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Exploring the Significance of Cytomegalovirus: From Diagnosis to Risk Reduction Strategies

  • Authors: Megan H. Pesch, MD, MS; Geeta Swamy, MD; Mark R. Schleiss, MD
  • CME / ABIM MOC Released: 11/21/2022
  • Valid for credit through: 11/21/2023, 11:59 PM EST
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  • Credits Available

    Physicians - maximum of 1.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 1.25 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for infectious disease specialists and others engaged in IDWeek who care for patients with or have an interest in CMV.

The goal of this activity is for learners to be better able to understand the burden of CMV and to identify patients to screen for CMV.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Prevalence of CMV infection in adults
    • Recommendations for CMV screening in patients who are pregnant or planning a pregnancy
    • Complications of congenital CMV in newborns


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  • Megan H. Pesch, MD, MS

    Assistant Professor of Developmental and Behavioral Pediatrics
    C.S. Mott Children's Hospital
    University of Michigan Health
    Ann Arbor, Michigan


    Megan H. Pesch, MD, MS, has the following relevant financial relationships:
    Consultant or advisor for: DiaSorin Molecular
    Speaker or member of speakers bureau for: DiaSorin Molecular


  • Geeta Swamy, MD

    Haywood Brown, MD Distinguished Professor of Women's Health
    Duke University
    Durham, North Carolina


    Geeta Swamy, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Pfizer

  • Mark R. Schleiss, MD

    American Legion and Auxiliary Research Foundation Professor
    University of Minnesota Medical School
    UMN Masonic Children's Hospital
    Minneapolis, Minnesota


    Mark R. Schleiss, MD, has no relevant financial relationships.


  • Iwona Misiuta, PhD, MHA

    Medical Education Director, Medscape, LLC 


    Iwona Misiuta, PhD, MHA, has no relevant financial relationships.

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  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Yaisanet Oyola, MD, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Exploring the Significance of Cytomegalovirus: From Diagnosis to Risk Reduction Strategies

Authors: Megan H. Pesch, MD, MS; Geeta Swamy, MD; Mark R. Schleiss, MDFaculty and Disclosures

CME / ABIM MOC Released: 11/21/2022

Valid for credit through: 11/21/2023, 11:59 PM EST



Megan Pesch (00:00:06):

Hi. Good morning, everyone. Wow. Yeah, you can hear me. That's loud. Good morning and welcome to our session exploring the significance of cytomegalovirus from diagnosis to risk reductions strategies. I'm so glad you all could join us this morning. I'm just thrilled with the full house we have. So a lot to cover this morning in 90 minutes, so please make sure you keep your questions or send your questions in as we go because we hope to make this as interactive as possible. My name is Dr. Megan Pesch. I'm a developmental and behavioral pediatrician at the University of Michigan. I'm the Director of our Congenital CMV Developmental Follow Up Clinic, and I'll be your moderator today. I'm joined by two all star faculty members. First we have Dr. Mark Schleiss from the University of Minnesota from Pediatric Infectious Diseases, and then we have Dr. Geeta Swamy, who is from Duke University and she's OB-GYN.


So just to get us oriented, where are we going? What are we going to cover this morning? So we'll start off, I'm going to give you a brief overview of CMV, why is it important and why is it important for us to increase awareness? We'll talk about CMV infection during pregnancy and we'll do that whole from screening to treatment and cover all of that. And then we'll do the same thing in the newborn perspective. I'll also talk about some risk reductions strategies and Dr. Schleiss is going to tell us about where we are with vaccines right now.


So that's a little bit about us and what we're doing this morning. I'd like to turn it over to you all just so we have a better idea of who we're talking to. So get out your devices and can you tell us what your profession is?


[NEW_PARAGRAPH]All right. Okay. Wow. So we've got physicians, nurse practitioners, nurses, pharmacists, other. Okay, great. We've got a good variety here. Fabulous. Let's see. And then next question, how many patients with congenital CMV have you cared for in the last year? Let us know.



That was some really inspirational. Okay. So zero for the most part. Some have cared for up to wow, 10 or even over 15. And a good chunk of you, I don't know. And I think that that's great. We'll dig into that a little bit more and maybe we will persuade you to perhaps screen a little bit more or well, we'll see. And then last question of this block. the healthcare system I'm associated with has a newborn congenital CMV screening program. Yes, no, or I don't know.


[NEW_PARAGRAPH]Okay. So wow, that's a good spread. So most say no and I don't know. That's fair. We should have also put not applicable for those not associated with the healthcare system. And then 20%, yes. Okay, very cool. So we're going to dig in now to the meat of what we're going to talk about this morning. So I'll start with just an overview of CMV infection. Why is it important to increase awareness? So when we think about the seroprevalence of CMV, it really varies across the world. And you'll see here for the places that we have data on, the ones that we don't have data on are white. But you can see the seroprevalence really very significantly. And especially you can see that dark red, that's where the seroprevalence is up into the eighties, nineties. And even in sub-Saharan Africa, it can approach 100%.


Especially in sub-Saharan Africa, that's a big issue, as many of you know about co-infection with CMV and HIV, which even in the antiretroviral era can be a really significant deal. So CMV, we call it the ubiquitous virus because it truly is everywhere. And here in the US, it's estimated that about 50% of people will have been exposed or become seropositive by the time they're 40. That used to say middle age and I changed that. You know, young adulthood. 30% of US children by the age of five years, and I think it's really interesting cause a lot of this transmission can happen from breastfeeding, and this estimates anywhere from 60 to 80% of North American women of reproductive age.


So why do we care about CMV? Well, there are a lot of reasons. Congenital CMV, which will be a focus of our discussion today, that has a real spectrum of sequelae, but it can be truly devastating. And then CMV, depending on the status of the host, can really infect almost any organ and do quite a bit of damage. So how is it transmitted? And this is why it's ubiquitous. It is transmitted through bodily fluids, almost any bodily fluids. So like I mentioned, breast milk, mucus, anything from semen, vaginal fluids, anything can transmit it. So as humans, we share bodily fluids for a lot of different reasons, even to kiss or breastfeed or whatnot with our family. So it is transmitted very readily and often.


