#89 Vaccines: Making History

Dr. Derrick Rossi, stem cell biologist, retired professor, co-founder of Moderna and Intellia Theraputics, and CEO of Convelo Therapeutics


January 27, 2021

Vaccine technology has come a long way in terms of safety and understanding the underlying immunological principles. The first vaccine that was made was against smallpox in the late 18th century. Since then, vaccines have become the key tool in fighting against infectious diseases that have affected humans for centuries, including chickenpox, measles, and polio. But as the world prepares for the largest mass vaccination campaign in history with the COVID19 vaccines, there are many people that are somewhat hesitant about the vaccination process but are curious to learn more. The emergence of mRNA vaccines has allowed for the fastest development of a vaccine in history and could be a sign of what's to come in the future. In this episode, we talk about the COVID19 mRNA vaccine with the co-founder of Moderna, Dr. Derrick Rossi and about how mRNA can be used in personalized cancer vaccines with Providence Therapeutics' Chief Development officer, Dr. Natalia Martin Orozco. We look back at the history of vaccine development with Dr. Christopher Rutty. Finally, We also speak with Dr. Nicole Charles to explore the complexity of vaccine hesitancy in marginalized communities.

Written by: Yagnesh Ladumor

Connaught Labs at UofT
History of Vaccination virtual exhibit
Dr. Charles' book - Suspicion. Vaccines, Hesitancy, and the Affective Politics of Protection in Barbados
Seminal paper from the Rossi Lab about Modified RNAs
Providence Therapeutics

Jenna Park [0:00] Before we begin, we would like to acknowledge that Toronto was founded on the traditional territory of many indigenous nations including the Mississaugas, the Anishinaabe, the Chippewa, the Haudenosaunee, and the Huron-Wendat. This meeting place is still home to many First Nations, Inuit, and Metis peoples, and we are grateful for the opportunity to live and work on this land. As we explore stories of medical science, we also ask our listeners to learn about and reflect on the long history of science and medicine as tools of oppression against indigenous peoples and the complex perceptions of and barriers to healthcare that are still experienced by indigenous peoples in Canada today.

CNBC Television [0:38] The FDA moments ago approved Moderna's vaccine for emergency use. This clears the way for the rollout across the country to begin, Health Canada

Global News [0:48] has given the green light to a second vaccine. The federal agency says its review found the Moderna vaccine to be both safe and effective. According to Madonna, the first dose could arrive in Canada by Christmas Day.

Jenna Park [1:03] vaccine technology has come a long way in terms of safety and understanding the underlying immunological principles. The first vaccine that was made was against smallpox in the late 18th century. Since then, vaccines have become the key tool in fighting against infectious diseases that have affected humans for centuries, including chicken pox, measles and polio. But as the world prepares for the largest mass vaccination campaign in history with the COVID-19 vaccine, there are many people that are somewhat hesitant about the vaccination process, but are curious to learn more.

Tsukiko Miyata [1:34] The emergence of mRNA vaccines has allowed for the fastest development of a vaccine in history and could be a sign of what's to come in the future. In this episode, we hope to explore and address some of the common concerns about vaccines by taking a deeper look into the history and future of the vaccine technology and development. I'm Tsukiko. And I'm Jenna.

Jenna Park [1:57] Welcome to Episode 89 of Raw Talk Podcast.

Dr. Natalia Martin Orozco [2:15] mRNA is messenger ribonucleic acid and mRNA vaccine is composed of the mRNA and lipid nanoparticle that encapsulates this mRNA. for delivery, the mRNA encodes for an antigen for the vaccine, in this case would be the spike protein of SARS-CoV-2, this mRNA contain certain elements that allow it to be stable for it to produce enough protein inside itself. So the way it works is at the moment that you get immunized in the arm. It's an intramuscular vaccine, the lipid nanoparticles fuses with the membrane, the cellular membrane, and the endosomes and delivers the mRNA into the cytosol. Once the mRNA reaches the cytosol, then it incorporates into the protein synthesis machinery of the cells to produce the spike protein and expresses the spike protein at the surface of the cell, the presence of the spike protein in the cell induces antibody response, and also induces a T cell response. This means that these antibodies are going to prevent the entrance of the virus into the cells. And that's why they're called neutralizing antibodies. And by the time you get a few weeks later, the second immunization, this expands the number of T cells and amplifies the amount of antibodies circulating in the body, such that in the event that you encounter SARS-CoV-2 either at a party or a supermarket, or in any situation, your body has already an army of antibodies, and T cells to prevent you from getting the disease. When you were a baby, you got vaccinated against polio and against these other infectious diseases. And of course, we don't remember that because we were all babies, right. But what happens is that created a memory response in your immune system that last until now, such that if you get close to polio, you won't keep the disease so that second immunization is very important not only to enhance the amount of antibodies to protect you, but to create that memory response in your immune system. More we help the immune system by boosting by exposing to the antigen, the better chance we have to create that memory response.

