Nasal Vaccine for Alzheimer’s Disease Enters Clinical Trial

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. I'm here with Dr. Howard Weiner, professor of neurology at Harvard Medical School and co-director of the Ann Romney Center for Neurologic Diseases at the Brigham and Women's Hospital. In November 2021, Brigham and Women’s Hospital launched a clinical trial for a nasal vaccine intended to prevent and slow the progression of Alzheimer's disease. The culmination of twenty years of research, this is the first human trial for an Alzheimer's intranasal vaccine targeting the immune system, and could open a new avenue for potentially treating Alzheimer's and other neurodegenerative diseases. Dr. Weiner, welcome to Dementia Matters.

Dr. Howard Weiner: Thank you. Great to be here.

Chin: I like to begin these interviews with understanding “the why” behind our country’s important scientists. So for you, Dr. Weiner, why Alzheimer's disease and why work in immune function or dysfunction? In essence, how did you get here?

Weiner: So there's two or three parts to the answer. I'll go to the second question first. I'm very interested in neurologic diseases. The primary disease I began with was multiple sclerosis which is an immune-mediated disease, so we really applied everything we know about immunology to MS. Now in our center for neurologic diseases, we study other diseases and it became clear that Alzheimer's could also have immune components, although it isn't an immune-driven disease like MS. When there was a trial, in the year 2000, of immunizing Alzheimer's patients with beta-amyloid, many of the patients developed an encephalitis that was very similar to MS and the trial was stopped. So being an MS doctor doing research in that area, that really piqued my interest in terms of how the immune system might be involved. At the same time on a personal level, my mother had Alzheimer's and so I witnessed it firsthand. And, of course, any time you have a personal connection to a disease it gives you more reason to want to study it. In fact, when my mother had it, she said to me, “Howard, you're a brain doctor. Can't you help me?” Kind of interesting. Course I couldn't; you know, at that time we didn't know anything but I always remembered that. She passed on subsequently. So when we began to study this event in Alzheimer's patients that got encephalitis - and this is the 20 years of work, and I won't go into all the scientific steps - it became clear that the immune system itself could be used to treat Alzheimer's and clear beta-amyloid. Now the major trials that have been used in Alzheimer's have been giving a monoclonal antibody that reacts with a-beta and there have been many many trials. We know the study of aducanumab - I won't get into the controversy on that unless you want to talk about it. But I was more interested in the immune system itself and particularly cells of the immune system, such as macrophages and monocytes. And in the encephalitis that occurred in the Alzheimer's patients almost twenty years ago there was some evidence of amyloid clearance, and in the laboratory we discovered that you could treat animal models by inducing an immune response that affected monocytes and macrophages that went to the brain and cleared out the amyloid so we published about four papers on this. And so then it was, can we do this in people?

Chin: That's a great answer, Dr Weiner. One of my questions for you, you've pioneered some really key work using immunotherapy and the mucosal immune system for the treatment of multiple sclerosis autoimmune diseases and other diseases like ALS and Huntington's. How do you see Alzheimer's disease fitting into this paradigm or this approach, knowing as you just said that the immune system isn't the primary cause or immune dysfunction isn't the primary cause of Alzheimer's but certainly is a component potentially?

Weiner: Well I think that we now know that the immune system has healing reparative or treatment qualities. After you clear bacterial infection, the immune system can repair different tissues. After people have heart attacks, macrophages go into the heart and repair things. This could apply to the brain as well and there could be immune cells that can be reparative or homeostatic for the brain. That's that idea. The other point is that the major immune cell in the brain is a microglial cell. The microglial cells are a primary immune – the brain has its own immune system. Many people feel that the microglial cells can be both protective or damaging in Alzheimer's, in ALS – it's a common theme. So if that's true, if you can modulate microglial cells it could help all of these diseases including Alzheimer's, ALS, Parkinson's disease, traumatic brain injury, etc.

Chin: And when people think of the immune system, they sometimes will then think of inflammation. There's always a lot of talk about inflammation being a potential mechanism somewhere in the spectrum of Alzheimer's pathology. Based on the things that you have been doing, do you have a suspicion as to inflammation and how it relates to amyloid? Whether it's a potential cause or some mechanism after amyloid has developed?