So I just wanted to touch on a brief overview, and I know I'm speaking to a crowd of experts, but just to make sure we're all on the same page talking about the clinical course of CMV. So as an individual has their first infection, a primary infection, we do see a spike in viral replication. Then over time the virus does become undetectable, but it does become latent. So over time it can reactivate. And most of the time folks don't have symptoms, so you don't even know if it's reactivating. I think the biggest, I'd say, exception to that rule is of course if one is immunocompromised and then reactivation can have a whole host of symptoms.


So in immunocompetent people, I always say in healthy children and adults, CMV is usually no big deal and usually asymptomatic, maybe in 10% of folks, and these are immunocompetent folks, they can have a mono-like illness, but most people you know would not even be able to know that they were having a primary exposure. Immunocompromised people, and these include folks with organ or stem cell transplant, people with HIV/AIDS, anyone on immunosuppressive therapy, CMV can cause end organ damage. And the spectrum, I'd say, of issues that it can cause is far ranging and often it can be deadly.


So how about congenital CMV? So this is what I'm passionate about. And so this is, I'd say, the other exception to the rule. So congenital CMV occurs when a fetus is infected in utero. And so then we say the infant has congenital CMV. Congenital CMV is the leading cause of non-genetic hearing loss in children. So it's thought to account for somewhere around 20% of all hearing loss in childhood. And there is a high risk of neurodevelopmental disabilities. So we do see kids and we'll talk about the spectrum of presentations, but really that the consequences can be severe.


And so these statistics blow my mind every time because I feel like there hasn't been much of a conversation about congenital CMV, certainly not during my medical training up until recently. So 30,000 infants in the US are born with congenital CMV each year, or one in 200 babies, which I think it's wild. I think it's wild. It's so common and it's more common than the conditions that are screened for currently on the RUSP, which is the panel of conditions it's recommended to be screened for at birth, the heel poke metabolic screening test. More common than congenital listeriosis, toxoplasmosis, even more common than Trisomy 21, Down syndrome, fetal alcohol. These other conditions that I feel like we talk about quite a bit yet congenital CMV, we really haven't had much awareness about it.


And I just wanted to give a plug for a few abstracts that are going to be shown at the conference this week. So this is Abstract 2126, and it talks about the developmental and sensory sequelae that can happen from congenital CMV. And this is from review of a health record of a tertiary, I believe, children's hospital. So recommend checking that one out. And then another abstract. So this is Abstract 2145. Sorry. We've got that so small down there. And this really just talks about the economic burden of CMV just looking at the healthcare dollars spent. And go see the abstract and look at it in more detail. The summary is babies with CMV cost more. But I think it's tough for me talking about the consequences of CMV in dollars.


And that's because I got into congenital CMV about three and a half years ago when my third daughter was born with congenital CMV. It took us a while to figure out what was going on because as you can see, she was perfect. I mean, she was eight pounds. It was a typical pregnancy. We didn't find out she had congenital CMV until we found out she was deaf at two and a half months, and then went on a diagnostic odyssey to find out later that she had severe symptomatic congenital CMV. It took us a while on this diagnostic odyssey, and we'll get into this a little bit later because as you can see, she had her older two sisters at home who were just vectors for CMV, just their slobber everywhere. And so when we tested her, she came back positive. But at that point we really couldn't tell quickly if it was a postnatal exposure versus a congenital exposure.


So now CMV has completely changed my life. And we talk about quality of life, and I don't mean to say that my quality of life is poor because of my daughter. She is spunky and just amazing. I can't believe how much this little girl has endured. She's been in physical therapy, occupational therapy, speech therapy since she was four months old. Her name's Odessa. She got cochlear implants when she was 12 months. And then she did really well for a time, but she's globally delayed. She most recently was diagnosed with autism. And I think because of the autism sensory issues, she stopped wearing her cochlear implants, which is fine, except now we're all as a family switching to learn ASL. So it's been a journey and it really can be devastating for a family. So I just wanted to share that background.


All right. So now we're going to switch over to Dr. Swamy who's going to tell us about CMV infection during pregnancy from the OB-GYN perspective.

Geeta Swamy (00:13:55):

Good morning, everyone. Thanks Megan, and thanks for sharing your stories as well. I think that we all, especially how life has been the last few years, I think we all need to be sharing more stories so that we can connect again as well, so thank you. So I'm going to, as Megan said, switch gears just a bit and talk a little bit about this from the perspective. So I am an OB-GYN. I'm an internal fetal medicine physician and primarily do research in infectious disease or perinatal infection and vaccines to prevent infection. So while Mark is going to talk a little bit about where we are, we don't have a vaccine yet, but it is really I think ultimately our hope that one day we will have a vaccine to prevent this. Because as you'll hear I think through the rest of the discussions, all the things that we're doing from the standpoint of screening potential treatments, potential interventions, would be a much better place to be with a preventive vaccine.


But how do we think from the obstetric perspective about counseling patients? So there's these two categories that we often talk about with individuals who have had either CMV in the past, currently have CMV in the pregnancy identified, whether that's a primary infection or potentially a secondary meaning a reactivation, a reinfection. But if we start first with individuals who are coming to see us as obstetricians to say I had a pregnancy where I had a CMV impact, either minor or even with some significant major complications. The first thing we start out with is generally providing reassurance. There certainly can be recurrent maternal infection, but the likelihood of having two pregnancies significantly impacted by CMV is rather rare. And as you likely know that in the recurrent maternal infection space, that a neonatal or infant sequelae are generally quite mild. Now when we say quite mild, that still could be significant hearing loss, but it generally means not a significant impact on learning or cognitive abilities.


There may also be a discussion of serial surveillance, but that's really more so in the space of monitoring things from an ultrasound perspective as well as in the infant, not really about monitoring serial labs because that actually hasn't been shown to be effective if someone has already had a prior pregnancy that was impacted because they'll be seropositive. So we can't really look for things like seroconversion at that point. But if there's congenital CMV in the current pregnancy, we'll get into a little bit more about offering potential diagnostic confirmation which is through amniocentesis. It still doesn't really give you any way to exactly predict what may be the sequelae or what might the complication rate be, but you certainly would know if the fetus actually has a CMV positivity or not.


There really is no standard therapy and that's the struggle that we have from the obstetric perspective. That even if we identify things, we have nothing truly to offer that is evidence-based that we can say with a clarity that actually will have success. We will review a little bit of the data regarding valacyclovir as well as CMV immune globulin as well. But I would advise and offer that individuals should be seeking out folks like me in maternal fetal medicine and particularly those with infectious disease expertise. There are not a lot of us out there. Thankfully another thing that we have figured out during the recent years is that telehealth is a very good modality for consultation. And I hope that as we see things progress with the healthcare policy, that we will be able to continue to do those things across state lines given some of the hindrance with licensing and so forth.