Tsukiko Miyata [4:38] One of the frontrunners in the COVID-19 vaccine race has been the mRNA-based vaccine made by Madonna. Next we spoke with Dr. Derrick Rossi, a stem cell biologist and entrepreneur who co-founded Moderna over 10 years ago while working on something completely different. Could you tell us the story behind founding Moderna?What was its focus or projects prior to the pandemic last year?

Dr. Derrick Rossi [5:05] So the founding of the doderna originally was in 2010, we were doing a project in the lab that was actually kind of a side project inspired by a study by a Japanese researcher, Shinya Yamanaka, who converted human fibroblasts skin cells into an embryonic stem cell like state something called induced pluripotent stem cells. So we started to work on this with the idea of trying to make these iPS cells without using or without affecting any type of genome modifications. So when Yamanaka first did it, he used retroviruses, which integrate into the DNA and become, you know, a permanent part of the DNA from that point forward. And that was not going to be very good for therapeutic translation. So many in the field, we're trying to think of ways to make integration free iPS cells, Our idea was to use mRNA, rather than any type of DNA based factor with the idea that mRNA is transient, it doesn't integrate with the genome took us a while to develop the technology. And really integral part of it was that when we first started introducing mRNA into cells, the cells would respond with a very adverse, robust, antiviral response, because we were introducing nucleic acid, which to the cell looked like a viral infection. And so the cells and our dishes were basically not happy about having introduced nucleic acid. And we ended up killing most cells in the dish, which is, of course, not what we wanted to do. So that could have been the end of the story.

Tsukiko Miyata [11:20] So what are some differences between traditional vaccines compared to the mRNA based vaccines?

Dr. Derrick Rossi [11:27] All vaccines work on the basic principle that you introduce something that's foreign to the body, and the cells immune system recognizes it as foreign, and mounts an immune response to foreign antigens, be, you know proteins or stretches of glycoproteins or, you know, typically capsid proteins and the virus. So that is always true of all vaccinations, the idea is to introduce something foreign that the body hasn't seen before. And our bodies are very good at surveilling constantly on surveillance for what is self that you don't respond to versus non-self, which you respond to, typically, in the past had been, you know, inactivated viruses. So you just take the whole virus, you inactivate it so that it's non infectious. And then you introduce that, which is nice, because you get a polyclonal response to, you know, various parts of the virus. Again, your body takes over and does what it does when it sees foreign antigens, it mounts an immune response, which involves T cells and B cells and B cell production for neutralizing antibodies, for example, in the case of an mRNA vaccine, the mRNA is actually encoding just not the whole of the virus, just one part of the virus, it's something called the spike protein, which is on the surface of the virus, because the spike protein is what interacts on the human cell with a receptor called the ACE2 receptor. And that initiates the sort of infectious cycle, the virus has to attach to the human cell to eventually to initiate infection and then inject its nucleic acid into the cell to begin the viral replication process. So it was known already that spike proteins, this is what they do, they land on human cell surface receptors. So it was an obvious target to make a vaccine against the spike protein. And so the mRNA vaccine, it does just that, it encodes the spike protein, when the mRNA goes into the cell and is now the vaccine is basically an mRNA encoding the spike protein. That's what the vaccine is, when it gets introduced into the cell, the mRNA gets into the cell, as I told you earlier, it doesn't elicit an immune response anymore, because it's got these modified nucleosides. And it does what all mRNAs do, it goes to the ribosome, and it encodes the protein that it's carrying the information for, in this case, it's the spike protein, and then the spike protein is made within the factory, the protein factory of the human cell. And it's either broken down or presented on the cell surface by cell types called antigen presenting cells, which then initiate this immune response, which is the same of every vaccine that you've ever got. When you now go out into the grocery store or the post office or wherever you're going to encounter the live vaccine. Now your immune system is primed, because it's been vaccinated and it's got an immune memory. It says, hey, I've seen this spike protein before and I have neutralizing antibodies for this already. And I can mount a very efficient immune response to blunt the infection very early so that the person doesn't get sick. And indeed, this is what the clinical trials show they're overwhelmingly effective, extremely effective at preventing people from getting SARS-CoV-2 viral infections, very, very effective at preventing anybody from getting sick and also effective at making sure that people don't die from this virulent virus.

Tsukiko Miyata [15:04] What are some advantages of mRNA vaccines over traditional vaccines?

Dr. Derrick Rossi [15:10] Well, the main thing is speed. Typically, vaccines are developed over the course of many years. And you either use a virus that's been inactivated or viral antigens. And I can just tell you and anybody out there on your podcast listening, if you know what the sequence is synthesizing nucleic acid is very easy. And it's very fast. For example, COVID was a new virus that entered the human ecosystem. Moderna got the sequence in January when it was published online by this Shanghai Consortia of Researchers and within 42 days of first seeing the sequence, they had clinical grade material to go into patients. That is unprecedented. You could never do that with attenuated virus, inactivated virus, because you would have had to get the virus, you had to had to develop a system to develop huge amounts of virus and then inactivate the virus and know that it's an activated so that you're not giving people back infection. So really, the main thing was speed.

Jenna Park [16:10] Before 2020, no mRNA vaccine had ever been approved before. But now with two approved vaccines and many more in development, the promise of mRNA-based vaccine technology might actually come to pass in the near future. Dr. Orozco is excited to see what the future holds in terms of utilizing this new technology and applying it to various fields. So Dr. Orozco, where do you see the future of mRNA vaccines?

