Federica Santoro 0:15

In case we had forgotten, the COVID-19 pandemic reminded us of how much public trust in vaccines depends on their safety. If a vaccine is unsafe or is perceived to be, people simply won't want it. And so having systems in place to detect and manage any side effects is not just a regulatory exercise. It's what will make or break vaccination campaigns. But what makes a successful vaccine surveillance system? And how do you even build one? My name is Federica Santoro and this is Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. Joining me today is Dr. Madhav Ram Balakrishnan, Medical Officer for Vaccine Safety in the Department of Regulation and Pre-Qalification at WHO, the World Health Organization. Madhav visited Uppsala recently, so I took the opportunity to pick his brain on vaccines. We discussed what it takes to set up an effective surveillance system, how to manage a vaccine safety crisis, and much more. So let's dive straight in. Hi Madhu, and welcome to Drug Safety Matters and welcome to Sweden, because you are spending a couple of weeks with us here in Uppsala, getting to know people that work at Uppsala Monitoring Center. How are you finding your visit so far?

SPEAKER_00 1:56

It's been absolutely fantastic. And I found not only that the reception was very good from all of you, but I also found that it has been very, very uh tremendous learning experience for me because in the last few days I have met a lot of people, learned a lot of new uh areas which I was not aware of. And I've also enjoyed my visit and I found it very useful. Thank you very much.

Federica Santoro 2:16

That's lovely to hear. So today we're talking about vaccine surveillance, your field of expertise. We will look at how systems to monitor vaccine safety are set up, how the pandemic challenged them, and also how to deal with vaccine safety crisis. But first, let's address a fundamental point. Why are vaccine surveillance systems important?

SPEAKER_00 2:41

Thank you very much for that uh very important question, Federica. We should understand something about uh vaccines and how they are manufactured. You know, vaccines go through very, very stringent manufacturing processes. Before the vaccine actually enters into the market, the first stage is a stage where they identify the molecule. Then once the molecule is identified, they may identify something like maybe about a hundred molecules. But to be very frank, finally maybe only one or two molecules might become successful. Now, even for that one or two molecules to become successful, it goes through a huge amount of research. First of all, animal trials, where you know they try to find out whether the vaccine is uh most importantly safe and effective, but mostly whether it is actually safe. Once they find that it is safe and by you produce some amount of uh protective response, what they do is they start introducing it into humans. But when they introduce it into humans, there are three phases of clinical trials, you know, the phase one, phase two, and phase three. Now, when you look at the phase one, phase two, and phase three clinical trials, the number of people who get where the vaccine is tested is very small. For instance, in phase one, it's just like sometimes like only 10 participants or something like that. Sometimes phase two might go into a few hundreds of participants. And phase three, usually it goes into several thousands. But even then, even if you see, it may not go more than like 50,000 to about 80,000 or so, even after good clinical trials. You see what I mean? Now, when you look at the adverse events which occur, and especially the adverse events which are rare and sometimes very serious, the rate in which it occurs might be like one in two million doses. So, you know, just because a vaccine has passed its clinical trial phase, it doesn't mean that when it comes into the market, it doesn't mean that it is good enough to detect this rare and very, very rare adverse events. So that is why a good surveillance system is important for us to have a system in place to pick up these events.

Federica Santoro 4:38

And obviously, vaccines are not the only medical products whose safety is continuously monitored. Drugs are under continuous scrutiny too. How do surveillance efforts differ for vaccines compared to drugs?

SPEAKER_00 4:53

What a nice question, Federica. You know, the thing we should look at the profile of people who take drugs and look at the profile of people who take vaccines. Now, vaccines are being given for people who are normal, and then you would then try to get the benefits of the vaccine. And many of the time the benefits of the vaccine are actually not visible. Why? It prevents a disease which you have not yet got. Whereas if you look at a drug, you're already sick and then you have actually taken the drug, right? And then what happens is you are expecting the symptoms to come down. So if I develop an adverse uh reaction to a vaccine, my level of tolerance or acceptance, I should say, is much less compared to drugs. That is number one. Number two, you should also remember the profile of people who take vaccines, except recently when you know when COVID came in, where we kind of vaccinated everybody. Historically, especially in low and middle income countries, most of the vaccines are administered for children. And most of them are actually under one year of age, and many of them are actually perfectly normal and playing. You see what I mean? You vaccinate, and sometimes if you develop an adverse event, then the blame which comes from uh everyone is kind of unacceptable. Those kind of responses are not acceptable. So that is what happens with regard to vaccines and drugs.

