[00:00:07] Angela: Hello and welcome back to Communicable, the podcast brought to you by CMI communications, ESCMID's Open Access Journal, covering infectious diseases and clinical microbiology. My name is Angela Huttner.

[00:00:19] Angela: I'm an infectious disease doctor at the Geneva University Hospital in Switzerland, and editor in chief of CMI comms. I'm joined today by my co-host, Annie Joseph. Annie is a clinical microbiologist at Nottingham University Hospitals and HS Trust in the United Kingdom, and a fellow editor at CMI Comms.

[00:00:38] Annie: Hello, Angela. Great to be back on the podcast. I've been sick all week with the virus, but managed to get my voice back just in time for this episode, so I'm hoping it holds out.

[00:00:48] Angela: Annie, so glad you're here. we are gonna be talking today about a virus, however not the one you had. . We're coming back yet again to our nightmare series. Anti-vax sentiment in the US and elsewhere is still surging. It may even become part of government policy in some places. As a result, we'll be seeing more and more preventable infections, infections that were prevented for entire professional lifetimes, and thus many doctors won't have seen them. We recently covered polio and rubella, and now we're turning to measles. Because of waning vaccination uptake in the last two decades. There are significant outbreaks ongoing in both the US and Europe at this moment, in addition to other places. So we've brought together two infectious disease experts who spend a lot of time dealing with measles. I'm delighted to welcome back Kerrigan McCarthy, clinical Microbiologist and Pathologist in Johannesburg, South Africa. Carrigan is based in the Center for Vaccines and Immunology at South Africa's National Institute for Communicable Diseases. Her responsibilities include surveillance, including wastewater surveillance at epidemiology and laboratory diagnostics and outbreak Investigations for measles, rubella, polio, and hepatitis viruses. Kerrigan. Welcome back.

Thank you. Lovely to be with you today, Angela and Annie.

[00:02:10] Annie: And our second guest is Natasha Crowcroft, senior technical advisor for measles and Rubella at the World Health Organization and professor at the University of Toronto's, Dalai Lana School of Public Health, and the inaugural director of its Center for Vaccine Preventable Diseases. Hi Natasha.

[00:02:29] Natasha: Hi. Thank you very much for inviting me to join today.

So as our listeners know, we start these episodes with a sort of get to know you question for our guests and also for our hosts. These questions tend to have nothing to do with infectious diseases or even medicine, and today is no different. So here it is. What is one of your favorite fictional characters and why? I'll start. I've been thinking about this one. I go back to the early literature I read when I was in school and I think of this classic American novel and it's called The Scarlet Letter, and the main character of the Scarlet Letter is Hester. She has had an illicit affair. She has had a child out of wedlock and she's been ostracized by, this very puritanical village, that she's living in, on the east coast of the us. She's not perfect by any means as a protagonist, but, she's quite strong if you ever go around to the, outskirts of Geneva, you see plaques every once in a while, to these, witches ,

[00:03:30] Angela: that were burned in that time period, in the, 16 hundreds. And, I actually think about Hester Prin and I think about, how she, I think for American literature, she was really one of the first, strong female characters, and I can't, forget about her. That's mine.

[00:03:46] Angela: Annie, what about you?

[00:03:48] Annie: yeah, I really like my dystopian fiction and, everything by Margaret Atwood. So I think I'm gonna say my favorite fictional character of hers is, aunt Lydia. So I'm sure people will have, seen the TV series as well. the thing I really like about Aunt Lydia is that she's just truly scary.

Fascinated by the idea of women who uphold the patriarchy and women who work for the patriarchy. And she's just the definition of this. So she's one of the few women who's working for Gilead. They're, you know, really cruel and violent patriarchal society, that the books all all based around, and, I won't ruin the second book The Testaments for anyone who hasn't read it yet.

[00:04:28] Annie: Aunt Lydia's story gets more developed. You get to know more of a backstory, and it, becomes an even better character in the second book. , it's not quite as inspirational as, Angela's but maybe a bit more subversive.

[00:04:38] Angela: Yeah. I really am gonna read the follow up book.

[00:04:40] Angela: I wanna learn more about aunt Lydia, even though I don't wanna spend any time with her because she's awful. okay. Sorry, guests. Natasha,

[00:04:48] Angela: ,

[00:04:48] Angela: how about you?

[00:04:49] Natasha: So, how interesting to hear we,

[00:04:50] Natasha: we've had an example of a dystopian past and dystopian future. picked someone much more recent ', I picked Elizabeth Zott from, lessons in Chemistry because the character is another strong woman, and she's a scientist. but a scientist from an earlier era who really struggled because of the structural barriers placed in her way. she actually couldn't do things and wasn't allowed to do things because she was a woman , she's a chemist who wasn't, able to, really, function as a chemist in the environment, but managed to find ways through and managed to make a successful life, . And one of the things that reminded me of is how many battles have been fought by generations just before us, to enable us to be here today. I'm reminded when I was having kids and trying to juggle a career and the younger women who are now coming through how their lives are very different and they may not know what went before them.

[00:05:44] Natasha: So I think of Elizabeth Zott she's fictional, but she's overcome things that were even worse than anything I've faced and how we are making progress. So it's a positive, step to the future and, a reminder that we need to be solid with the women in much of the world who don't, and not for a long time or have the opportunities that we've had.

[00:06:03] Angela: Yeah, too true, too true.

Carrigan, no pressure.

[00:06:08] Kerrigan: Yes,

[00:06:09] Kerrigan: Yeah, I was reminded about PPI long stocking. I dunno if any of you remember her,

[00:06:14] Angela: Yes.

[00:06:14] Kerrigan: I suppose it comes from, reading stories to kids and, grandchildren or grand nieces and nephews.

[00:06:20] Kerrigan: Anecdotes from, from, Astrid lre. as a young child, I suppose, I was inspired about her, her spunkiness and, her not standing on convention and her

[00:06:31] Kerrigan: maverick home environment and how she lived on her own and she was quite independent. And, I think that, draws a commonality with the strong woman, fictional characters you've all chosen, in the sense that, she was prophetic and she remains, inspirational, in, many ways for me too, as I thought about it.

