#031 - The Case for a CMV Vaccine with Dr. Sallie Permar

Hello friends 👋

In this episode of At the Bench, Misty Good and David McCulley interview Dr. Sallie Permar, Chair of Pediatrics at Weill Cornell Medicine and Director of the Pediatric Scientist Development Program. Dr. Permar shares how her early global health experiences in Zambia inspired her career as a pediatric infectious disease physician-scientist and vaccine researcher. She discusses the challenges and advances in developing vaccines against HIV and congenital cytomegalovirus (CMV), the importance of newborn CMV screening, and a novel strategy to prevent breast milk–acquired CMV infection in premature infants. She also reflects on mentorship, advocacy, health policy, scientific communication, and the importance of translating clinical observations into discoveries that improve children’s health.

Link to episode on youtube: https://youtu.be/3F3egm8T-MU

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Featured Manuscripts From Dr. Sallie Permar

Permar SR, Fong Y, Vandergrift N, Fouda GG, Gilbert P, Parks R, Jaeger FH, Pollara J, Martelli A, Liebl BE, Lloyd K, Yates NL, Overman RG, Shen X, Whitaker K, Chen H, Pritchett J, Solomon E, Friberg E, Marshall DJ, Whitesides JF, Gurley TC, Von Holle T, Martinez DR, Cai F, Kumar A, Xia SM, Lu X, Louzao R, Wilkes S, Datta S, Sarzotti-Kelsoe M, Liao HX, Ferrari G, Alam SM, Montefiori DC, Denny TN, Moody MA, Tomaras GD, Gao F, Haynes BF. Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission. J Clin Invest. 2015 Jul 1;125(7):2702-6. doi: 10.1172/JCI81593. Epub 2015 Jun 8. PMID: 26053661; PMCID: PMC4613557.

Nelson AN, Shen X, Vekatayogi S, Zhang S, Ozorowski G, Dennis M, Sewall LM, Milligan E, Davis D, Cross KA, Chen Y, van Schooten J, Eudailey J, Isaac J, Memon S, Weinbaum C, Gao H, Stanfield-Oakley S, Byrd A, Chutkan S, Berendam S, Cronin K, Yasmeen A, Alam S, LaBranche CC, Rogers K, Shirreff L, Cupo A, Derking R, Villinger F, Klasse PJ, Ferrari G, Williams WB, Hudgens MG, Ward AB, Montefiori DC, Van Rompay KKA, Wiehe K, Moore JP, Sanders RW, De Paris K, Permar SR. Immunization with germ line-targeting SOSIP trimers elicits broadly neutralizing antibody precursors in infant macaques. Sci Immunol. 2024 Aug 30;9(98):eadm7097. doi: 10.1126/sciimmunol.adm7097. Epub 2024 Aug 30. PMID: 39213340; PMCID: PMC12302664.

Jenks JA, Nelson CS, Roark HK, Goodwin ML, Pass RF, Bernstein DI, Walter EB, Edwards KM, Wang D, Fu TM, An Z, Chan C, Permar SR. Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans. Sci Transl Med. 2020 Nov 4;12(568):eabb3611. doi: 10.1126/scitranslmed.abb3611. PMID: 33148624; PMCID: PMC8058742.

Otero CE, Barfield R, Scheef E, Nelson CS, Rodgers N, Wang HY, Moström MJ, Manuel TD, Sass J, Schmidt K, Taher H, Papen C, Sprehe L, Kendall S, Davalos A, Barry PA, Früh K, Pollara J, Malouli D, Chan C, Kaur A, Permar SR. Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model. PLoS Pathog. 2023 Oct 23;19(10):e1011378. doi: 10.1371/journal.ppat.1011378. PMID: 37871009; PMCID: PMC10621917.

Manuel TD, Moström MJ, Crooks CM, Davalos A, Barfield R, Scheef EA, Kendall S, Midkiff CC, Sprehe LM, Trexler ME, Boquet FA 3rd, Shroyer MN, Danner VW, Doyle-Meyers LA, Weinbaum C, Mirza A, Lammi S, Mitchell L, Otero CE, Lee MR, Rogers LW, Granek J, Owzar K, Malouli D, Früh K, Kowalik TF, Chan C, Permar SR, Blair RV, Kaur A. A rhesus macaque model of congenital cytomegalovirus infection reveals a spectrum of vertical transmission outcomes. Commun Biol. 2025 Nov 24;8(1):1647. doi: 10.1038/s42003-025-09033-4. PMID: 41286406; PMCID: PMC12644875.

Schleiss MR, Plotkin SA, Permar SR. A Vaccine to Prevent Congenital Cytomegalovirus: Where Do We Go Next? JAMA Pediatr. 2026 May 1;180(5):469-470. doi: 10.1001/jamapediatrics.2025.6432. PMID: 41770579.

Barrett KJ, Cooley TM, Schwartz AL, Hostetter MK, Clapp DW, Permar SR. Addressing Gaps in Pediatric Scientist Development: The Department Chair View of 2 AMSPDC-Sponsored Programs. J Pediatr. 2020 Jul;222:7-12.e4. doi: 10.1016/j.jpeds.2020.01.054. PMID: 32586535; PMCID: PMC8852247.

Crooks CM, Barfield RT, Fuller AS, Hughes BL, Swamy GK, Ananyev S, Mitchell L, Connors MR, Karthigeyan KP, Otero CE, Saccoccio F, Eudailey J, Weinbaum C, Chan C, Permar SR. Maternal antibodies to primary CMV infection link to fetal transmission. medRxiv [Preprint]. 2026 Sep 13:2026.09.10.26362772. doi: 10.64898/2026.09.10.26362772.