Weiner: So again, it depends on how you define inflammation. I think there can be good inflammation and bad inflammation. I think that the microglia – after the amyloid is deposited, the microglia can become toxic. Microglial cells are inflammatory cells and I think that's bad. Earlier on in the disease the microglia can be good, if you will, because they can clear amyloid and prevent us from getting Alzheimer's. Now the immune system is constantly patrolling the body and protecting us. In fact, in cancer – one of the reasons we get cancer as we get older is that the immune system doesn't become as effective because during our lives, the immune system is clearing out cancer cells. There are abnormal cells and they're clearing it out. I think the immune system is also clearing out the abnormal amyloid that occurs as we get older. Then as we get older, it isn't as effective. So the immune system loses its protective inflammatory component and then develops in the brain itself a detrimental inflammatory component in response to amyloid.

Chin: So tell us about the vaccine and its immune modulator Protollin – or correct me if I'm wrong – 

Weiner: (correcting pronunciation) Protollin.

Chin: – Protollin, that you're studying. What exactly is it? And then how does it work specifically?

Weiner: The vaccine itself is actually a combination. It's called Protollin. So Protollin is an adjuvant and an adjuvant is used to stimulate the immune system to get a response. It was used initially in people for Shigella vaccines, used for influenza vaccines. It's a compound of outer membrane vesicles and LPS of Shigella and Neisseria. That’s how it was put together. Adjuvants stimulate the immune system by stimulating the innate immune system such as monocytes, macrophages, dendritic cells. The Protollin stimulates these cells via TLR-2 and TLR-4 lycans. That’s how it works, so it elicits a strong immune response. We had really beautiful results in animals, really beautiful results, and understood the mechanism. So then it was can we do this in people? When you want to treat people, it isn't easy. You have to be able to manufacture it. You have to have the funds. You have to get FDA approval. So it took a few years but we did succeed. We then treated our first patient with this nasal vaccine in November. Now we've treated our second and third patient and it's going along very nicely. Many of my colleagues are optimistic that stimulating the immune system in this way to have the body itself fight off Alzheimer's has a good chance of success, but of course, you know, the proof is in the pudding. We'll see what happens.

Chin: So when you say innate immune system, that's that immediate response. That isn't one of the memory cells that we traditionally think of when we think of vaccines later on and reoccurring exposures?

Weiner: Right. The immune system is the innate and the adaptive, okay? The adaptive immune system has specificity, so antibodies are part of the adaptive immune system specific for COVID, Polio, whatever. There's also adaptive T cells, part of the adaptive immune system. In order for the adaptive immune system to get stimulated, the innate immune system has to help it along and so it's kind of the immediate immune response. What it does is it gets the immune system activated and then the adaptive immune system comes in.

Chin: And the vaccine will trigger an immune response to beta-amyloid in the brain. So how do you know that the body's immune response is actually going to go specifically to the brain and attach to beta-amyloid?

Weiner: So that's a good question. We know because of experiments. We know that both macrophages and T cells are patrolling the body all the time. They're already patrolling the body. We have beautiful data in animals that if you stimulate the innate immune system macrophages with Protollin in the periphery, those cells will go to the brain and clear the amyloid. In fact, we can take a mouse, give it the nasal Protollin, take out immune cells, and give those immune cells to another mouse and those cells will go into the brain and clear the amyloid in the other animals. So we know that one of the features of the immune system is the constant patrolling of the body, so it goes in and out of all the tissues.

Chin: It also speaks to the importance of all of the other work leading up to this particular trial in the 20 years of research and understanding all of these different pathways and mechanisms. This particular one that we're talking about is a phase one study. For our audience, what exactly are the goals and are there any particular side effects that you're looking at specifically or potentially anticipating?

Weiner: So a phase one study is to make sure the drug is safe and to find out what's the best dose. We don't expect it to not be safe because it's already been given to people. We don't expect any side effects, but it's never been given to people with Alzheimer's so you don't know. They can have an idiosyncratic reaction or something. We have to monitor them very carefully. They get a dose. They have blood pressure, EKG's, and blood tests, everything. With some drugs, there might be certain side effects that you expect. Maybe there's a drug that you want to treat something in the brain but it interacts with something in the heart. So you wonder whether you'll get a heart side effect. We don't expect any side effects but we want to find out what dose to use in the phase two trial. So we're gonna give four doses. We start with the lowest dose. We give it to three people. We give it a group of 4 – 3 people and 3 people get a placebo. We’ll draw blood on them. If there's no side effects, we go up to the next dose. The first dose is like 100, the next is 500, the next is 1,000, the next is 1,500. Then we take blood samples and we look at the monocytes or macrophages to see whether they've been stimulated. That'll tell us what dose to give when we do the next trial, sort of like with COVID. We're giving two doses – two doses sort of like a COVID vaccine. They're given two weeks apart. Like in a COVID vaccine, you'll measure antibodies against COVID. Here we’ll measure stimulation of monocytes. So once we get the dose – you're probably gonna answer this question but I'll answer it anyway – what do you do next? Okay, so once we have the dose, we'll then probably take about 150 people who have Alzheimer's and we’ll give them one or two doses and there’ll be a placebo group. They'll be treated for a year and then we'll measure amyloid in the brain and cognition and everything. So that'll be a big study to show that it has some effect on Alzheimer's. If things work out and that's positive, you would then move to a phase three trial which is a big trial. That's like thousands of patients for FDA approval and licensing.

