COVID-19 Vaccine by Patch: Dr. Louis Falo Describes Exciting New Vaccine Delivery System

Richard Jacobs: Hello, this is Richard Jacobs with the Finding Genius podcast. I have Dr. Louis Falo. He is a professor and chairman and he is at the University of Pittsburgh School of Medicine and he is working on a new method of vaccine delivery which appears to be a patch that has a micro-needle on it. It sounds really innovative and interesting and we are going to discuss that. Now we are at a time of SARS-CoV-2 and everyone is looking for a vaccine. A new delivery method may be very interesting for this other vaccine. So, Louis, thanks for coming.

Dr. Louis Falo: Thank you for having me.

Richard Jacobs: Yeah. So tell me a little bit about your background.

Dr. Louis Falo: Sure, so I am a dermatologist and an immunologist. I did my undergraduate work at the University of Pittsburgh and then, when I went to Medical School at Harvard, I developed an interest both in science and in medicine with a particular interest in immunology and so during my time there, I decided to spend some dedicated efforts developing skills and expertise in immunology and get a Ph.D. in immunology and my focus gradually united both my clinical interests and my scientific interests as I became very focused on the immunology of the skin in particular.

Richard Jacobs: Okay, at what point did you conceive of a delivery mechanism using that micro-needle array? Was that project your conception or is it a project you joined?

Dr. Louis Falo: Yeah, so the idea of, first of all, delivering vaccines to the skin is not a new idea but it’s very rarely used. As you know, most vaccines are delivered with a needle injection into a muscle of the upper arm. What most people don’t realize, I think, is that the first vaccine which was one of the most effective vaccines ever was the smallpox vaccine and that was actually developed in the late 1700s and was a skin vaccine. So, for smallpox, what was actually done was small amounts of the virus was actually placed under the skin in the form of a droplet and then they used a needle to actually scratch that virus into the skin. So, to get through the outer layer of the skin and deliver that virus to exactly into the skin and that turned out to be extremely effective not just locally in the skin but systemically.

So, it gave a good antibody response that was able to protect people including their respiratory tract from contracting the virus. So, because that approach was not particularly reproducible, left a scar, was inconvenient, it gradually faded away and we went into the intermuscular delivery mode. What I think is very interesting is the skin is incredibly immunogenic. It’s actually, if you think about it, the first line of defense and so, through evolution, it’s been designed to be very effective in mounting defenses against invaders. So, your skin is constantly exposed to viruses, bacteria, and other harmful invaders and because of that, it’s become very efficient in mounting immune responses to these organisms. So, the skin can very quickly adapt to the environment and it contains a really high density of what we call antigen-presenting cells which are the professional antibody response creators of the immune system.

These cells actually crawl around in the skin as sort of sentinels or scouts and what they do is they capture pieces of foreign invaders and then take that into the lymph nodes and program a systemic immune response. So, our idea was to try to figure out a way to deliver antigen effectively into the skin, that was reproducible, that was safe and that was actually convenient so that it could be used for global immunization strategies. So that’s how we came up with the concept of micro-needle arrays.

Richard Jacobs: So, when you say that you are delivering to the skin, I mean there are micro-needles that are going through certain layers of the skin. So, just as a refresher, how many layers are there of skin, and which should be a preferential layer to inject a vaccine, for instance? Or is it a multiple piercing?

Dr. Louis Falo: Right. So, the skin has 3 major layers. There is a stratum corneum which is essentially dead cells that really act as a physical shield or physical barrier. Right underneath that is the epidermis which contains some of these powerful antigen-presenting cells and then the dermis which contains both the antigen-presenting cells and a host of other cells, mass cells, T cells, other what we call other accessory cells that help develop an immune response. So, the micro-needle arrays that we developed have micro-needles that are obviously very small, micro-scale. You can kind of imagine them as being about the width of the human hair and they are a little more than about half a millimeter in length.

