[0:40] Introducing Dr. Lowy
[2:19] Can you tell us more about your previous research work on the HPV?
[5:20] How does vaccine testing work in the lab?
[14:50] How quickly can we go from creating the virus to implementing it without compromising safety?
[17:07] With COVID tests, is there any worry for false negatives?
[20:57] When do you think we can return to "normal society"?
[29:34] How long would it take until there's been enough level of vaccinations for normalcy to return?
[32:05] Are there any major differences or potential similarities between SARS-COV-2 and HPV?
[34:46] What resources have helped you along the way? How did you decide to pursue a career in scientific research after graduating from Amherst?
[38:08] Is there anything you wish you would have done before you started your career?
Publisher: Amherst STEM Network
Podcasts Coordinator: Julia Zabinska
Music Composer: Grace Geeganage
Cover Art Designer: Chloe Kim
Cover image courtesy of www.cancer.gov
Episode 3: Dr. Douglas Lowy '64
Hosts: Scott Song '21 and Hill Yin '21
In this podcast, Hill Yin and Scott Song (COVID advisory board that manages the ACBACCI database) had the opportunity to speak with Dr. Douglas Lowy '64. As the Acting Director of the U.S. National Cancer Institute and Chief of the Laboratory of Cellular Oncology within the National Cancer Institute, Lowy spoke about COVID19 knowledge. His HPV research led to the development of the HPV vaccine, so he also spoke about his previous work and what the process of vaccine development entails.
Hello everyone. Welcome to Amherst STEM Network Podcast. My name is Hill. I am a senior BCBP and Math, double major.
I'm Scott, a senior at Amherst College, majoring in BCBP and computer science.
We are both members of the Amherst STEM Network COVID advisory board. What we do is we review COVID-related journals and articles that you, the ASN audience, submit to ACBACCI. We select important information from these resources and add them to the ACBACCI database for you to understand the pandemic better. Today's conversation is designed to help you better understand COVID-19.
In this podcast, we'll be having a conversation with our guest speaker, Dr. Douglas Lowy specifically a conceptual discussion revolving around vaccines in light of the current pandemic. Dr. Douglas Lowy is a deputy director at the National Cancer Institute and a part of the NIH, the National Institute of health. Would you like to introduce yourself and your history and involvement with Amherst College?
Dr. Douglas Lowy (01:02):
Sure. Scott and Hill. Great talking with you. I graduated from Amherst quite a long time ago. I'm class of 64. And instead of telling you just about my connection with Amherst College, because needless to say, I have been an alumnus since then, let me tell you why someone from the National Cancer Institute might have some competence in the area of vaccines against SAR COV 2. My laboratory developed the technology that underlies the FDA approved vaccines against human papillomavirus, the so-called HPV vaccines and I have conducted research for a long time on viruses that cause cancer when there was the COVID-19 epidemic, we turned some of our attention to COVID-19 and the virus SARS COV2 and therefore I have learned a fair amount about the virus and the issue surrounding of vaccine development.
Great, great. Can you tell us more about your previous research work on HPV?
Dr. Douglas Lowy (02:25):
Sure. So I run a research laboratory that is focused on cancer research and some of the research that we do involves genes that are responsible either for promoting cancer or inhibiting cancer. But the research that I've done with the human papillomavirus was first with genes such as that, but more recently, which really means over the last 25 years or so, we have studied HPV more as a virus than something that encodes single genes. And as a result of that, we studied the proteins that are encoded by the virus and those different proteins. Some of them make up the shell or the capsid of the virus, and they are the proteins, which if you give them in a vaccine induce the kind of immune response that leads to strong protection. And so over the last really 15 years, a fair amount of the research that we have done is first to try to understand the mechanisms by which the vaccine works. And second, to try to improve the utilization of the vaccines. And right now, for example, we are involved in a large clinical trial that's supported not just by the national cancer institute, but also by the Bill and Melinda Gates Foundation to see if the vaccine actually can work with just a single dose.