Federica Santoro 6:10

Yeah, so for all those reasons, vaccines tend to be under more rigorous scrutiny and perhaps more in the public's eye than um drugs.

SPEAKER_00 6:20

Drugs, absolutely.

Federica Santoro 6:21

And now onto a topic that I know is dear to your heart: setting up vaccine surveillance systems from scratch. What are the main things to consider in that process, especially in low resource settings?

SPEAKER_00 6:36

Right. Now remember something, whichever be the surveillance system which we are setting up, whether it could be for surveillance for the occurrence of a disease, or even in this case, we are actually talking about surveillance for adverse events following immunization. What is the most critical and the most crucial thing is to understand is basically the health-seeking behavior pattern of the person who's affected by that particular condition. So when you look at the type of AEFI or the adverse event following immunization occurring after a particular vaccine, we should try to understand who is the person whom the vaccine recipient who's affected by this adverse event going to meet and take treatment from. That's number one. The second thing which we also need to understand is at the time of vaccination itself, the surveillance system should actually be created in a way in which the person knows whom to approach when something goes wrong. And also the person should be sensitized as to what is to be expected after a vaccination. Now, let us be very honest. All vaccines can cause adverse events, but all those adverse events are minor, like pain at injection site, fever, but sometimes very rarely, very, very rarely, it can become very serious or sometimes very severe, like you can get severe pain, sometimes you can get febrile seizures or convulsions, sometimes you can even get other complications like anaphylaxis. So when we set up surveillance systems, it's important to understand what is the kind of adverse events to anticipate with that particular vaccine. And also make sure that both the vaccine recipient is also aware of it. The person who administers the vaccine is also aware of whom to approach, and also the person whom the recipient approaches knows what to do when this event gets reported and how to initiate the chain of steps so that you are able to respond to the treatment of the patient and also to go back and understand the underlying cause which resulted in the adverse event.

Federica Santoro 8:33

Right. So what you described so far is obviously in a normal condition in the absence of a global health crisis. How did the COVID-19 pandemic change the rules of the game, so to say?

SPEAKER_00 8:48

Absolutely. The COVID-19 pandemic was a game changer. I mean, if you ask me, it also highlighted the importance of vaccine safety not only among the public but also from the healthcare professionals. And also people began to understand the need to identify adverse events early, to report the adverse events early, and also to identify if there are certain patterns of reporting, you know. Now, if you just look at it, first of all, let us look at it in terms of the vaccine manufacturing itself. Normally we should understand something. You remember in the beginning I was just telling you about the phase one, two, three clinical trials. Now, these usually, when you look at the phase one, two, and three clinical trials, followed by, you know, the vaccine licensing, and then there is something called a post-marketing phase. It can actually go on for several years. In fact, in certain vaccines, the clinical trials can go on for several decades. Now, this whole thing was actually compressed to about approximately a year or even less in some cases with regard to the COVID vaccine. Now, people keep on asking us whether there has been anything which has been cut short. The answer is actually no, because what happened was the process was done, but the whole thing was actually compressed into a shorter period of time. So that is number one. But then because the sample sizes were not reduced, for instance, like what I just mentioned, the total number of people who were screened. But what did not take place was that the screening did not take place for a longer duration of time. Because if you just look at it, some of the adverse events can occur sometime six months or a year later and things like that. So those kind of adverse events have to be actually monitored in the post-marketing surveillance phase, you know. So that is why we are also from WHO's side. We also encourage countries to strengthen their surveillance systems. We also brought in guidelines for countries just to take into account this newer context on how to establish surveillance systems very quickly, not to establish, I would say to upgrade the existing surveillance systems so that they can match and meet the emerging new requirements, particularly in the context of COVID, which we had to rapidly scale up. And I should say many of the countries have done a remarkable job because when you look at the results which have come out in terms of reporting of those adverse events, we should say that they have done pretty well, I should say.

