September 8, 2022 – Rabies is an ancient disease but there's still a lot to be learned about prevention, treatment, and the impact the disease has on global health. Dr. Kelly Diehl talks with Dr. Darryn Knobel, an epidemiologist and rabies expert, about his work on rabies in animals, the effect of rabies on human health, and his hopes for the future.
Resources:
WHO: https://www.who.int/news-room/fact-sheets/detail/rabies
Zero by 30 initiative: https://rabiesalliance.org/resource/objectives-zero-30-global-strategic-plan-end-human-deaths-dog-mediated-rabies-2030
World Organisation for Animal Health (OIE): https://www.woah.org/en/disease/rabies/
CDC: https://www.cdc.gov/rabies/index.html
A great review article with excellent graphs on human rabies in the United States from 1938-2018: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613553/
Dr. Knobel information and publications: https://veterinary.rossu.edu/about/meet-our-faculty-staff/darryn-knobel
0:00:07.9 Dr. Kelly Diehl: Welcome to Fresh Scoop, Episode 48. A Rabies update. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation, Senior Director of Science and Communication. And today we'll talk to Dr. Darryn Knobel. Dr. Knobel is Professor of Epidemiology and Population Health at Ross University School of Veterinary Medicine. Welcome Darryn.
0:00:29.7 Dr. Darryn Knobel: Thanks Kelly.
0:00:31.9 DD: Before we get started, can you tell us a bit about yourself and what ultimately led you to study rabies?
0:00:39.9 DK: Sure, I'm from South Africa, and I did my veterinary degree at the University of Pretoria, and I remember sitting in my first lecture on rabies and just being fascinated by what I was being taught and what I was learning about the disease. The fact that we still don't have a treatment for this disease, the fact that even though it's one of the oldest described diseases of both humans and dogs, we're no closer to a treatment for the disease than we were thousands of years ago. And I was always fascinated also by the way the virus works, this entity that can essentially hijack the brain, change the behavior of the host in a way that facilitates its spread, as the host in many cases is becoming more aggressive, more likely to bite, the virus is also in the salivary glands and ready to move into a new host, and the fact that, unlike a lot of infectious diseases, it almost always kills the host once it reaches that point, so it's a really diabolical kind of disease, and as I said, I've been fascinated about it since learning about it, that very first lecture, and I've really devoted my research career into trying to learn more about the virus.
0:02:03.0 DD: Yeah, it's a really peculiar virus, and I wanted to talk with you because I was actually having a conversation with some folks about our interview today, and I think a lot of veterinarians would talk about how they have trouble sometimes discussing rabies with folks in North America, because we have a very skewed perspective on rabies in this country. But we have people who listen from around the world, but can you talk a little bit about rabies and also about rabies’ significance globally, which I think we just don't have a sense of in this country.
0:02:42.2 DK: Sure, yeah, I agree. As we were chatting about before we started recording, I'm actually a visiting professor at the moment here in Northern Colorado, in Fort Collins at Colorado State University and then... Same sort of thing when I tell people what I'm working on, that I work on rabies. I often get the response of, is that still an issue? Is that still a concern? Because here, I think in North America, as you said, there's maybe one or two cases every year of people who have maybe been exposed to bats, and it's almost thought of as a forgotten disease, but the reality is in the rest of the world it's still a danger. And it's an every day danger in a lot of people's lives. We estimate that probably about 60,000 people still die every year on average from dog transmitted rabies. So, in the rest of the world, it's really a virus that affects dogs. It's probably unrecognized as a cause of health issues in dogs. Just in the number of dogs that probably die as a result of the disease either directly or indirectly.
0:03:50.0 DK: It's probably in the millions. Reliable estimates would probably put it in the millions. Dogs that either die from the virus, killed because they have the virus, killed because they are suspected of carrying the virus, or even killed just out of fear that they might be spreading the virus or have been in contact with dogs who do have the virus. So, it's a real issue for animal health and welfare, and of course it's a public health issue and mainly in resource poor communities in parts of the world where there's not a lot of veterinary care for dogs and there's not a lot of easy access to medical care for people who have maybe been bitten by dogs. So, it's still a major issue in these other parts of the world.
0:04:33.0 DD: And I was going to... I may ask you to expand on that. I don't want to put you on the spot, but can you give us a perspective of maybe the human cost as far as how many people globally die of the disease every year?
0:04:49.4 DK: Sure, so in terms of actual numbers of deaths, we estimate. It's very difficult to actually get accurate numbers because the disease is almost certainly under-reported officially. We've learnt, in my experience, a lot of people actually, even though those who do go to hospital and do get a diagnosis of rabies, often don't die in the hospital there, they often go home and die at home for various reasons, and I've heard... I was on a recent trip to India, and one of the things I'd heard, which really shocked me, but when you think about it, it's a reality, a lot of these patients don't have a lot of resources. So even just to get to a hospital is difficult for them. The patients who then are diagnosed with rabies and essentially told that the prognosis is hopeless, they're often also told, or the family are told, just to take the patient home, and for the patient to die at home because it is more difficult and more expensive to transport a body in a casket, back to the village for burial or whatever the case may be. So, they'll often take the patient while the patient is still alive and they'll die at home, and then those cases often not recorded as official rabies deaths.