So, these needles penetrate the outer layer, the stratum corneum of the skin, and then enter into the epidermis in the upper layers of the dermis. Now, what’s neat about these micro-needles is that they are entirely dissolvable and so, the needles themselves are made out of sugar and we integrate the target that we want to immunize against, which in this case is a protein from the SARS-CoV-2 virus and that protein subunit is part of the needle. When the needle is solid, it’s very sharp, very hard, and can easily enter the skin. Once it’s in the skin, it hydrates very quickly and sugars dissolve and release the antigen into these upper layers of skin which initiates the immune response and so, it’s a very targeted system for delivering antigen very specifically to a micro-environment within the skin.

Richard Jacobs: So, is it the needle itself; the entire needle itself in the body as host of the antigen or the vaccine component?

Dr. Louis Falo: Yes. So, the needle is the vaccine. The entire body of the needle is made out of sugar and the protein antigen and then, there is a backing behind that where you basically; think of it as the working of a band-aid. So, you basically apply the patch with some gentle pressure that can be done with your thumb and that’s enough for these needles to actually enter into the skin and then start to absorb moisture and dissolve. So, you can imagine, this could, in theory, be a vaccine that everyone could apply to themselves. It could be shipped. One of the features of this vaccine is that once this protein has been incorporated into these micro-needles, it becomes incredibly stable. So, unlike most vaccines that need to be refrigerated or frozen, from when they are made until when they are injected, these micro-needle array vaccines are stable enough to be stored and shipped just like band-aids. So, for global immunization campaigns, this could be a major benefit.

Richard Jacobs: You know, what’s interesting is that the vaccine component is literally fixed in space, so I would think that it would make the immune response more effective because the signaling that goes on to attract a lot of immune cells can go to a localized place over and over and they can go up on this localized place because it’s not moving around. So I would think that it acts as a beacon for the immune system.

Dr. Louis Falo:  So, that is exactly right and this is a very localized delivery system where all of the cargo that you are delivering is kept within a very confined space. Part of the advantage of this approach is that unlike needles where you are literally using force to push a fluid which causes that fluid to kind of go right through the skin and into the extracellular spaces. This is a more gradual method and so the deposit doesn’t have this hydrostatic pressure and is able to stay in the areas where the needle has dissolved. As you said, that stimulates the local immune response which then calls in more immune cells and more antigen-presenting cells into that area. So, essentially, you’ve got a little immunization factory going there in a micro-space within your skin.

Richard Jacobs: I guess, depending on the number of needles, you could probably I guess, I’ll call it to titrate the immune response. You could start with a patch with a few needles, maybe add a secondary patch and then a certain period of time where the immune system gets going and then you present more of the antigen for it to work on. So, you can again, titrate the amount of vaccine presented.

Dr. Louis Falo: That’s exactly right. So you can very finely control the amount of vaccine presented and it is important that there are much lower levels of vaccine needed for this approach than with traditional approaches where you are injecting into muscle and that is because of the concentration effect of having all that antigen in one place. As you suggested, you can send out both your initial immunization and your booster dose in the same package in the mail or you could pick it up at your drug store and you would have both of those and the instructions would be to apply one now and then, 4 weeks later apply a second band-aid for your second dose of the immunogen. I suspect that in the future, we will actually be able to incorporate time to release formulation within the same micro-needle arrays so that we deliver; when we put a patch on, we deliver an initial burst dose and then also a formulation which would stay in the skin and not release for a period of time and then is at some point afterward released so that you could actually get both doses in the same micro-needle array.

Richard Jacobs: I guess you could have a gobstopper effect too where the outer layer gets pulled away and it reveals an inner layer with a different type of antigen that would, band-aids, the body is able to work on that one too. I mean you could do a lot of things.

