Dr. Dermody

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Dr. Terrence Dermody, Physician-in-Chief and Scientific Director, UPMC Children’s Hospital discusses the efforts underway in the Pittsburgh region in the development and testing of potential COVID-19 vaccines.

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– [Announcer] This podcast is for informational and educational purposes only. It is not medical care or advice. Clinicians should rely on their own medical judgments when advising their patients. Patients in need of medical care should consult their personal care provider.

– Assisting in the efforts to test potential COVID-19 vaccines. Hi, I’m Tonia Caruso. Welcome to the UPMC HealthBeat podcast. And joining us right now is Dr. Terence Dermody. He is physician-in-chief and scientific director of UPMC Children’s Hospital. Doctor, thanks so much for joining us.

– Tonia, it’s my pleasure to be with you.

– So scientists from around the world, including those right here at UPMC, are all working on potential vaccines for COVID-19.

– Our vaccine development efforts thus far have focused on a spike subunit vaccine that’s administered intradermally. That vaccine is being developed by my colleague Lou Falo in dermatology, and his colleagues will begin human trials soon. A second vaccine is being developed by my colleague Paul Duprex, who leads the Center for Vaccine Research, and Dr. Duprex is re-engineering measles virus vaccines. So these measles virus vaccines now express the spike protein to elicit an immune response to coronavirus in addition to measles virus: a twofer, if you will. And then my colleague William Klimstra, who is also in the Center for Vaccine Research, is working to develop an RNA-based vaccine. So those are the efforts that we’re pursuing here in Pittsburgh.

– And while all of that work is underway, you and others have also been busy working on efforts to help test these potential vaccines in human trials.

– This is right, Tonia: We’ve been working for the last three months to develop a unit to test COVID-19 vaccines as a first initiative in vaccine testing. We call this unit the Pittsburgh Vaccine Trials Unit. It’s led by my colleagues, Drs. Judy Martin and Alejandro Hoberman, and brings together a large group of investigators in the Pittsburgh community. Experts in clinical trials, vaccine development, immunological assays, as well as engagement with community partners. This multidisciplinary team has pulled together to begin to develop the infrastructure, lay the groundwork for COVID-19 vaccine trials. The trials we plan to do are phase three efficacy trials. These are trials that are focused on determining whether a vaccine candidate is safe, whether it induces an immune response that’s protective, and whether it prevents disease as caused by the infectious agent. These trials typically enroll tens of thousands of study subjects at a number of sites across the country and then follow the study subjects after immunization to determine whether the vaccines are safe and effective. We’re particularly excited that we’ll begin enrollment in a trial of a vaccine candidate developed by Moderna and NIH. This is an RNA-based vaccine that has shown in pre-clinical animal studies as well as in smaller studies with human subjects to be safe and to induce antibody responses against the COVID-19 coronavirus. We’re now going to be enrolling Pittsburghers, 250 Pittsburghers, to participate in this trial as part of a huge effort in which the latter part of the summer into the fall we’ll enroll a total of 30,000 study subjects across the country. It’s hoped that this vaccine or others we’ll be soon testing in the Pittsburgh Vaccine Trials Unit will show safety, immunogenicity, and efficacy, such that we can begin the large-scale ramp-up so that we can start immunizations across the country truly and across the world.

– And the Moderna vaccine is one of the vaccines the government is hoping to fast-track as part of Operation Warp Speed. Can you talk a little bit about that?

– Operation Warp Speed is a U.S. government initiative to move as fast as we can through the phases of human vaccine testing: phase one, two, and three. All the while, manufacturing doses of vaccine such that if it is determined that one of the Warp Speed vaccines is safe, engenders an antibody response, and is protective — in other words, it works — then doses will already be engineered, manufactured for use, so that we can begin immunization of humans very quickly. The five Warp Speed candidate vaccines were all chosen on the basis of the first to come through laboratory and animal development and the first to be introduced into human trials to show safety and to show immunogenicity. There are five of these candidates. Two of them are based on messenger RNA, the genetic material that encodes the coronavirus spike protein. Two are based on adenovirus, and the adenovirus here is really used as a delivery vehicle to deliver the gene which encodes the spike protein at coronavirus. And then the fifth is also a vectored vaccine using an animal virus called vesicular stomatitis virus, or VSV — again, to deliver the spike protein. All of these vaccines have been fast-tracked with huge investments to begin the phase three clinical trials to test whether they will be safe and effective. Here in Pittsburgh, through the Pittsburgh Vaccine Trials Unit, we’ll be testing all five of those vaccines at some point in the development, either with our investigators, or those that we collaborate with in Pittsburgh. We’ll be contributing to the vaccine effort as best we can to get answers as fast as we can.

– So, of course, we know there are members of the public that don’t believe in vaccines at all. And then there’s a big segment that do but might be questioning at this point, this is really fast. When you hear about all of this and the efforts to get a vaccine quickly, the next question is, is this safe? And can you talk a little bit about the process?