So what is the risk of congenital CMV infection? So this is data looking at cohort of individuals, a cohort of pregnant individuals with a group that was seronegative during pregnancy and a group that was seropositive. And you can see here that the risk of CMV infection amongst pregnant women who were seronegative demonstrates that about one to 3% of them will acquire a primary infection during the course of pregnancy. There's then about a 30 to 40% chance of in utero transmission resulting in about somewhere around three to 12 of those out of 1000 ending up with congenital CMV. If you then look though at the seropositive group, you can see that somewhere around 20 to 30% of those will actually have a CMV reinfection. But as I mentioned before, the sequelae are much less likely in severity and you see a much lower risk of intrauterine or in utero transmission. But just based on the momentum, the sheer numbers starting with a higher pool from the beginning, you'll see that around six to 12 of those will have congenital CMV as well.


So I mentioned a little bit also about severity. What we know is that the CMV infection earlier in pregnancy is less frequent, but it is actually then more severe. So in other words, the likelihood of in utero transmission increases over the course of pregnancy. However, those that have transmission in the early part of pregnancy are the ones that have significant severity and that likely has to do with the timing of fetal impact or the impact on the fetus, meaning at the time of development of brain development as well as other fetal organ development going forward, that peak time up to about say as early embryology formation is in the first say 10 weeks, but then we certainly know there is significant CNS development as well as cardiac development all the way through about 18 to 20 weeks as well.


So then if we look at this from the perspective now of thinking about this as primary versus recurrent CMV infection, now we're talking about maternal infection and what are those risks then to the neonate? So if we go down this left hand side, this is thinking about it from a primary CMV infection perspective. About 30 to 50% of women of childbearing age are susceptible to primary CMV infection and somewhere up to 4% of them will experience that primary infection during pregnancy. 40% of those fetuses will then be infected, but only about 10 to 15% will be symptomatic at birth. And about 25% could develop sequelae up to age two. As you heard before, when the symptoms or the signs are maybe not as severe, they often go undiagnosed for quite some time. Those that are more severe are the ones that we tend to see during the course of pregnancy based on ultrasound findings that I'll show you some of what that might look like.


If we then look to those women who have recurrent CMV infection, we know that about 50 to 70% of women of childbearing age are susceptible to recurrent infection. But of those previously infected, just a few percent, up to maybe 2% will have a fetal infection as well. Less than 1% of those are going to be symptomatic at birth, again because the likelihood of severity is very low, and about 8% of those will develop some sequelae by age two.


So then of course when we talk about this, we think, well if we know all these things, should we be screening during the course of pregnancy? I know I saw that we have lots of trainees in the room. For those of you who've been out of training for a little while like most of us up here, I think, if we go back to our standard thinking about sensitivity and specificity of diagnostics, when do we implement screening, thinking about cost effectiveness, all of those details, there are really specific criteria to think about when implementing an effective screening program. First of all, the disease that you're screening to try to prevent or treat should have pretty serious consequences. It's why we don't routinely go around and screen for say the common cold. Many of us in our healthcare settings and so forth might have implemented a much lower threshold screening program, say for COVID-19.


So we want to think about things that have serious consequences in some way. Is there a high prevalence of detectable preclinical disease? So in other words, we are looking at say, colonoscopy screening because we know that you can actually detect some preclinical phase if you see dysplasia or some other things that you could then treat polyps and whatnot. So there really should be some high prevalence phase where you could detect that before the disease occurs. There really should be little pseudo disease, which means that you shouldn't have a lot of things that look like it but aren't that because then your screening and treatment can get really fuzzy. And there should be that same high accuracy for being able to detect it. The detection of the disease should be before that critical point. If you can only detect it at the time that all the complications have occurred, then it's really not a screening test anymore.


And there also should be little morbidity from the screening test. Now that may mean that it's as simple as doing a swab or a blood test, but the morbidity also could be related to the downstream impact of the test results. If you have a high false negative rate or a high faults positive rate, is there essentially morbidity associated with either of those? They certainly need to be affordable and it needs to be available. It doesn't help us a lot if we have a good screening test that costs a lot of money because it gets very hard to implement. There should be treatment that exists. And that's really a key here in the screening perspective from the OB-GYN point of view, because we really do not at this point have effective treatments that exist, again, that are proven to be evidence-based and effective. There again, that treatment should be ideally affected before symptoms begin and there should be little risk of toxicity from either the treatment and even the screenings I mentioned before.


So current maternal screening guidelines, these are guidelines here from US base, which are from American College of OB-GYN and Society for Maternal Fetal Medicine compared to those from Canadian comparable societies. But in the U.S., we do not recommend routine serologic screening of pregnant patients for CMV. A lot of that has to do with the limitations of IgM as well as maternal immunity not really being able to eliminate congenital infection. As we mentioned before, there is a lot of reactivation or reinfection. And I already mentioned there's a lack of proven treatment to prevent congenital transmission. In the Canadian recommendations however, there is actually allowability that says can be offered. Does not come out as far as to say that you should be doing or this is recommended to do. But there is the opportunity if there is availability of IgG avidity testing to offer screening. However, if that is not available, then they directly recommend against screening during pregnancy.


So what do you do if you think a pregnancy is complicated by a maternal CMV infection? So again, I'll just briefly mention here things about the IgM and IgG screening. So the classical teaching amongst infectious disease folks is that the presence of IgM indicates acute infection. We know that in pregnant women with a positive CMV IgM, that less than 10% of those will go on to have a congenitally infected infant. So patients that seroconvert however, have around a 30 to 50% chance that their child would be infected with CMV congenitally. And there's a significant difference then that's due to this high false positivity of CMV IgM assays because they often have cross-reactivity with other non-primary infections like Epstein-Barr virus and others.


And IgM unfortunately can persist, at least CMV IgM can persist for many, many months and possibly even years. So it gets very difficult to interpret what its presence means. IgG avidity testing has been much more helpful. It is more accurate to detect primary infection than IgM alone. At the time of primary infection, antibodies will have a lower antigen avidity than those present at the time of recurrent or later in a primary infection. So over time, as the antibodies mature, you have a higher avidity and the so that low to moderate avidity we believe indicates infection following 16 to 18 weeks from the primary time point.