Dr. Douglas Lowy (04:19):
Would that be able to provide strong long-term protection? The principal rationale for that is that the main cancer that is caused by HPV infection is cervical cancer. And on a global basis, cervical cancer is one of the most common cancers of women. And it's responsible for more than a quarter of a million deaths worldwide from this single cancer. And so if you could reduce the number of doses that are needed to just one dose, it could be transformative to allow people in low and middle-income countries to get vaccinated against HPV and thereby play an enormous role in controlling HPV infection and thereby controlling cervical cancer.
One question that we've had regarding like the vaccine development processes, like how does vaccine testing really work, especially like, like in the lab, I know that you can sort of test to see whether like an antibody or I guess the vaccine would work in like a, like a research environment, but when it when you obviously like you can't really directly test on humans, you can't directly be exposed to the virus after you've injected them to do it like ethical reasons. So how do we like, see, would it be like in a purely epidemiological approach or how does that work?
Dr. Douglas Lowy (05:54):
Sure. Scott, that's a terrific question. Let me say that the first part of development is what you're describing, which is what we usually refer to as preclinical development and preclinical development, depending on the vaccine is really trying to essentially first, if you can, to understand what are the protective immune responses that get people over an infection, and can you make a vaccine that more or less mimics that protective immune response? And you can test that in a number of ways, but as you point out just in the laboratory or in an experimental animal model in order to go further and do testing in people, the general approach is to do what are usually referred to as phase one, phase two and phase three trials. Phase one is really trying to establish efficacy, I'm sorry, is, is trying to establish the safety of the vaccine and in addition, the dose of the vaccine that should be used.
Dr. Douglas Lowy (07:18):
And then in phase two, if there seems to be that safety is okay then you generally try a larger number of people say a hundred people instead of 10 or 20. And then you look at, in phase two, do you see that it still seems to be safe? There don't seem to be any showstoppers in terms of serious side effects. And in addition, do you get some indication that the vaccine might be protective and those indications, depending on the way the phase two trials are done can be one of two things. What you usually are doing with a preventative vaccine is trying to induce what is called neutralizing antibodies. Those are the class of antibodies that interfere with virus infection. And so an important measure of a vaccine in phase two does you induce those responses that are associated with neutralizing antibodies. A second way of doing it is some phase two studies, you actually look for efficacy. Do you actually see some degree of protection when it comes to the source SARS COV 2 candidate vaccines virtually all of the early phase trials one and phase two, what they're looking for is first safety signals, that there don't seem to be any serious side effects from the vaccine and second, or is there a reasonable immune response? And by that, it usually means looking at are their development of antibodies, which are either directly shown to be neutralizing antibodies or some kind of antibody tests that correlates closely with the neutralizing antibodies. You then get to phase three trials. And the phase three trials of which are currently enrolling patients for at least a few of the candidate vaccines, or usually a large enough number of people so that you can get a sense of, is there going to be sufficient safety from the vaccine because you're testing, let's say 10,000 or 20,000 people. And under those circumstances, you should be able to see side effects that are relatively uncommon, although not the most uncommon side effects.
Dr. Douglas Lowy (10:12):
Second, you want to have enough events that can compare the placebo group, because usually these are placebo-controlled trials, and are there enough events that occur so that you see that there is substantial protection in the group that gets the candidate vaccine compared to the group that gets the placebo. And these are randomized placebo-controlled trials. Neither of the people who are getting the candidate vaccine nor the people who are evaluating them know who has actually received the vaccine and who has not, after there are a certain number of cases that have been seen people then look to see what is the distribution between the number of cases that have occurred in the placebo group compared with the number of cases that occurred in the vaccinated group. And by measuring also the responses in the infections, do people clear their infections? You know, the kinds of questions you would be asking are first, are there fewer infections in the vaccinated group compared to the placebo group? A second question would be, is their clearance of the infection faster in the vaccine group compared to the placebo group. The third kind of question is, are there more serious infections in the placebo group compared to the vaccinated group, but those are the classes of questions that are being asked and biostatistics are very important in phase three trials because you need to have enough of what is referred to as vaccine endpoints, to be able to say with a degree of certainty, that the vaccine confers a certain degree of reduction in risk and either risk of infection of risk or clearing infection or risk of serious infection, but those kinds of parameters or endpoints measured with the vaccine. Before I finish. Let me just say Scott, that there is theoretically a situation where you actually can challenge people with a vaccine dose deliberately after they have, or have not been vaccinated.