Chin: And that's often when people can do it across the country, so you might have multiple sites for that bigger trial.

Weiner: I think we'll have multiple sites for the phase two trial because if you have 150 patients, you need more than one hospital.

Chin: Now you talk about the participants and you did mention those with Alzheimer's disease. Can you describe sort of what you're looking at right now for this phase one – the type of individual who's enrolling. Have you had any trouble with recruitment?

Weiner: So these are mild Alzheimer's patients, so they have an MMSC of like 20 to 29. That's what their thing is. We haven't had trouble recruiting as you may have known and your listeners may know. The hospital actually put out a press release that we're going to do this. You know, they just kind of put it out. I didn't even know about it, per se, and it really created a stir. I was quite surprised. It became a great interest to people around the world. So a lot of patients heard about it. Because of that we haven't had any trouble recruiting people. If there's anyone listening that wants to participate, there's a number that they can call. I think the interest from the press and the people shows how important Alzheimer's is. Something like a nasal vaccine that has the potential to have widespread implications on Alzheimer's has caught the public's attention.

Chin: And you did mention that currently we're looking at monoclonal antibodies and aducanumab has made a lot of news but just taking it from a general perspective. Why would a vaccine be potentially better as far as an approach to treatment than something like a monoclonal antibody?

Weiner: Well I think that – of course I won't get into the controversy on aducanumab unless you want to talk about it – but there's a lot of studies using monoclonal antibodies. Monoclonal antibodies have been very successful in medicine so we hope it works. I've worked in multiple sclerosis and I was on a call with Alzheimer's scientists and MS Scientists and everything. If you look at MS, over the last twenty years there's fifteen approved drugs for MS and it started with one and just gets better and better. I think that's where we are in terms of Alzheimer's. With all the people in the world with Alzheimer's, you can't make enough monoclonal antibodies to treat everybody, quite frankly. A nasal vaccine that you give via spray, you know, that could be given to large segments of the population. I think ultimately we want something more than a monoclonal antibody. Also this could be used not only to treat but in a preventative way. So we're hoping the monoclonal antibodies will work. There's more coming. We hope that it'll give some relief to some of the Alzheimer's patients, but I view that as the beginning. I think that the nasal vaccine has a better long term applicability, although it could be used in combination.

Chin: Yeah, you really know how to answer the questions I'm about to ask you, Dr. Weiner. So this idea that – I mean this is our own body that's fighting elevated amyloid proteins in the brain – that leads me to think of prevention. This idea that if you're at higher risk you're asymptomatic, but you have elevated amyloid or maybe you're just at the cusp of developing elevated amyloid. I mean do you see this as a potential route for healthy people who have elevated proteins in their brain?

Weiner: Absolutely. No question about it. Think about it in terms of high blood pressure, okay. We treat people with high blood pressure because we want to prevent stroke and heart attacks. They don't have a – if your blood pressure is 140/100, you don't feel anything but if you don't do anything, you're going to get – and so the same thing is true. There are people – we now know that people in their fifties and sixties, they’re beginning to develop Alzheimer's and they don't know it. They have amyloid in the brain just like someone has elevated blood pressure. I think that's how we're ultimately going to cure Alzheimer's, not by treating people who have it but by treating people early. The other interesting thing is that we've used amyloid PET imaging to identify these people. Now there's blood tests, some phosphorylated tau and other amyloid blood tests. Those blood tests could be given to large segments of the population to identify people who are at risk. In fact, not necessarily at risk – identify people who have the equivalent of high blood pressure and treat their high blood pressure. So in that sense, a nasal vaccine, I think that's ultimately what's going to happen. In fact, one of the doctors in our hospital Reisa Sperling is treating asymptomatic Alzheimer's or asymptomatic cognitively normal with monocular antibodies. Of course it's an academic trial that I don't think that could be widely used.