Dr. Natalia Martin Orozco [16:36] I think it has been an amazing ride in a year to show us that mRNA vaccines work, and that are feasible as a technology for vaccine development. I think this has opened the door for a new industry of how to make vaccines, but also how to make therapeutics in general, we are fortunate to be in the field of mRNA. And I think everybody is now looking to invest in infrastructure. We're really products because we see the value and we see how fast they can be produced. So this has a lot of potential to prevent every country from being in a situation like this pandemic, right? If we structure for vaccine production or therapeutics production that can be fast and delivered to the population, but put us in a better place in case of another pandemic. Well, several groups and several companies have already started vaccine development or HIV, influenza, Zika virus, Ebola. So all of this acute infectious diseases, definitely mRNA vaccines will have a high impact on, but I think mRNA-delivering lipid nanoparticles can be used for therapeutics, though cancer vaccines is one example, but we could produce really any protein that is required. It could be a cytokine for an immunostimulator that can be combined with a cancer treatment. It could be a ligand, a receptor, an antibody, really anything that you can encode in reading. And you can also think about multiple diseases like autoimmune diseases where you can produce something to dampen the immune response, right? You can produce blockers of inflammation, things of that kind, or help people that have bone marrow transplants where you need to reduce the attack against the transplant, I can think of so many things. The other big field where mRNA has been used is in protein replacements. So metabolic diseases where there is a lack of production of a protein, that's where mRNA has been very useful. There's so many applications, I think we're just starting to learn about it. And I think the new generation will come up with more ideas of work required, but certainly it has a big future.

Jenna Park [19:07] Another exciting project at Providence therapeutics has been looking into making personalized mRNA-based vaccines against various cancers. Could you tell us more about the mRNA cancer vaccine.

Dr. Natalia Martin Orozco [19:20] Cancer is a very complex disease, their cellular processes are modified because mutations or other cellular processes that are dysfunctional. So we learn over the past few years, that the immune system actually can recognize some of these mutations that are present in the tumors and attack the tumors. There is always a balance between the growth of the tumor and the immune system being able to detect rare cells in the body and eliminate. However, when the cancer cells take control, and they become a cancer, a disease, and the new system gets sort of control, they suppress the T cells, they suppress all the elements of immune system that can eliminate it. So cancer vaccines was an idea that has been growing over many years in the field, that is identifying those tumor antigens. Those specific mutations are antigens that are created by the tumor that can be recognized by the immune system, and then create a vaccine for these to treat the patient. And this idea would allow the patient to have its own protected immune response against the tumor, like audio, or like we do for Hepatitis B or any other infectious diseases, but more importantly, to be able to create that memory so the tumor won't come back and metastasize. Now, the difference between a cancer vaccine and a known therapy would be that it's very mild, it's safer. It's a natural response of the body. It would be milder than chemotherapy, let's say. And more importantly, it allows the body to develop assistance over time. Now, why did we selected a mRNA technology? I think it was because it is a very fast and easy way to produce a vaccine. It's a synthetic process. We don't need to use cells or viruses or bacteria, we can produce the template which is a plasmid DNA. Within a few weeks, we can synthesize the mRNA. And deliver a vaccine within eight weeks, which for a cancer patient is equally important, these patient's time to wait for therapies. And the fact that we wanted to make it personalized, identifying the specific mutations and causes for these tumor to grow into patient, we're going to be the target of our vaccine. So it was only possible to be done with the mRNA. And also because we were able to identify multiple antigens that can be encoded in the mRNA and attack different fronts against the tumor.

Jenna Park [22:03] That sounds very promising. Are you going to start clinical trials for the cancer vaccine soon?

Dr. Natalia Martin Orozco [22:09] Yes, so we were in the process of submitting a CTA to Health Canada for the cancer vaccine, and started when COVID started, so we didn't really have a chance to show efficacy. However, all our preclinical data and experiments done in mice indicate to us that we can induce a very strong cellular response against the tumor, and that these can eliminate loads of tumor in the animals. As I said, we are ready that program was put on hold because of COVID. But one program, it's progress, we want to go back and really evaluate this in a clinical trial. We believe that the efficacy of the cancer vaccine is really going to depend on the selection of the antigen and the status of the immune system of the participants, such that they can really build up an immune response against the cancer.

Jenna Park [23:07] While there is little debate in the scientific community about vaccines and their effectiveness, social media and the internet have helped spread a lot of misinformation in the past few years. There have also been questions and worries from the public about the mRNA vaccine since they've never been used before. In a recent poll. 63% of Canadians indicated that they would take the vaccine while 37% are still hesitant or object to receiving it. We asked Dr. Orozco and Dr. Rossi to address some common concerns and misconceptions about mRNA vaccines in general and more specifically about the COVID-19 vaccine. Dr. Orozco, how safe is it to use mRNA as vaccines? Should we be having any concerns?