Dr. Douglas Lowy (13:01):
And those are referred to as human challenge trials. The usual way of doing this is where you have, a successful rescue treatment in the event that the challenge really doesn't, you know, leads to serious infection at the moment. The ethical view is that the seriousness of some SARS COV 2 infections are such, and we don't yet have a really successful rescue treatment. So at the moment, it's not felt that this would be an ethical way of approaching things, especially at the moment, because doing the randomized control trials, you can get the results, at least as fast as the time it would take to develop a challenge dose, et cetera. On the other hand, the NIH has decided that it might be ethically problematic to do it. Doesn't want to put all of its eggs in one basket. And so we actually are developing a challenge dose, which would probably be ready in about a year. And if it turns out that the candidate vaccines don't provide the degree of protection that we would like, we might end up going to some kind of a challenge trial, but I think that would happen only after we had some really good rescue treatment for people in case they were to develop a serious infection.
With the human challenging trials, how quickly can we go from creating the virus to implementing it without compromising safety?
Dr. Douglas Lowy (14:57):
Well, firstly ethical issues are not crystal clear in the sense that some people think it would be ethically. Okay. Even if you don't have a rescue treatment by exposing people who don't have a likelihood of developing serious infection, for example, let's just say college students, okay. Who doesn't have an underlying disease that would place them at high risk of having a serious infection? And some people feel that the risk, you know, if you just volunteer and you know, what the risks are that it would be okay. Other people feel that even if you were willing to volunteer until such time as you had a really effective rescue treatment because we can't with a hundred percent accuracy determined, even among low-risk people. And there are some people who might have a serious infection that it's not ethical to do that, but what really takes the time is developing a challenge dose so that you need to know how much virus there is ELA, et cetera.
Dr. Douglas Lowy (16:10):
And that takes a fair amount of time to do that under conditions where it is okay to give that challenge dose to a person. So we're holding off first because we think that it's faster to do the randomized control trials. And but I would also point out that when you are challenging people because they will not be people who are at high risk, you won't be able to determine directly whether you're reducing the risk of developing a serious disease. And ultimately for most vaccines, what you're really trying to do is to prevent the development of a serious disease, rather than just preventing the development of asymptomatic or disease that has very little in the way of symptoms.
On the topic of college students, so I know on campus currently Amherst is doing like, I think every other day they're testing for the virus. And one of the questions I had was rather than focusing on a vaccine for like tests itself, I know there's like three different types of tests there's through the nose. I think there's a pharyngeal swab as well and one worry that I guess we had was that since we're testing every other day and we're getting a lot of negative results as a result, is there any worry for false negatives? Cause I remember searching up articles, but these are kind of old articles, but they did a reverse transcriptase PCR and they reported like a sensitivity rate of 70%.
Dr. Douglas Lowy (17:52):
It's slightly worrying, but that's an old figure.