[00:06:51] Angela: Yeah, I think it's really interesting how we need these characters, you know, these are, in some ways our guides. yeah.

[00:06:58] Annie: Okay, so now we're onto the nightmare of the day. Natasha, can you give us a brief refresher on the measles virus itself?

[00:07:06] Natasha: Yes, of course. So, the measles virus has been first mentioned in the ninth century. This virus has been around for a long time, infecting us and getting used to us and figuring out how to be the incredible pathogen it is, in terms of its ability to infect and spread.

[00:07:23] Natasha: It's one of the most infectious virus. Viruses we know of. and, it causes, as I'm sure everybody's listening knows, it causes a rash, fever illness. the incubation period is generally seven to 14 days. it starts with a fever and cough and, the three Cs are cough cor and conjunctivitis, that, appear initially.

[00:07:44] Natasha: And then you get the rash appearing three to five days later, commonly, starts at the hairline and then spreads down the body. Most people do recover from measles, but if complications develop, common complications would be pneumonia.

[00:07:57] Natasha: That's a very frequent reason for being hospitalized. diarrhea, which can be severe and really exacerbate malnutrition or cause malnutrition or both. and then the worst complications probably, although less common would be an acute encephalitis that, most frequently follows a sort of post-infectious type of encephalitis or the delayed type of encephalitis called subacute sclerosis Panencephalitis, which is a delayed by several years and causes progressive neurological deterioration with, leading almost inevitably to death.

[00:08:29] Natasha: So in that situation, a child recovers from measles and then seems to be absolutely fine for a period of years before they start, going downhill and, finally dying from these late complications, , I don't know why. It just, it strikes me as being a particularly nasty sting in the tail of measles when you think it's over and behind you and it isn't.

[00:08:47] Angela: Yeah. Yeah, indeed. Like a lot of these viruses. So speaking of Kerrigan, can you remind us briefly of the pathophysiology of measles virus?

[00:08:58] Kerrigan: Yes. So, the virus enters, in the form of respiratory droplets, of variety of different sizes, and then attaches to a receptor on, macrophages or dendritic cells. So these are white cells that are found in epithelial surfaces, and after infecting these cells, they're drained to the lymph nodes and then spread to a whole variety of organs, in the body, as the virus replicates and, a period of viremia, ensues. So that's when we find the virus, in the blood. one of the interesting places that cells, infected with the virus disseminates to is the skin. And, As the infection progresses, an adaptive immune response ensues. And as soon as the IGM, which is the first, antibody, to be formed in response to any infection, as soon as IGM becomes apparent, it starts attaching to infected cells. And when this happens in the skin, it manifests as a mild rash. And so what we see, evolving, in terms of the, clinical [00:10:00] course of measles is that, the symptoms start off in a very non-specific way with these symptoms of cough and riza, conjunctivitis, runny nose. and mom gets more and more progressively worried and eventually she's very worried and she says, tomorrow I'm taking the child to the clinic. And on that day, the rash erupts. and of course the diagnosis makes itself apparent with, the combination of the rash and the fever and the prodromal onset. but. Ironically, usually, the clinical course improves, as the rash appears because it's a, symptom of immunological, activity and recovery. perhaps I should add, one of the, areas that the virus also disseminates to is, the lung. And I think we're gonna talk more about that because that leads to one of the complications, that Natasha mentioned.

[00:10:46] Annie: And Natasha, you mentioned measles is often thought to be one of the most contagious viral infections in humans with an r Naugh of up to 18 or so, being quoted with the RN being the number of unvaccinated or non-immune people who would become infected after a contact with an index case. What factors contribute to that RN number being so high compared to other viruses?

[00:11:11] Natasha: I think your question about the infectivity, you are probably thinking about the virology of it, and I'm a public health physician, so I think more about the epidemiology. but I think from a historic perspective, it's interesting to think about how long the virus has been around because, one of the reasons it may be so infectious is because it's had so long to adapt to us. and one of the features of that adaptation is that we are human beings. We are the only reservoir. There isn't an environmental reservoir. There isn't another animal that, in which this virus hides. and it's sort of perfectly adapted to the way we are. And a component of the way we are is we're social animals who gather together. We share each other's air. We, live in groups. Combined with its high infectivity just as a virus. And the fact that it in affects children so well, means that it spreads like wildfire amongst children that are not protected through immunization and it spreads like fire globally. People are becoming infected who've just walked into a room that somebody with measles had been in recently. but they weren't there anymore. So you can catch measles because the virus is still hanging in the air. It's not really a reservoir, it's just a residue of the person that they left behind. You know, and it does dissipate eventually. but it's that infectious

[00:12:25] Natasha: so this is one of the reasons we say in public health that measles anywhere is a problem everywhere. and that unless we control

[00:12:34] Natasha: measles everywhere, it will spread and it will find children that are not protected

[00:12:38] Angela: do we know how long it can live outside the body, like on a surface or in the

[00:12:43] Natasha: in, in the air, we quote two hours being the sort of upper limit of how long it, can cause a problem. I mean, it's a difficult thing to measure, but that's, what our infection control guidelines tend to, go to two hours.

[00:12:56] Annie: And contact tracing an absolute nightmare if you are trying to trace contacts who were just in a vicinity rather than who had direct contacts.

[00:13:05] Natasha: exactly. Yeah.

[00:13:06] Annie: Wow.

Natasha, I'm reminded of a story. We had an outbreak at school and then for some reason there were a number of cases in the public that appeared unrelated, and we were putting the line list of cases together and then noticed that two of the cases had, addresses on the same street. And when we investigated further, the, two were neighbors.

[00:13:28] Kerrigan: So one was a school boy and he'd picked up his measles at school and then he'd evidently passed it onto his neighbor. , . They had no contact with each other that they could recall. And so, you know, maybe they passed each other on the pavement or something.

