Louis Pasteur special edition: Rabies

Louis Pasteur was involved in the creation of the first rabies vaccine in the 1880s, but today one person every ten minutes still dies from rabies, with all of the deaths concentrated in low and middle-income countries. Prof. Katie Hampson joins Gavin and Jessamy to talk about the history of the vaccine and why it's proven so difficult to eliminate rabies.

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Transcript

This transcript was automatically generated using speech recognition technology and may differ from the original audio. In citing or otherwise referring to the contents of this podcast, please ensure that you are quoting the recorded audio rather than this transcript.

Jessamy: Hello and welcome to The Lancet Voice. I'm Jessamy Bagenal. It's December 2022 and I'm here with my co host Gavin Cleaver. We're releasing this episode timed with a special theme issue celebrating the birth of Louis Pasteur, the French scientist whose germ theory of disease laid the foundation for hygiene and sanitation within public and global health, among many other contributions to science.

He also developed the first rabies vaccine in 1885. Today we speak with Katie Hampson, Professor of Disease Ecology and Public Health at Glasgow University about rabies, an ancient and infamous disease that continues to be a significant source of mortality and morbidity in many low and middle income countries, despite us having the necessary tools to combat it.

We hope you enjoy the conversation and engage with written comments, viewpoints, and research in this special issue. As always, you can find us on our Twitter handles. At Jessamy Baganel and at Gavin Cleaver.

Okay, so we're here because we are talking about the 200 year anniversary of Pastor Az. He obviously discovered the vaccine for rabies. You've got a very interesting background and we thought you might be able to give us an interesting perspective on where we are with rabies now. So maybe you could just start telling us a little bit about your background and your interest in rabies.

Katie: Yeah, so I'm actually an ecologist by background and I started to get interested in rabies during my PhD when I was initially invited to a project and I was based in Northern Tanzania. near to Serengeti National Park. And the project was trying to look at the transmission or the risks of transmission between wildlife, domestic animals, and people.

And rabies was one of the diseases that was being considered, but it turned out on arrival and having spoken to People in different communities, there was actually a, a rabies outbreak ongoing. And I was really quite shocked at the issues that bite victims were facing in trying to get post exposure vaccination after being bitten by rabid dogs.

And I also could see that it was possible to track how these rabid dogs were moving through the people they had bitten and the animals they were bitten. And that's really where everything, my involvement in rabies started. 

Jessamy: It's interesting, isn't it? It is a fascinating disease. Could you maybe just tell us a little bit about when rabies was first discovered and, you know, when the vaccine was created and what type of vaccine it is?

Katie: Because rabies is such a clinically distinctive disease, we actually rarely have records that we can identify as being rabies from. Thousands of years ago, sort of ancient texts from Mesopotamia about 4, 000 years ago, actually give descriptions which are clearly associated with Rabbit dog. But as much as we think of it as being a really ancient disease, it's also a disease that has been somewhat self-contained in certain geographical locations because of barriers like mountain ranges and the sea and so on.

So the virus that kills thousands of people around the world today, much of it can be traced back through. The spread of empire, and you can see colonizers reaching Southern Africa, Southeast Asia, Latin America, and the Caribbean all brought with them. Incubating rabbit dogs and we've seen those epidemics really spread over the last one, 200 years.

You, you also asked about the vaccine. Sorry. So yeah, this is really interesting. So it was in the late 1800s. There were, there were a few different scientists who were kind of experimenting on whether you could develop vaccines by attenuating the virus and they passaged the virus in nerve tissues in rabbits.

And then there's this infamous experiment, Last Resort, where a young boy was vaccinated for the first time using this experimental vaccine. And he, this is Joseph Meister, and he did not develop rabies following his exposure. And since that time, that vaccine has proved to be remarkably effective in preventing people from getting rabies following a bite.

And it's not just that that vaccine was effective in humans for prevention following a bite, but also the same process was used to develop vaccines that and prevent transmission in domestic dogs, which are the primary reservoir today in most parts of the world. And the vaccines at that time, it was produced in a very difficult way.

And it's why the, the Pasteur Institute became into being and people were coming from far, far away to access the vaccine at this particular clinic. But now the process of vaccine production has improved dramatically. Those nerve tissue, original nerve tissue vaccines were sometimes associated with very serious side effects.

But today, Modern shell culture vaccines, they're 100 percent safe and basically 100 percent effective. And the first time those vaccines were used at scale in animals was in the very early 20th century in Japan, where they had dog vaccination campaigns that were super effective. 

Jessamy: Interesting. And I suppose we should say that the, the discovery of the rabies vaccine and Pasteur himself doesn't, isn't without controversy.