Dr. Douglas Lowy (17:56):
Yeah. Scott sensitivity is always an issue. And for any test, you're not just worried about false negatives, but also about false positives and the test that is being, you know, being done. I don't know what test is being done at Amherst, presumably, it is an FDA approved test, and so presumably it has good sensitivity and specificity characteristics, but there's always an issue of false negatives and false positives for any test. And that's why if somebody is positive, you know, you follow it up by usually with another test to confirm that it really is a true positivity, especially when the percentage of positives is very low. And there are always going to be some false negatives because when somebody is very early on in the infection, their level of infection may be quite low. But I would say that testing every other day should be a very good approach for quickly identifying people who are positive. But if there is someone who is positive, what becomes really critically important is to be able to do a good contact tracing of the people that that individual might have exposed. And that really is the way to crack down on there being some kind of super spreader event or something like that. And I would imagine that Amherst has those kinds of safeguards in mind in the event that somebody has a positive test.
Yeah. I think Amherst like every time a case is reported, they send out an email and it seems like they have pretty effective contact traces cause they always give an exact amount of who they were in contact with. So I think Amherst is doing a good job there and also keeping like cases isolated on campus based on what I've heard from other students experiences on campus.
Dr. Douglas Lowy (20:19):
Yes, I would imagine that, you know, it is easier in principle with a school that has a population of less than 2000 people. And right now I would assume that it's well under a thousand than it is with a large university where people come back where people come back and it's thousands and it's thousands of people. So I would anticipate that Amherst has a lot of safeguards in place that will keep the infection rate low.
When do you think, when you think we can be off mask after, like masks that will no longer be needed after a vaccine has been made. Like when do you think we can return to the normal society?
Dr. Douglas Lowy (21:11):
Yeah. Hill that's a terrific question. It is not a question to answer right now because what it will depend on how many people get vaccinated and what happens to what we refer to as the prevalence of SARS COV 2, in the population. The issue really, the issue really will be, does the prevalence go down substantially so that we have a very low level of virus so that your risk of being exposed, whether you've been vaccinated or not ends up being very, being very low. The first thing that will need to be done is for there to be good uptake of the vaccine and the responsibility of the FDA is not just to approve a vaccine, but also to make sure that even though we're trying to shorten the amount of time that it usually takes for a vaccine to be approved, that none of the rigor is w there aren't shortcuts to the rigor.
Dr. Douglas Lowy (22:33):
In other words, that the safety of the vaccine is evaluated just as stringent as it would be for any other vaccine. And in addition that the efficacy of the vaccine is evaluated as stringent as for any other vaccine and for the public to be aware that after any vaccine is approved, that the CDC and the FDA follow people who are vaccinated as a group to make sure that when you go from, let's say having a clinical trial involving 20,000 people to now giving the vaccine to several million people, that there aren't some unexpected, very serious side effects related to the vaccine that come out during that time. So all of these safeguards are in place, and we need to be able to correctly assure the public that all of them are in place when it comes to the testing of SARS COV 2 vaccines, before they are approved. And again, after they are approved, this is what will lead to the highest uptake of the vaccine in addition to educating people about the safety and efficacy of the vaccine.
One question that a lot of people worry about is that there've been a lot of comparisons of the virus to the flu and that corona, like COVID, could become like a seasonal flu like that. Like, we'll have to give vaccines like every year basically.Is there a chance that the virus becomes like that or that it can mutate and that we'd have to all get revaccinated cause, and that, like, there won't ever be a time where like, masks won't ever go away based on what you know about the virus?
Dr. Douglas Lowy (24:34):
Yeah. I think that's another excellent question, Scott, what my view is first that because of the way that Corona viruses are put together, the development of mutations is going to be much slower than the development of mutations with influenza virus. O could there be variance that really change the virus dramatically? Yes, that's possible, but it wouldn't be at the same rate as we get with flu vaccine. In addition my own view is that it will probably be easier to develop a vaccine that gives a high level of protection against SARS COV 2, or other corona viruses than it is to develop vaccines that give a high level of protection against influenza. I think that what's what people need to understand is that what's being tested right now. Our first generation vaccines, these vaccines are the ones that are the easiest to manufacture and produce in large numbers.