0:06:00.5 DK: So, there's a lot of reason to believe the disease is under-reported. So, a lot of our estimates are based on modeling assumptions based on the number of dog bites, the availability of post-exposure prophylaxis in those cases. And so, we do estimate about 60,000 people every year, on average, might die from the disease, and that's just dog transmitted rabies that doesn't include bat-transmitted rabies.
0:06:27.8 DD: And I think that before we leave the human aspect of it, I think people... That's a shocking number, and I think you said it, it sounds like in a lot of... We take it for granted, maybe if we had exposure here in the United States, we can go and get a post-exposure series, it sounds like that's just not available to people globally. Is that correct?
0:06:54.8 DK: There's a big push to make it more available, there's a big push to get more investment in provision of post-exposure prophylaxis, but yeah, I think the reality at the moment is that it can still be challenging for a lot of patients to get access to timely post-exposure prophylaxis, because it also time matters in those circumstances, so it is something that people are working on, but there's a big push now also in parallel with that, to really focus on vaccination of dogs as one of the main ways of really preventing human exposure, and of course that has other benefits to animal health as well.
0:07:38.0 DD: Do you... Again, last question that I hope I'm not putting you on the spot for... It's a North American question. I probably knew this once in vet school, but what... Can you give everyone here a sense of... because rabies was a big problem, right? I have grandparents who can remember, rabies was scary, what... Maybe the magnitude of difference between when rabies vaccine became very common for dogs, what happened to rabies in dogs and people in... Let's say in North America?
0:08:11.8 DK: Yeah, I mean, North America, and the USA in particular, actually managed to eliminate the canine strain of rabies through vaccination of dogs, and that's really shown us how we have the tools to control this disease, it's just a question of the resources to vaccinate enough dogs and maintain the vaccination coverage in dogs, and if you look at the graphs, the number of human deaths really fell dramatically over that period of time as these vaccines were being used more and more commonly in the dog population, and as the legislation really required people to be vaccinating their dogs and so it has a dramatic impact, coupled also with proper post-exposure prophylaxis, but really one of the mainstays of rabies control, because there is no treatment, that kind of prevention is so critical and really focusing on vaccination of domestic dog populations.
0:09:15.1 DD: So, is it sort of a model, it sounds like we have done the experiment here in North America?
0:09:21.8 DK: Yeah, absolutely, and I think now South America has really replicated that to a large extent. I know Mexico was also declared free of canine rabies recently, and we are seeing huge reductions as a result of mass dog vaccination in other countries in Latin America and South America. So, it is certainly a possibility. I think it's a question of political will, it's a question of resources, and particularly for resource-constrained settings, like in many of the communities I work in, in Africa, how do we achieve that with the kind of limited resources we may have in those settings? So, it's really about how we optimally apply dog vaccination in those settings.
0:10:10.4 DD: And we're going to get... For everyone listening, we're going to talk a little bit about Darryn's work, before we get there though you... I think this is always confusing to me, it's confusing to a lot of people that rabies is not like one rabies. Right, and then we hear about it in wildlife when we hear about bats, and I used to hear about terrestrial rabies when I was in school. Can you talk about rabies is not just one virus?
0:10:38.0 DK: Sure, yeah, no problems. So, rabies is actually, it's a disease and it's a manifestation of the results of infection with a number of closely related viruses, the Lyssaviruses. The main... The archetypal Lyssavirus is rabies virus, the classical rabies virus. And so, I kind of think about it... It helps to think about a distinction between the old world and the new world. So, the new world being North and South America. There, the only Lyssavirus you have is rabies virus, and that's the only place that rabies virus is actually carried by bats, is in the new world. So, in the new world, you have only one Lyssavirus, and that's rabies virus, and that's carried by... Yes, dogs, in the absence of vaccination. Other wildlife hosts, you have raccoons, you have skunks, they tend to...
0:11:33.2 DK: Particular strains become adapted to particular host species, but it's all the same species of virus, at least in the new world. So, in the old world, the situation is somewhat more complicated. We don't have the classical rabies virus in bats, but we do have a whole bunch of other Lyssaviruses, these rabies-related viruses in bats, but what we do have is the classical rabies virus in the terrestrial hosts, mostly in wild carnivores and of course in domestic dogs, and it was really around the 1700, 1800, during the colonial period, that that rabies virus lineage really spread around the globe in the dog population, and that's known as a cosmopolitan strain of the rabies virus, but the disease itself, when we're talking about rabies, that's a disease that manifests from infection of hosts with any of those Lyssaviruses.