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The transcript of today's episode can be found below 👇

Misty Good (00:01.218)Welcome back to At the Bench, the physician-scientist podcast of The Incubator. I'm Misty Good, Division Chief of Neonatology at UNC Chapel Hill, and I have the pleasure of co-hosting today with Dr. David McCulley. David, would you like to introduce yourself?

David McCulley (00:16.921)Thank you, Misty. This is a great opportunity to highlight physician-scientist work, particularly in neonatology and newborn medicine. I'm a neonatologist and physician-scientist at the University of California, San Diego and Rady Children's Hospital. Today we get to highlight another outstanding investigator, and we are super excited to have Dr. Sallie Permar as our guest.

Dr. Permar is the Chair of Pediatrics at Weill Cornell in New York. She is an outstanding, NIH (National Institutes of Health)-funded vaccine biology researcher and a leader in our field. She is also the director of the PSDP (Pediatric Scientist Development Program). We are extremely excited to talk with you today, Sallie. Would you mind giving a brief introduction to who you are and your research? Then we'll start asking you questions.

Sallie Permar (01:14.123)That's great. First, thank you so much for having me and for making this podcast what it is. I'm really a fan.

I'm Sallie Permar. I'm a pediatric infectious disease physician-scientist, and like David said, I focus on vaccine development, especially for preventing neonatal viral infections at the earliest stages of life. My goal in my research has always been to give kids the healthiest start to life. I've grown that into more than just preventing deadly viruses. It's also how we deliver their health care, how we support their community of providers, and how that reverberates through society to make strong families and a great society.

Misty Good (02:07.65)Sallie, that's really terrific, and you're so inspiring to all of us. Looking at all the success over your career, I want to rewind and go way back. Talk to us about how you first started, how you became interested in the focus of your lab, and then how you expanded that beyond newborn health to child health advocacy more broadly.

Sallie Permar (02:34.037)Well, thank you, because I do love to tell an origin story. I think everyone should have theirs in both a long form and a short form. Storytelling is one of the tools I've learned that is so effective in our work. Mine started in undergrad. I grew up in North Carolina and went to school there, at Davidson College, one of the great colleges out there. But I hadn't really left that area much in my childhood. When I got to college, I thought, wow, there is a bigger world out there that I should experience. I got the opportunity to spend time in a mission hospital in a rural part of Zambia.

It was the late 1990s, when the HIV (human immunodeficiency virus) epidemic was untamed. It was wreaking havoc in that part of the world. There were no therapies and no prevention, just societies trying to deal with the consequences. I was so overwhelmed by the sickness and death those communities were experiencing. What really hit me was seeing grandparents trying to take care of the children because so many of the parents were sick and dying. And then, when children were dying of the same infection, I thought, this is unacceptable. How does a place like this ever come back from what it's experiencing? And I thought, well, it has to be a vaccine.

So I went back to my small liberal arts college and said, "I would like to be a vaccine scientist," but they didn't even teach immunology. So I went to my favorite mentor at the time. He had really taken me under his wing and told me, "Yes, women can be scientists. You can be a scientist." He said, "Well, I work with antibodies to stain tissues, and antibodies come from the immune system, so you should work with me." So I did. My first research experience was in college, and I got the bug then. That's where it all started for me.

Misty Good (04:58.252)That's terrific. Go ahead, David.

David McCulley (04:58.765)It's one of those things where you have an amazing experience out in the world, seeing a virus have a devastating impact on a community. Then you begin to understand how you could have an impact on that disease and its trajectory. And you take advantage of a relevant mentoring opportunity and learn from it to start doing basic science research. So how did you begin to expand on that and focus more on vaccine development, vaccine biology, and the immune system? What were the next steps?

Sallie Permar (05:42.177)The first next step for me was that I wanted to spend more time in that community. I was able to go back to Zambia on a Fulbright fellowship, and this time I got to be at the University Teaching Hospital, their research-powered institution. I made my way to the pediatrician-in-chief there to work with him on understanding which opportunistic infections were unmasking themselves with the HIV epidemic. We wanted to know which pathogens were transmitted to babies in utero or during delivery, and which were transmitted after birth. I remember literally writing him a letter, snail mail, telling him I wanted to work with him on his published studies of HHV-8 (human herpesvirus 8).

Misty Good (06:34.136)Love that.

Sallie Permar (06:40.53)HHV-8 is also called KSHV (Kaposi sarcoma-associated herpesvirus), and the question was whether it was transmitted from mother to child. When I arrived in Zambia, he said, "You're here. I forgot about that letter you sent me so many months ago, but now you're here. Did you bring all your reagents, your PCR (polymerase chain reaction) primers? Because I have the babies here. We can get their blood, and you can test it in the lab." And I sort of broke his heart a little. I said, "I just got here from undergrad. I didn't bring any reagents with me." And he said, "Well, it's going to take months and months to get PCR primers here. Let me take you to the virology lab, and you can see what they're up to and work with them."

So we never really got to do that HHV-8 study. But I was able to start working on other studies the virologists at that teaching hospital were running, especially ones related to the pediatric population. They were studying measles virus, which is very relevant now. It was still endemic there and circulating in populations that were also affected by HIV. So I started working on a project.

In the meantime, or even before the Fulbright, I had thought that a PhD would get me to being a vaccine scientist, so I had applied to PhD programs in microbiology and immunology. And there was a coincidence that paid off for me. I'd already decided to go to Johns Hopkins, and the chair of the Department of Microbiology and Immunology there was launching a study in the same virology lab in Zambia that I happened to find myself in. Sometimes luck puts you in the right place at the right time.

Misty Good (08:22.558)That's funny.