Dr. Natalia Martin Orozco [23:48] I think people were concerned about mRNA because it's a genetic material, right. So if I introduce genetic material in my body, it can modify my DNA. So that's something that does not happen with mRNA. Because first of all, the mRNA cannot migrate into the cell nuclei and incorporate into the DNA. mRNA sequence as we design it doesn't have the elements to do that. So it will only stay in the cytosol. So it cannot modify any of your genetic material. Secondly, mRNA gets degraded very fast. Once it enters protein synthesis, it lasts a very short time, and then it gets degraded by itself. So therefore it would you wouldn't be in carrying this mRNA for a long time. And also the lipids that are used to deliver are eliminated very fastly. And the volume that we inject in the vaccine is very, very small is on its way inject half a milliliter. And out of that a very small proportion is really the liquid nanoparticle. So therefore, there is no long term effects in terms of, of the mRNA vaccines. Now, in the short term effects like any other vaccine, because we're trying to induce an immune response, there's going to be activation of immune system, there could be some inflammation, but some of the secondary effects are mostly some pain at the site of injection. So people have shown to develop low fever, and headaches, that is a good sign, because that means that we're inducing an immune response in your body, and then you would be ready for the SARS-CoV-2. We have heard that in some people arrested development of allergies. But at least the cases that I have read, these people had previously histories of allergies. So we need to be careful when we immunize to really learn about the person that's going to get immunization and consult to see if this is going to be beneficial for the scenario, we are in the process of starting our phase I. And I think if we talk back later, I would probably have more information. And in more detail in this respect.

Jenna Park [26:20] What is the process of vaccine approval look like?

Dr. Natalia Martin Orozco [26:23] There are three phases for developing not only a vaccine for a drug in general, we have to show that we can produce a product that can be injected into humans with no major effects, and that we follow our good manufacturing practices, what we call GMP. And it's produced in a clean environment so that we don't carry any other toxicities and things of that kind. In Phase I is just for a small number of participants that could receive this vaccine to show that he's safe, in a Phase II the cohort grows. But also, the requirements for the manufacturing are more stringent to show that it's a robust process, it has a better quality, and can be scalar. In Phase II, we need to show efficacy, we need to show that some people even call it proof of concept. So it's very important that we have enough number of participants to show efficacy. And to demonstrate that is worth continuing to a phase three. In a phase three, what happens is, it's just before going into commercialization. So everything that has to do with manufacturing has to be scaled up to the size of manufacturing that you want reviews to vaccine. So let's just say you want to immunize millions. So you need to prove that your process can produce millions of doses. And that every step of the process is controlled, qualified, verified, and that you pass all the testings and requirements by Health Canada. So now, at each step, you have to submit an application, which is called a Clinical Trial Application, we call it CTA and that CTA mainly consists of three parts. One part is to show all the testing that is done in animals. So all the preclinical testing including safety, toxicity, tolerability, immunogenicity efficacy, even if you have a challenge model to show it here, all the proof of concept, everything goes to that first part. The second part is the manufacturing, where you show the results of the manufacturing or your testing, stability, endotoxin levels, or the quality of the assays that you're performing. Or the raw materials that you're using that are pharma quality, you have to present certificates of analysis to show that everything is for human use, and also that your closed phase is reproducible. And that is something that you can quantify appropriately. And the third part is your proposal for immunization or your clinical plan. How are you going out to do the immunization, how you're going to monitor the patients? Or in this case, the volunteers or the vaccine are going to measure your endpoints, whether it's safety, immunogenicity, level of antibodies, and also what are you putting in place in case something goes wrong with the participants. How you're going to prevent them from fanting you're going to keep them in the clinic for how long? And also how you're going to establish a safety committee that's going to evaluate all these secondary effects. So all of these components you present to Health Canada, and they evaluate one by one to say yes, you can go ahead to Phase I, you can go ahead to do Phase II or a Phase III.

Tsukiko Miyata [30:03] So Dr. Rossi, some feel that the decision on emergency approval of COVID-19 vaccine was rushed, raising questions on side effects and risks. Why did the timeline for COVID-19 regulatory approval look so different from other vaccines?