[00:13:42] Natasha: It's a really good example and people often dunno where they got infected. It often happens, and you can tell from the virus if there's whole genome, sequencing, you can tell the virus is linked to an outbreak, but you can't find out how that person actually was exposed.

[00:13:56] Natasha: So it's a very common phenomenon.

[00:13:59] Kerrigan: I remembered and it flows nicely into, the conversation is that, one of the, salient features of measles. Infection is that because it infects white cells, it lands up depleting both t and B cells, from the immune system. people have noted that the immune response to various common antigens, such as bacterial pathogens, is diminished or absent after measles infection. in fact, it was noted, historically that children, as population groups before or after measles, vaccination, had a much, lower mortality. So countries where measles vaccine was implemented, reported a lower, all cause childhood mortality and. it was later elucidated. The immune mechanism of this, relates to depletion of cell antibody manufacturing cells or B cells. So, in context where communicable diseases are prevalent, measles infection can have a number of sequelae, not only directly related to measles, but also indirect, related to pathogen exposure and vulnerability to common childhood infections.

[00:15:10] Annie: That lead. Sound quite nicely actually, doesn't it? to the, next question, if there's anything you want to add on that, Natasha, how the, infection with other viruses or other bacterial pathogens can influence the severity of measles related complications,

[00:15:25] Natasha: I think Kerrigan's really addressed that, in her previous comments. And, I suppose the only thing I'd add is in terms of the countries that I'm mainly working with at the moment, this immunosuppression that occurs due to measles and this immune amnesia, where the infection, the, antibody cells causes the immune system to forget things that it was previously immune to. It may be something that, a child can recover from and if they've got good nutrition and they're in a high income country and where there's access to antibiotics, if they get. an infection with, for example, they get pneumococcal pneumonia or they get some kind of gastrointestinal infection, they can get treatment. But in a low income setting where children, have got malnutrition or on the margins, or where there's not access to sufficient care, if they do get sick, it can be really devastating. You can get a child that's, that's doing okay and they get measles and they're tipped into severe malnutrition and then they get something else, and then they get something else and they die. , as ker, laid out very clearly, like we don't necessarily measure that very well because we don't have a death from measles. Then we have a really, what's measured in all cause mortality, So there are these very general effects of measles, and that means that when we vaccinate, we also get some very general benefits.

[00:16:39] Natasha: So children grow up to be healthier because of the vaccine. You know, vaccinated children do better at school, and the economy is stronger as a result. So there are all these benefits that we, you know, we don't, talk about enough, but they, they really are, they, it really strengthens the community and the economy and everyone, when we have a good, well-functioning, measles immunization program, oh, it's true for many vaccines.

[00:17:01] Natasha: But I think measles is a kind of, probably the, strongest example with the best evidence behind it.

[00:17:05] Angela: And that'll be actually really interesting to see whether increasing measles cases also ultimately leads to more antibiotic use, which is something we saw with Covid pneumonia. I mean, just antibiotic use through the roof, right? . And when you put it like that, Natasha, I really wonder, what's gonna happen.

so moving, more towards. Immunity. Speaking of, you know, vaccinated, unvaccinated Kerrigan, how much of a role does waning vaccine derived immunity play in outbreak dynamics? Do adults who are traditionally considered to be fully vaccinated need to get booster shots right now?

[00:17:43] Angela: and if so, how long after that early childhood vaccination that they had, what do we need to be doing now?

It's an interesting question. I think the different answers for different contexts. we investigated in South Africa whether or not we should, consider boosting certain categories of people. but then came to the conclusion that there was no firm evidence to advise, boosting of, adults or young adults. The measles vaccine is, incredibly effective about 93% approximately. seroconvert will develop protective antibodies after one shot and about 95 to 98% of people, seroconvert after, two shots. but having said that, that's all dependent on the time of vaccination, relative to birth and also the context. So there've been some lovely studies and I'd, love to hear, Natasha's perspectives on this, That have shown, a loss of immunity in, younger and older adults. and this, is probably not, a consideration in our context where we have endemic and circulating measles. that varies, year on year, depending on the population of susceptibles because, individuals are exposed to measles multiple times through their lives and are probably boosted through, this natural exposure. Whereas environments where, measles has been eradicated, there may be, different considerations and, waning immunity may be a factor. Natasha, your thoughts.

[00:19:09] Natasha: Yeah, so it's a really interesting question that, whether or not wan immunity is important and it's something we do worry about, especially where, in context where the immunization program starts quite early, where vaccine effectiveness is lower, especially where there isn't a good second dose, program. but having said that, all the work that's been done to look at this, although it's very clear that immunity does win over time, it's not life long the period of time over which it does weigh and it's very long from what we can see even in settings where measles has been eliminated.

[00:19:39] Natasha: So we're not seeing a big. Issue at a population level where you'd say we need to boost adults. And it's not currently WHO recommendation to give a booster to adults. and strictly speaking, you know, we could argue about whether you'd call it a booster 'cause it's a live vaccine virus. So that's another semantic discussion, which I don't feel strongly about, but [00:20:00] just to mention that it exists. the thing that does happen from time to time is there have been small outbreaks where there seems to have been a people in the outbreak who got a very mild form of measles who were previously vaccinated and who were proved to be immune, but had low-ish antibody levels. And so, that they've played some part in an outbreak.

[00:20:19] Natasha: Sometimes they're only discovered because there were typical cases in the outbreak and then somebody else has got something that normally no one would say, oh, well maybe you've got measles, you know, An atypical rash or, know, just very mild symptoms and they, they test them and find, they've got some kinda acute reaction if they're stored serums from before they can look, or their antibody levels were like before and figure out that this was some sort of modified measles. and some of those cases have transmitted it seems to other people, but most don't. Mostly the risk of transmission is much lower. So it's little bits of evidence on the margins at the moment and not strong evidence and no recommendation for a booster currently.

[00:20:57] Annie: That's really interesting. I think you've probably just answered my next question about the more atypical presentations. Was there anything else on that point, Natasha, that you wanted to bring in about atypical presentations in partially vaccinated or any other group?