0:12:35.3 DD: Okay. Yeah, it's a little complicated. I find it... You probably don't, but I find it complicated because I think the terminology we just use the word rabies. Right? To mean, a lot of... And the strain thing can be a little bit interesting. Before we get to the last question, before we get to your study, and this is a little bit again off the beaten track, but you're here... Is rabies a conservation problem, and it doesn't seem to be in the United States, but is it a conservation problem for endangered species?
0:13:11.3 DK: It certainly is, particularly for small, vulnerable populations of carnivores, canids. So, populations like the Ethiopian wolf in the Ethiopian Highlands, they are really threatened by rabies that can be introduced from surrounding domestic dog populations; African wild dogs, or as they're known, painted hunting dogs, another endangered canid in Africa. We have seen these small, isolated populations in particular, large die-offs from rabies and some other diseases spread from domestic dogs as well. So yes, in certain circumstances, rabies is definitely a conservation issue.
0:13:53.2 DD: Alright, yeah, I was just wondering about it, because I will say that as a Foundation, we've done some work with distemper virus as a conservation animal threat, but I don't think we've ever done rabies beyond what you've done, which was not focused on endangered species. So, tell us about your first grant, because this was a really cool grant, because it also brought in, I think, the population... Like you went into communities and engaged them in this, so tell everyone about that grant, like the methods and what you'd measured and how it turned out.
0:14:31.8 DK: Sure. Yeah, that was a First Investigator award that I got from the Foundation, I think it was around 2010 or so, and that really helped, really established my research line in rabies, so the Foundation still holds a special place in my heart as a result of that. So, what we did, it really did focus on this question of how do we best apply or optimally apply vaccination in these kind of resource-limited settings. And in these settings, domestic dogs in Africa largely are owned, we don't tend to find large populations of unowned dogs, but there's not a lot of access to veterinary care for these dogs, certainly not affordable or accessible veterinary care that their owners can easily access. So, they tend to be free-roaming dogs, but they are provided for, they're fed, and they're looked after as best as owners can in those circumstances.
0:15:37.1 DK: So, what we were interested in is how do the population dynamics in those circumstances affect our ability to achieve the herd immunity against rabies through vaccinations, because that's really what we're trying to achieve with vaccination, mass vaccination of dogs, is about getting that critical threshold, that proportion of dogs immune to the virus that actually breaks the chain of transmission. So, we've heard about herd immunity in the context of COVID, I think people have a better understanding of what it is and what we've been trying to do. And so we wanted to understand what it would take in those circumstances, because one of the things that erodes herd immunity in those kinds of circumstances, first of all, because of the absence of veterinary services, rabies vaccination tends to happen only annually, so once a year, the government veterinary services will come in and conduct a mass vaccination campaign, and then they'll go away, and if luck and budgets and resources allow for it, they'll come back a year later.
0:16:42.7 DK: But what happens in that intervening period, those 12 months between these mass vaccination campaigns? We see herd immunity or the proportion of immune dogs declining over that period. Obviously, some of the vaccinated dogs do die, but one of the main things is the fact that reproduction is not controlled in those circumstances, there's very little opportunity for sterilization, surgical sterilization of females or males, and so we see this huge influx of susceptible puppies, non-immune puppies into the population, and so we wanted to try and understand those processes better and how those processes might interact with our ability to achieve herd immunity in these annual campaigns.
0:17:26.1 DK: And then if we take those into account, what proportion should we be aiming for in those annual campaigns that will allow the threshold to be maintained above that critical proportion in the intervening period. So essentially what we did is we followed the entire population of dogs in the community. It was about 2000 households that we followed, and we followed every household, every dog, over a period of four years to measure those death rates, measure those birth rates, and then measure migration rates of the dogs in and out of the community to really try to understand those population dynamics.
0:18:06.0 DD: And that was pretty... What did you... So, you were able to put a number on it, if I remember the papers, and talk about... And you got a good idea of the influx and efflux. Talk a little bit, because this actually dovetails with your next grant that you have right now, which is the effect of vaccination on the health of these dogs, because it was interesting beyond just rabies, right?
0:18:36.4 DK: That's right, yeah. So just to talk about some of the findings, what we were doing in that follow-up is we were going to audit... We did an initial census of the whole population of dogs in the 2000 households, and then we went back, probably about every five or six months is the best we could manage, we tried to go more frequently, but we just didn't have the resources for it. And so, during those visits, we were asking about, Okay, we were here six months ago, you had this number of dogs, what's happened to them? Any died, were any born, or did you acquire any new dogs into the population? At the same time, we were also asking about vaccination history, but we weren't validating that against vaccine certificates or anything, people tend not to keep their vaccination certificates, so we were just asking owner reports, was your dog vaccinated against rabies or not. So, first of all, overall, we did find huge mortality rates in the population, really surprising. I think nobody's really looked at in a lot of detail, particularly in the very young dogs. From...