Dr. Derrick Rossi [30:19] Okay, so most of what you said is untrue there, because the FDA discussions for emergency approval were actually public, and you could have actually tuned in to them. So both the Pfizer BioNtech and the Moderna committee discussions on emergency approval were, and they were intentionally and this was unusual to actually done live and to the public. So I spent a day watching those myself, so nothing was hidden. In fact, it's all in there in the report. So if you do your research, and you know where to look, there's actually nothing hidden in it at all. Moreover, over and above, there's been more transparency with this than ever before, because those meetings are not generally broadcast to the public. So there's actually more transparency, not less. That's number one. So the first part of the question was fundamentally incorrect. Now, why was it sped up so quickly? Well, a global pandemic, that's extremely deadly, we'll do that! The sequence was known in January, emergency approval was first granted in December, that is unprecedented. But it's unprecedented, because of the scale of this pandemic, and how deadly this pandemic was. And some very good decisions were made very early on by both biotech companies and governments like to invest heavily in a response to this invest, both manpower and financial power to speed up the process of the development. Moreover, this was very unusual in that the clinical trials rather than waiting for Phase I to end, Phase II to begin and end, Phase III to begin and end. They were actually done overlapping, so that they could shorten the time frame, now that was done at risk by the companies and the governments and the government money. I mean, it could have been that the BioNtech, Pfizer, or Moderna vaccines in the end proved to be 94% effective, both of them, which is astronomical efficacy, but it could have been that it was 25%, in a large placebo controlled trial, or 10%, or 12%. Nobody would be excited about approving those vaccines, but they got approved because they were they worked really, really well, I think that the level of transparency done, and if you read the the clinical reports, which are available for everybody to download and read, they're actually extremely extensive. You have to be a scientist, you know, you know, the general public's gonna have a hard time reading that because you know, it's in the language of science and health, and not everybody knows that language. They convene regulators and committees and panels of people who have deep expertise in this area to review this data. And they spent days asking questions, did you look at this? What was the response to that? What did you do with this? Really pointed, informed questions, and, you know, with a good clinical trial results, and with a good design of clinical trial, and you gain enough data, and you gain it with enough statistical power behind making statements, so the statistical power to have powered the conclusions is very, very high, because there are many, many people and the data is so overwhelmingly good. So actually, I would argue that this has been the most transparent vaccine trials ever done.

Jenna Park [33:37] Could you also comment on the fact that officials do not recommend this COVID-19 vaccine to those who are pregnant or are planning to get pregnant.

Dr. Derrick Rossi [33:46] They just haven't been included in the clinical trials, plain and simply, similarly, children under 16 for the Pfizer BioNtech and under 18 for the Moderna, remind you, they're running trials now for kids that are 12 plus, you can never recommend any new medicine to a population that hasn't been represented in your clinical trials. So pregnant women have not been represented in the clinical trials, nor have children. So you don't give the vaccine to that. Is there a specific reason for that? Well, there has been cases in the past of drugs. And this is actually the origin of the FDA in the first place of thalidomide, that was given to patients are given to everybody and given to pregnant women that cause severe deformities to their kids. So pregnant women with you know, a fetus or an embryo inside them. There's a history there that some drugs that have been given have led to deformities in the in the kids. So this is why they're always flagged as a very high high risk and until you do a proper clinical study on, you know, enough pregnant women to say that it's safe to get that vaccine no health agency will recommend that they get it. But it's really it's more of a historical content, there's not a specific reason for believing that there should be an adverse reaction in pregnant women or young kids. But if it's totally unstudied, you can't, it's better to avoid if it's not studied.

Tsukiko Miyata [35:20] And what about the new variants? Will the COVID-19 vaccine protect us from the disease?

Dr. Derrick Rossi [35:26] Well, viruses mutate, they're about the best evolutionary units that the planet has ever seen. mutation is a great way to come up with new variants to get around whatever selective pressure happens to be on you. Now, let's remember though, that this vaccine is targeting very specifically, the spike protein. So unless the spike protein, and it's also a polyclonal response, to be honest, because it's the spike protein and multiple different antibodies are made on the spike protein. So I would argue that 95% of the SARS-CoV-2 virus could mutate. But so long as the spike protein is still less mutated or not mutated at all, or still allows interaction with the immune response, you're still going to get an effective response. Really, what you would need is for the spike protein to really mutate to a point that it it really is doesn't look anything like the sequence that was used for the immunization in the vaccine for vaccines not to work. That's again, the beauty of this approach, you're targeting just one. But you could also argue, well, if it does mutate around the spike protein, which is possible, then it can get around the vaccine. Well, again, this is an ultra fast technology, if a new spike protein, it's still going to use the spike protein to get into cells, it may just mutate enough. On the other hand, if it mutates too much, it's not going to bind with the ACE2 receptor anymore to allow infection so it can't mutate so much that it can't get into the cell. Can only mutate enough that it starts to avoid the antibodies generated by the current vaccines. So I actually think that this idea of the variants are propagated in the media and people don't really know the biology behind what that actually means. And what actually has to happen. No question that viruses are great at adapting they generate billions of copies of each other. And just mutation which is natural to that type of replication, of course generates variance. But like I said, you could change 95% of the SARS-CoV-2 virus and so long as the spike protein more or less look the same, the vaccine is still likely going to be effective.

Tsukiko Miyata [37:38] Vaccines have been used extensively throughout the world for more than 100 years. And over time, the technology and development processes have undergone huge changes. To get a better perspective on the vaccines of today. We spoke to Dr. Christopher Rutty to understand how they were developed and perceived in the past. Dr. Rutty is a historian of science and adjunct professor at Dalla Lana School of Public Health at University of Toronto and the founder of Health Heritage Research Services. Could you walk us through the discovery and development of the first few vaccines?