Dr. Louis Falo: Yeah. So that’s one of these advantages of technology. So, in addition to putting in an antigen, you can also put in what we call an adjuvant which is a non-specific immune stimulant. So, you could boost the effectiveness of your vaccine by including an adjuvant with that same antigen. Again, the important point here is that you can use very low levels of adjuvant. So, one of the problems with adjuvants and the reason that they aren’t in the clinics yet to any large degree is that they are non-specific immune stimulants and there is concern that if you put an antigen and an adjuvant systemically, you would have off-target effects that might lead to auto-immune effects or fevers that would obviously be undesirable, basically non-specific immunity, that risk is greatly reduced by using extremely small doses and keeping them localized to the skin. So, combination agents are definitely a possibility and you could even imagine getting multiple immunizations within the same patch. So, your next flu vaccine could also be a vaccine against coronavirus at the same time.

Richard Jacobs: The needles themselves, do they get passivated by the immune function of the body and cover it up or how do they work to make sure that they get a useful life?

Dr. Louis Falo: so the needles themselves are completely inert. So, they are made out of very simple sugar and they actually completely dissolve and that sugar, once it’s solubilized just ends up in the interstitial fluid and gets carried away. So, the substrata of the needle itself doesn’t have any activity. The activity is in whatever cargo you choose to deliver and these needles are already in clinical use. So our group is actually involved in two clinical trials, both of them are actually focused on skin cancer and so, in those applications, for example, we actually deliver a chemotherapeutic agent directly to skin cancers in patients and we localize that chemotherapy to that specific skin cancer and we deliver it in such little doses that it doesn’t have all the adverse effects you see with systemic chemotherapies that are used for several other types of cancer. So that gives us hope not just for the vaccine application but also for the cancer application and I think that so far, we’ve shown that this micro-needle technology, in general, is safe and is effective at delivering cargoes in patients.

Richard Jacobs: Is anyone contemplating using the micro-needle patch in conjunction with surgery? Let’s say you have to work on a given organ, you have a liver. Could you open that person up and put a patch itself on to the surface of the liver so it would act locally but you wouldn’t normally be able to get to it through the surface of the skin.

Dr. Louis Falo: So, exactly that concept is something that is under development and so whether it’s a patch or the same substance as a patch that is deposited by a needle that is able to get into the liver without actually opening a patient up. The same concept of having something which is in a substrate that is solid and is able to penetrate so that it reaches the target and then dissolves and releases its cargo is something that is definitely of interest to several groups now as a new way to administer drugs very specifically to different organs within the body.

Richard Jacobs: That is really interesting. Are there any patches that are being developed that will act as a scaffolding for a tissue to grow or there is some specific geometry in that. Was the geometry of the micro-needle array, did you have to play with it a lot? Did you have to have certain spacing, depth, and number, etc. so they could affect it?

Dr. Louis Falo: Yeah, and that’s actually a terrific point and so when we started down this path, we were sure to optimize both the needle geometries and the geometry of how the needles are to be arranged on the patch for penetration into human skin. So, if you can imagine, the better nails effect works against you, so if you have your needles spaced too closely or they are not sharp enough, you get a lot of, there is a lot of elasticity in the skin and you just end up pushing the skin down rather than puncturing the skin. So, you have forces working against you in that the thinner and sharper than a needle is, the less volume it has that you can deliver. On the other hand, if the needles become thicker and of different geometries, it’s more difficult for them to penetrate into the skin. So, we basically now are using two types of geometries. One is an obelisk shape, so think the Washington Monument, which has a very sharp tip and yet has a tapered body so that it is able to hold a considerable amount of cargo.

The second geometry that we really enjoy now and have high hopes for is one that has actually been enabled by 3D printing. It, basically, is like an arrowhead. So, if you can imagine an arrow where the tip of the arrow is very sharp and contains your cargo and the shaft of the arrow is made to dissolve very quickly, you can basically, once you apply pressure, the arrowheads will penetrate into the skin, the shafts will quickly dissolve and the arrowheads will remain in the skin where there can be a depot for a drug release. The same type of technology has been used and is under development for wound healing, for example, so that you can create a scaffolding for re-epithelialization of wounds and I can envision several other uses that could be developed in the future.