And, you know, the sort of way that he approached it, the ethics, the research integrity is not of the standard that we would expect now. 

Katie: Yeah, that's, that's absolutely true. But at the same time it was kind of a last, a last chance resort. And it's true that even today, if someone has been bitten by a rabid animal, and they've, once they show symptoms, There is nothing that can be done apart from palliative care.

So whilst we might be concerned about, well, we might recognize the inadequacies of the early vaccine development, actually it's been a hugely life saving intervention. 

Jessamy: Maybe you could just give us an update on where we are globally now about with the sort of epidemiology. What's the situation?

Katie: Around the world, we, we think that one person dies of rabies. Roughly every 10 minutes. So we think there's around 60, 000 human rabies deaths every year. And those deaths are basically happening in places where people have dogs, but there is no dog vaccination. So we have had the same situation of rabies endemic in different countries across the global North throughout the last century or so, but we've effectively got rid of it.

And so now those deaths are occurring exclusively. in low income countries. And if you if you don't mind, I can try and elaborate more on what I mean in terms of the statistics, because one person every 10 minutes is, it doesn't sound good, but it's kind of hard to relate to. So if I was to take myself to East Africa, which is where I've done most work and was to think about a pretty standard rural community, where I'd work and a school of a similar size to where my, where my kids go to in Glasgow in Scotland, where there's maybe seven or 800 kids in the school.

Essentially in a school like that, you would expect every year to get three or four people bitten by rabid dogs and in need, urgently getting one of these life saving post exposure vaccinations. And every two, maybe three years, one, person in that community would die of rabies. So it's not huge, huge numbers in the way that we might think about malaria and so on, but it means that in every small village community, they've been touched by, they know someone in their community who has died of rabies.

And if there's any way that you do not want to die, it's from rabies. It's a really traumatic, terrifying disease. And it's because of that, that it's associated with so much trauma and so much anxiety. And this is happening all the time and in rural communities in low income countries, we don't have these deaths for all of this century and many decades previously in high income countries because we know that vaccination programs work and we don't accept those kind of things in our communities.

Jessamy: So there's huge inequity and inequality there, which is It's devastating. 

Katie: Yeah. And I think, you know, this comes down to two different elements. There is of course, post exposure vaccination, and this is the, the Vaccines that Pasteur developed, and if you get immediately post exposure prophylaxis, you're essentially protected from going on to develop the disease.

But in these kinds of areas in certainly in sub Saharan Africa, usually it's district hospitals, but maybe only in large cities that will stock these vaccines that almost inevitably sold at a high price. So maybe 20 to 30 for a vial of vaccine and you need to take a multi dose course. It used to be done over many weeks, but now it can actually be completed in a week's time using fractionated vials.

I mean, the modern approach to post exposure vaccination is much better. It's efficient and cost effective. But the problem is the people who need these vaccines still have to pay a very high price. And for many of them, they may not make that choice to seek out the vaccine. And even if they seek it out, they might get to the clinic and find it's either out of stock or they can't afford it.

and most governments in the world. Certainly in Sub Saharan Africa, do not provide it for free because it's somewhat rarely and unpredictably used. So it's probably makes more sense then to invest in cheap medicines that people will buy and that will solve many other important problems. But it really is inequity and access to a really emergency life saving vaccine.

Jessamy: In this context, what does elimination look like for rabies? Because there's, you know, for, for different diseases, sometimes you hear, 

Katie: I 

Jessamy: think it's going to be gone completely, but actually it means, you know, under 30 cases a year or something like that. Yeah, exactly. What does it look like in this context?

I've got to say just now, 

Gavin: I feel like every time we ask an expert what elimination looks like in their field, they always break out in a big smile. Such an intense question that kind of differs so much across different fields and so controversial. 

Katie: Absolutely. It's, it's very, we think about it in a very semantic way but the semantics become super important.

There's multiple definitions, but elimination. As a public health problem would be the first step and that would mean that nobody dies of rabies, which in theory, if you can make sure everyone has access to the vaccines post exposure, you, you should be able to achieve that overnight. But as I mentioned, people don't always have access to the vaccines and don't seek it out.

We can vaccinate dogs and eliminate the source of transmission. the way that we vaccinate children to eliminate and interrupt transmission of diseases like measles. And that is what we have done in high income countries. So you do mass vaccination across large areas for extended number of years and slowly break the chains of transmission until there's no more virus circulating in these populations.

And that's really what we want to achieve with elimination. One is achieved primarily through dog vaccines and another through post exposure vaccines. And you really have to have the two of them working together because dog vaccination is going to take time to implement. It won't happen overnight. And during this time, when radiance is still circulating in domestic dogs, there will be people who are bitten and they still need those urgent life saving post exposure vaccines.