Sallie Permar (08:33.622)So I started my PhD thesis work even before I entered the program. I studied how measles virus infection presents in HIV-infected children and what its immune consequences are. How does it present differently? How does it change the immune response when you've got two immunosuppressive viruses at the same time? That's what I studied when I went back for my PhD and did all the coursework. I was asking very pathologically relevant questions, very close to human translation.

Then it really hit home for me when I met a couple of physician-scientists in that lab at Johns Hopkins. They were pediatric ID (infectious diseases) fellows who would go from the clinic, seeing babies with RSV (respiratory syncytial virus), back to the lab to work on an RSV vaccine. And I thought, wait a minute, I have to do that. I want to be able to talk to the families and see the kids, get inspired by the biggest problems, and come back and work on them. That's what I got to do in the short time I worked in Zambia. So I went to my PhD mentor and said, "I think I want to go to medical school, but I didn't plan for that, and I haven't even taken the MCAT." Luckily, she was an MD-PhD, and she said, "Yes, you do. I think that's a good idea, and I will help you do it."

Misty Good (09:59.501)Wow, it's such a great story. First, how people get interested in science, and then, when you're already in science, deciding, "No, I also want to take care of patients." That's a really amazing story. I actually didn't know it wasn't until your PhD lab that you decided. That's wonderful to hear. That's the long way.

Sallie Permar (10:25.194)And it shows just how impactful those exposures are. I think that's my takeaway too.

Misty Good (10:29.646)It's true. Mentor exposures are so important. It looks like you were going to say something, David.

David McCulley (10:38.591)Yeah. I think you're the first person we've talked to who did the MD-PhD in that order. You were inspired to do basic research first, saw the potential application and the value of contact with patients, and then explored medical training afterward. A lot of the people we've talked to intended to go to medical school, then learned about using basic science techniques to understand complex disease pathophysiology in much more detail. Then they either applied directly to MD-PhD programs or explored research later in their careers. So it's great to hear the opposite scenario in your case.

And like so many, it's a matter of being exposed to people and seeing what inspires them about their work. As a physician-scientist, you can move between the hospital or clinic and the laboratory, take samples from patients, and literally go study them in the lab. That is so inspiring, and it's such a great thing we get to do as physician-scientists.

Misty Good (12:02.762)I love that. I'd love for you to tell our listeners about the next steps. Fast forward: you finish your PhD and go to medical school. Were you able to do research throughout that time? You obviously chose pediatric infectious disease, so walk us through that journey of your training.

Sallie Permar (12:24.18)Whenever people ask me whether they should do a PhD and then an MD, or vice versa, I always say that what happened to me was sheer luck. There aren't really pathways set aside for PhDs to go to medical school, but you can always add research as a physician. So I actually advise people to go for the MD and add the research. But if you find yourself in a PhD program and realize you want to work with patients, don't let that hold you back either.

For me, I actually went to medical school in the middle of my PhD, which I also don't recommend, but I made it. I'm here today. It worked because I had started my research before even entering the program, during the Fulbright. Being able to kill multiple birds with one stone at any point in your career is helpful, and that's what I was able to do. I was a step ahead as I entered each program.

I went to medical school in a different city than my PhD. That wasn't intentional, but as we know, medical school admissions are really tough, and you have to go where you get in. I thought staying at Hopkins would work best, but I got into Harvard, so no one feels bad for me. I remember going to my mentor and saying, "I'm not going to be able to go to school here. Should I just get a master's and go on to do my MD? I can still do research." And she said, "The MD-PhD really took me places in my career. I think you should do it, and I'm going to work with you to make this work." So I asked, "Could I get a mentor in Boston who would help me continue the research?" She said, "Yes, let's do that," and she called up a friend.

David McCulley (14:00.27)Yes.

Sallie Permar (14:20.596)He happened to be giving a talk on campus, so I met him within a few weeks, which was again a stroke of luck. I remember him saying, "Of course you'll work with me." I suppose it was a little easier because I was a medical student, so he didn't have to find funding. But he said, "If you got into Harvard Med and this mentor says you're good, I would like to work with you." That's the power of mentors and sponsors, and of people being open to working with someone intent on this type of career.

David McCulley (14:56.463)Exactly.

Sallie Permar (15:18.902)So I got to pursue research during medical school. I mostly focused on the measles and HIV work, and I started some non-human primate studies, because we could model HIV and measles co-infection in non-human primates. I remember I didn't study very much during microbiology and immunology. That's when I did my most time-consuming experiments, because I thought, well, I've done most of a PhD already, so I'll be good there.

Then I started to think about which specialty I would choose. First of all, I loved my experiences in children's hospitals. They are joyous places, and adult hospitals often are not. I was the camp counselor type growing up, so it really fit my personality. And I thought, who do we vaccinate? If you want to give someone lifelong immunity from deadly diseases, you don't wait. You start right away. So I wanted to be in the world of pediatric health, and I chose infectious disease because it made sense.

I was able to continue research throughout, and staying in the same place for medical school and training helped with that continuity. I stayed in the HIV world, and I still work in it today, because we still don't have an HIV vaccine. Part of what I bring to that field is thinking about it as a childhood vaccine. So far, what has been tested in phase 3 trials is adult vaccination, and it hasn't worked: eight different phase 3 trials have failed to produce an HIV vaccine. But the immune response is so distinct in childhood, especially in those first few years of going from a fetus to an infant, which you all know very well. We're trying to see how the unique features of the pediatric and newborn immune system could help generate the B cell responses that protect against HIV, which are very difficult to elicit.

So I still do that work today, because we don't have an HIV vaccine, and to be most effective it must be a children's vaccine. The steep rise in infections happens in adolescence. And of course babies are still being infected, even today, with all the antiretrovirals we have that can interrupt transmission.