Dr. Douglas Lowy (25:59):
But I anticipate that going forward, even if these candidate vaccines are successful, that over the next few years, there will be second generation and third generation vaccines that have an even greater likelihood of being protective against SARS COV 2 related infections that are different from the current source of COV 2 infections, which I think will further reduce the likelihood of mutations leading to another serious pandemic. Obviously, in order to do all of this, we need to continue support the development of vaccines and the development of these public health measures, even after there is a one or more successful first-generation vaccine. But I think that there is strong support in Congress for this kind of research. And I don't imagine that it would be reduced regardless of which presidential candidate is elected in November.
Yeah, that is very true. I have one question. So aside from developing vaccines, do you believe that like continuation of this quarantine would be like a temporary, more effective measure to deal with the pandemic?
Dr. Douglas Lowy (27:34):
Well, I think that the, the question of even if we had a good treatment you know, a good rescue treatment, let's say for example, the the cocktails of neutralizing monoclonal antibodies that are currently being tested, let's say that they really work well even with them. I think that you would want to have more than just one level of protection. In other words, well, if you get infected, you can take the monoclonal antibodies, usually public health measures that are most successful are a series of measures rather than just relying on one measure itself. And what we can do to try to reduce the infection rate itself, I think is really useful. So for so I think that the notion of social distancing and masks at least for the foreseeable future will continue to make sense. I didn't mean to come across as pessimistic when I was answering the question of, well, you know, how long will we need to wear masks? My guess is that within six months of the approval of a vaccine, we will have sufficient protection that it will be possible to really go back to a large degree,to business as usual interactions as usual et cetera. So that's a speculation on my part, but I would expect that within six months there'll be sufficient uptake of the of the vaccine that people will be able to be more or less back the way things were before the epidemic.
That's really, really, reassuring. Actually, I did not like I didn't really have, I tried searching at like time tables of like, when, you know, like how after, even after a vaccine would develop, how long would it take until like, there's been enough, like level of vaccinations for which like a sense of normalcy can return.
Dr. Douglas Lowy (29:52):
There's let me just say, Scott, that there's this notion of herd immunity, but it's extraordinarily controversial right now. How many people need to be protected, whether it's by a vaccine or because they are protected after they've had their first bout of SARS COV 2 infection and the speculations are all over the map, what that tells you is we don't know. And I think that it's, you know, I think that right now, there's just not enough information to know what degree you know, what percentage of the population needs to be protected. And to some degree, it also depends on the ages of the population, what the transmission dynamics are of the infection, et cetera. What the actual answer is Scott, if I interrupted, I apologize.
Oh, no, no, you're good. You're good. I think that's like the concept of herd immunity was kind of like what else thinking of from before.
Dr. Douglas Lowy (31:04):
Yeah. And I just think that we know that we certainly herd immunity exists for virtually all infections, but it is not known what percentage of the population needs to be so-called immune and I've seen hypotheses that are as low as 20 to 25% and others that are as high as 75% and what that tells me is we just don't have enough data, and therefore it is not useful at the moment to make these kinds of speculative hypotheses, if they are going to lead to changes in policy, we really shouldn't be making changes in policy based on these speculative and as yet unproven hypotheses.
I know your expertise is more on the research on the HPV vaccine. Are there any major differences or potential similarities between the two diseases, the two viruses, SARS COV 2 and HPV?
Dr. Douglas Lowy (32:21):
Well, yes. I mean, there are similarities with almost between almost all viruses and there also are critically important differences. One similarity is that most people who are infected with HPV don't even know they have the infection and it goes away on its own. And it's very analogous to SARS COV 2, where, you know, people of your age, probably, you know, 40 or 50% of them have totally asymptomatic infections that they resolve spontaneously on their on their own without ever having any symptoms. The big difference is the length of time that it takes to have a serious problem with the infection with SARS COV 2, you know, within a week or two of getting the infection. It is serious, or it is not serious; with HPV, it takes years because what you are worried about with HPV is the development of cancer.