And There's a, there's a similar kind of equity argument in that, sure, we can try and make these post exposure vaccines available for everyone who needs them. But if you only did that, it's like saying we accept there are rabid dogs running around in the community who might bite our children and, you know, you have this window of time to get someone vaccinated.

It's pretty scary and they get some pretty horrific injuries. Personally, I think. The approach is this joint approach, and if we only focus on the human vaccines, we're going to have a problem that just, just escalates and we never get to the source of the problem. And contrary to some misperceptions, you really can interrupt transmission.

In domestic dogs, and there will be a few places around the world where there's some other reservoirs and you might have certain lists of viruses circulating in bats, but they are largely self contained, and they are not the cause of people being bitten and dying from rabies in 99. 999 percent of cases around the world today.

Jessamy: And is that approach, because there's an endorsed sort of framework to try and get to elimination by 2030, by the sort of tripartite. Sort of organization is, is that the approach that is the sort of endorsed and agreed approach or is that, is it that plus other things? Yeah, 

Katie: no, it's, it's absolutely this joint approach you have improving access to human rabies vaccines, scaling up mass dog vaccination areas around the world where it basically doesn't exist at a scale today.

You also need to be able to see your target. So you need to strengthen your surveillance, be able to detect cases, to be able to say where your vaccination programs and your access to care are working and where it's not working and where it needs strengthening. And of course, all of that requires sensitization in affected communities, sensitization and building of relationships and skills to deliver these different interventions collectively, and I think that whole community, whole intersectoral joined up approach is actually what makes it the hardest thing to do, because you can't, you can't just do one thing on its own.

Jessamy: And so is it quite hard to sell to government? Is that the sort of, or to get buy in, to get buy in from people? It 

Katie: is in a, in a kind of a strange way. So people who've experienced rabies, they know how awful it is. And they're usually very bought into it, but the people who suffer from rabies, the communities that are hit tend to be remote communities without a vocal voice.

And in most, in most low income countries, when you're asked to prioritize zoonotic diseases, so diseases that spread from animals to people. Rabies is almost always top of the list, but the question is whose responsibility is it? And almost inevitably ministries of health will say, well, it's an animal problem.

So we shouldn't be dealing with it. And we're dealing with a post exposure proplexus anyway. But ministries of livestock, ministries of agriculture, their budgets are largely for trade. So for livestock trade, for food security. And dogs are not seen as a source of money, you know, and inevitably the animal sector has very small budgets compared to the health sector.

And so even though investing in animal vaccination in the long term is likely to really bring down costs for the human health sector, the budgets are not allocated in a way. And many of the budgets for health in low and middle income countries where AIDS is such a problem. Are also very dictated by global health priorities.

And for reasons that I can go into, rabies just does not really appear on that agenda. And maybe I can just, you know, people ask why diseases certain diseases get neglected. Like everyone knows rabies, everyone knows it's pretty scary, there's zombie films and vampires and so on. And it's, you know, it's got a very distinctive and charismatic thing, but for the most part, people in high income countries don't think it's a problem anymore because it hasn't been for decades.

You could argue on multiple lines of evidence why we should invest in rabies. One is because it's all about equity. You know, the high, the high income countries have access to the vaccines and it's. It's really inequitable that poor people are dying in poor countries because they don't have access to vaccines that they really, really should do.

There's also a technical argument. Rabies elimination is cheap. It's really, it's cheap to vaccinate dogs. When you give post exposure prophylaxis to someone who's been bitten by a rabid dog, if they didn't get that vaccine, there's a one in five chance that they would Start developing rabies and then they're, they're bound to die.

So the economics are cheap as well. So there's an equity argument, there's a technical argument, and then there's the health security argument. Like we're, we're all talking about One Health and what we need to do to stop the emergence of zoonotic diseases, scary diseases. We all know about those, but how do you get the animal health sector and the health sector to work together to investigate?

outbreaks in rural areas of fatal diseases and get them to go, stop them from being ignored before they become a much bigger problem. Literally that is what we do when we work on rabies. We investigate outbreaks. The health sector, in theory, will let the animal sector know if they've got a suspicious rabid dog, they will investigate it.

When that works well, it really builds. a level of intersectoral working and trust and relationship. Those outbreaks are happening everywhere in low and middle income countries where there are dog rabies, but yet the global health security approach has largely been about thinking about what might seem like a hypothetical disease.

Now, of course, we've all experienced this in real life, but how do you build that kind of relationship and that trust when you are trying to. Do a stimulation exercise and, and some international agencies have invested money into investigating these diseases, which it does make total sense. I mean, I, I certainly think it's important to do that, but I think rabies is a real opportunity to build that capacity.