So if we look at avidity testing, this is actually then linking it to the likelihood of congenital infection. And this was around 2,500 pregnant women who tested positive for IgM antibodies for CMV and then were followed again for the IgG and avidity. And you can see here that those who had a true IgM plus low to moderate avidity, again indicating recent infection, had a significant incidence of congenital infection, about 25% of those. But again, those with primary seroconversion was around 30%, so not too far off amongst those two groups.


So I mentioned already that IgG avidity does have some disadvantages though because we do not know a specified cutoff point to say that something has low avidity or either high avidity. And so we don't know what the significance is of the intermediate space. Serum and urine virology testing are available and out there, but it's not really clear how to correlate that with neonatal outcomes. And there's also discussion about interfering gamma or intracellular cytokine stating assays that these are newly used in other patient populations. So we do not have data on that in the space of pregnant individuals. So for women suspected of having a primary CMV infection in pregnancy, we really recommend that diagnosis is either de novo by the IgG seroconversion or in that space again of having an IgM positive, IgG positivity with low to moderate avidity.


So how do you know if there's been transmission to the fetus? So one, as I mentioned already, that we often see ultrasound findings. These are just an array of things that we see. Hydrocephalus is present in the pain labeled A, where you see an enlargement of the ventricles within the fetal brain. You also can see hyperechogenic areas in the brain and even as you see also in C that you might see those in the ecogenic bowel as we say as well. And in the frame in D, this is a fetus that's already been diagnosed as being growth restricted relative to its gestational age. And those flow dopplers that you see then help to identify how severe that growth restriction may be and if there's placental insufficiency. So we follow all growth restricted fetuses in that way.


Other things that you may see would be fetal ascites, microcephaly, enlargement of the liver and spleen and even ventriculomegaly as well. So how do we diagnose that when we see those things on ultrasound? So amniocentesis is helpful, but it is also something we have to be very cautious about how we do it and when we do it, because doing it too early in the pregnancy can certainly give you documented false negatives. The reason for that is that think about what an amniocentesis. It's actually fetal urine. So that means that there had to be maternal infection, then has to cross the placenta for the fetus to actually have virus to then have viral shedding so that it's then detectable in the amniotic fluid.


So if you do that too early, you would very likely not detect it and then say that this is not impacted by congenital CMV or there's not a fetal infection. So we really recommend if that's going to be done, that it's done somewhere after 20 to 21 weeks during the course of pregnancy. And that can become difficult when you have early test results to advise waiting for that time period as well. What could we do to prevent or ameliorate transmission? We'd love to say that we have treatments that we could screen and identify. Unfortunately, I'll go through here some of the data, but I will just preface this by saying again, we do not have a treatment that is universally recommended in pregnancy. That doesn't mean that people might not be utilizing treatments, but I can say right now that there's not clear evidence to say that it actually is effective.


So we did conduct a study of hyperimmune globulin or CMV specific hyperimmune globulin during the maternal fetal medicine network, or NICHD funded network. And in that study we enrolled thousands upon thousands of women, screened around 200,000 women to enroll individuals. And unfortunately it was not demonstrated to be effective. So here are actually the data. You can see around 206,000 pregnant women were screened across 17 clinical centers. That actually took about six years to then enroll the 400 women or so. This is actually still the largest study in pregnant women that was done from a treatment trial perspective to prevent congenital CMV. And unfortunately you can see that there really was no significant difference between the treatment group and the placebo group. There was some maybe trend to see that on the symptomatic CMV. Again, that first the primary outcome was based on CMV testing of the infant. We do have our waiting for additional data analyses ongoing. We followed those infants up through two years of age with neurocognitive testing and evaluations as well. And that data is being analyzed this time.


There are studies that look at high dose valacyclovir to prevent congenital CMV. And some of this data is probably the most promising so far that has shown in this phase 2/3 study that there appears to be some benefit potentially from high dose valacyclovir to reduce vertical transmission. The issues of course is that one of these studies was observational. The study that was randomized, while it is really helpful for us to think forward about how to do these studies and additional studies that should come, there are some questions about how individuals were randomized. There's also some questions about the primary outcome and use of data as surrogates for say actual laboratory testing or amniocentesis results as well. There are of course also side effects of valacyclovir, including neutropenia, thrombocytopenia, and the others that are listed here.


So I come back then to CMV management and pregnancy and what are the recommendations? So at present, the American College of OB-GYN states that there are no therapies that are recommended for treatment of maternal or fetal CMV infection. The Society for Maternal and Fetal Medicine specifies that ganciclovir and valacyclovir are not recommended and that treatments really should only be offered through research protocols. The Canadian recommendations differ ever so slightly and say that you can consider use of valacyclovir, but hyperimmune globulin should not be utilized. I think that, again, I will just say that there is data to suggest that valacyclovir might be beneficial. The data on hyperimmune globulin I think are pretty clear. It is an incredibly expensive therapy. It also has side effects and is not easy to administer. So it is a little disconcerting when we see people continuing to use that.


So at present in the US, we really are not recommending treatment during the course of pregnancy. And as I showed you, there are other data out there from other countries or other recommendations that come forth. So I will hand over to, I think, to Megan and Mark.

Megan Pesch (00:34:19):

Thank you. That was great. I like that. Keep calm. Conduct clinical trials. Yes, fun.

Geeta Swamy (00:34:19):

It's hard.

Megan Pesch (00:34:26):

Fun clinical trials. That too. All right, so we'll shift over. I'll talk about congenital CMV in newborns and really talk about the pediatric perspective. So when we think about congenital CMV presentation at birth, the classic, and still today people talk about this dichotomy in disease and these labels of symptomatic versus asymptomatic, which I put in quotes and we'll explore that in just a little bit, really is based on how these babies look at birth. So it's actually really not symptoms. Technically it's signs. So 10% are born with signs, so the classic blueberry muffin baby, and I'll go over that in just a little bit. And then the other 90%, they appear completely healthy and are undetectable unless one was to do further studies or screen these babies. And so I think that's one of the reasons why we're not hearing about this so frequently is because really it goes undetected quite often.