[00:21:13] Natasha: I mean, it's worth making sure if you are doing an outbreak, investigation in a highly vaccinated population, that you look for things that don't look like typical measles. You know, it's just if you're in that situation, and it's probably particularly important in healthcare settings because you've got such high risk people around.

[00:21:29] Natasha: the other thing, which again, is a bit semantic, but there is a thing called atypical measles, which refers to a really serious reaction to measles that followed the use of an inactivated measles vaccine that seemed to actually make measles worse.

[00:21:41] Natasha: So That's a historical phenomenon. We don't use that vaccine. It was used for a very narrow period of time, and then this complication was recognized. So it's just that the expression, if, listeners look up atypical measles, they'll probably get a lot of papers on this bad reaction to this experimental vaccine.

[00:21:58] Natasha: And that's not what we're talking about right now. We're talking about really like vaccine modified measles, which is a mild version or a very mild version of the real thing.

[00:22:06] Annie: Yeah, I guess that's a good point. Semantics are important, aren't they here? Especially with sort of vaccine hesitancy and the word atypical appears a lot in medicine and no one really, really knows exactly what atypical anything means in medicine. So yeah, We had an interesting scenario, in one of our hospitals. we had an, immunocompromised, young girl who was being treated for an acute leukemia of kinds, and she developed a pneumonia with, no discernible cause and was thoroughly investigated. And eventually somebody suggested that they test her for measles. And it turned out that her PCR reaction was positive and she had what's classically called a giant cell pneumonia. Remember I mentioned that the measles infected cells in the skin, are responsible for the rash that develops when antibodies appear. Well, this young girl was not able to, mount an immune response, and so she didn't have a rash, and so she presented with an unusual presentation of measles. the other population that, we see more frequently than, person's immunocompromised through cancer treatments is people with advanced untreated HIV. And again, early on in the HIV pandemic or epidemic in South Africa, I was working in a children's home and we had, 30 children. It was before the rollout of antiretroviral therapy, and we had. Measles just swept through this, children's home. And, more than half of the children died from complications of measles. It can be extremely virulent in immunocompromised persons, particularly with deficiencies in cell mediated immunity. That's the kind of immunity that responds to, viruses or abnormal, in, contents inside a cell. It doesn't rely on antibody. So prevention against initial infection is antibody mediated, but to cure yourself from measles to recover, you need cell mediated immunity. And, fortunately things have changed and, we have had, , a very successful rollout of antiretroviral therapy and also a very good prevention of mother to child. Transmission, programs, and these have reduced the impact of measles in our population of persons living with HIV.

[00:24:17] Angela: Carrigan. What were those children dying of? Exactly. I mean, of course it was measles infection, but what was the mechanism? Was it pneumonia? encephalitis? What was happening?

[00:24:27] Kerrigan: it was a combination of complications. usually it was, respiratory, in, progression. as the clinician, I would land up sending them to the referral hospital. And so I didn't really monitor them daily, but the reason for primary admission was often, respiratory, insufficiency.

[00:24:45] Angela: Hmm. Wow.

Okay. so moving on to diagnosis. as with most viruses nowadays, we are very reliant on the PCR polymerase chain reaction. how sensitive is PCR for measles kerrigan? And is there still any role clinically in, serology or IGM testing, or even viral culture?

[00:25:06] Kerrigan: PCR is very sensitive. and, serological diagnoses are also, but what's critical is the timing of the specimen collection and the kind of test that is done in relation to the timing of the specimen collection, as well as also the type of specimen. So, if one looks at the progression of, virus, in the blood, during the period of primary viremia, and then, the excretion of the virus in the nasopharyngeal. secretions, and in the urine, PCR is only going to work well, during those periods of high viremia. conversely, antibody production is only going to, demonstrate, a measles infection after antibodies have been produced. So if samples are collected early on in the clinical course of disease, PCR has a very high sensitivity, and again, it also depends on specimen quality. , so, you know, a good nasopharyngeal swab that has a lot of, excreted material is going to have a greater likelihood of being, positive if measles. Is in fact present. in South Africa, we routinely subject our, blood, samples to serological testing as a first line test. because it is, less costly. And, there are automated processes that we can use to, do the, the diagnostic testing, uh, especially during times of, outbreaks. if our, serological tests are negative, we then move on to a PCR. we also ask for a submission of a case investigation form that gives us these critical dates, the date of sample collection, the date of measles onset, the rash onset, and then the date of symptom onset.

[00:26:50] Kerrigan: And those are often different. And, we can then tell the progression of the course of disease. We found that PCR testing is really not helpful after four days, after, rash onset. So one has to be judicious in interpretation of, measles, serology and PCR results.

[00:27:08] Annie: Is there a particular site in the respiratory tract that's has the sort of highest yield from PCR? Is it the nasopharynx? 'cause we often use just buccal swabs or oral fluids. Is there a, difference or are they kind of equally as sensitive?

[00:27:22] Natasha: Now the virus is basically everywhere. So I think, you know, it's the timing as Kerrigan said, that's really important. I, I guess the only thing I'd add, on the serology side is, in many places, , there isn't a timeliness to get. The viral detection, methods that many countries really rely on serology 'cause it's the only kind of feasible thing, especially you've got remote communities and, so we are really interested in trying to get rapid diagnostic test methods, out to communities, like remote islands and places where, specimen transport's very challenging. And you can get virus detection from some of these methods as well, which, helps. I'm not an expert on RDT technology, but that's a direction of travel for remote areas. and the other thing I wanted to mention about serology is it also tells you whether somebody's actually susceptible.

[00:28:09] Natasha: Like if they've had a fever rash illness and it's not measles and they're antibody negative, then you have an opportunity to protect them so they don't get measles. So it's got that other upside as well.