Dr. Douglas Lowy (33:38):
And although the virus sets in motion, a series of steps that leads to cancer, it takes years for that to develop. So if you will, those are two of the similarities and differences. The HPV vaccine induces a very high level of herd immunity when you vaccinate even a half of the population but that's because the vaccine is more than 95% protective. We don't know what the rate of protection is going to be for these candidate vaccines, or even for subsequent vaccines against SARS COV2, and the degree of efficacy is going to have an important impact on how many people need to be vaccinated in order to develop herd immunity.
I know there are many students here at Amherst who want to pursue a career in scientific research. Personally, I wanted to pursue a career in clinical research. Can you share with us what resources have helped you along the way, or how you decided you want to pursue a career in scientific research after graduating from Amherst?
Dr. Douglas Lowy (35:05):
Yeah, I had, when I graduated from Amherst I had majored in art history and I learned an enormous amount with that major, but I anticipated that I was going to be a physician who mainly took care of patients, very analogous to both of my parents who were primary care physicians. But when I was in medical school I was exposed to advances that were made as a result of research, and it seemed very intriguing to me. And so I actually started doing a little bit of research when I was in medical school and it whetted my appetite for it, so that after I graduated, I actually in addition to getting clinical training I went to the NIH to get more training in research. And it was really critical for me to have the support of my supervisor or mentor when I was at medical school because he actually thought that I had more potential for doing research than I thought I had.
Dr. Douglas Lowy (36:30):
And he really helped me get my job at NIH, which was a training position. And again, my supervisor or mentor was extraordinarily pivotal in helping to give me a strong training which actually was in viruses that cause cancer in animals and served as a stepping stone to my developing my own laboratory and my own research program. And even after I did that, I was extraordinarily fortunate in that my laboratory was physically part of another laboratory where the head of that laboratory really sort of took me under his wing and helped me to further hone my skills for doing research. So yes, I think that I have some abilities in being a self starter and trying and having confidence that I know how to work on problems that I haven't worked on before that plays an important role. And my training at Amherst, even in art history really was critical for that. But the specific help that I got from multiple mentors was indispensable for developing my career.
That's great to hear, but just, if you have the chance, is there anything you wish you would have done before you started your career?
Dr. Douglas Lowy (38:20):
Yes. If I had known that I was going to be doing laboratory-based research, I would have been better off to have majored in a science when I was undergraduate at Amherst. Majoring in art history gave me some opportunities that I would otherwise not have had. For example, I did my junior year abroad you know, in, in Paris, I learned how to speak French well, and I learned about, and I learned about art in ways that I otherwise wouldn't have learned, but majoring in a science at Amherst would have given me the tools for doing research that I simply didn't have when I when I started. I think having an experience doing research as an undergraduate is really beneficial because it gives you a real taste of what it is like to work in a laboratory.
Dr. Douglas Lowy (39:30):
And this is something that you like doing, this is something that you hate doing, and this is something that you have some talent for or not really. So I actually think that there is a lot to be said for trying to do some kind of undergraduate project, especially if your supervisor or mentor is someone who can really talk with you in a constructive way about your potential and also how to further develop it, et cetera.
Dr. Douglas Lowy (40:13):
I'm just saying that for me, the mentors that I have had at each level have really been instrumental in my scientific development and my ability to be a better researcher and really that's because they have been willing to spend time talking with me about my research and how to make it even better.
This was very informative discussion, we learned a lot about how vaccines are tested specifically with different phases and different trials. We just want to say, thank you so much for joining us today, Dr. Lowy, and thank you for listening to our podcast.
Dr. Douglas Lowy (41:00):
Well, Hill and Scott, I really think that what you folks are doing is terribly important to try to become as well informed as possible about this serious epidemic that has upended everyone's life during this period. Anyway, so it's been a pleasure to be able to participate with you. Thank you.
It was a pleasure to inviting you to join our conversation.
Hill and Scott (41:31):
Thank you very much!