Misty Good (17:31.405)I'm struck by what you said about working in non-human primate models as a medical student. You go from the bench to the bedside, and everywhere in between, very seamlessly. How did you learn to decide which question needed which model system, and when and how to translate to patients throughout your training? And why non-human primates?

David McCulley (18:08.023)I'm wondering that too. One thing we try to explore on this show is the model systems people use. That one is particularly challenging, but so relevant and necessary in this field, so it's a great thing to touch on.

Misty Good (18:19.424)And expensive, right? Especially early in your career.

Sallie Permar (18:26.856)Absolutely. This is something I think about a lot, and all translational scientists think about their models. To take on a difficult large animal model like non-human primates (I don't know, there are some pig biologists out there too), working with a team that already does it well is crucial. I was lucky in that way.

I trained in the lab of my mentor in Boston, Dr. Norm Letvin. He was one of the discoverers of SIV (simian immunodeficiency virus). That's a cool story. He was actually an oncologist. He had finished his training and was asking, "What am I going to do with my life?" A mentor told him there was something interesting happening at the primate center. Harvard had a primate center at that time, and monkeys there were dying of opportunistic infections nobody understood. That was right when the HIV epidemic was emerging in humans, so the coincidence is high.

It came from primate centers bringing together different species of monkeys from different parts of the globe. Some of them carried endogenous viruses that others had not evolved with. Not using universal precautions, meaning needle sharing, led to SIV infecting animals that had never evolved with it, and they developed an AIDS (acquired immunodeficiency syndrome)-like illness.

David McCulley (19:51.587)Wow.

Sallie Permar (19:53.607)That's how he dove in, and after developing the animal models, he became a leading HIV vaccine expert. So you never know. Follow something interesting that someone presents to you. I was really lucky to get that exposure, learn the networks, and learn what the non-human primate centers across the country do.

I remember telling my mentor, who had developed those models for HIV vaccines, "I want to take what you developed for HIV and do it for another virus." In my clinical training I had realized how common that virus was, which I hadn't understood in medical school or even residency: congenital CMV (cytomegalovirus). In my pediatric ID fellowship, it was like a Zika outbreak in front of my eyes, because I was assigned to the congenital infection clinic. Every single baby was coming in with the same infection. If 1% of all babies are born with it, why don't I know anyone working on a vaccine? I knew a lot of HIV vaccinologists, but I didn't know anyone working on a CMV vaccine.

So I told my mentor I wanted to develop a non-human primate model for CMV vaccines. He was literally in the last days of his life when I told him this. This is a true story; he died early of pancreatic cancer. I was visiting him, I had just moved to a new faculty position, and I said, "This is what I want to do." And he said, "Sallie, that may be the best idea I've ever heard you say. And that's after working with you, and you have a lot of great ideas. This one is really good." And I thought, okay, I'm going to do it. So I worked on developing a non-human primate model for congenital CMV that could mirror what had been achieved for HIV vaccines, and I'm still working on that today.

David McCulley (22:09.005)It seems like both HIV and CMV have let you learn a lot about fetal, newborn, and early childhood immunity, and also about the immune interaction between the fetus and the mother. Could you talk about that a little? It seems like that's still a major focus of your research. Is that right?

Sallie Permar (22:30.014)Yes. What fascinates me, and I'm sure neonatologists across the board, is how much change the immune system has to go through. A fetus that is only half genetically matched is grown inside the mother's body without being rejected. Then comes the complete reverse: the baby is exposed immediately to pathogens it never encountered in the womb, viruses and bacteria of all kinds, and has to be ready to fight them off. The immunological shifts that have to occur for that to work out most of the time are remarkable. We probably understand about 10% of it so far.

Think about it: if we could harness that, we could transplant organs that are only half matched with no rejection and no GVHD (graft-versus-host disease). Think of all the death and despair we could prevent. And if we could understand how a newborn's immune system immediately protects against very deadly bacteria the baby is directly exposed to coming out of the birth canal, we could probably prevent a lot more infections. There is so much to learn from natural immunity in that time window, which is self-limited but also the basis of life. That's what makes it so fascinating.

Misty Good (24:03.15)There's so much to unpack there. You had this mentor who, in a really special, endearing moment, endorsed your idea. But sometimes mentors say, "That's too big," or "You don't want to go down that rabbit hole." I actually struggle with this sometimes with graduate students and other mentees. You want to save them from a career of rabbit hole after rabbit hole, and you want them to be successful. So in that moment, your mentor said it was the best idea you'd ever had and you should pursue it. What if he had said, "That's going to be really hard"? Would you still have gone forward, or would you have taken a step back and reassessed? It seems like that moment changed your whole career trajectory.

Sallie Permar (25:12.97)Yes, that's so true. We have to think about ourselves in that position now, as you said.

Misty Good (25:18.742)Yes, and what do you say in that moment?

Sallie Permar (25:42.487)It may be just another comment to you, but it becomes someone's career trajectory. As mentors, we have to think: is it the right time for me to tell this person to lean in? I probably had enough behind me at that point. I'd had a K award (an NIH career development award) and a couple of other awards, and I was a recruited faculty member. I had a startup package, I needed a new direction, I needed to define myself, and I was motivated by my clinical experiences. So it was probably the right time for him to say, "Go develop something the world does not have. If you see it as the pathway to solving this clinical problem, lean in."

But if he had told me that years before, when I was trying to get a K award, it never would have worked, because I wasn't working with a mentor who worked on CMV. Everybody would have rejected that one. So think about the timing of your endorsement. And the hardest part, to me, is telling someone when to stop doing something.

Misty Good (26:43.0)Yeah, that is true.