Dr. Christopher Rutty [38:16] Well, the first vaccine literally was smallpox vaccine mean the idea of smallpox inoculation or being able to protect people from smallpox is an old, quite an old idea goes back to like 11th century China and East Asia, people knew and sort of empirically when he had smallpox, the pustules that kind of break out, excrete a fluid and people kind of have trial and error would have noticed kind of scratch some of that material between from one person to another, it can instill a mild reaction, which can immunize sort of, as an observation called inoculation or person to person inoculation. And that seemed to work I mean, it's obviously not perfect, but it had some control exercise some control over smallpox, which was pretty deadly. The vaccine part started when, in 1790s, Edward Jenner, he noticed that milkmaids, young girls and milk cows, often have very clear skin, which was very unusual. Most days most smallpox was pretty ubiquitous and left its mark on everybody, whether it's mild or severe. And he noticed that the bellies of the cows that they were milking often had a smallpox-like infection. And he knew about the other story I just told you, and kind of surmised that maybe the cows something in the cows, but similar to smallpox was protecting the girls when they milked the cows. And so he gathered some of that material and scratched it into his nephew in the middle of an outbreak and it worked. So, vaccine is literally from Latin for cow? Vaca is Latin for cow. Vmallpox vaccine is made from vaccinia virus, which is a cow pox, which is a relative of smallpox vaccine, but mild and immunizes against it. And so vaccinia virus is what we've always made smallpox virus from sort of variations of it, but and we've eradicated smallpox. So from that beginning in smallpox set the scene in a way, but it was done in a context of not really knowing necessarily what was going on, like a smallpox virus, you can see a virus until much later. But you could see the effects of it empirically, really, the first modern vaccine was diphtheria toxoid. And in the mid 20s, if there's a bacterial disease, it leads to a toxin that spreads in the body and leads to a blockage in the throat, that's can be deadly. It's a strangler, it's called. In the mid early 20s, scientist in the pasture Institute in France, Gastown Ramon, notice when you expose that toxin to formaldehyde and heat, in that kind of careful way, it became a toxoid. It detoxified it, so it, but it could stimulate immunity, but not cause disease. So when you inject the toxoid, same way into a person, it stimulates immunity. And it's actually that was the first modern vaccine because it worked very well. So that set a stage and that was the beginning of kind of modern vaccination and immunization programs when you have an effective, very effective and fairly easy to produce safe toxoid vaccine. You could, you could have toxoid, we could have collaborative exercise between Public Health, the Health League of Canada, which was new, doctors, the media to bring parents in and to get their kids toxoided, and it worked. Diptheria had been one of the largest public health threats through the 20s really into the 30s, almost. But once you start using the toxoid it sharply went down.

Tsukiko Miyata [41:26] So what has been the impact of vaccines on public health over time?

Dr. Christopher James Rutty [41:32] Well, it's it's self evident in so many ways. It's kind of the root of why we have vaccine hesitancy in many ways, because people don't see the diseases that they're getting vaccinated against. So it's easy to kind of be sensitive to: "Oh, I heard about, you know, all this causes this reaction to that reaction". But I mean, smallpox was the first vaccine and the first disease eradicated, so it killed millions of people, year in and year out, it was pretty well under control here in Canada, by the 30s, 44s at the very latest, there were still a few things, outbreaks, mostly associated with people not getting vaccinated. polio has been much more complicated, but it's come a long way from 1988. There were some 300,000 cases globally. Now we're down to hundreds if that. The smallpox experience kind of set the stage for polio eradication. But polio eradication is much more complicated. It's just the nature of the of the disease itself. The smallpox, every case is visible. polio, it's the other way around. As polio, we have effective vaccines, but almost every case you don't see, when you start to see a few parallel cases pop up in a region, then you know, you're in trouble. Because it's it's circulating. And so the impact of vaccines is this to mean, we don't see most of these diseases are classic ones, unless people aren't getting vaccinated.

Tsukiko Miyata [42:49] So has vaccine hesitancy increased over time, as these diseases have become less visible?

Dr. Christopher Rutty [42:55] Well, it began with smallpox. So the first vaccine and, you know, there's a lot of, because of smallpox vaccines used cows, cow pox, and so in the public mind, when they're not really no understanding what's going on, can see how how ideas, you know, get complicated, apart from the actual vaccine itself, which may or may not have some problems. But when people start to perceive there's a problem, and then you add in political factors, or, you know, like in Canada, and Quebec in 1885, actually, there's a lot of anti vaccine, not so much, so much because of the vaccine so much, but it was equated with the English doctors, you know, and the French Canadians and other tensions going on at the time. And, you know, same thing in the US in the colonial period, smallpox, even before there's this vaccine, but the person to person inoculation, there's a lot of distrust. And so it gets tied up with other factors like politics or general distrust of authorities of medicine, of companies, of politics, whatever. And so that's kind of the foundation, it kind of ebbs and flows, though. When something's new, or there's, you know, there's a lot of other factors involved that kind of make it kind of ripe for picky people picking up on issues for when things are working well, like I said, with public health and things are working well, not much happens. Well, there wasn't a whole lot of anti vaccine against diphtheria toxoid because it worked. There was not a lot of basis, in those days to the 20s and 30s the public trust in media, in the government, public health was pretty high, you know, relatively because you actually could see it dipheteria, living memory of families, they could see the difference. They knew epidemics, they knew the impact of diphtheria on their children, and then how they could see that it was actually working. So that's a big part of it. And there wasn't a similarity with polio. There wasn't a whole lot of anti vaccine. I mean, there was always there's always some, but nothing to speak of, really, again, the 50s, early 50s was another big time of pretty high trust in Government in Public Health in Science. What's the 70s was when things started to change, again, with things like Thalidomide that was in the 60s, but sort of accidents of medical accidents or drugs, mostly on drugs, not solely a vaccine issue. But there's that context of, of distrust. So is that those sort of were the elements that kind of grew through the 70s and the 80s. And then you have in the Wakefield's in the that's a whole nother kind of level of, sort of outbreak, no active efforts by one particular person, that can be magnified.