I think the dichotomy of symptomatic versus asymptomatic is it just hasn't held up over the years as we are learning more and more about the developmental outcomes of these children. And I think as we all know, when we think about long-term neurocognitive outcomes, there's a heck of a lot more that goes into it other than presentation at birth. And so we can see as these kids grow up, they may develop hearing loss, they may develop other disabilities. And so I'm more of an advocate for a spectrum. As a developmental pediatrician, I do a lot of autism, so I'm a big fan of a spectrum. And so children might be born looking one way but then may move around the spectrum. And this has been true for my daughter.


So here's your classic symptomatic, congenital CMV baby. And that's defined by one or more of these signs at birth. So small for gestational age, microcephaly, you can see this little one here, petechia rash, jaundice, which is a direct hyperbilirubinemia, hepatosplenomegaly, they may have seizures and really the seizures stem from intracranial abnormalities, which obviously you cannot see unless you may have a sign with seizures or the microcephaly, and then laboratory abnormalities. I will say that hearing loss does not count as a symptom. So when we think about babies with asymptomatic CMV, if one was to be born with profound bilateral hearing loss alone, they would still be considered asymptomatic.


So of those asymptomatic babies, about 20% will go on to develop sensory neural hearing loss during childhood. And it's really tricky because not all of them, actually, only about half of them, are born with any hearing loss, not even born just in that neonatal period. So there's delayed onset which makes this really tricky to catch. And other disabilities are certainly less common in asymptomatic CMV. However, I think the research isn't exactly robust in this area. So I'm hoping that, well, we'll go into that in a sec. And then symptomatic congenital CMV. And you think these are often the babies with intracranial involvement, so their sequelae have the potential to be more severe. About three quarters will develop hearing loss, and then there's a whole host of other developmental neurocognitive delays or sequelae that can happen. We didn't talk about intrauterine fetal demise. That's I think an area of ongoing research. But in terms of mortality, I should say, about 5% of babies with symptomatic CMV will succumb to their disease.


And so this is how I think about the neurodevelopmental sequelae. So CMV is like a neurotropic virus. I wish we had time to nerd out on the neuropathophysiology because it's fascinating. But just to look at it from a general point of view, CMV loves the fetal CNS. And so it makes sense. The earlier a fetus is infected and then that typical development of the CNS is disrupted, the more downstream effects that can occur.


And so back to hearing loss, about 50% of these babies will have hearing loss in the neonatal period and then about 50% will progress over time. So they can be born with a mild hearing loss and end up with a profound bilateral. It can be fluctuating, too, which it's very tricky to catch these kids. And then of course half will be late onset. And so some of these children will lose their hearing. The majority will present by age five. But I've had patients who progress to progressive bilateral hearing loss in their teen years. Not common, but it does happen, which really I think emphasizes the point that we need to keep a close eye on these kids.


And so asymptomatic, 20% with hearing loss by age 18. About 45% will have vestibular engaged stability dysfunctions on testing. How that translates into real world disabilities, I don't think we really know and balance difficulties as well. But this is where I think the research is lacking. In my clinical work, and I think, Mark, you'd probably agree, we see autism in these kids all the time. I don't think the research is there to support it yet, but it makes sense. If you think about like a CNS insult in utero, learning disabilities, developmental delays in these asymptomatic kids. I mean, Mark's doing a great study that will help us answer these questions. But the research has looked strongly at symptomatic kids, obvious kids. And so I think we just really need to drill down more into this area. But asymptomatic, symptomatic, it's a confusing misnomer. I'd like to do away with it if I could.


And when you look at these babies who present to have a typical exam at birth, this is a study from Europe. And so when they looked at these babies, they examined their eyes, they did hearing tests, labs, and then neuro imaging of these 34 infants, 56% had more than one finding pop up. And this is in Europe so the criteria for treatment with antivirals is a little bit different than it is in North America. But all these babies were then, by European standards, switched over to symptomatic and then received antiviral treatment. The difference here is mostly the isolated hearing loss. We don't in North America tend to treat for that, definitely not by guidelines, but there is variation between practitioners. So I'm going to switch over. I'll hand it to Mark. And Mark's going to tell us a little bit about the diagnosis of congenital CMV in pediatric patients.

Mark Schleiss (00:42:16):

Thank you, Megan. That that last study, that raunchy study, it's a very important study, isn't it? And we'd like to think as clinicians, our physical examination skills, that the bedside history and physical should be sufficient, but it appears they aren't. Well, let's talk about our physical exam skills and the bedside presentation of a couple of cases. Here's a baby born at 38 weeks gestation, a little boy with rash and icterus, a normal spontaneous vaginal delivery to a young mom, 18 year old G1, now P1, admitted to the NICU for treatment and evaluation. And in addition to intrauterine growth retardation, has hepatosplenomegaly, fails the newborn hearing screen and the preferred nomenclature now is a refer on the newborn hearing screen.


We don't want to label a newborn failure this early in life, but the ophthalmologic exam shows retinitis. The platelet count shows thrombocytopenia, the transaminases are elevated, and there are periventricular calcifications in ventriculomegaly. So this one I think most of us would identify on physical exam. The next question is how do you confirm the diagnosis, the presumptive clinical diagnosis of congenital CMV? Get out your voting devices and let's vote. Would you do serologies for IgM, IgG? A urine PCR? A saliva PCR? A urine culture? Good luck finding a place that will still do a urine culture for CMV. Or would you pull the new newborn blood spot for testing? Or would you do all of the above?


[NEW_PARAGRAPH]Okay, so urine PCR, and I think this would be my answer. I think this is the preferred modality for diagnosis. A little disconcerting to see almost a third of the audience, a little over 25% of the audience pick serology. And I think that this is a useful adjunct as a part of the overall diagnostic evaluation, but it's rarely if ever really diagnostic in its own right. So I think we need to get away from serologic diagnosis in these babies. A lot of you picked saliva PCR and that's a good choice, generally reasonable. The trouble we have, and I think we're still trying to get our arms around this in the CMV world, is what to do with a baby that's already gone to breast. We know that in a seropositive woman, viral DNA is present even in colostrum. And so I usually will respond to a positive saliva PCR by recommending a urine be done. Anyway, a lot of you picked all of the above.


So these are I think, good answers. And the other key point here is by convention, we do want these diagnostic studies to be done prior to 21 days of age. Now there are always exceptions to that rule of thumb, but this is to really differentiate in utero acquisition of infection from postnatal transmission or transmission in the birth canal, which is also known to occur.