Sallie Permar (26:43.056)So think about the timing and the stage. How can you mentor for the stage of the career that person is in?

Misty Good (26:57.134)I think that's really great advice: knowing when the pivotal moment is to say something. David and I have talked about this. Gary Silverman was my division chief at the time, and when I was trying to decide whether to be a physician-scientist, he said, "Why save just one baby when you can save them all with your research?" I think it was something off the cuff for him, but for me it was very profound. Obviously I'm still talking about it now, and I think it changed my whole career trajectory. So I'm always inspired by those pivotal moments, and how what someone says can change another person's career. That was one of those for you. It's really lovely.

Sallie Permar (27:41.204)It's a power, and we have to recognize that too.

David McCulley (27:45.22)It has a huge impact on people's futures, and I think it's hard as a mentor to always keep that in mind. You're always trying to help your mentees be successful, but also to be efficient with their time and think about the most likely path to success. Even if something is a burning interest they're clearly invested in, it may not be the most direct path. Maybe they can still explore that question, but if they focus on something else in the short term, there might be a better payoff. It's always hard to know the best way to help people navigate that.

Sallie Permar (28:23.494)And get help from your friends, right? That's why I've always promoted getting career counseling from a group of people, not just one. I tell this story as an example of why that's important. My first postdoc mentee, whom I still work with today, is Dr. Jenny Fouda. She just recently achieved tenure as a professor at Cornell University.

David McCulley (28:52.069)Wow. Congratulations.

Sallie Permar (28:53.462)So that's another level. The pediatric infectious disease division at Duke made sure we set up a mentoring committee for her. Dr. Coleen Cunningham was adamant about that: you must do your mentoring committees. At the time, I was used to doing everything myself, and I had a young family. And I remember the committee saying to me, "Hey Sallie, when you get asked to speak, maybe you could elevate Jenny. Say, 'I'm unable to go, but Jenny Fouda would be a great person for this.'"

This huge relief came over me. My goodness, my husband had just had a sit-down with me about how I was traveling too much and he couldn't do it anymore. What a gift that was, to be able to say, of course I can do that. It just hadn't occurred to me. That's the power of group mentoring, and again of pivotal moments as a mentor, because I had never really known how to sponsor someone. It doesn't just have to be you. It's a team sport.

Misty Good (30:14.836)It is a team sport, for sure. I just sent my research coordinator to a conference on my behalf. Yes, you need to sponsor other people, but you're also spread thin sometimes, right? So you need to help others.

Sallie Permar (30:33.332)And it can help you while helping them. It's beautiful. A two-way street is always the best one.

David McCulley (30:40.185)Can we dig into the biology a bit more? I think our audience will be excited to hear about it. I freely admit I'm not an immunologist, but I was trying to learn about the challenges of an HIV vaccine versus a CMV vaccine. Because you've explored both so thoroughly, could you talk about why they're different? It seems like a CMV vaccine might be a bit more within reach, while it's hard to know when an HIV vaccine might happen. Is that correct?

Sallie Permar (31:17.942)I would absolutely characterize it that way, but both are advancing. This is something I think about a lot. It's actually an example of how all the innovation that went into aiming for a protective HIV vaccine advanced vaccinology in ways no one expected. The mRNA (messenger RNA) work pretty much came out of the HIV field. All of the COVID vaccines came out of the HIV field. So did the first applications of B cell sequencing and of understanding antibody-antigen interactions.

Because of the animal models and some translation from human work, the immune correlate of protection for HIV vaccines has been identified. It's even identified down to the titer: a neutralizing titer of approximately 1:300 against the majority of circulating viruses. Of course, the challenge is the huge number of variants and their diversity, and getting that response into your plasma. That is the be-all and end-all goal. We haven't been able to reach it yet, but we've shown it's possible in non-human primates. It's also been validated with pre-formed antibodies given to humans who were then exposed to HIV. So the animal models really worked to establish what the goal of the vaccine is.

Now it's kind of nice, because we don't have to run big phase 3 trials to find out which vaccine will work. We know we must get broadly neutralizing antibody responses in plasma before we even think about a large efficacy trial. That's where the HIV vaccine field sits now. There's been some great progress in designing the one protein on the surface of the virus, which I'll highlight because it's very different from CMV. You can design a version of the HIV envelope that engages the types of B cells that, we know from infected people, can go on to make broadly neutralizing antibodies. A lot of people didn't think that would work: changing just a few amino acids to open access to germline antibodies that could then evolve into broadly neutralizing antibodies. People thought it might not change the B cell responses at all, but it has. So far, though, it has mostly changed things at the B cell level. We're not getting enough of those rare antibodies into plasma to reach that 1:300 neutralizing titer across most variants.

In some ways that's nice, because the pathway is clear. But at this point, the industry groups have stepped back a bit, saying a new innovation is needed to overcome that barrier. Non-human primates are important because their immune system is most similar to humans', so we do a lot of preclinical work there, plus some early-phase human trials. That's where the HIV vaccine world sits.

Now, CMV. I won't say "fast forward," because both viruses have been evolving with primate populations for millions of years.

David McCulley (35:00.056)Yes.

Sallie Permar (35:13.756)What these viruses have in common is that both evolved to outcompete the primate immune system. HIV came from chimpanzees. And every single mammalian species has its own version of CMV. But they differ in strategy. HIV mutates itself to get around your immune system really well. CMV instead carries a ton of genes that are there just to evade or confuse your immune system. And unlike the one protein on the surface of HIV, CMV has at least 14 different glycoprotein complexes on its surface, and we don't even know for sure which one is most important to target.