, I love a good diagnostic test that'll allows you to do multiple things at once. Annie's asking some really good questions and it's making me really think, about, diagnosing, measles. And my parallel is often covid. We've had cases of, covid pneumonia where, you know, you do, a nasopharyngeal swab and you know, you really don't see much virus at all. And then if you're lucky enough to get a, bronchoalveolar lavage. You see a lot of sars Cov. have we got enough information? I know it's not easy, in certain settings to get, lavage specimens. can there be this kind of split with measles as well, where you see , clearly somebody who has a clinical pneumonia, but you wouldn't necessarily diagnose measles unless you get that, lavage that deeper, more invasive test.

[00:29:07] Kerrigan: there are many factors at play. you know, the course of the illness, the burden of disease, as Natasha said, the cell type that's infected is, the immune cells and they are ubiquitous, they're found everywhere in every tissue. And so one's likely to be able to pick up measles, from a variety of tissue types. another diagnostic test we didn't mention is a lung biopsy, but of course that is a really invasive specimen and one's only really gonna do that if, you know, if there's a good clinical indication and other diagnostic tests have failed to yield. helpful information. Natasha, your thoughts.

[00:29:42] Natasha: Yeah, I, I was sort of thinking, well, the big thing is, apart from the really great example, Kerrigan gave of an immunocompromised patient, for the most part, you've got somebody who's immunocompetent, who gets measles and gets measles pneumonia, and so you have the rash story as well. and as Kerrigan was saying, [00:30:00] the virus is kind of everywhere. So I, don't know how often it's needed. , it may well be, there's more virus on a b, a L, but it's

[00:30:06] Natasha: just not done because, you know, it doesn't arise. So,

[00:30:09] Angela: Yeah, I think you're both saying basically that is a theoretical worry and it's just not a real issue, I think in, in real diagnostics. that's good to know. That's comforting. so yeah, I think we've covered complications pretty well. we've talked about pneumonia. we've talked about populations, you know, who are more vulnerable.

[00:30:29] Angela: you did talk about, uncontrolled HIV infection. can you both kerrigan, Natasha, who is the person who's going to be more at risk for actual complications, pneumonia being the most common, but other complications due to measles virus?

[00:30:43] Kerrigan: In the developing context, we see, children under the age of one. And, those who are immunocompromised through being malnourished, low, vitamin A levels, particularly. these are the children who have the highest mortality. We had an outbreak in, 2009 to 2011. and over 20% of our cases were in children under the age of one. And, even, more so, I think it was about 15%, of the overall total were in children too young to be vaccinated. We were vaccinating at nine months of age at that time. And, these are the children who suffer complications. We've had outbreaks in communities that are vaccine hesitant, and then they say, tell us, oh, but I had measles as a child, and I got better. And so there's a perception that, measles is not. Serious infection. And it may well not be in a robustly healthy growing 7-year-old, but put it in a different context. the malnourished child in the informal settlement community over the road, and we have vastly different disease profile.

what I love about this conversation is how we're bringing very different perspectives on the problem. So I'm kind of at 50,000 feet working in my job at the World Health Organization and Carrigan. You're giving these lovely examples that probably really speak to people better than the 50,000 feet. Perspective. I think every year we estimate the deaths from measles and we have to estimate them because the data are just not good enough to really get an accurate picture of, the actual numbers of reports of deaths from measles. so that's how we came up with the estimate of, over a hundred thousand deaths, last year from measles. And to tie this back to the discussion of, who's most vulnerable based on what we observe in the field and the literature, , the case fatality rates that are applied for those youngest, the infants, the under ones, and for areas where malnutrition is prevalent, and all the other factors that increase case fatality, they are always a magnitude higher. So we have this concentration of, the majority of the deaths in that are occurring in the world are In those sorts of contexts of fragile humanitarian settings, countries where there are multiple challenges for children, you know, migration, internal migrants, you know, displaced people, where children, they're just not getting the nutrition and, there multiple stressor and, measles comes on the top of all of that.

[00:33:11] Natasha: So, at the societal level, we, we can see it from outer space where the deaths are happening. You know, they're in these areas of the world where there's multiple disadvantage. and where the solutions don't rely just on nutrition, but on systemic change. for. Those communities. I mean, not easy things to do to end war and to improve economies and to, strengthen health systems and strengthen immunization programs and feeding programs and everything else that gives a child a chance at growing up to be in a healthy adult. from the public health perspective, that's, where we need to save the lives. It's in those areas where these children are the most disadvantaged and they really are the, the youngest as well.

[00:33:57] Annie: Can I just ask a quick follow up question there? What, what's the global measles vaccination rate like now in 2025?

[00:34:05] Natasha: I love the idea that we'd have our data ready for 2025. the latest data we have is for 2023 because we don't get the final data from all the countries at WHO until we bring it out in the summer of the year after. So, in 2023, the global level was 83% for first dose. and that was a drop from the high of 86%, back in 2019. And then for the decade before 2019, we were pretty flat globally at 85 to 86%, that was where we were stuck. So we have really a systemic problem, getting coverage any higher at a global level. Right now the challenges are even greater, like the, the horizon.

[00:34:45] Natasha: I know everybody's feeling multiple challenges globally. You know, global funding is reducing from every direction. with the reduction of support for the World Health Organization at every level at global and regional and the country level, with countries in economic crisis and countries that were previously doing quite well, going backwards, we're not seeing a solution to this. in the coming years we're just gonna be firefighting and trying to fill the gaps as best we can.

[00:35:13] Annie: So we mentioned at the beginning about, late onset complications, in the form of subacute sclerosing PANENCEPHALITIS or SSPE. what are the risk factors for SSPE and are there any interventions that can help to mitigate that risk? Natasha.

[00:35:30] Natasha: from the public health perspective, the biggest risk factor for SSPE is, just age. So the younger you are, the more at risk you are from getting, developing SSP. so that's a bit of a challenge for parents because they're really relying on other people to get their kids vaccinated, to prevent their child getting infected when they're too young to be vaccinated. so it's like a big trust game in a way. Someone else protects their child, then your child is, safer. and then when your child is old enough to be vaccinated, they'll be protecting everybody else as well as themselves. It's a, you know, win-win. so age is the number one factor.

and the main solution to that is having high vaccination coverage. And what we recommend is 95% coverage with two doses. And that herd immunity that you get from that protects infants who are too young to be vaccinated. And when we say they're too young to be vaccinated, it's not that it's dangerous to vaccinate in the under ones, it's just that it doesn't work as well. , for two reasons. One is that, very young children that have, maternal antibodies, the vaccine won't work as well. But then even after those maternal antibodies have gone, there's still a maturity issue with the infant immune system. they just don't respond as well to those vaccines.