0:19:39.6 DK: We found in a later study, we were able to put a close number on it. Half the puppies born died before six weeks of age. So, it's... It's a massive mortality rate in these, in these puppies and likely from other infectious and, and parasitic, diseases maybe compounded by malnutrition, but really huge mortality rates. But those are offset by these huge birth rates as well. So, we, see a lot of churn in the population, but not a lot of growth overall. So, the, overall numbers stayed fairly consistent. But that sort of belies this underlying, really high turnover in the population as a result of births and deaths. But even in the face of that, what we found is, is a 70% vaccination coverage, during these annual vaccinations. So, if you can vaccinate 70% of that dog population during those annual, campaigns, that should be enough, even in the face of that high turnover to maintain herd immunity, in those intervening periods.
0:20:39.2 DK: So that was one of the main findings of that, and, certainly has implications for the design of these, of these campaigns, but there was something else interesting that we, that we found in that. And this is it... It got quite interesting from an epidemiological perspective around that time. We became aware of this theory or this other body of work within vaccine research, which was talking about what is known as nonspecific effects of vaccines. And this was interesting to us. So, we wanted to look at our data, a little bit more closely to see if we could see anything along those lines. So, what are nonspecific effects of the vaccine? Obviously we know vaccines are designed to contain particular antigens that, that stimulates obviously an immune system, an immune response to those antigens.
0:21:30.6 DK: And the idea with that, being that if, the animal or the person is then exposed to those antigens, as part of the actual infection with the parasite or disease or pathogen of interest, the body will mount a very rapid and specific immune response and protect the host against the disease or infection from that. So that's the specific protective effect of a vaccine that we all know, and think about when we talk about vaccines, but what other researchers had been finding is that vaccines may have other, what they call non-specific effects, which manifest as changes in mortality rates or morbidity rates in populations that can't really be explained by that specific protective effect of the vaccine. And are these nonspecific effects, or sometimes they're called secondary vaccine effects.
0:22:29.3 DK: They can be beneficial, or in some circumstances and some subgroups, it seems they can potentially be detrimental. So, there's been a lot of research looking at the beneficial effects, and probably one of the best characterized vaccines in that respect is the, the human, the infant, BCG vaccine, which is given at birth to protect children against tuberculosis. But it's been shown that in children who receive the BCG vaccine at birth, they actually have better survival rates overall than unvaccinated children. And it seems to be that the BCG vaccine does protect against unrelated diseases, things like neonatal sepsis or viral respiratory diseases. So, it seems to have some sort of non-specific stimulatory effect on the immune system that... On the innate immune system, that actually in a sense trains the innate immune system to better respond to these other pathogens.
0:23:24.4 DK: So, the general pattern in these nonspecific effects of vaccines is that the live vaccines of which BCG is one, the measles containing vaccines are another group, some of the live oral polio or the live oral polio vaccine also, these are the vaccines that have these beneficial non-specific effects, but then there's another group of vaccines, the inactivated vaccines. So, the killed vaccines of which rabies vaccine, is actually one. So, in, children, at least in some circumstances, there is some evidence it's not well established, fairly controversial area of research still I would say, but in some circumstances, those inactivated vaccines do seem to increase mortality rates when they're introduced or when they're used. And it's very difficult to understand these effects or to do these kinds of studies in children because the vaccines are all in routine use.
0:24:30.0 DK: And there seems to be a switching of effective, depending on what your most recent vaccine was, whether it was live or inactivated, the effect sort of switches between beneficial and detrimental. So, it's very challenging to kind of study those. But long story short we decided to look at our data from that study that we did because we had the owner reported vaccination status, and we did find actually a positive association, a beneficial effect at least of... Or a beneficial association between owner reported vaccination and overall survival rates of the dogs. So it was, we thought that interesting because rabies vaccine being an inactivated vaccine, that could've been the first time that an inactivated vaccine would've been reported to have these sort of beneficial effects, but we knew the study was not optimal in the sense that the estimates were likely biased because the study hadn't really been designed to test that effect. And there are probably a couple of ways in which that those results may have been biased.
0:25:36.8 DK: One of the ways is probably owner behavior, we never accounted for owner behavior. You can imagine that owners who are getting their dogs vaccinated against rabies are maybe doing other things to improve the health and therefore overall survival of those dogs, they may just be taking better care of the dogs, better nutrition, maybe other vaccines, things like that. And we didn't measure any of that. So, there is this element of potential for uncontrolled confounding that may have explained that beneficial effect. The other thing that we think was maybe more... Resulted in a more severe bias is the fact that we were only asking about vaccination history, sort of retrospectively we'd come to the household six months later, we'd say, okay, you've got this dog, it wasn't vaccinated six months ago. It's still here. Was it vaccinated over the intervening period.