Richard Jacobs: Yeah, this is really cool. Do you own all the patents on this or are you just working on it?

Dr. Louis Falo: No, we sure do. There is a very robust patent portfolio that is protecting micro-needle design, micro-needle delivery, and then each of the various user applications. We have spun out one company for the cancer application. The name of the company is Skinject and they are now in clinical trials and we are rapidly progressing with the SARS-CoV-2 vaccine that we are developing now and hope to have that in the clinic in the not too distant future.

Richard Jacobs: When the patch is on someone, how long do they keep it on? When they remove it, do they just pull it off and it comes off easily like a band-aid or what happens to it?

Dr. Louis Falo: Yeah, so think Velcro. I’ve been told it feels like Velcro and when you take the patch off, first of all, the patch is only on for minutes. So, 5 minutes, 10 minutes to be super sure that you’ve delivered everything but realistically, probably one or two minutes is sufficient. When you take the patch off, the drug is no longer there. So, all of the drugs is loaded into the distilled ends of the needles, so the part that goes into the skin first and that has dissolved and is all in the skin. So what you are left with is basically sugar on a band-aid. So, there is no harmful waste here. You can just throw that in the trash like any other band-aid and the other interesting thing is because the needles are so short, they don’t cause any pain and there is no bleeding because they aren’t long enough to reach blood vessels or nerves and so it’s a pain-free immunization approach.

Richard Jacobs: I’ve worn like a continuous glucose monitor and they have a microneedle which is prior to yours, I don’t know. But that one doesn’t6 hurt either. It’s maybe like itchy for a second. So, there is really no pain.

Dr. Louis Falo: Exactly, just some pressure is usually what happens. Now, the one side effect that we might see and we haven’t done vaccines in patients yet but one side effect that we might see is that if we are very successful and we induce a robust immune response, we might expect to see some erythema at the site over the next day or two but for us, that would be a very positive sign in that the immune response in the skin was actually working. I doubt that it would be any more uncomfortable than maybe, at worse, a mosquito bite.

Richard Jacobs: In the needle array, is there a few of the needles that go deeper to trigger more of an immune response, or is it good enough that they all go into the epidermis, or do you have to drive any deeper?

Dr. Louis Falo: so, the needles that we are using go through the epidermis and into the upper dermis and that’s the ideal place to deposit the antigen ad so they are all the same size. The technology is incredibly flexible. We can make them as long as we need, so if there were other applications where we wanted to go deeper, potentially even into the fat layer underneath the skin, that could be done. We haven’t done that yet and I think, in those few cases, you probably would see some pain and bleeding because the needles are longer at that point and they are able to reach some of those other structures.

Richard Jacobs: So, the skin, anywhere on the body, there are probably multiple factors that make it a great place to cause immunization. I guess the body is used to providing an immune response to the skin, it’s a huge service area. I guess the full ability of the immune system would probably be best used there because that’s the spot where most of the battles happen, I guess, on a continual basis.

Dr. Louis Falo: Exactly! Every day, you are under attack. So, viruses, bacteria, and other harmful invaders are trying to get to you and your skin is protecting you. So, it has this first line of defense which is just this barrier stratum corneum that we talked about a little earlier and then after that, it has an epidermis which is layers and literally looks like a brick wall of cells that we call keratinocytes which are also very important for barrier functions and antigen-presenting cells mixed in with them and then deeper than that are the other cell types including different types of antigen-presenting cells that are more specialized as well as accessory cells like mass cells, the cells that are involved with giving you hives, for example, and other immune stimulators. So, all of these systems are very well controlled networks that work together to generate an immune response and one of the remarkable things is that the immune response that is enabled through the skin isn’t just a skin immune response, it’s actually a systemic immune response because these antigen-presenting cells actually are conditioned based on what is happening in the skin and then circulate into draining lymph nodes more centrally where they make the responses of both T cells and B cells and antibodies which then, distribute throughout the body and so, it’s fascinating that you can immunize in the skin and then find specific antibodies and T cells in the lung tissue against the antigen that you immunize in the skin and that’s just what part evolution has developed to protect us.