Federica Santoro 10:58

Let's talk about public perception of vaccines. First of all, what are people's most common concerns when it comes to vaccine safety?

SPEAKER_00 11:09

Right. So when you look at it from the public perspective, there is uh several reasons by which people have a fear from the public perspective. Most of it, actually, when you look at it, it is actually fueled by what people read in the print literature, see on the TVs, and uh and also obtain from the social media. You know, that is what happens. But when you look at it in terms of pure science, and when you really follow up, you find that the ground realities are actually completely different. Many of them actually, more than the fact that they have uh personally experienced, you know, they give anecdotal examples about some other people who have actually experienced these adverse events and then they fear for themselves whether this could also happen to them. Now we are not trying to say that it will not happen to them, but we should always remember that vaccines do not get licensed just like that. It goes through a very stringent process, manufacturing process, regulatory process, licensing process, and even after it is introduced, the systems are in place to identify and respond to them. So, from the public's perspective, even though the amount of information which is collected from the media, they need to really weigh on the risk versus the benefits which is there for vaccines. Because again, nobody denies, like, for instance, we have evidence to say that uh certain vaccines can, especially COVID vaccines, for instance, can cause conditions like myocarditis and pericarditis, like cardiac complications. We know it can cause clotting problems, like you know, certain COVID vaccines, you know, the especially the viral vector vaccines can cause clotting problems, blood clotting problems, and things like that. Now, we are not saying no, but then you should also understand that the same conditions, if COVID were to occur, the probability of you getting these complications are several hundred times, several hundred times higher compared to what you can get with vaccines. So one needs to actually balance the risks of getting the disease and the complications of the disease versus the benefit of the vaccines and the few adverse events which can also very rarely occur after vaccinations.

Federica Santoro 13:10

Again, it's a balance between the benefits and the risks, and it's important that people perceive those correctly. We devoted a whole episode to risk perception and communication, so I know that's a vast and complicated topic. I actually invite our listeners to go back to that episode if they're interested. But what I'd like to talk about with you now is the process of causality assessment. So if we observe a particular symptom after vaccination, it's not enough to just observe that, to conclude that the vaccine is causing that suspected side effect. But we really have to go in, collect information, analyze all that information at our disposal before we can confirm our suspicion and conclude that the vaccine is responsible for what we're seeing. So this process is known as causality assessment. Is there any difference in how that analysis is done for vaccines compared to drugs?

SPEAKER_00 14:12

Very nice question. Thank you, Frederica, for asking that, because actually there is. So when you look at it from the vaccines perspective, we need to understand the question which we are asking is did the vaccine or the vaccination process cause the adverse event? Whereas when you look at it from the drugs perspective, most of the time we are asking the question, did the drug cause the adverse event? This is a very important difference to understand. Now we should also realize something from the vaccines perspective. When we look at the vaccines side, as I was mentioning earlier, most of the people who receive the vaccine get adverse event, like pain at injection site, fever, fatigue. Sometimes you feel, you know, very tired, especially after COVID vaccines. Even I felt very exhausted, I should say, you know, for two days after the vaccine. It was not like as though I was uh spared of it. Now, this is something to be anticipated. So, in other words, we have something known as known adverse events. But all these known adverse events are mild and minor. What we are looking for is actually the serious adverse events, like you know, the death, hospitalizations, disability, sometimes congenital anomaly, and sometimes you know other medically significant events. Now, when we look at these kinds of conditions, it is actually extremely rare for these conditions to occur. And when we have actually done investigations and then causality assessment, by investigations, what do we mean? We actually do a thorough investigation. We interview the patients, we look at the clinical case diagnosis. If they become ill, we try to meet the doctors, interview the doctors, we go through the cold chain processes with which the vaccine went through. We also visit the community sometimes to find out if there are some similar events which are also occurring within the communities. Now, in real life, if you see during investigation, we have actually found that most of these cases are coincidental. When you investigate those cases in detail, we find that most of the serious adverse events are actually coincidental. Sometimes we find that it could also be a programmatic error where the vaccine product itself was not an issue, but the technique of administration, for instance, or the way in which the vaccine got stored, might have had some problems, and that is what caused the adverse event. Only very, very, very rarely do we see this actually the one adverse event where the vaccine product itself, where the substance within the vaccine actually caused the adverse event.