0:26:30.0 DK: And the fact that the dog was still alive and in the household legally, the dog needs to be vaccinated, so we do think there was this element of owner bias in reporting vaccination of dogs that were still alive at the time. And conversely, if a dog had died in the intervening period, they are more likely to have forgotten if it was vaccinated, maybe more likely to report it as unvaccinated. So again, just from an epidemiological perspective, it's what we would call a misclassification bias, because we're classifying the exposure based on knowledge of the outcome being survival. It is likely that dogs that survived at the time of the visit were more likely to be reported as vaccinated and dogs that had died were less likely to be reported as vaccinated. So, we were aware of these potential biases, we did discuss them in that particular publication, but we're still interested in this question because around the same time, they'd been a paper that came out from a group of human epidemiologists who actually reported that the human rabies vaccine may have had similar beneficial, non-specific effect and actually protected against unrelated infection CNS infection... central nervous system infections in children.
0:27:45.5 DK: So we wanted to explore this a little bit more in a little bit more detail, so we actually did a follow-up study in that same population, and we designed it as a randomized controlled trial but we focused in a young age group, so a group of dogs at six weeks of age, which is younger than the vaccine recommended, what the vaccine manufacturers recommend as the optimal age of first vaccination, which is three months. We focused on the six-week-old group because that was the group with very high mortality rates, and if these effects are going to manifest, they're probably going to manifest in that group for reasons I'll explain a little bit later. Also, it allowed us to have this unvaccinated control group because legally, again, all dogs needed to be vaccinated at three months of age, and also in the context of rabies control, the World Organisation for Animal Health, they recommend vaccination of dogs at any age in these annual vaccination campaigns, so it did allow us to have an unvaccinated control group for comparison, so we were able to randomly assign puppies at that age.
0:28:56.4 DK: We followed them up for seven weeks and interestingly, at the end of that study, when we looked at that data, it actually didn't support the conclusion of the previous study of the beneficial effect. Overall, the vaccine really had no effect on survival, but things got interesting when we separated it out between males and females, because we knew as part of this theory of non-specific effects, it did seem to be the sex difference between males and females. And it was actually true in our study as well, the vaccine didn't really have any effect on overall mortality in males, but for whatever reason, and we still don't really understand it, amongst females, the vaccinated group did have higher mortality rates, and that difference was statistically significant. So that really left us with a little bit of a conundrum as to what might be going on, and it certainly raised a number of questions that we're still trying to answer.
0:30:04.6 DD: Yeah so a couple of things for folks who are listening, if you've never heard of BCG it is, as Darryn mentioned, a vaccine that's given against tuberculosis, which we do not receive in the United States. And I worked at National Jewish, I did my postdoc there, and we had a whole bunch... Of course, they're big into TB. We had a whole bunch of international students, and I actually participated in a trial because we needed Americans who had never received BCG, we had a bunch of folks from Europe who had been vaccinated for BCG and Australia, I believe, and they were the other group, and they mixed, they were looking at the immune function in that, so that's something that if people have heard of that or you're like, wait, I didn't get a TB vaccine, that's why... And it has to do with, for those of us who get those little tine tests for TB, if you've been vaccinated against BCG you're going to react to that like you have TB, but you don't or just... And also, the killed versus modified live, I think we know a little bit about that vaccine because... Or that conundrum because a lot of vaccines are killed because there is a slightly higher chance of you getting the disease if you have even a modified live virus.
0:31:19.8 DD: I think people have heard a lot about that with COVID these mRNA vaccines, which is a whole different ball of wax, but if I can summarize it, it sounds... Again, the big thing with when we went to modified live or even live vaccines is you get a much more vigorous in general immune response, but of course, there's always the chance that disease is going to break through, and I can remember... I'm old enough to remember the days of modified lives rabies vaccine back in the day, and they are not that anymore, because of course, there is always the possibility you'd have a pet develop rabies. Yeah, this... I remember Darryn's paper, because we got very excited about the non-specific effects we were like, "Oh wow, great, more puppies and then the next paper came out with the female/male thing, and we're like, Oh, that's a problem, which is... I'm trying to segue gracefully into your new study with that.
0:32:17.7 DK: That's it, yes. Obviously, that finding raised a number of questions. The first one was, Okay, now, we've had this observational study and we found a beneficial effect, now we've done a randomized control trial we found what could potentially be construed as a detrimental effect in the female, so which of these is really true. Obviously, the randomized control trial was a more robust design but there is still a possibility that there might be some un-explained post-randomization factor that is influencing the results or just random chance. Obviously, one of the first things we want to do, because of the implications, there's a lot to replicate the study and replicate the finding, so we did apply and actually that component of this study is funded by the NIH under the vaccine safety study call. And we're also adding another arm to the study in trying to replicate this and understand what is going on. And obviously one of the questions it raises is if this effect is real, what is the mechanism? What might be going on here? And so, our new study is really designed to try and test a couple of hypothesis in that. One of the things to keep in mind is this effect is...
0:33:32.2 DK: It has only ever been reported in populations that suffer high burdens of infectious and parasitic diseases in general. So, we think it's likely to be an interplay between the effect of the vaccine on the host immune system, that non-specific effect and which may alter the immune response to unrelated infections or pathogens. So that... That's kind of my guiding hypothesis. And in a way, it also might explain what is the sex difference as well, why we only see the effect in females and not in males. One of the things that might be doing it in these inactivated and in these killed vaccines, because, as you said, Kelly, these killed vaccines don't generate as good an immune response as the modified live vaccines.