[00:36:42] Natasha: And you just don't get the same level of protection as you do if you, give it from nine months, 12 months or even 15 months. it works better at that, you know, the older that it's received.

also the vaccination may not work well in our context is that the vaccine is a live attenuated virus and it's incredibly heat labile. So it loses about 50% potency if it's maintained at room temperature, after reconstitution from powder to, active form. And, this can be 27 degrees is not hot. And so, you know, what we see in our clinics often is the queue outside for vaccination is, high and the nurse is very busy and she forgets to put the vaccine back in the fridge. by the time the 10th dose is extracted from the vial, the vaccine's no longer potent and it doesn't, actually expose the child to the antigen. So, those kind of factors at play and there's some interesting new developments, for vaccination, using, methods that are less dependent on, the cold chain. And the needles and syringes. I dunno if you want to talk to that, Natasha. Is the WHO involved in some of these, activities?

Yeah, I was actually gonna bring that up. at the end we were gonna talk about research priorities. I think, what you're talking about, the microarray patch vaccines are a real game changer. So va, this new vaccine delivery system, it's like a, it's a bit like a Velcro, you know, the rough side of the Velcro, that sticks to the skin.

[00:38:07] Natasha: And they're these little they call the microneedles, but they're not really needles. they just penetrate the outer layer of the skin and they, provoke a really good immune response. and these have been under development for some years now, and we're getting closer and closer to them being actually available. the idea is that you stick them to a child's skin and they sit there for about five minutes, and then you peel them off and the child is, you know, it's all done. so it's kind of magic. no needles. the delivery mechanism is more expensive than the standard. Which is going to be a challenge in terms of selling it to governments. but it's such an amazing step forward at the moment. We've just got measles and rubella vaccines in development. I really hope myself, this is my personal view, that at some point we have measles, mumps and rubella or measles mumps, rubella and varicella produce so that high income countries can use them because I think this might be one of the solutions to vaccine hesitancy, in a low income setting where we are really relying

[00:39:06] Natasha: on campaigns. if you have a vaccine that's in a patch form, it makes it much easier to do more than one vaccine at once because then you don't have like multiple injectables to give. and then in a setting, like a humanitarian setting where you are scrambling, where you may not have, very many health. staff who can give injections. Having something like these patches would be miraculous. I know Med Frontier is very interested in this technology. and I really hope we have it soon. I think the current idea is it may be available by 2030. I wish I had a magic wand and could have them available

[00:39:40] Natasha: yesterday,

[00:39:42] Angela: And so would these patches, take you outside the need for, you wouldn't need the cold chain with these patches. Are they, are they heat stable

[00:39:50] Natasha: So they're not, you would store them in the cold chain up to the point of the sort of local distribution and they can be carried and they're lightweight. you get rid of a lot of medical waste 'cause you've got no needles, no [00:40:00] syringes. so the volume because they're boxed up isn't necessarily that much smaller. But they're much lighter. And then the other piece of it that's really important is safety side. 'cause there have been some tragic issues with, vaccine safety where children have died because the wrong din has been used.

[00:40:14] Natasha: There was a cluster of deaths, due to, Sian from an anesthetic trolley being used to reconstitute vaccines. And so, yeah, I think, There are so many good things

[00:40:25] Natasha: about it that I think this technology should be used , for every vaccine, in my opinion. I in the future parents should just get a letter in the post with, stick these on your child now, and they'll stop everything.

[00:40:34] Angela: Yeah. Well, you know, sadly, we are gonna start seeing the disease more, which will make the vaccine or the prevention again, finally more attractive. Right. you know, generations now have not seen the disease and they just don't understand the devastation. so we've covered prevention and we've gone in the right order because we should always be talking about prevention before treatment, right? We would rather spare everybody in the first place coming to treatment. There is no proven antiviral therapy for measles, carrigan. Are there any, under investigation, is there anything on the horizon

[00:41:12] Kerrigan: down south, this is not, our, major area of expertise. We do have a lot of clinical trials units, but I've never been involved or aware of a clinical trial for an antiviral against measles active in, our context. So I, had to do a literature search to see, are there any, antivirals under, play from measles?

[00:41:29] Kerrigan: So, I'm, I'm hoping that Tasha will put my mind to rest to tell us that there's a treatment available next year.

[00:41:36] Natasha: I think we are still, at the stage of, the supportive treatment in terms of, you know, antibiotics for co-infections and things like that. But one thing that we. Can do is make more use of the one thing we do know about, which is the Vitamin A treatment. the two doses that is recommended, it used to be thought that it was just children who were deficient in vitamin A who needed treatment, but, it turns out that measles infection, it actually reduces your vitamin A levels in itself. so two age appropriate doses of vitamin A are recommended. And there was a, report from the, national Foundation for Infectious Diseases in the US saying that only, this is about five years old now, but only about half of the centers they looked at were actually using this as standard of care and recommending that everyone should get this, including, every child should get this if they have measles. And, one study found I think it was about it, 62% effectiveness with the right dosage of vitamin A, of preventing death from measles. So. We have that, it's not really treatment, it's more prevention of complications should we say.

[00:42:39] Annie: Yeah, I found myself looking up vitamin A dosing on up to date when we had an unexpected measles cluster in Nottingham. And it was my first weekend as a consultant and it was the only thing I could remember from medical school. I was like, there's something about vitamin A And thankfully all the doses were there. and yeah, we managed to get hold of some high dose vitamin A for, for two very poorly children on our intensive care unit. So yeah, vitamin A, hopefully there's the evidence backing it there that it does attenuate mortality.