Federica Santoro 16:43

So you say the majority of them are medication errors then?

SPEAKER_00 16:47

I would say majority of them were actually coincidental, most of them. And the next highest level would actually be what we call as immunization error-related adverse events. Whereas in medication error, it's used for the drugs, whereas the equivalent of that in the vaccines world is actually called the immunization error-related adverse events. Sometimes we also have a very peculiar condition called ISRR, immunization stress-related responses. This is actually seen particularly with COVID vaccines. We have had several instances, especially among older people, and especially we have noticed it occurring as clusters. You know, during what happens is at the time of vaccination, people fear the vaccines, and there might be one person standing in the queue who faints. And then when other people see this and when they get vaccinated, this actually produces a chain reaction. We have actually had in the last uh this year itself, or in the last uh one month, we have actually in WHO had uh two independent reports of clusters of AEFI reported from uh Africa, where in one case it was 14 uh cases, and in another case where it was more than 100 cases, which were actually reported as clusters of anxiety-related adverse events.

Federica Santoro 17:58

Okay, so I guess this is what we would in everyday language call being afraid of the needle.

SPEAKER_00 18:04

Absolutely. It's called the needle phobia.

Federica Santoro 18:06

Yeah. Okay, so did COVID help characterize this better?

SPEAKER_00 18:10

Right. If you ask me this question, have these kind of events been reported earlier? The answer is yes. It's not like uh as though it is something which is only COVID-specific. Historically, even in the 1990s, if you look at uh the literature, there have been cases of cluster anxiety-related adverse events. But actually, with social media coming into the play now, you know, when people get vaccinated, they share information that they are getting vaccinated, and when a person faints, the picture is taken, and sometimes videos are circulated, frightening videos, and this actually further adds fuel to the fire and causes more immunization stress-related responses. This is what we have actually seen. And in those kinds of conditions, if they see that an ambulance comes and picks up the video of the ambulances also becomes viral on the net, and then you know, this further uh adds fuel uh to the fire of uh creating more such adverse events.

Federica Santoro 19:04

And we'll get back to social media and digital communication in a little bit. But uh first, to stay on the topic of causality assessment. So we know from experience that even when that assessment concludes that actually the vaccine has nothing to do with the observed adverse event, people's perception can still be that the vaccine is causing it. So, how do you address the public's concerns in that situation?

SPEAKER_00 19:34

That is actually a difficult question because from our experience, what we have noticed is we can provide the science. We can also try to logically explain the process by which we do the causality assessment. Now, we should also understand that in many countries the causality assessment is not done at the whims and fancies of one person. It is done in a very, very scientific way. And usually it is done by a group of experts, by a committee. We actually call it the AEFI committees, the adverse events following immunization committees or the national committees. So these committees who are a group of experts, they are the people who are actually doing the causality assessment. And there is a very logical scientific way in which WHO has come up from 2013 in the way in which we do this causality assessment. It is used all over the world because we find that uh based on the statistics which we collect, we find that almost all countries in the world are using this method. But then it is sometimes, I fully agree with you, that the people still feel that the vaccine only causes the event. Our job is basically to explain our logic, but then it's up to the public to understand the science behind the decisions which are being made.

Federica Santoro 20:45

It's tricky, I know. Um so even when we've conducted the most thorough assessments and communicated as clearly as possible, crisis can happen. So I know this is not an easy question and it could take up a whole episode, but what is the best way to handle a vaccine safety crisis?

SPEAKER_00 21:06

If you ask me, you know, we should be honest, truthful, and transparent. Okay. And also the most important thing is to understand the sensitivity of the situation and communicate appropriately. It's very important to take into account things like, you know, the cultural factors, the social factors, and the context in which you are communicating and also creating the communications messages. And once we understand the context in which the communication is going to happen, we try to understand the perspective from the other side, from the vaccine recipient side, from the public side, and also from the other stakeholders. You know, it's very important to understand their perspective and communicate in the most appropriate manner so that it will result in less misunderstanding. I won't say no misunderstanding, I would say less misunderstanding. But I would say that the bottom line is to be very transparent and honest because we are not trying to say that vaccines do not cause adverse events. We are just trying to say that vaccines do cause adverse events, but among the adverse events, the serious ones occur very, very rarely or sometimes in such uh very minute levels where it is sometimes blown up out of proportion when one or two very rare events are proved to be connected to the vaccines or vaccination.