0:34:29.6 DK: We do tend to add adjuvants to the to the vaccine to try and enhance the immunogenicity of the antigen itself. And there is some evidence, at least in vitro studies or in some laboratory animal studies, that some of these adjuvants may alter the host immune response and actually suppress a pro-inflammatory response and shift it more towards an anti-inflammatory response. And that might be going on here. So that's one thing we do want to test. So even though the vaccine is generating a good response to the antigen itself, is it maybe pushing the immune system away from a protective, pro-inflammatory response against concurrent infections or infections that might happen a week or two down the line? So that's really the main hypothesis we want to test.
0:35:25.2 DK: So, the third arm that we're adding to the randomized controlled trial, so we'll still have the placebo group, we'll have the rabies vaccine group with a normal adjuvanted vaccine, but we're adding a non-adjuvanted rabies vaccine group to that to see if there's a difference between those two groups in terms of this potential effect. The other thing that we're going to be doing is just taking samples more regularly from these puppies to really see if we can pick up a signal in terms of the immune response and in terms of the susceptibility or the burden of these other infections, that maybe there's a lot of tickborne infections in these populations, there's a lot of other viral infections.
0:36:12.1 DK: And these puppies, unfortunately, are not getting any protection against those through other vaccines or other prophylactics that might prevent tick or flea infestations. So that's really what we're aiming at, first of all, really replicating this to see if the effect is real. And then secondly, to try and understand that mechanism of action ultimately so that we can really make recommendations about what might be going on and what we could do to mitigate this effect if it is replicated.
0:36:46.9 DD: Mm-hmm. And can you remind everyone where, this is not taking place in North America? Right. This is back in Africa.
0:36:55.4 DK: That's right. That's right. Yeah. So, the first study was done in South Africa in that same population where we did the... That initial study and the new study is actually taking place in a dog population in Kenya. So, it's an area where I did some of my postdoc and PhD research out in western Kenya. So again, a lot of dogs, low resource community. These dogs unfortunately are not getting much in the way of veterinary care other than the rabies vaccine because of the public health aspects of that. So, what we are going to be doing as part of the study is vaccinating as many dogs as we can against rabies to try and at least provide some benefit to the community. So, all of the adult dogs and all of the households that we enroll will be vaccinated against rabies. As part of this study.
0:37:46.9 DD: And based on the outcome of this, what are you thinking next? Like you would look at in... Depending whatever you think, whether it approves or disproves your working hypothesis.
0:38:01.6 DK: We're certainly keeping an open mind about what we might find. It's possible that we may find no effect. We may find no difference between the groups. I think if we do find an effect, if we do replicate that that same effect of seeing an increase in mortality in the vaccinated female group, I think it will cause us to relook at how we use the vaccine in that young age group. First of all, let's just keep in mind that this is an age group that is really younger than the manufacturer recommended age of vaccination. So, I think in the context of rabies control, we do want to be making sure we continue to vaccinate because rabies is such a dangerous disease, because there is no treatment, we really wouldn't be recommending any move away from vaccination at all.
0:38:55.1 DK: But depending on what we find in terms of the mechanism of action, maybe a use of a non-adjuvant vaccine in that very young age group, maybe if we do find it's more about the susceptibility to these other infections, then maybe concurrent vaccination with parvovirus or distemper vaccines at that same age, different doses for males and females. And we know females respond differently to vaccines. Females in general across the species tend to have better immune responses to vaccine. So, do we really need to be using the same dose in males and females? That might be something we will look at, but obviously we want to make sure that any dose that you do use is protective. So, I think there's a number of different directions it could go depending on what the outcome of this next study might be.
0:39:52.1 DD: All right. And what other projects are you working on? because I know you have a lot of other things that aren't Foundation funded. What other things are you looking at right now?
0:40:02.7 DK: Yeah. This one. So, this particular study that we've been discussing, it was delayed during the pandemic, during the COVID pandemic. So, I was thinking about other areas of research that I could contribute to in terms of rabies, and really going back to that very first lecture I've ever had on rabies that... The fact that rabies is still an untreatable disease. So learned a bit of thought to that during the pandemic, when things were on hold a little bit, and came to the conclusion that we as veterinarians could probably be doing a lot more in terms of clinical research in rabies, there's not a lot of opportunities for that in, amongst human physicians, because rabies remains quite a sporadic disease, even though it still occurs overall at a high burden, but in particular geographic areas, it still remains fairly sporadic.
0:41:00.0 DK: And physicians remain reluctant to undertake any aggressive therapeutics for rabies. We did have that one case of a patient who survived rabies as a result of that very aggressive therapy, but that protocol unfortunately was never really replicated, and so human physicians remain reluctant to undertake any kind of aggressive critical care that could keep patients alive long enough for a therapy maybe to take effect because of the cost and because of the uncertainty of the outcome, but we as veterinarians at least in a lot of these areas where I work, we do see a lot of rabies cases.