Chin: Yeah so we're having Dr. Sperling on this show and so we'll be talking about the AHEAD study, which we're a site for as well. Do you think then vaccines potentially there could be a vaccine to tau protein, which causes other things besides Alzheimer's disease. Is that something that’s possible?

Weiner: Absolutely, no question. Yep.

Chin: Okay, and so then I know you answered this question earlier, but why nasal versus a muscle? When you think of the vaccine most of us are used to an injection into our muscle for COVID or the flu. Why the nasal route?

Weiner: We chose the nasal route because it's a natural route of stimulating the immune system and it also isn't as toxic as stimulating the immune system, say, by the intravenous or the subcutaneous route. We didn't do it to get the treatment in the brain. Some people think you're giving it nasally because you're trying to get it in the brain. The vaccine we use does not go into the brain, but it uses the nasal route because it's more physiologic. So that’s the basic reason. We think you'll get an immune response that's more physiologic that can help the body with less side effects.

Chin: And then to end my last question for you is, can you share with us a little bit about your documentary, What is Life: The Movie?

Weiner: So I was a philosophy major in college and there's all these big questions. You know I don't have to tell you. Is there a God? Why is there evil? Where did we come from? What came before the Big Bang? You really can't study those things in the lab. And I've had an interest in the arts. My son actually is an Emmy award-winning comedy writer. He wrote for 30 Rock and Silicon Valley, so he encouraged me. So I made a movie where I go around the world and I ask life's big questions and ask them for different people and try to explore what life's big questions are. I don't try to proselytize. I don't try to say you should believe in god, you should – I wanted to raise what the questions were. You know you ask, is there a God? Obviously when I asked a priest or a rabbi, they gave an answer. When I asked a physicist, they gave an answer. You know what I mean? There's funny answers. Do you have a unique soulmate? You get different answers for that. One of my responders said, “I hope there's more than one”. Do you know what I mean? And so it won Los Angeles Film Awards. It's called What is Life: The Movie. You can view it on YouTube. I actually went on to make another movie. It's actually a Hollywood movie that came out a couple years ago called Abe and Phil's Last Poker Game so that's a movie I made with Martin Landau and Paul Sorbino. It premiered at the Tribeca Film Festival. It's streaming; people can watch it now. We're talking about Alzheimer's – one of the main characters has Alzheimer's. The story of Abe and Phil's Last Poker Game is an old Jewish doctor goes to a home because his wife has Alzheimer's. That's played by Martin Lando. There he meets an old Italian guy who was a womanizer and a gambler and that's played by Paul Swarvino. So they become friends, improbable friends. Then there's a story of a nurse in the nursing home who's adopted and she had a note that her father is there. She wants to know who her biological father is so she meets these two old guys. They both want to be her father. It's a very nice story. One of the doctors is married to someone with Alzheimer's. It's a very poignant picture of his relationship with his wife, what she understands and what she doesn't understand. She's connected to a fur coat. She wonders what he's doing. He finds himself as a doctor with people who don't remember things or whatever. So it was very nice – it premiered at Tribeca. In my office, I have a picture of myself with Robert De Niro because he runs Tribeca. It was a lot of fun and it relates to dementia and Alzheimer's so there you go. It's streaming – Abe and Phil’s Last Poker Game. People can watch that as well.

Chin: Well, that's incredible. While initially it seemed a bit of a difficult thing to get but a philosophy major and then neurology that studies the brain and the brain's amazing function, Alzheimer's disease, and then creativity with your artwork, I guess it all does really make sense, Dr. Weiner.

Weiner: I think it does. I see that and I have other movies planned. They deal with the brain and they deal with philosophy. Then this book that I wrote, The Brain Under Siege – I wrote that to try and tell stories about these diseases that people can understand.

Chin: Well thank you for your time today and I would love to have you back on the show. We can talk about one of your other projects whether it is scientific study or your writing.

Weiner: Thank you for having me. I'm always happy to join.

Outro: Thanks for listening to Dementia Matters. Be sure to follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you get your podcasts to be notified about upcoming episodes. You can also listen to our show by asking your smart speaker to play the Dementia Matters podcast. And please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing.

Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers.

This episode of Dementia Matters was produced by Rebecca Wasieleski and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions.

To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu. You can also follow our Facebook page at Wisconsin Alzheimer’s Disease Research Center and our Twitter @wisconsinadrc. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.