Here's another case, and this is a little bit different. So this is one of these babies that we may not have identified in the past. A well baby ready to be discharged, feeding normally, passes all of her newborn screens, normal physical exam, but she refers on the newborn hearing screen. What would you do with this baby? And so would you recommend a urine PCR for CMV? A saliva PCR? A blood PCR? Would you work her up right out of the gate with a blood count hepatic panel? Refer her for a full ABR? Do brain imaging? Ophthalmology referral? All of the above? How does the audience feel about this question?



Okay, so most of you, the plurality said all of the above. And then 24% said CMV PCR from urine. 17% said get a full ABR to confirm hearing loss. And I think that this is a judgment call. My personal preference would be to focus on diagnosing CMV if you can. Now, there are a lot of caveats there. Most babies that refer on the newborn hearing screen actually hear normally when they have their follow up evaluation. Most babies who refer don't have hearing loss and don't have congenital CMV. But this is your window to really definitively make the diagnosis of congenital CMV. Because by that time that baby trickles down the pathway of diagnostic evaluation, repeat hearing screen, ABR, invariably when they first see an otolaryngologist, they'll be fluid behind the ears and that will precipitate another visit in a couple of months, that baby may not have CMV testing done in our current standard of care until they're six, nine months of age and then it's impossible to know that they had congenital CMV.


So I think that's why we've seen so many legislative initiatives around the country focus on testing babies who refer on their newborn hearing screen. This slide demonstrates some of the other approaches one can take. The dried blood spot is problematic because we don't know the sensitivity in this setting. But in a baby who is found to be shedding CMV at nine months of age and has confirmed hearing loss, this may be the only way to make the diagnosis if that family lives in a state where the dried blood spot is still accessible and is not destroyed. So diagnosis after three weeks of age, again, problematic, hard to differentiate congenital from postnatal infection. And that's why I think in this hypothetical scenario that was laid out, I think it's probably premature to do the LFTs and CBC and neuroimaging until you know that the baby's shedding CMV.

So I think definitely needs hearing follow up and needs a CMV test. And this can be really important because as Dr. Pesch alluded to earlier, it can also help us avoid that diagnostic odyssey of working a baby up for all of the genetic and other ideologies of hearing loss. Because you don't know. You can't be certain that that's congenital CMV if that baby's shedding at nine or 12 months of age. So congenital CMV, I think we miss most of the cases because most of the babies are asymptomatic. Only about 1% of babies with congenital CMV are diagnosed on clinical suspicion alone. And this becomes, I think, an important talking point when we think about universal newborn screening. Have we reached the point now where we should be just testing all newborns for congenital CMV?


How do we approach treatment of these babies after their diagnostic evaluation? The studies cited in this slide, and there'll be some discussion about this at the PIDS symposium at 1:30 PM later today, are to focus on antiviral treatment only for those babies that fall into a symptomatic category, recognizing, as Megan already alluded to, that the definition of symptomatic disease is different in Europe than it is in the rest of the world. And so we need to figure this out, the CMV community. We need to get our arms around this whole business of what's really symptomatic infection and what isn't. But if a baby meets these criteria as outlined in the Rollinson et al reference, which was referenced on an earlier slide, at least in the United States, we would recommend treatment with valagancyclovir for symptomatic babies commencing at less than 31 days of age if possible. And I think the results of the CASG multi-center collaborative study does speak to an improved outcome, both in terms of hearing as well as neurodevelopment.


Valganciclovir is not an innocuous drug, however, and these babies need to be monitored. They need to have their labs monitored closely in particular to look for neutropenia and also to look for hepatitis. In some animal models there's a concern about carcinogenicity and azoospermia, although that's not been validated in humans. Congenital CMV is really a team management effort, especially for symptomatic babies. I personally feel the focus of the evaluation and follow-up should be in the audiology suite because after all, this is the most important long-term developmental disability, by important I mean most common, from congenital CMV hearing loss. And to my thinking, this is the justification for universal congenital CMV screening to capture those babies that would otherwise be missed, who would go on to have hearing loss and the attendance speech and language development concerns.


But developmental monitoring is critical. Treatment of sequelae and then support for the family, particularly helping the family get engaged with support systems that are available to help provide resources to monitor these babies over time. We recommend repeat blood counts at least weekly for six weeks, measuring the ALT at least monthly. And I usually recommend an ophthalmologic evaluation as well as a serial audiological assessment and developmental assessments as well. So it really requires a team based approach.


Interesting and often overlooked on this slide is the role of the dentist. We know that congenital CMV is associated with dental abnormalities in utero. It infects the odontoblast, one of those cells that's responsible for development of teeth. And so children with congenital CMV are really prone to dental caries. And of course, all of these other consultants and experts are a part of a larger interprofessional team that can help optimize the management of these babies.


Screening, I've already alluded to the issue of newborn screening. It's provocative to me to look back on the work of Robert Guthrie, who was the father of newborn screening. Guthrie had several family members with the metabolic disease fetal ketonuria, and he devised a screening test for this. And very interesting to look back at these papers and position statements from the AMA opposing the adoption of the Guthrie newborn screening test, including some experts who were very concerned about the risk of false positives, the risk of the vulnerable child's syndrome, even though that term hadn't been coined yet at that time, and rather reminiscent of some of the same discussions we had about universal newborn hearing screening 30 years ago when the American Academy of Pediatrics, at least initially was not supportive.


And so Guthrie, who was a graduate of the University of Minnesota, stuck to his guns and Massachusetts was the first state to adopt universal PKU screening. And where do we stand today with the recommended uniform screening panel or so-called RUSP? Where do they stand on CMV? This RUSP list is put together by a committee that reports to the Secretary of the Department of Health and Human Services, and it provides a framework and suggestions for how individual states might approach adoption of newborn screening assays as a part of their newborn panels, recognizing that there's some state to state variation in this and some states nominate conditions and bring conditions online before others. For example, in Minnesota three or four years ago, we were the first state to bring on spinal muscular atrophy or SMA screening.


The RUSP has not yet agreed to hear any detailed discussion about adding congenital CMV to the list. They want more data and I think more data is always great, but parents are voting with their feet. They're going to their state legislatures, they're going to their representatives and they are asking for newborn CMV testing. And to me, ultimately this becomes also a health equity issue. I would hate to see a situation emerge where only the families that have resources for CMV testing at birth will be able to get their babies tested. That's why I think state health departments should own this because every baby should be treated the same when it comes to this issue, every issue really. And we know that congenital CMV disproportionately affects children of color and that that's a concern that I think we need to talk about more in the years ahead.