0:41:46.3 DK: Could we be doing more to learn a bit more about the pathogenesis of the disease in a way that really, obviously the ethics of this is going to be front and center. I'm not talking about prolonging the life of these animals in any way, but really sampling cases, studying cases at the point of euthanasia when with these animals are... Their suffering is ended. Can we be learning more about the disease in that by careful study of the disease, can we be learning more about potential biomarkers for early diagnosis of the disease, can we maybe identify a biomarker that would allow us to diagnose the disease even before or very early on, in the clinical onset.
0:42:27.6 DK: Biomarkers that might allow us to manage patients better and establish a prognosis in terms of potential for response to therapy, so I think we could be doing a lot more of this on the veterinary side, so we have started an initiative called the Canine Rabies Treatment Initiative. And ultimately where we want to go with this is to really talk about and challenge the notion that rabies is, and forever will be, an untreatable disease. I think we have that in our heads. Certainly, from veterinary school onwards, it was beaten into heads that rabies is untreatable, we've got to be focusing on prophylaxis and prevention, and this is not to say in any way that we should be...
0:43:11.1 DK: We should be removing the focus from vaccination and prevention, but maybe something we could be doing is looking at treatments and maybe using the case load of veterinary patients that we see, maybe we can be doing more in terms of clinical research in these animals. So, it is an area that we're exploring. As I said, the ethics will really be front and center of this in terms of what these animals might gain from participation in these kinds of studies versus, of course, any pain or suffering that they may encounter, so that's something that we're really engaging on at the moment. And then in the background, we're also looking at potential therapies for rabies, I think monoclonal antibodies really offer some hope in that regard, the challenge as always is going to be getting the treatment into the central nervous system really where it needs to encounter and then neutralize the virus.
0:44:15.6 DD: Yeah, I think it's really challenging. I don't know if our listeners are aware, we're not totally immune here in North America, right? I think there's been some discussion of, unfortunately dogs that have been rescued from other areas of the country. Right? Bringing rabies into Canada and some diseases. I think that we're vulnerable here, I have a neighbor who was unfortunate enough to get bitten by a bat on a camping trip and had to undergo post-exposure and he had got sick and turned out he had West Nile in addition to having been bitten by a bat, but it was a big resource heavy thing. We know that we've lost, we've had a couple of people at least one person, I think, die in the United States this year because they got nervous about vaccines and refused the post-exposure series, right?
0:45:09.9 DK: Yeah.
0:45:11.1 DD: And died of the disease, so I think there's a lot we still don't know. As you pointed out about this really, really ancient disease that we've learned about, and yeah, it's a really weird and interesting but scary disease. And I think that's a really interesting idea. I know that I certainly got beat in my head that there was like, "Don't even try to treat a pet." Right?
0:45:33.9 DD: And we do have a lot more medical technology at hand that we... I think you're right, we just don't use. And of course, there's... As you said, the ethics, and there's also having a rabies positive animal in your clinic would be... Is it right putting a lot of other people at risk... People at risk there. I have a question for you, that's totally off the beaten path a little bit, but for those of you who are listening, a lot of us, and especially of a certain generation, I was vaccinated against rabies. I'm sure, Darryn, you probably have been vaccinated. Has anyone ever looked at rabies in veterinarians or looked at us immunologically?
0:46:21.9 DK: So, from what perspective? Sorry I lost you.
0:46:24.0 DD: Maybe looking at our immune responses because we've been rabies vaccinated or looked at us epidemiologically for other diseases maybe.
0:46:34.1 DK: In the context of these kind of non-specific effects of vaccine. Yeah, it did occur to me, and it would be quite interesting to try and get a data set, to explore that in a little bit more detail, I don't think...
0:46:47.3 DK: There are occupational data sets as well that talk about that sort of classify causes of death or illness rates by occupation. But to my knowledge this is just sort of speaking off the top of my head. I'm not aware of any studies that have sort of been done in that... Having said that I did actually do a randomized controlled trial amongst our students at Ross because Ross is on the island of Saint Kitts which is rabies free. So, our students don't need to be vaccinated until they leave the island to go off and do their clinics in their seventh semester. So did it give us the opportunity of doing a randomized control trial when the students were in first semester and then following them over the next two years to see if there were differences.
0:47:37.2 DK: We didn't see any major difference among the females. We did get an indication of the protective effect amongst males for some common infectious disease outcomes. However, we have so few male students that we didn't have the power really in that study to confirm that that effect might be real. So, there's some evidence and I'd like to maybe try and do a larger study as long as we can recruit more male students into the study to see if that effect might be real. One of the interesting things that I forgot to mention that led us to propose this hypothesis, that it may be an adjuvant effect is that the human rabies vaccine is non-adjuvant for whatever reason. So, animal rabies vaccines are for the majority of animal rabies vaccines. So that might explain this potential effect we saw from that other study where the children were protected against these nonspecific... These other infections. So, there is a possibility on that front that there may still be a real, nonspecific protective effect of the rabies vaccine.