– These vaccines after development in the laboratory, are first tested in animals and only those that show absolutely safety in animals progress to human trials. The very first human studies involve a few number of study subjects — 10, 20, 30. They use low doses of the vaccine, and these study subjects are carefully monitored for any potential adverse effect of the vaccines. Once shown to be safe in that small number of healthy study subjects, the vaccines are then used in progressively larger and larger numbers of study subjects — again, with safety being of paramount concern. We think it is absolutely essential that COVID-19 vaccines are safe. These vaccines will be used in people who are healthy: they have no health problems, they’re well. We’re trying to prevent disease in these folks, we’re certainly not trying to cause any kinds of symptoms in these individuals. So vaccines need to be safe.

– And so who are you looking for to join the registry? Who makes a good candidate?

– Well, right now, we’re largely focused on older adolescents all the way up to the elderly. We’re interested in truly all comers. Those who would be absolutely in a pristine state of health in the middle part of the age spectrum to those who are younger, and those who are older, and those who might have comorbidities that would place them at increased risk for COVID-19 disease.

– So are you looking for people who have had COVID-19 and recovered, or are you looking for someone who has not had COVID-19 at all?

– Ideally, we would like to immunize those who have had no exposure to COVID-19 whatsoever. We think that prior infection with COVID-19 virus will induce some protective immunity. We don’t know for sure how much protective immunity, but we think there’ll be some induced. The way the vaccine trial is conducted, some of the study subjects will receive a placebo vaccine and would not be expected to be protected. Other of the vaccine recipients, the study subjects will receive vaccine, and we would expect them to be protected. So clearly, the trial will give us the strongest signal of protection, if no one we enroll has been exposed to COVID-19 virus prior to immunization. Then the placebo-inoculated study subjects would all be potentially susceptible, and the vaccine-inoculated study subjects would all be potentially protected. We’ll then follow them for several months to determine whether, indeed, those placebo-immunized study subjects have higher rates of COVID-19 infection than those who received the vaccine. If indeed that’s what we see, we can conclude that the vaccine has efficacy — in other words, it works to prevent disease. And then by judging from the numbers of infecteds in each group — the placebo group and the vaccine group — we’ll be able to calculate a percentage of effectiveness. In other words, how good the vaccine really is. We don’t plan in these vaccine trials to expose anyone to the virus in any type of controlled setting. Right now, in Allegheny County, there’s plenty of COVID-19 virus circulating, and we expect that even in practicing careful COVID-19 precautions, that some of our immunized study subjects will be exposed to the virus. And then in following those study subjects over a several-month interval, we can determine whether those exposures have resulted in infection or disease caused by the virus.

– So if someone does want to be considered to take part in a clinical trial, what do they need to do?

– If you would like to register, you can find us on the Children’s Hospital of Pittsburgh website. If you search for “COVID vaccine registry” and can input your information, we’ll contact you if you’re interested in participating in the Moderna trial, or one of the trials to come later this year or the early part of next.

– So you touched on this before: There are so many phases to vaccine development. There’s the laboratory phase, the phase with animals, and then human clinical trials, and those trials are actually divided into several phases.

– Human trials are also divided into three: We call them phases — phase one, two, and three. Phase one clinical trials involve a small number of study subjects, usually numbered in the 10s. So maybe 20 or 30 or 40. There, the purpose of this very small study is to discern whether the vaccine candidate is safe. That’s really the primary goal of a phase one vaccine study: safety. Sometimes in those early studies, a couple of different doses are used to see if a safety signal is maintained, even at higher doses of the vaccine. If a vaccine is safe and it looks like it elicits an immune response, well, then, phase two trials are conducted. They typically number in the hundreds of study subjects, and there the study subjects come from different demographic groups, different ages, different communities in the country, and typically one dose is used. And there, the signals are safety and immunogenicity: in other words, does the vaccine induce an antibody response? And if a vaccine is safe and immunogenic, then it moves into phase three studies. Phase three studies usually number in the thousands and thousands of study subjects. And here, in addition to safety and immunogenicity, the study is designed to test whether the vaccine is efficacious, whether it has efficacy, whether it works. There, study subjects receive either a placebo vaccine or the vaccine candidate, and then are followed for several months in an environment where they may be exposed to the infectious agent, like the COVID-19 virus. Clinical scientists then carefully monitor the study subjects for any symptoms or signs of a respiratory infection in the case of a COVID-19 vaccine trial. And if such symptoms and signs develop, the study subjects are cultured to determine whether or not they have infection with the offending virus, in this case the COVID-19 virus. Vaccine recipients are compared to the placebo controls to determine whether the vaccine works. And once, with a huge trial with tens of thousands of patients, there’s a signal that the vaccine is working, then the vaccine data are reviewed by the FDA for licensure. Once a vaccine is licensed, then large-scale manufacturing begins for distribution of the vaccine to the populations initially at highest risk, and then future vaccine administration efforts are focused on administering to the population at large. So those are the stages of vaccine development.