These are the well-known Wilson and Jungner criteria for newborn screening. I won't belabor them in any great depth except to just point out that these were published in 1968. And Wilson and Jungner in this booklet on principles and practices for screening for disease, talk about it in their little booklet. They say we recognize this will change with time and technology and in this genomic age now where it's possible to get your baby's genome sequenced today, we need to rethink these Wilson and Jungner criteria. I would encourage the RUSP to keep this in mind when they gather in their committee meetings to talk about this moving forward. I think a case can be made that early identification of congenital CMV allows diagnostic evaluation, most importantly of all, anticipatory monitoring for hearing loss. And we get these phone calls all the time from pediatricians who have a two year old or a three year old in their office who's not speaking. Any good pediatrician obviously will test that baby's hearing, discover the baby has hearing loss, pass the newborn hearing screen.


Well, I think to myself, there's another one. And there we've missed that critical 1-3-6 EDHI mandate, early hearing detection and intervention, where if we'd only been monitoring that baby, we could have made a difference in that baby's speech and language development. Antiviral therapy, neurodevelopmental evaluation, all of these issues are also issues that speak to inclusion of congenital CMV in the universal screening panel. Naysayers would say, "Well, we've got the concern about the vulnerable child syndrome. We may overuse antiviral therapy." Yeah, we may, and I'm worried about that. I think we do use overuse antiviral therapy in asymptomatic babies. We may create undue parental anxiety. We need to think about cost issues. We need to think about the vulnerable child's syndrome. But most babies who are identified, parents are actually very happy to know. They want the knowledge. They want the information. And I think it's very paternalistic to say that we shouldn't offer newborn screening for CMV because of these concerns. Let families decide this for themselves.


These are some of the approaches to congenital CMV screening, dried blood spots, urine, saliva. Of course, dried blood spots are so much cheaper. Because the most costly thing in our practice of medicine is the cost of our time and the blood dried blood spots are already collected as a part of infrastructure of newborn screening. If we say that somebody has to put a bag on every baby to collect a urine sample before discharge from the normal newborn nursery, that becomes a prohibitively costly intervention. But dried blood spots, they're already being collected. So why not test these for CMV? In the landmark CHIMES studies of the early 2000s, the sensitivity was suboptimal. But we've seen now with better DNA recovery modalities and overall sensitivity of over 75%, this was work done by my laboratory as well as Sheila Dollard's laboratory at the CDC.


And then when we combined our sensitivity between the two labs using different primer sets and different real-time PCR conditions, the overall sensitivity was over 85%. So don't let the perfect be the enemy of the good. If you've got a test that will identify three out of four babies with congenital CMV and offer those families the opportunity for some follow-up and some early intervention, I think we should do it. And this was the inspiration behind this bill, this piece of legislation that made its way through Minnesota. First started this work in 2016 with actually one of my patients and her mom. We went down to the state legislature with a stack of handouts and looking for somebody who would talk to us. And six years later, we got this legislation passed. Great kudos to Leah Hendrickson and her family for their advocacy work as well as the work of Karin Housley, the Senator in Minnesota who sponsored the legislation, and so many families that came out of the woodwork to advocate and help get this bill passed.


Hearing targeted screening is also becoming very common and legislatively mandated in several states now in the United States. We know that from this, the work of Karen Fowler and others in the CHIMES cohort, that newborn hearing screening alone, will miss most cases of congenital CMV associated hearing loss. And so although newborn hearing screening is vital and has really changed pediatric practice, we know that CMV associated hearing loss is delayed. And so we will capture some babies by targeted screening, that is to say testing for CMV and any baby that refers on the newborn hearing screen before they go home. But I think a strong case can be made for universal screening, which will roll out in Minnesota in 2023. We also have seen universal screening move forward in some Canadian provinces as well. It's now standard in Ontario and being adopted in Saskatchewan. And in the United States, you can see the states that have passed legislation.


Unfortunately, most of these state legislative initiatives are unfunded mandates. And so we do see state legislatures that mean well and want to see this move forward and pass bills not only instructing state health departments to provide educational modules, but also do targeted screening. But often no funds are allocated. We did get a robust fiscal note as the legislators like to talk about roll this out in Minnesota. So we'll have a pretty comprehensive program not only for testing, but for follow-up of these babies as well. So I look forward to your questions in the question and answer period, but I'll turn it back over now to Dr. Pesch, our moderator.

Megan Pesch (01:02:57):

Awesome, thank you. Really groundbreaking work happening in Minnesota. I think all eyes are on you, so no pressure. So let's talk about CMV risk reduction strategies. And I used to say prevention, but having gone through this myself, having transmitted CMV to my daughter, I feel like you can only do what you can to reduce your risk. Because if someone can acquire a CMV infection through breastfeeding, well, what are you going to do? So here are some things that one can do, we'll talk about, to reduce risk. I'm just going to skip through this. So I think the first thing we need to do to reduce risk is increase awareness. So only about 9% of women have even heard of CMV. And so really we need to increase awareness. No one's going to change their behavior if they don't know that it's a problem.


So here's the figure about awareness versus incidents of congenital conditions. And so you can see the blue bars. That follows with the number of children. You can see it on that top X axis. Number of children who are disabled, you could say, by the condition every year in the us, so about 6,000 for congenital CMV. Or sorry, 6,000 orange dot. The blue bar is a percentage of women who have heard of it. And so you look down, that's about 9%. You compare that to say Down syndrome, second bar from the bottom. We've got about 90 something percent of women who have heard of it. And that's proportional to the number of cases each year. Of course, the cases of CMV are higher, but these are the children who end up developing as far as we know, long-term sequelae. So a lot of work to be done here.


So how do you reduce your risk and who's at highest risk? So anybody who works with young children or has young children at home. So there have been studies that have sequenced the virus of children with congenital CMV infants and then gone and swabbed the sibling. And it's the same. So I mean, when I was pregnant, and hindsight 20/20, but when I was pregnant, if my kids took a bite of their waffle I had made for them and just left it, I was eating that waffle, for sure I was hungry and pregnant. But then you think about the saliva that was left or the kisses on the lips or things like that. So women, and we say pregnant women, but it's anytime to acquire the virus.