[00:43:09] Angela: So Kerrigan, let's say we've now diagnosed a patient and we're supporting the patient, but what do we do with the people around that person who've been exposed?

[00:43:18] Angela: What are post-exposure prophylaxis procedures? Who should get the vaccine and when should they get it? Who should get immunoglobulin and when? And what about I immunocompromised people? That's always a challenge. What, what do you say for, for these scenarios?

[00:43:33] Kerrigan: Yeah, so, we encounter the situation quite often. what we try to encourage is, early notification at rash onset, because obviously the earlier one is able to, initiate, contact tracing and, ring vaccination, we call it. the more likely one is able to arrest person to person transmission. One of the problems with measles is that individuals, start, becoming infectious before the rash onset, and the symptoms are generally nonspecific with, a cough and, a fever, runny nose. And so it could, for all intents and purposes be an influenza or a ordinary cold or a covid infection for that matter. and the individual doesn't necessarily know that there's anything else afoot until. The measles rash appears. so by the time the public health authorities are aware of the case, there's often already been onward transmission. So, you know, what should we do then? Well, this is where we rely on, the high vaccination coverage rates to prevent this person to person transmission.

[00:44:33] Kerrigan: But, what we teach is that, contacts under the age of five, should be, vaccinated. and there we, you know, have an, investigation. We understand who the contacts were and where the child was, or the individual with measles was, who they were exposed to. the vaccine, if given within four days of exposure, may. Either abort or lead to a very, mild infection. But as I indicated, an individual, the index case may not know that they have got measles and the rash appears on day four. So the chances of getting a vaccine into, close contact is unlikely. there's this adage that, we hear, amongst people who've been working in the public health space for a long time around measles, that you can't chase measles. You know, some diseases, for example, like diptheria, the organism is transmitted in droplets and there's a, colonization period in the pharynx, in the upper airways, with what turns out to be a slightly longer incubation period. And you can abort infection by giving antibiotics to close contacts. But this is not really possible with measles. So one of the ways, to mitigate this is. Having a very low threshold for declaring an outbreak. One of the challenges in outbreak response, in vaccinating larger communities or health districts is that, the earlier you are aware of, cases and certainly onward transmission, the earlier one can plan, procure the measles stocks, et cetera. We've been, consulted on a number of occasions when pregnant moms have been exposed to a case of measles. And, this is always a difficult one because, live attenuated vaccine is not indicated or is contraindicated in pregnancy, although it is deemed to be safe, um, it's unwise to administer it.

[00:46:20] Kerrigan: So in these cases and in cases of immunocompromised persons, cancer patients and, people. with advanced untreated HIV, one could consider giving human normal immunoglobulin, which, contains sufficient measles antibodies to either report or, render an infection. much milder. this is a difficult scenario for us, in practice.

[00:46:40] Kerrigan: , when we have these cases, we, do vaccination of the surrounding schools and, hope to contain, the outbreak, but it's often very difficult.

[00:46:48] Angela: thanks a lot because this is very helpful now that we're going to be seeing, cases and, and having to deal with the, you know, protecting the contacts. So, , looking at a, better way to prevent, measles, uh, using vaccines. beyond traditional public health messaging, what have you seen to be the most effective strategy or strategies for improving vaccine uptake in communities that seem to really persist in their hesitancy?

[00:47:14] Natasha: well, one thing actually does improve. And address hesitancy, unfortunately, is outbreaks. it's interesting how many people are worried about vaccine and don't get vaccinated 'cause they haven't heard there is any measles around, and then suddenly there's an outbreak and they're rushing to get themselves vaccinated or the kids vaccinated. So, unfortunately that's not the way we want to address vaccine hesitancy through outbreaks, but it, it does seem to be quite effective. so I have a colleague Lisa Menning at WHO who works on vaccine hesitancy, and I wanted to channel her messaging , which really resonates with me, which is having, really good services is a really important factor in addressing vaccine hesitancy. we don't talk about it enough because we focus on the people who are hesitant and not on really the reasons they are. people who have great family doctors or great nurses that they work with. They are confident in their own healthcare providers.

[00:48:04] Natasha: Generally, people have huge trust in healthcare systems in general, but especially if they're good ones. But if they have a bad experience when they go to get their kid vaccinated, they're dismissed or it's just difficult. Or they can't get appointments when they need them. I mean, I saw a survey recently where one of the reasons people didn't get their kids vaccinated was because the clinic was dirty. You know, like are asking people to come forward and

[00:48:26] Natasha: do something that's for their good, but also for the good of the community. And so, when they bring a child to be vaccinated, to have, you know, friendly staff who are respectful and a, a decent environment. It doesn't have to be luxurious, but it should be, you know, clean and serviceable and appointments that fit with the community that that's being served.

[00:48:45] Natasha: You know, sometimes you have issues with, certain communities that move around a lot and they can't get services. It's all those kinds of, you know, we have to make sure our services are really good, our staff are really well trained, and a good communicators. I think it's, it's not rocket science, you know, having a friendly person at the reception desk. For somebody who's a bit nervous about

[00:49:05] Natasha: getting their child vaccinated and they come with their first baby and then they get treated a bit dismissively, these little things can have a big impact. That's one of the messages I really wanted to get across today that, you know, let's, just do the basics really well, so that people feel like they're getting a really good service and they're being really well cared for.

[00:49:22] Angela: that's really interesting. so you, might say that it's hesitancy, not necessarily to vaccines, but hesitancy towards our healthcare systems. what we're providing and vaccines are kind of a, a weather vein or a biomarker, let's say, of this greater hesitancy towards Yeah.

[00:49:41] Angela: what we're able to do or not do. yeah. Interesting. Hmm. Hmm.

[00:49:45] Annie: So, stepping back a bit and looking at more of the long-term prevention, again, how do variations in the vaccine schedule, like early versus delayed dosing, that goes on in different regions, impact long-term immunity and outbreak control?[00:50:00]

[00:50:00] Natasha: so I just wanna say something very quick about this rather than

[00:50:03] Natasha: dive into the schedules, because really the schedules don't matter that much and they're pretty robust. I think the number one issue is coverage. If you get high coverage, you'll control measles, whatever, whatever the schedule. people obsess about moving doses around and giving them a different ages. That can be important, but in the great scheme of things, in the big picture, it's much more important to get high coverage of two doses of measles containing vaccine.