Federica Santoro 22:18

Do you have an example of that kind of communication tailored to the context?

SPEAKER_00 22:23

Right. So what we normally do is when we are faced, especially with uh media, it's important, for instance, to come up with a set of frequently asked questions which we normally prepare, because we know that these are the kind of common questions which are coming up. It also helps us to prepare in advance, review the literature, go through the context in which these kind of crises have occurred, find out if similar events have occurred in the past, and look at it in the present context and see if what is the difference, and also explain to the public in a simple but in an honest manner and also in a very transparent manner about why this event has taken place, what was actually the underlying cause, and who was responsible, and also what needs to be done in future to prevent similar episodes from occurring.

Federica Santoro 23:14

Yes, as we often say in crisis management, you cannot predict a crisis, but you can definitely take steps to prepare so that you can manage them in the best possible way when they occur. And now back to social media for my last question. All of what we've discussed is obviously made more complicated by today's digital communication, where, as you said, rumors and concerns can spread quite fast and unpredictably. So, what should I do as a regular citizen if I come across such rumors on social media?

SPEAKER_00 23:49

Thanks, Frederica. That is a really beautiful question because I have faced it several times. You should understand my background. You know, I'm a medical doctor, and you know, I am also a part of several groups in social media myself. And sometimes the kind of communication which comes into me and which gets circulated and which I see which is being perpetually circulated, is appalling when you look at the level of truth inside that. You see what I mean? So, what we are expected to do, you know, one of the important things is we should not be adding fuel to the fire by perpetuating a falsehood. So, what we should be doing as soon as we get a message, it's very important for us to think logically. Is it really telling us the truth? Do you think it has to be verified before I really forward that message or communicate that message to the next person? Now, there is one very good thing also in social media is it's very easy for us to verify authentic news because you can always put it into certain websites to verify whether this is a fake news or not. And if you find that it is a fake news, it's very important one, to inform the person who sent the message to you, saying that this is found to be a fake news. And if you're a part of a social group, to communicate that message as a fake news proactively, that's number one. Number two, never forward or communicate fake information because the amount of harm which it does is phenomenal because lives have been lost, because people have kind of forwarded fake messages. Because I myself know that it is not only related to the area of vaccines, but also to other areas where fake messages, especially with regard to for the diagnosis, treatment, etc., have actually killed people. So we should be very, very careful when we receive messages in the social media and also communicate it and you know, don't make false messages go viral and be a part of that uh process.

Federica Santoro 25:45

So think twice before you share.

SPEAKER_00 25:47

Absolutely. Even more if necessary. Thank you.

Federica Santoro 25:50

Thank you very much for taking the time to talk to us, Madhav.

SPEAKER_00 25:54

Thanks a lot. It's been my pleasure, Frederica. Thank you very much.

Federica Santoro 26:02

That's all for now, but we'll be back soon with more conversations on medicine safety. If you'd like to know more about vaccine surveillance and WHO's guidelines on the topic, check out the episode's show notes for useful links. The episode on risk communication that I mentioned during the interview is available in our archive, along with many other episodes on vaccines. If you like our podcast, subscribe to it in your favorite player so you won't miss an episode, and spread the word on social media so other listeners can find us. Apart from these in-depth conversations with experts, we host a series called Uppsala Reports Long Reads, a selection of audio stories from UMC's Pharmacovigilance magazine. So do check that out too. Uppsala Monitoring Center is on Facebook, LinkedIn, and Twitter, and we'd love to hear from you. Send us comments or suggestions for the show, or send in questions for our guests next time we open up for that. For Drug Safety Matters, I'm Federica Santoro. I'd like to thank Madhav Balakrishnan for his time, Matthew Barwick for production support, and of course you for tuning in. Till next time.