So women who work with toddlers in daycare especially. So there have been studies that have shown that any time up to 70% of toddlers in group daycare settings can be shedding virus in their urine and saliva, and so individuals who work with children. And we always talk about women, but it's really on everybody because if a man or anybody contracts CMV and then kisses that pregnant person, well there you go. So I feel like we put a lot on women, and so I'm getting up on my feminist soapbox here to say it's everybody. And so the interventions that we're doubling down are hygienic counseling. Well, it would be very odd to contract CMV through just casual contact. It's really that swapping of bodily fluids, so really doubling down on hand hygiene after diaper changes.


And I think at home people let down their guard. You're changing your toddler's diaper. Oh, it's just pee. Oh, don't run down the stairs and you forget. You forget to wash your hands or get that Purell. But I think tying this to these consequences can help people get it and really start to make those changes in their behavior. And so that's what we have seen through some initial studies. So avoiding contact with saliva, putting the pacifier in your mouth to clean it after it's fallen. So gross, but many people have done it. Don't share utensils, straws, don't eat that waffle, washing hands, things like that.


And so Mark's group has shown in this amazing study that I think it wasn't planned to happen, but the COVID-19 pandemic provided a great opportunity for us to test these hygienic practices. In Mark's work, he's screening thousands and thousands of babies universally for congenital CMV. Pre-pandemic, about one in 200 were identified. But post-pandemic, that number dropped four fold. And that's because the daycares were shut down. Everyone was home with their children. We weren't at work. And also doubling down on that hand hygiene. The masks, it's not a virus that is transmitted generally through respiratory secretions so it's not so much that. But really the hand hygiene. And now everyone's extra cautious, I think, in the workplace, too. So Mark, I'm going to have you take us home here and just tell us where are we with vaccines? Because we can do all we can to reduce our risks, but really this is what we need for prevention.

Mark Schleiss (01:08:45):

Sure. So yeah, the vaccine story we'll run through very quickly and talk about the active clinical trials that are currently enrolling in the United States. Just by way background, the first CMV vaccines were actually tested in the 1970s using that classic vaccinology approach of taking the virus and then just packaging it in cell culture repeatedly and hoping that something happened to it that attenuated it. Well, that worked for polio. It worked for measles. It worked for mumps. But those vaccines we discovered in the early nineties, that just the act of passage and cell culture resulted in the deletion of a lot of genes. CMV is actually the largest human virus in terms of the size of the viral particle as well as the size of the viral genome. So we still have a long way to go in understanding the genetics and gene expression of CMV.


I say that for trainees in the audience who might be interested in research opportunities in the future. This is a virus that we still have a lot to learn about. Vaccine studies beginning in the seventies have evolved over the last 50 years now to the point where we understand the virus well enough to know what some of the specific viral gene immunogens are, a sub-unit vaccine concept, the idea of picking viral gene products that we think could be key to protective immunity, protective immunity for the mom, protective immunity at the level of the placenta, protective immunity for the fetus. Because if you can block maternal infection, then you won't have congenital CMV. If maternal infection occurs, but you still have enough of an immune response to protect that fetus, that too would be a successful vaccine. Vaccines in the pipeline include messenger RNA-based platforms, so-called disabled single cycle vaccines that take the whole virus particle but inhibit its ability to replicate, and then vaccines that are based on protein subunits.


This is a cartoon just showing what some of these gene products are. And the cornerstone of CMV vaccines for 50 years has been the idea of developing antibody to the glycoprotein B or GB complex. Everyone who's CMV seropositive, everyone who's ever had CMV infection, which is probably two thirds of the audience, you have antibodies to glycoprotein B. So that's the one that's reliably immunogenic in everyone who's had the infection. More recently, that cluster of genes that were deleted by passaging the virus in the tissue culture incubator that now is emerged as a leading vaccine candidate is the so-called pentameric complex, or PC. So you can see in the cartoon the pentamer and this vaccine is also currently in a protein subunit formulation.


And then finally, more for probably the transplant oncology population, the tegument protein, that middle amorphous layer in the cartoon of the virus particle, we know that T cells that respond to that particular protein are instrumental in CMV control after bone marrow or solid organ transplantation. Whether or not that particular immunogen will be important in pregnancy and congenital transmission remains to be seen. So we have different CMV vaccines in the pipeline for different indications. But the Institute of Medicine, when it outlined a CMV vaccine as its top priority for the new millennium in their report from 20 years ago, identified congenital CMV as really the major benefit of a CMV vaccine.


These are the clinical trials that I alluded to. One is this so-called V160 vaccine, which is the whole viral genome but with a targeted mutation that impairs its ability to complete its replication cycle. It also has deletion of a few other genes that may be worthy of further investigation as the vaccine story moves ahead. Data at ID week presented a year ago showed only a modest efficacy for this vaccine. It's unclear what its developmental pipeline will be. There's a messenger RNA vaccine. The spectacular success of mRNA vaccines for COVID-19 has helped drive this study. And we currently have a phase 3 efficacy study underway to look at prevention of congenital CMV using this messenger RNA that encodes for that GB immunogen that I mentioned, as well as this pentamer that I mentioned. Those six RNAs together become the cocktail in that vaccine and it's highly immunogenic and it may prove to be successful.


And then finally, there's a recombinant protein vaccine with proprietary adjuvant from a major pharmaceutical company that mixes again, the GB protein and the five protein constituents of the pentamer. Item three in contrast to item two, again, it's a protein vaccine, whereas number two is the mRNA vaccine. Other preclinical program development ideas that are out there. There's also a vaccine in development for transplantation by company in Europe that's using a vectored approach with a lymphocytic choriomeningitis virus vector. Unclear if that vaccine has any future use for pregnancy. Modified vaccinia virus ankara, smallpox-like vaccine platform is also being looked at in transplant and oncology. But these are the most recent vaccine clinical trials active in the United States for congenital CMV is a major indication.

Megan Pesch (01:15:01):

We're going to have to wrap up now. But thank you to Dr. Swamy and Dr. Schleiss and everybody who joined us today and stuck around. We really appreciate it and for the questions too. And we'll be here to answer more questions in real-time as well if you want to come up. But thank you. This is a great site if anybody wants to get more into CME about CMV, great site and resource and thank you so much. Oh, and this, let's make sure.

Geeta Swamy (01:15:36):

And thank you, Megan, as well.

Megan Pesch (01:15:39):

Oh, my pleasure. Earn your credit. So make sure you claim it and yeah, thank you guys very much.

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