[00:50:31] Angela: Carrigan, do you agree?

[00:50:33] Kerrigan: Fully, completely.

[00:50:34] Annie: so Natasha, can you talk us through some of the W HO'S current efforts and activities in the measles prevention sphere? And do you know yet what recent cuts to W Ho's budget will mean for some of these prevention activities?

uh, yeah, absolutely, and thanks for that question. It's a little bit difficult to answer right now because the cuts have really pulled the rug from under us, so we had lots of plans for this year. on supporting countries, for example, with the introduction rubella vaccine, which it's, I know it's not the topic today, but it goes with measles vaccine.

[00:51:07] Natasha: So there are many countries that are planning to introduce Rubella vaccine, and we wanted to really support 'em in that. so what's happened is essentially the US government was funding the whole measles vaccination program at global level, at regional level, and a lot at country level as well. And there's been a lot in the news about the Global Measles Rebello Laboratory Network, which gremlin it's called, which it funded a hundred percent of that as well. And that is a huge challenge for the laboratories in many, many countries. the piece that's not been in the news quite as much is the fact that, that the leadership, the surveillance staff, the outbreak staff, the people who helped support countries with their campaigns were also all funded by CDC. we had, participants in the stock program, which is known about for polio. We had a measles cadra that were going in and helping with outbreak response in, particularly in the African region. most of whom have had to be pulled back and been sent home because we didn't have the funding for them. the other thing to mention is that the CDC also provided people who incredibly experts. So we had a whole group of. colleagues who were helping support the program around the world in every region who were the most fantastic people, but also incredibly experienced. and so the expertise has been pulled out. If we had the money to replace 'em, we couldn't just replace 'em because the people themselves were so extraordinary. so we're, kind of up a gum tree, as you might say.

[00:52:31] Angela: How much clarity do you have right now, Natasha? On what, programs you are going to lose? What we are all gonna lose?

[00:52:39] Natasha: It's not that clear because it happens so suddenly, so we're trying to adapt and reprioritize.

We don't know. It's the bottom line. We know the immediate issues. For example, in the African region, we have measles and rubella catch up campaigns in Nigeria and DRC. Those are huge campaigns where rubella vaccines being introduced for the first time. we have a measles campaign planned in Ethiopia this year, and we have a measles rubella follow-up campaign in Pakistan planned this year.

[00:53:06] Natasha: Those are four high priority big populations, and we don't have the spare capacity to help countries with their planning and execution and evaluation of those campaigns. So, we are looking and hopefully we'll find support from somewhere. we're doing our best and exploring options, and if anybody's got some spare cash, please send it our way. I really appreciate the support for WHO. We we're hearing from many quarters that people who do understand that, it's a complex organization. It's not perfect, but we do our best to do good work, and to reach the most, underprivileged. People in the world, we're doing what we can and so do appreciate all the messages and support that we are getting.

So my next question could either be extremely cruel sounding or perhaps optimistic, because I'd like to know what you both see as the most urgent research priorities in measles control are over the next decade. So right now, obviously we're not gonna get the things we need, we want, but maybe next decade, maybe we can get outta this mess. So. what for you are the, real priorities right now? . Natasha

Well, for me, I've already mentioned ML maps, but I'd like to be greedy and say, I think electronic systems for identifying which kids have been missed by vaccinations.

[00:54:24] Natasha: having systems either on phones or just a way in which countries can find kids more easily , who've missed out, and get them vaccinated. because we really struggle that way and we end up doing, you know, these huge campaigns where we immunize every child we can, find, and we know many of them already been immunized.

[00:54:41] Natasha: So some information systems that's one of my areas of interest.

from our perspective, as, as Natasha has alluded to, the health system challenges, Vaccine, supply chain management, is critical. One of the reasons for under vaccination in our context is that mothers arrive or caregivers arrive at a health facility and the vaccine is out of stock and they have to come again.

[00:55:03] Kerrigan: And, obviously this imposes a, burden on the family, and in hard to reach areas may then account for, under vaccination, at a personal interest level. rapid diagnostic tests are, particularly helpful. if they have sufficient sensitivity and that of course is the problem, they will, support, More effective and targeted outbreak response. There is a differential diagnosis for people who present with fever and rash, and, it may not be rubella or measles, it could be one of the other viral illnesses of childhood. something that I find particularly exciting is our work in, surveillance. so wastewater surveillance for measles, is incredibly promising. We've, successfully sequenced measles from wastewater, constructed phylogenetic trees. And the potential from a bioinformatics perspective to understand the transmission of the virus in communities, will only strengthen our, ability to control, measles, in specific locations, particularly, underserved areas and areas where there is low vaccination coverage.

[00:56:05] Kerrigan: So, yeah, I think there's a lot, to be learned.

[00:56:08] Angela: Thank you so, so much. Kerrigan McCarthy of South Africa's National Institute for Communicable Diseases in Johannesburg. And Natasha Crowcroft of WHO in Geneva, Switzerland. And thank you for listening to Communicable the CMI Comms Podcast. This episode was hosted by Annie Joseph in Nottingham and me Angela Huttner, editors at CMI, comms Estimates Open Access Journal. It was edited by Dr. Katie Hostetler, oy and peer, reviewed by TAE member Dr. Daniella Yeshiva of the Military Medical Academy in Sophia Bulgaria. Theme music was composed and conducted by Joseph McDade. This episode will be citable with a written summary referenced by A DOI in the next eight weeks. And any literature we've discussed today can be found in the show notes. You can subscribe to Communicable on Spotify, apple, wherever you get your podcasts, or you can find it on SID'S website for the CMI COMMS Journal. Thanks for listening and helping CMI, comms and Esid move the conversation in ID and clinical microbiology further along.