, Jeanette takes a Q-tip, dips it in a bacterial culture, rubs it on the head of the mice, and then we wait and we start monitoring antibody levels against tetanus. And you can imagine my surprise when starting around the same time for five or six weeks, we see an antibody level against tetanus in the bloodstream of these mice that was probably a hundred fold higher than it needed to be to protect the mice against a lethal challenge with tetanus toxin.

22:40These are tetanus vaccine levels of antibodies as if you had vaccinated with the good old fashioned tetanus shot, or is it even better than that? even higher than that, more than you would have gotten with a conventional tetanus shot. This is the Future of Everything with Russ Altman. We'll have more with Michael Fishback next.

23:09Welcome back to the Future of Everything. I'm Russ Altman. I'm speaking with Michael Fishback from Stanford University. In the last segment, Michael described the initial set of experiments that indicated that a bacteria that lives on our skin may be a vessel for delivering small pieces of pathogens that can then be used to develop immunity. Vaccinations. These would be vaccinations that are delivered on skin. In mice, it seems to have worked great, but it's a long way between mice and people. Mice are not just little people. In the next segment, he's going to tell us what the benefits of such a vaccine system might be, where we are in terms of basic understanding of the mechanisms and what are the next steps to see if this is really going to be a thing.

23:52Don't forget, we're going to end this episode with our new feature, The Future, in a minute. I'm going to ask Michael a few quick questions. He's going to give me some quick answers. So, Michael, now we really are talking about a potential vaccine. Like, this looks and smells a lot like a vaccine for a mouse. So, what would a vaccine look like if this can make it past mice into things like humans? Great. I think it would have four characteristics that set it apart from the vaccines you and I are used to. The first is that there would be no needle, and that means there's no need for a healthcare worker.

24:25So this is the kind of thing that could arrive in a ketchup packet in the mail, maybe from Amazon, and you would apply it to yourself. And I think that would not only be convenient, but it could make certain things possible that wouldn't ordinarily be possible. Life-altering for many populations. Life-altering for many populations, both here and in low and middle income countries. The second is that, and I think this is a very important point that I'm not sure I appreciated until recently. When you get a COVID shot or a flu shot, you feel lousy for a day or two. That's called reactogenicity. And it's the feeling of your innate immune system kicking in.

25:05For reasons we don't fully understand, the mice don't seem to be feeling any of that reactogenicity. And if that holds through monkeys and into humans, then it would remove one of the most important barriers, a stubborn barrier in the way of vaccine update. Yeah. The third, and this is a bit of a connoisseur's point, is that most vaccines that poke through your skin and into your muscle give you a lot of antibody in your bloodstream. But the connoisseurs in the audience will appreciate that people who are making vaccines, new vaccines these days, are looking for something in addition to that, which is antibody in the mucus that lines your nostrils and your lungs.

25:48That could help protect against respiratory pathogens. And for reasons that I think we're beginning to understand, when you colonize mice with staph epidermidis, you get a robust antibody response in that muc, not just in the bloodstream, but also in the mucos. Wow. That could make for a very potent vaccine. So you get kind of a more complete distribution of the protective antibodies throughout the body. That's right. In a way that I think would protect not just against infection if you've already been infected, but could help prevent you from being infected in the first place and spreading it to other people.

26:18Right. And then finally, you know, I would never take my kids to the pediatrician to get six shots. There'd be some kind of mutiny. But your skin is a big organ. And I could ask them to rub one tab of cream behind their left ear for flu, their right ear for SARS-2, the left elbow for RSV, and so on. So I think this could be multiplexed more easily than other vaccines. And that could make, for example, one product that would cover you for the whole respiratory virus season, which I think would be really impactful. Great. OK, so this is very exciting. And Matt, you've painted a picture of vaccines that I think many people would find very attractive.