– Because we’re in the middle of a pandemic, the timeline is so important. What’s the fastest a vaccine has ever been made?

– Tonia, the fastest we have developed a vaccine from inception to delivery in humans has been six months. And that was the pandemic H1N1 influenza vaccine, a little over 10 years ago. But the important point to make with that vaccine is that we had plenty of experience in engineering and manufacturing influenza vaccines. Recall that every year we make new influenza vaccines for immunization across the world. And so we do this routinely with flu, where we can make a new vaccine every year. We have no established licensed platform for coronavirus vaccines in human beings. We’re developing this vaccine essentially from scratch. There are animal coronavirus vaccines that provide clues, and clearly there’s a lot known about how to make vaccines and a lot known about coronaviruses, including the closely related coronaviruses, SARS coronavirus and MERS coronavirus, the Middle Eastern Respiratory Syndrome coronavirus. So, vaccine development for those viruses has provided some clues that we can use to develop vaccines against SARS-CoV-2, the COVID-19 coronavirus.

– So what are your thoughts on how quickly a vaccine for COVID-19 potentially could be produced?

– There’s no guarantee that any of the Warp Speed vaccines will emerge as the absolute safest, most effective vaccine. That vaccine candidate may still be in the laboratory. Or it may have advanced to animal studies, or it may be in early stage in human studies. It takes time to develop a vaccine. I think cautiously, if one of the Warp Speed vaccines is safe and effective, we should be able to begin immunizations of at-risk populations United States in the spring of 2021. And if those immunizations go well, we should be able to expand immunizations to other populations in the summer and fall of 2021. That’s if one of the Operation Warp Speed vaccines is safe and effective. If indeed, those vaccine candidates don’t pass phase three trials, then it is harder to predict when we’ll have safe and effective vaccines for use in the population. I would think then, sometime in the year 2022 would be possible, perhaps even later. We’ve not developed a vaccine from scratch, like we’re doing with COVID-19 vaccines, in less than several years. I think the shortest is approaching 10 years. However, none of that vaccine development was done in the face of a worldwide pandemic of such profound health and economic consequence. And so the effort that we’re placing to develop COVID-19 vaccines is absolutely unprecedented. There is no precedent for this kind of effort. And what provides confidence, optimism, for me, is that there are lots of animal studies that show that coronavirus vaccines can be administered safely and are protective, and that gives me confidence that we’ll see similar situations in humans. And truly, only time will tell, and we’re moving quickly to get those answers.

– And you’re not looking to test on children at this point. So how or why is the trial unit being organized out of UPMC Children’s Hospital?

– Well, investigators at Children’s Hospital have a long history in research on infectious diseases, and specifically vaccines. It was approximately 70 years ago that Jonas Salk developed the first poliovirus vaccine in the United States. This rich tradition in vaccine development and vaccine evaluation has fueled discovery around infectious diseases, anti-infective therapy, vaccine research, through to this day. In fact, we have several initiatives at Children’s that focus on infection biology and vaccine research. Perhaps the most prominent is our Institute for Infection, Inflammation and Immunity in Children. We call it the i4kids, Institute for Infection, Inflammation and Immunity. This institute is led by John Williams, who also leads our division of pediatric infectious disease, an expert in respiratory virus infections. And actually, John and his team have been involved in surveillance for the SARS-CoV-2 virus. This is the virus that causes COVID-19. Early in this year, as the virus was just starting to emerge in the United States. John has abundant experience in how viruses infect the lung, induce immune responses, cause lung injury and eventually elicit protective immunity. John leads our i4kids and has been extraordinarily helpful in launching our vaccine evaluation efforts. Moreover, my colleagues Judy Martin and Alejandro Hoberman, who are in our Division of General Academic Pediatrics, have been testing vaccines in children for a couple of decades now. They’re expert clinical investigators. They’ve enrolled thousands of children in various studies of vaccines and antibiotics. In fact, much of what we know about how to treat ear infections, sinusitis, urinary tract infections in children come from studies that Alejandro Hoberman, Judy Martin, Nader Shaikh, others of their colleagues have conducted. So we have the perfect environment and the outstanding scientists to do this kind of work.

– And actually you are on board and planning to participate in future trials?

– We wouldn’t enroll study subjects in vaccine trials that we wouldn’t participate in ourselves. I’m a proud member of the Pittsburgh Vaccine Trials Unit registry. I don’t know if I’ll be picked for the first one. I sort of hope so, so that I can be immunized early and have my immunization completed, but I look forward to participate in these trials. My colleagues look forward to participating in these trials. The world needs us to participate in these trials. We need to put COVID-19 in the rearview mirror. And the way we’re going to do it is with a vaccine.

– Dr. Dermody, some really interesting information. Thanks so much for your time today. We appreciate it.

– Tonia, it’s my pleasure to be with you. Grateful for the time.

– And I’m Tonia Caruso. Thank you for joining us. This is UPMC HealthBeat.

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