Richard Jacobs: are there certain parts of the body that are more amenable, I guess the arm if it’s caught or…

Dr. Louis Falo: Yeah, so all of those spots would work. I think the biggest issue is you want to look for a non-hair bearing spot or one that doesn’t particularly have a large amount of hair because the hair would actually create a physical barrier to the needles to some extent. We are intending this to be an upper arm for a vaccine, pretty much in the same spot that you would get a needle IM injection. However, we’ve already learned from our skin cancer experience that skin cancer could appear anywhere, and thus far, we’ve treated multiple sites, face, back, legs, etc. and the micro-needles appear to be fully effective in all those sites.

Richard Jacobs: So, cynically, is this news and when will people, you think see it used extensively clinically?

Dr. Louis Falo: Yeah, so clinically right now, it’s in clinical trials. So phase 1 clinical trial for cancer. After phase 1 trials, as many folks have heard, the testing process then involves phase 2 which is a much larger number of patients, and then phase 3 which is a very large number of patients and all of these are assessed for safety. As far as vaccine applications, there has been one or two phases 1 clinical studies with different types of micro-needle arrays. So, it’s starting, the technology is starting to get into the clinics. We would hope that our vaccine will be into the clinic by the end of summer and once we get started, we’ve designed the trial to advance very quickly. So I would hope that we would be able to progress through those phases at a fairly rapid rate, assuming everything goes as expected and we don’t see any adverse events or safety issues that would need to send us back to the drawing board.

Richard Jacobs: is a micro-needle array patch being used scientifically for anything now?

Dr. Louis Falo: No, it has not yet been clinically approved for any applications at this point.

Richard Jacobs: I guess, it’s funny, you know, if the first one you do works, that’ll open the door for faster adoption of any micro-needle array technology or the technology used for other types of interventions. But do you pick the one that’s most likely to work, so you can open the door and make it faster, or do you pick the one most needed?

Dr. Louis Falo: So, it’s a combination of the two. I think that the skin cancer application is an application that has a very high likelihood of success that would open the door for this technology and then, obviously the vaccine application efforts accelerated dramatically when COVID hit us. So we had already been working on micro-needle array delivery of other vaccines, that we had already published papers with micro-needles for the Zika virus vaccine and one of the SARS-CoV-2 relatives, the MERS vaccine and that’s one of the reasons that we were able to so quickly, get the micro-needle array technology into the animal models for SARS-CoV-2 is that we have this active vaccine projects already underway.

Richard Jacobs: very good. What do you think is the timeline plus the window of how long till this can be actually used clinically?

Dr. Louis Falo: Yeah, so, from the vaccine standpoint, we would hope to begin clinical trials, phase 1, maybe phase 1 / 2 clinical trials by the end of the summer and then the progress would really depend on how well the vaccine works. So safety is always the first and most important concern and assuming the vaccine is safe. We will be able to accelerate quickly through phase 1, 2, and 3 studies. If the vaccine is effective, obviously that would be great motivation not just for moving quickly through the trials but from scaling the vaccine, to be able to manufacture the multiple millions if not a billion MNAs that would be needed for global applications of an MNA vaccine for COVID-19.

Richard Jacobs: Very good. Louis, what is the best way for people to find out and keep tabs on your progress?

Dr. Louis Falo: Yeah, so you can check out our departmental website. The Department of dermatology at the University of Pittsburgh. We update it regularly with progress on this project, micro-needle arrays in general, and the other work that’s going on at the University of Pittsburgh.

Richard Jacobs: Very good, Louis. Thanks for coming. This is really cool. I found you because of an article that came out and I’m glad we had a chance to talk. So it’s great and I hope it works.

Dr. Louis Falo: Thank you very much for inviting me.