The good part about CMV, and why it's seen as achievable, is this. No HIV vaccine has shown efficacy. For CMV, we've applied what we know empirically from other viral vaccines by taking the main fusion protein, glycoprotein B. Usually you enroll women of childbearing age, sometimes at higher risk of exposure because they've recently had a baby or have kids in daycare, since toddlers are the main source of CMV transmission. You immunize half and give half a placebo. Efficacy with just that one protein has actually been pretty high, up to 50% prevention of new acquisition, in at least three phase 3 studies, one of them in a transplant population.

That's already a playing field above where HIV vaccines have been, so the view is that we just need to do a little better. That's where we were with the most recent Moderna vaccine. CMV was Moderna's first product, when they were a baby company. COVID, of course, surpassed that, and they were very successful there. But they came back around to run a phase 3 trial for CMV.

David McCulley (37:31.054)Yes.

Sallie Permar (37:34.465)They added a second glycoprotein complex, one known to be a target of neutralizing antibodies and required for entry into epithelial cells. I was totally a believer that this would work. Adding a bit more immunity to what was already pretty good protective immunity should work. It did not improve on what had been achieved with glycoprotein B alone. We're still trying to understand why, but it showed that we cannot rely on empiricism for this vaccine.

So what I've been working on in the field is identifying the immune correlates. With HIV, we know exactly what we're targeting. How do we get there with CMV, so we can down-select a vaccine based on our knowledge of natural immunity? Here's something remarkable. When a woman gets CMV for the first time in pregnancy, she passes it on only about 30% of the time. Why is that? And women who were previously exposed to CMV have a much lower chance of passing it to the baby when they're reinfected during pregnancy. So something is getting us 97 to 99% of the way to protection. How can we learn from that? That's where I've been focusing: what are the immune correlates, and then using our models to show whether they're enough. And then using rational vaccine design: once we see which type of immunity matters most, how do we design a vaccine that elicits that response?

Misty Good (39:14.796)I have a question about all of this, because it's so interesting when you think about the fetus and the mom, and we're always worried about any exposure for our babies. When you're developing a CMV vaccine, are you anticipating pre-pregnancy vaccination, like in adolescence? Or during pregnancy, or after birth? And since it's so ubiquitous, in all species it sounds like, how do you decide?

Sallie Permar (39:55.681)Those are the hard questions the community is asking right now. Misty, you've zeroed in on it.

Misty Good (40:01.742)I'm sorry.

Sallie Permar (40:25.566)No, no, this is exactly what we have to talk about. One thing is that we may be designing our trials incorrectly, in a way that will never achieve success. It's not acquisition of CMV we're trying to prevent; it's congenital transmission. And that may be easier, because you don't pass the virus on 100% of the time even if you get it during pregnancy. That's what we're trying to focus on now. We may never get a vaccine that's 70, 80, or 90% protective against new acquisition, because the virus is so good at evading our immune responses. But we may be able to bring congenital transmission as close to zero as possible.

But how do you test that? You'd need so many women who will become pregnant and then be exposed to CMV. It's too big a trial for any company to do. So we'll have to think differently and likely rely more on real-world outcomes. As long as it's safe, as long as we get the immune responses we think are important, and maybe with some prevention of acquisition, the real test of the vaccine will be giving it to millions of people and seeing whether the number of congenital CMV cases goes down.

As for who we target, I think it should be placed as an adolescent vaccine. There should probably also be shared decision-making with women who are trying to get pregnant. If you're not immune to CMV, you're at risk, especially if you have a toddler in daycare. That's a high-risk group. We've got to get ahead of pregnancy, because only half of pregnancies are planned, but women trying to conceive should have this available to them. Then we see whether it protects against congenital transmission in that setting, and look at whether it should be broadened. Take the rubella vaccine: it's really designed just to prevent congenital infection, and we give it to toddlers. So should a CMV vaccine eventually move even earlier? Toddlers are the ones spreading it, so you may get even more benefit from that immunity.

Misty Good (42:30.114)That would go in parallel with universal congenital CMV screening, right? We could talk about that and what your thoughts are.

Sallie Permar (42:38.259)Amen. Absolutely. I could not be more in favor of universal CMV screening of all newborns, so thank you for asking. And let's just say it here: especially the preterm ones. As you know, preterm babies don't get their hearing screen until later, when it's too late to diagnose congenital CMV. So in any state that has mandated hearing-targeted CMV screening, which is somewhere in the twenties, you're not complying with the law if you're not testing all the babies in your NICU (neonatal intensive care unit). So if you aren't already testing all your NICU babies for congenital CMV, start working on that. That's one message.

Second, where are all the states in terms of testing every baby? Here's why we need it. Antivirals have only been shown to work for babies with the most neurologic involvement, where they do reduce hearing loss and developmental delays. But even if you're not one of those babies with neurologic impact at birth, you can certainly benefit from developmental and hearing screening. So I see no reason for us not to be doing this universally now. The test isn't perfect yet on the blood spots, which are the easiest option because you already collect them.

Misty Good (44:04.28)That's what I was going to say. We need a better test on the blood spots. They're getting their blood drawn all the time.

Sallie Permar (44:08.81)We do need a better test on the blood spot, so we need some innovation there. It's about 70% sensitive now. But Minnesota and Connecticut are using it, and we used it for one year in New York State. It worked really well. We had ninefold more babies diagnosed with congenital CMV at our one center. That's how many we were missing, even with the less sensitive test. So I think we should get started; it's doable. And then we should keep working on a better test.

David McCulley (44:29.475)Wow.

Sallie Permar (44:37.92)All of this will drive awareness, which is really what we need to get to a vaccine. Congenital CMV is more common than Zika ever was at its peak, and it happens every single year. It's not only a cause of hearing loss and developmental delays; it's also a cause of conditions as common as ADHD (attention-deficit/hyperactivity disorder), and it has been strongly associated with autism. So this is a vaccine that will prevent autism. That's not what you often hear in the media these days. It's also been linked to allergies, asthma, and leukemia risk. There are probably many more diseases that will decline once we can eliminate this one infection. That's why I'm so focused on it.