Jenna Park [45:48] As we just heard, vaccines have always had some level of hesitancy for many reasons, since mass immunizations were first started. While a lot of hesitancy to vaccines is fueled by fear mongering based on misinformation. Dr. Nicole Charles explains how this isn't always the case for many black, indigenous and other marginalized communities. Dr. Charles is an assistant professor of Women and Gender Studies in the department of historical Studies at the University of Toronto and the author of the book Suspicion. Vaccines, Hesitancy, and the Affective Politics of Protection in Barbados. So first of all, could you define vaccine hesitancy?

Dr. Nicole Charles [46:27] The WHO defines vaccine hesitancy as either a delay in acceptance or complete refusal of vaccines in the context of available immunization services and according to the WHO people who are vaccine hesitant can be said to lie on a continuum, and that spans complete acceptance all the way to refusal. So it's a pretty broad term. And I think, while vaccine hesitancy might exist alongside what's colloquially termed anti-vax sentiment, for some people the two ought not be conflicted, right. So you might ultimately accept a vaccine but still be considered vaccine hesitant because of your delay, by definition, right. So you know, in my research with Afrobarbadians, in relation to the HPV vaccine, suspicion is less an active attempt to resist the vaccine and more this embodied feeling that attaches to the vaccine and its promotion and you know, the very complex postcolonial and neoliberal politics in which it is in mesh.

Jenna Park [47:32] Do you fear that vaccine hesitancy may pose a threat to global health?

Dr. Nicole Charles [47:36] Vaccination is a safe and cost effective way to prevent disease, and a lack of vaccine confidence and low vaccine uptake, specifically against communicable diseases really gravely, threatens to halt and more concerning reverse the progress that has been made in mitigating vaccine preventable diseases like measles and polio. Measles, for example, has something like a 30% increase in cases globally. And we're seeing that poliovirus transmission is expected to increase in places like Pakistan and in many under immunized areas in the African continent, and really deadly measles outbreaks in places like the DRC. Amidst nearly two year long outbreak of Ebola is another devastating example of low vaccine uptake. And we see this all across North America as well, right? I'm sure many people remember the 2015, the outbreak of measles in Disneyland. If vaccine hesitancy results in vaccine refusal, this is a really serious challenge to public health efforts to eradicate vaccine preventable diseases and save lives.

Jenna Park [48:50] What are some reasons for vaccine hesitancy?

Dr. Nicole Charles [48:53] It's hard to kind of say even like an umbrella definition of what some of those reasons are, but, you know, they might range from a perceived lack of need for a valid place on vaccines, religious beliefs, misunderstandings of science or distrust in science or vaccines or medical establishment. The scientific community calls this the three C's of vaccine hesitancy, so Confidence and how much trust one has in a vaccine safety or efficacy. Convenience, so how easy it is to access the vaccine physically and economically. And then Complacency which is described as the perception of one's risk, but something that the World Health Organization also notes and that my research has shown is that vaccine hesitancy is very often vaccine specific, right? Reasons for hesitancy vary depending on the vaccine, and also the population. So you know, I'm going to keep referring to my research with Afrobarbadians parents and these parents who I spoke with overwhelmingly previously accepted all childhood vaccines and yet they were expressing suspicion over the HPV vaccine which was being offered to the 11 and 12 year old daughters. And you know, the reasons for doing so ranged from their unfamiliarity with this vaccine, you know, the ways in which it was being advertised in Barbados by pharmaceutical companies and international agencies, which really differed from how most vaccines are rolled out through public clinics by nurses in the country, and also, you know, unique to this vaccine and HPV in the relationship with cervical cancer, were tropes of hypersexuality, which were attaching themselves to the vaccine, which is intended to intervene upon the bodies of primarily young black adolescents in Barbados.

Jenna Park [50:37] Could you explain to us some differences between antivax groups and vaccine hesitancy and communities of people of color?