And we've seen how that capacity when it's built. I mean, that's how countries who have been dealing with Ebola. Have been in many ways prepared at some level investigate these kinds of outbreaks. 

Gavin: Are there any other diseases that kind of fall into this trap that you've talked about where there's kind of a, this differentiation in, in government departments about who's responsible for it, you know, in terms of cannabinoid acid one.

Katie: Absolutely. Absolutely. I mean, rabies is a particularly prime example, but things like Nipah virus things like anthrax, things like plague. These all involve diseases that initially will start with, when we see them, it's human exposure to a very serious pathogen, but you can typically trace them back.

And the question becomes, whose responsibility is it to deal with them? Can we build the capacity to deal with them before they become more serious? And I think that the, the unfortunate feature of rabies, that means it gets neglected, but I would argue is all the more why we should be focusing on it, is because the global North is not worried about rabies crossing its borders because it doesn't tend to travel by air.

That said, Australia is pretty worried about it. And you can watch this clockwork spread of dog mediated rabies across Indonesia heading towards the Northern Australian coastline. But so far, Europe is not so worried about it, North America, less so. It's a real tragedy. It's a, it's means that the hard to reach people, as we tend to call them, are actually the ones that are easy for us to ignore.

But they shouldn't be. That's where we should be building capacity and so on. 

Gavin: Are there any other major barriers as you see them to, to rabies elimination? 

Katie: So most of the barriers, I think not so much technical. It's about investment and time and energy into the problem, but there's an enormous number of areas where we could really strengthen rabies control and elimination, for instance.

During the pandemic, rapid diagnostic tests have gone from being something that people were not very clear about to being a very valuable tool. The kind of arguments that people have discussed about rapid diagnostic tests for use in COVID are Very much the same kind of arguments that have been discussed in the rabies community.

There's obviously serious concerns about any diagnostic test for rabies, because it's a fatal disease. You absolutely wouldn't be making decisions about whether to give life saving vaccines to people on the basis of a test if you're not sure it's 100 percent sensitive. But, that said, rapid tests can be used in remote areas where there is no laboratory access, or if there is laboratory access, it's a long way away.

So, I would like to see there be improvements in the quality of rapid diagnostic tests, the regulation of rapid diagnostic tests and the access to them, so they could be used in a pragmatic way to help us understand the scale of the problem and whether we're getting rid of it. And the same kind of lessons.

From the pandemic apply to genomic surveillance of rabies. Many of the approaches are directly transferable and similarly, the quality of the dog vaccines. There's really good regulation of human rabies vaccines on the whole. We really wouldn't want to see life saving emergency vaccines have poor quality and fail for human rabies.

Yet the same kind of standards are not really in place for dog vaccines. There are very, really good dog rabies vaccines, but we need to make sure high quality vaccines are affordable and accessible at scale. So there's, there are technical. technical improvements that really couldn't be made and regulatory improvements and capacity building.

But at the moment, the, the biggest barrier I think is that we haven't seen this scale up of the interventions are really. And maybe I can just mention one other real opportunity for rabies that I'm a bit tentative about. So back in 2018, after 10 years of sort of gathering evidence and processing, Gavi decided that they would invest in human rabies vaccines, which was kind of monumental for rabies.

Or a monumental prospect because there's never been investment in human, there's never been investment in rabies that would be on the scale of Gavi. The really exciting prospect with Gavi would be that Gavi investment in human vaccines could catalyze countries to actually act on the dog rabies problem.

Because Gavi surely don't want to be vaccinating people forevermore. Or paying for these vaccines forever more, but the, the, the kind of the strategic outcome would be that countries that are supported to have reaccess, better access to these really valuable human rabies vaccines. Also demonstrating that they are committing towards scaling up and building up the capacity for this joined up One Health approach, where you'd ultimately have an end goal inside insight that's totally achievable, but without some kind of spur and investment like Gabby, that's kind of the, the stumbling block at the moment, and I think COVID has obviously.

put a barrier in front of all these different infectious disease or all sorts of health programs around the world. But GAVI investment has been delayed and now we're holding our breath.

Gavin: That's it for this episode of the Lancet Voice. If you want to carry on the conversation you can find Jessamy and I on Twitter on our handles at Gavin Cleaver and at Jessamy Bargainal. You can subscribe to The Lancet Voice, if you're not already, wherever you usually get your podcasts. And if you're a specialist in a particular field, why not check out our In Conversation With series of podcasts, tied to each of The Lancet's specialty journals, where we look in depth at one new article per month.

Thanks so much for listening, and we'll see you again next time.