David McCulley (45:29.623)Sallie, you're such an outstanding speaker, and every time I listen to you, I learn so much. On one hand, you can convey really complex biology and vaccine research. On the other, there's this very impassioned health care advocacy work you do. You can make such clear statements, like you just did, about how something that seems so straightforward can have such broad impact. How do you balance your work as a physician-scientist with this amazing child health advocacy? And with your work getting pregnant and lactating women enrolled in vaccine studies? I've heard you talk about that, and it's an amazing opportunity you've had to increase advocacy and awareness for this research and this aspect of health care. Can you talk about that?

Misty Good (46:31.168)And wait, while you're formulating your answer to that very long question: with the PSDP, you're building a roadmap for the next generation of physician-scientists. Beyond your own work, you're literally building infrastructure across the nation. So maybe you could build the PSDP into your answer as well.

Sallie Permar (47:01.374)Yes. First, I don't do that part alone, because you two are both very big physician-scientist advocates, and we can't do it enough. You can't go far in children's health without finding the story of a physician-scientist who leaned into their clinical observations, figured out the problem, went and solved it, and now children live where they often did not. So there's no shortage of inspiration.

But I have worked on my ability to communicate, because we're also losing the battle there. Trust in experts, including us, has eroded. Outside forces are communicating more effectively to the public than we are. That's also a science we have to take on. We have to communicate the value of expertise, of evidence-based medicine, and of science, and we're the best people to do it. We went into this because we wanted to help people live better lives. We're smart people, and we got trained to identify problems, analyze the data, craft a solution, test it, and modify it where needed. That's what we do every day in our labs, our clinics, and our public health research.

Then I started asking: why are we not seeing the needle move enough? Especially for children, who get left out of trials, and pregnant women, who aren't included. They enrolled 50,000 people in a COVID vaccine trial, at least 25,000 of them women, and not a single one was pregnant. How can we make sure we're not leaving out some of the most important populations to protect? It came down to working not only on advocacy, but on identifying the policies that are holding this back.

David McCulley (49:23.063)Yes.

Sallie Permar (49:25.736)That's where I took a journey when I moved to Cornell as department chair. I started looking at the P&L (profit and loss), and I could not understand why pediatricians, who are often the lowest paid of all physicians, can't come close to covering their own salaries from the very tedious, high-expertise work they do in the clinic every day. I thought, this is not okay. It's broken. How can I fix it? That started my journey: I found policy experts I could work with on why it's like this. It isn't easy, and it won't be fixed in one shot. But every time we see the system break down and a child not get the care they need, we need to elevate that and keep going.

I learned the other day how individual health insurance came to be in this country.

Apparently it traces back to one child with diphtheria. Her parents brought her to the hospital and were told, "I'm sorry, you're unable to pay, so she can't come in." She died a few hours later. That child is apparently the reason we have individual health insurance in this country. I'm not saying that was a good move, but one child changed our whole health system. So how can we, as communicators, make one child, or the tens of thousands of children we see, change the way we deliver health care, because it's not working? That's what I got inspired to do. None of it is easy, and that's why we have to lean on each other and find where we can collectively use our voice.

Misty Good (51:17.249)That's a really great way to sum it up. You brought up your role as department chair at Cornell, which is such a major leadership role. Could you talk to our listeners about what it's like being a department chair and a scientist? How do you keep your finger on the pulse of the lab while running a massive department and doing all the advocacy initiatives you mentioned?

Sallie Permar (51:49.739)Well, I won't say I kick my feet up on every vacation and go home at five o'clock. It's not for those reasons. I kind of love working; that's one thing to know about me. Not everybody needs to love working as much as I do, but I just love making progress. My family knows that I'm happiest on vacation if I can have an hour or so to check my email, and then I'm happy to enjoy the rest of the day.

Misty Good (52:20.835)My husband would agree with that statement. I'm much happier if I can check my email.

Sallie Permar (52:26.624)Not everybody's like that, and that's totally fine. But I got good at delegating early in life, which is important, along with realizing what you need to spend your time on and what you can delegate. The more people you can empower to do the work, the better. I take the approach of "expect and inspect." You have high expectations that someone can do the work you envisioned needs to get done. But you don't just leave them to figure it out. You check in: "How can I help you more? What barriers are you facing?" I actually learned that from the woman who ran our summer camp, and it really applies.

And I just love being able to pull all the strings. I think physician-scientists are really important, so in this role I'm able to say, "Okay, how many dollars are we going to put into that?" Not only can I do that in my own department, but I can also say to David, Misty, and the other department chairs I work with, "I don't think we're meeting the mark on this nationally. How can we do better? How can we put a workshop together at PAS (Pediatric Academic Societies) to talk about it and get input from people on the front lines?"

David McCulley (53:42.147)Yes.

Sallie Permar (53:48.437)In fact, on one of my calls earlier today, we were planning a strategic planning session for the next forty years of the Pediatric Scientist Development Program. And we said, you know what, we need to hear from the actual trainees right now. One thing I'm trying to get better at is listening across the board. Don't assume you know the best way just because you did it a long time ago and came through the gauntlet. How can we hear more about what people on the ground are experiencing? That applies to patients and families as well. How can we put their voices into our decision-making and priority-setting, and even our country's? How can we elevate youth voices in decision-making? They're the ones who will be most affected by the policies being put in place today.

Misty Good (54:38.351)Amazing. A beautiful summary.

David McCulley (54:39.747)Really incredible.