0:48:54.8 DD: That's... Yeah, just I was thinking about it because I was like, "Well, you kind of have this population though, the rabies vaccine... " Again I'm going to really date myself. And yesterday was my birthday and I turned 60. And when I went to vet school there was rabies, we got the preexposure series and it was a little scary. Like you had to sit in the health place for like half an hour because they were duck pass... It was duck passage. So, if you...
0:49:20.9 DK: Yeah.
0:49:22.0 DD: And but I always had heard it promoted a very vigorous response in people, but there were classmates who could not get the second or third in the series because they had a reaction. And so, I was... But it's changed obviously quite a bit from the ancient days when I was...
[chuckle]
0:49:39.7 DD: That was before the internet kids and cell phones and stuff. But yeah, it would be... I thought maybe you'd have a ready made epidemiological group to study. As we wrap up, and this has been so great, thanks so much for joining me Darryn. What's your take home message for listeners, because I think there's a lot of scary information about rabies. There's a lot of triggers about vaccines. And there's all this information, like what do you tell people?
0:50:09.9 DK: Look I don't think we've learned anything from these recent studies that could change any recommendations around rabies vaccination. Rabies is a reality, it is a lethal disease. It hasn't gone away from the United States or north America. It's lurking in the background, just waiting for us to drop our guards. So, I think it's really important that we continue to maintain vaccination coverage in our pet populations, in our dogs and cats. I think it's really important that people, veterinarians who might be exposed to the disease continue to get vaccinated and continue to check antibody titers regularly. As you say the vaccines that we have nowadays are much more effective and safer.
0:50:57.4 DK: What I would say in terms of the scientific community and those of us who are involved in vaccine research is not to shy away when we do uncover potential evidence of concern around the use of vaccines. When we say vaccines are safe, really what we are saying that short term the benefits of receiving vaccine far outweigh the risks. We know nothing in life is risk free. They're always adverse events associated with the vaccines. Normally they are fairly minor, but I think we... It is incumbent on us to investigate these concerns thoroughly if we are to maintain public trust in... Or confidence in vaccines and more generally public trust in science, I think we have to have these kinds of conversations. And I think the public... The listeners need to see us as scientists kind of grappling with these issues and investigating them as thoroughly as we can to their conclusion, whatever they may be.
0:52:03.8 DD: And also, I want to put in a plug, we are recording this in July but you guys are going to be listening to this in September, which is always world rabies month. There's a lot of different... I don't know, activities surrounding the WHO the World Health Organization. I think it's 2030, right? That they want to eliminate human death...
0:52:29.1 DK: Elimination of human... Yeah. Human deaths from dog mediated rabies.
0:52:31.8 DD: Rabies. And it's an ambitious goal, but it's certainly something we can achieve. And there's some great information at the WHO website and there's going to be tons during the month of September. They always have really great information and we'll link to it in the podcast. And we will also link to some of Darryn's work with the Foundation. And I... Again, I really appreciate him jumping on here. I can honestly say he's our only rabies researcher right now.
[chuckle]
0:52:58.5 DD: And probably the only one we funded as since the very early days of the foundation, which is 75 years ago where I do see some rabies studies cropping up. But as Darryn mentioned, that's about the time that people really started vaccinating dogs in this country. So, we don't have... For those of us also old enough to remember Old Yeller and To Kill a Mockingbird where a rabid dog plays a central role in one portion of that movie and books, if you haven't ever read it. That's like a thing in the past. And even when I was a kid in the '70s. We didn't worry as much about our pets anymore, but I certainly had grandparents who worried, and it was ever present danger. And I think Darryn reminded us it is still an ever-present danger for those of us and it's a terrible disease.
0:53:47.1 DD: So again, that was it for this episode. And as I mentioned, thanks for Dr. Darryn Knobel for joining us from just up the road. It would've been lovely if you had like the beach at Saint Kitts in your background [laughter] instead of hot old Fort Collins. But we'll be back of course, next month with another episode that we hope you'll find just as informative, because as we discussed today, the science of animal health is ever changing. And sometimes not so changing. If we think about rabies and some diseases that have been around a long time and as veterinarians and pet owners, we need cutting edge research to give our patients and our pets the best care.
0:54:29.1 DD: And that's why we're here. You can find us on iTunes, Spotify, Google podcast and Stitcher. And if you like today's episode please, we'd sure appreciate it if you could take a moment to rate us because we're actually doing well as far as veterinary podcasts go, but we'd love to do better. And that will help folks find our podcast. To learn more about Morris Animal Foundation's work of course, go to morrisanimalfoundation.org, and there you'll see just how we bridge science and resources to advance the health of animals. And you can also follow us on Facebook, Twitter and Instagram and I'm Dr. Kelly Diehl. And we'll talk soon.