Dr. Nicole Charles [50:45] Across I guess communities of anti vaxxers, and those whom we might refer to as vaccine hesitant, so again, I think it's really important to make this distinction between these two groups. There is quite a diversity across income groups and education, though a large proportion of anti vaxxers have been identified as being University educated, having higher median incomes, largely white, both the US and Canada. And something else I'll say is that a pillar of anti vaccine and an anti vaccination ideology is that vaccines cause autism and other injurious effects. And these sentiments are, as I just mentioned, often associated with conspiracy theories or a concern around individual freedoms and liberties. And so these ideologies are increasingly aligning with and being enmeshed with those of far right groups. And generally, hesitancy among communities of black and indigenous people of color, has to be examined and addressed much differently and more closely. Like I think we need to be differentiating between BIPOC hesitancy. So I think, you know, really injurious histories of medical injustice and scientific racism have caused many black and indigenous people of color to have skepticism and hesitancy towards biomedical interventions like vaccines, especially today living in what Saidiya Hartman has termed the afterlife of slavery. Hartman says, If slavery processes an issue, it's not because of some obsession with the past, or being burdened with the past, but because black people's lives continue to be devalued, and imperiled, you know, politically, socially in all the ways and this is something that this systemic racism has been entrenched into the very fabric of our society. And both of some of the really egregious, outrageous and well known acts of medical abuse that have been directed at black and indigenous communities historically. So things like the Tuskegee syphilis experiments, and the forced sterilization of Indigenous women, but also the no less disgraceful abuses that occur every day, right. So the ways in which black pain and suffering often discredited or disbelieved the ways in which Indigenous women are berated and abused in hospitals while seeking care. We just saw the tragic death of Joyce Echaquan and Quebec as one example of this devastating trend, in fact, and in light of these things, it's no wonder that current COVID-19 vaccine campaigns are often not deemed credible by many black and indigenous, people of color. So before black, indigenous, people of color, and black folks are expected to willingly and eagerly accept medical interventions, there needs to be an acknowledgement of a reckoning with this history of slavery and with the ways in which medicine was an integral part of colonialism, the ways in which scientific racism existed and continues to exist.

Jenna Park [53:54] Today, we see COVID-19 vaccine campaigns utilize social media, how does social media play a role in vaccine hesitancy?

Dr. Nicole Charles [54:01] I think social media really becomes an echo chamber for anti vaccination ideologies. So in relation to COVID-19, we're seeing this rhetoric find a home in conservative groups and news outlets, even here in Toronto. And I think there's no debate to be had on the science behind like the mRNA vaccine. But this is kind of what a debate seems to be arising and there's no debate to really be had. Right? So we see misinformation abound around the vaccine. And I don't think we should give this misinformation, too much airtime. Like we don't need to go through what's on social media, but I am encouraged, I think, to see more and more public health professionals and black and indigenous, people of color who work in, in the health field and who are doctors using social media to kind of combat some of this information. So you know, creating slide decks and answering Q and A's. I'm seeing that on Instagram more and more, so I think That's great.

Jenna Park [55:00] How should we promote vaccination for the communities of people of color?

Dr. Nicole Charles [55:04] Knowing our history, we have to know right, the heavy involvement of the government in the distribution of the COVID-19 vaccine, it's going to raise huge concerns and questions for those most disenfranchised by the very government, here in Toronto. The irony of this is reflected in the disproportionate numbers of black and indigenous people who are dying from COVID-19. Both because they are more exposed and less protected to COVID. Folks most vulnerable to this pandemic are low income, communities of color whose jobs are very often put them at risk and who are essential workers without paid sick leave, and who have precarious housing because of the disinvestment in social services. So overall, you know, I think my takeaways from vaccine hesitancy are that public health agencies and scientists, service providers, governmental bodies, policymakers all have to do better to challenge these things and the systemic racism to build the trust of the most marginalized and to protect essential workers, you know, to do things like place a ban on evictions to stop the spread of COVID. And this should absolutely be happening alongside efforts to vaccinate but I'm just kind of trying to pull the lens out to show that it's a system of racism. If we know that racialized communities are deeply affected by the racism that's endemic in the Canadian health system, and that it impacts their confidence in medical technologies like vaccines, then we have to begin with more credible public health companies that don't dismiss these community's concerns, but rather seek to overcome them with transparency and accountability. In some cases, to your question we do and we have seen this, there was an effort to include more block participants in the trials of the vaccines. This is something that can build credibility, but I think we also need to have more black and racialized doctors in communities. This can be a start along with trusted community partners like faith groups and leaders that encourage communities to ask questions, and who can be involved in efforts to promote the vaccine and to address concerns at all levels from the science of vaccines to the distress of pharmaceutical companies.

Tsukiko Miyata [57:23] Vaccine technology has come a long way since the development of the very first vaccine against smallpox, and is now an essential part of public health efforts. Although mRNA-based vaccines are a relatively new development, the immunological basis behind how they work is well studied. new vaccine development does bring hesitancy and some misconceptions, but the ability to respond rapidly to ongoing pandemics is a paradigm shift. The future of vaccines looks to be very bright and promising. A very special thanks to our guests. Dr. Christopher Rutty, Dr. Derrik Rossi, Dr. Natalia Martin Orozco and Dr. Nicole Charles for speaking with us and sharing their insights. And of course, thank you for listening. To learn more about their work and other information on vaccines. Check out the links in our show notes.

Jenna Park [58:13] This episode was hosted by myself Jenna as well as to Tsukiko. Yagnesh and Anam helped conduct the interviews and Adrine helped develop content. Yagnesh was our executive producer, CJ was our photographer, and Esther was the audio engineer. Be sure to check out our next episode in two weeks where we discuss racism and health care. Until next time, keep it raw.