Sallie Permar (54:43.88)There's one scientific, clinical translation thing I want to tell neonatologists about. Can I do this quickly?

Misty Good (54:49.049)Yes, please. We love that.

David McCulley (54:49.305)Please, that's what we're here for. We would love to hear it.

Sallie Permar (54:54.174)This is maybe my biggest current dream. I work on CMV and on a lot of antibody responses. As an ID doctor, sometimes you all call me to the NICU for a postnatal CMV infection that has caused a lot of disease. It's given the baby a sepsis-like illness or hepatitis, their GI (gastrointestinal) tract isn't working, they can't come off the ventilator. Should we use ganciclovir or not? It's a whole thing, and a lot of those questions aren't answered. But I think we all know there's real disease from what is the one downside of making unpasteurized human breast milk a baby's main source of nutrition. We're between a rock and a hard place. It's the best nutrition, but it gives them a virus that we know affects their brains and the rest of their bodies.

I happened to be at a conference where the company that took on CytoGam had a booth. They bought it as a product and started producing it. I was talking to someone there and said, "We put a lot of things in breast milk before we give it to babies. What if you just put CytoGam in breast milk? Why not?" And he said, "That seems like a good question we should ask." So Kamada, the company that makes CytoGam, helped fund some work in our group. We also got an R21 (NIH exploratory/developmental research grant) together with some of your colleagues, Cammie Martin, Liana Senaldi, and Krithika Karthigeyan, on this new idea of adding protective antibodies that neutralize the virus before the milk is given to babies. We showed in vitro that it works.

And I just learned from Kamada, after working with them and talking about this in different settings, that they've decided to make this one of their main translational priorities for the next couple of years. So I'm thrilled to say that something I do is going to touch humans, because that's not always foreseeable in research.

Misty Good (56:59.087)That's fantastic. Wow, wonderful news.

Sallie Permar (57:19.466)We could eliminate the only downside of breast milk feeding that I can see from the NICU. And it may have implications for other things, like preventing the terrible antibiotic-resistant organisms that somehow end up in these babies' guts. There could be more protective additives to breast milk we could think about. But I'm excited for at least the CytoGam hypothesis to be tested for safety. It's already an approved product, so it may have an easier route into your hands as neonatologists.

Misty Good (57:52.176)That's so exciting. Thank you for sharing that. It's remarkable. It takes so long to get things to the bedside, and this would be a really unique approach and an incredible transformation for our field. David is speechless.

Sallie Permar (58:18.006)Speechless.

Misty Good (58:19.171)All right. I know we've taken up a lot of your time, but it's been so wonderful speaking with you. We always like to close with something fun. It could be something unique to your lab, or how you write grants. Do you listen to music? Do you pound one out on a weekend or after hours, or do 30 minutes at a time? Anything you want to share, and any words of wisdom for our listeners.

Sallie Permar (58:55.614)Maybe I'll take you up on the lab question. One thing I leaned into early on and have kept doing: you know how you have lab jobs, like somebody has to clean the incubator? You're both nodding vigorously. Somebody has to make sure all the autoclaving is done, et cetera. One lab job I realized had to be formally assigned is social committee chair.

Misty Good (59:23.759)That's true.

Sallie Permar (59:24.116)Because engagement across your team is so important. If people just come into work, do their own thing, leave, and don't connect with the team, you won't get the outcomes you're looking for. At times, people in the lab are naturally drawn to leading the social committee and planning what we'll do together, outside of work or even using some work hours. I've gotten okay with that. At first I was very sensitive about it, but you know what? Team building is part of the work.

There have been periods when people really loved doing that, and times when nobody did. That's when I assign the lab job: it's actually your job to make sure we have activities that aren't just about getting the samples processed. I keep coming back to that. When I let it slip, I realize, you know what the problem is here? We don't have a social committee chair leading the work. So promote the idea that the work outside the lab is almost as important as the work inside it for building the team.

Misty Good (01:00:37.443)What's your favorite team-building activity for your lab?

Sallie Permar (01:00:42.836)We're about to go bowling soon, which is a favorite. Having people over to my house, or my apartment now, has been a go-to. At the end of the academic year we have a barbecue. My husband cooks every time, because I still don't know how to use a grill, but I marinate the steak, and I'm very good at that. We give out lab awards and say goodbye to people who are moving on. That's a favorite too, and we'll never change it. It's a really critical moment of recognition.

Misty Good (01:01:26.223)That's awesome. I love that.

David McCulley (01:01:28.493)I think that sense of community is so important: building community within your group and keeping that cohesion, knowing you're all in it together and there for each other. I think it's critical.

Misty Good (01:01:40.417)And it keeps you tied to your lab's focus, right? This is why we do what we do. Yes, it's hard work, but for us, we're trying to save the babies. For you, you're trying to save everyone from these terrible viruses.

David McCulley (01:01:58.287)Thank you so much, Sallie, for taking the time to talk with us today. Your story is so inspirational, and you're such an outstanding speaker. It was fantastic to talk with you about what has inspired your work and the exciting things you're doing.

Misty Good (01:02:17.315)Yes, we're grateful for all your expertise and for sharing your journey with us. Thank you so much.

Sallie Permar (01:02:24.63)And again, kudos to you both for such a great forum and for inspiring so many people. We owe it to kids to keep the pediatrician-scientist pipeline strong, and that takes work beyond just doing our own thing. So thank you for taking that on in a real way.

Misty Good (01:02:47.673)Our pleasure.

David McCulley (01:02:48.655)We're so excited to do it. Thank you again to our audience. This is such a great opportunity to learn about the work of physician-scientists in neonatology, and we'll be excited to talk with you again soon. Have a good day.