Respiratory Syncytial Virus: The Need for a Maternal Immunization Strategy

About the Webinar

This webinar, “Respiratory Syncytial Virus: The Need for a Maternal Immunization Strategy,” explains the importance of annual influenza immunization for patients, especially pregnant women.

Learning Objectives

Upon completion of the presentation, the participants will be able to:

• Communicating the burden of RSV disease in infants
• Discuss rationale and need for RSV maternal immunization
• Update on current recommendations for maternal vaccines and how they can be integrated into antenatal care

This webinar is supported by an independent educational grant from Novavax, Inc. ACOG does not allow companies to influence ACOG’s programs, publications, or advocacy positions.

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Video Transcript

Moderator: Hello everyone. Thank you for joining us today. Today's webcast is entitled Respiratory Syncytial Virus: The Need for a Maternal Immunization Strategy. We'll focus on currently recommended maternal immunizations as well as RSV disease and vaccines in development. The webinar is supported by an independent educational grant from Novavax, Inc. ACOG does not allow companies to influence ACOG's programs, publications, or advocacy positions.

The faculty and planning committee wish to disclose the following information.

Now, please, let me introduce our program faculty for today's webcast. Dr. Rhoda Sperling has a formal training in Ob-Gyn, infectious diseases, and epidemiology. She's a professor in the Icahn School of Medicine at Mount Sinai, with a joint appointment in the Department of Obstetrics, Gynecology, and Reproduction Science, as well as the Department of Medicine, Division of Medical ID. She's a member of ACOG's Immunization Expert Work Group. She's also the ACOG liaison to the CDC's Adversary Committee of Immunization Practices, Adult Immunization Working Group, and the Immunization Action Coalition.

Joining her is Dr. Flor Munoz, an Associate Professor with the Departments of Pediatrics and Molecular Virology and Microbiology, Detection of Infection Diseases, Baylor College of Medicine, and Texas Children's Hospital, and a member of ACOG's Immunization Expert Work Group.

Here are the learning objectives for this presentation.

Rhoda Sperling, MD: By the end of the webinar, participants will be able to communicate the burden of disease of RSV in infants and pregnant women. They'll be able to discuss the rationale, need for RSV maternal immunization, and be aware of current recommendations for maternal vaccines and how these and an RSV vaccine can be integrated into routine and to natal care.

I want to start the webinar with a big picture talking about advancing maternal vaccination. Maternal vaccination is already an important strategy to protect against diseases that disproportionately threaten newborns and young infants. That, again, is an important strategy to protect tetanus, influenza, and pertussis. New vaccines are in development. Those include vaccines for group B strep as well as respiratory syncytial virus.

The benefits of vaccinating mothers during pregnancy are numerous. Maternal vaccination enhances maternal immunity for both mother and the baby. The maternal antibodies will protect the mother from infection. The maternal antibodies will cross the placenta and also protect the newborn and young infant. Transplacental antibodies provide protection during a very vulnerable period before a baby's own immune system matures and can adequately respond to a vaccine. Breast milk antibodies could also contribute to infant protection.

When you're looking at the currently recommended vaccines in pregnancy, there are both flu and Tdap. I want to discuss those before I turn things over to Dr. Munoz to talk about RSV. In terms of flu vaccine, it's recommended for all pregnant women and women who will deliver during the influenza season. It can be given at any gestational age and given with every pregnancy.

An activated influenza vaccine is either a trivalent or quadrivalent vaccine. It's given as an IM shot. The intranasal live attenuated flu vaccine is not recommended for pregnant women. In fact, during the last few flu vaccine seasons, it hasn't been recommended for anyone. The flu vaccine will prevent influenza and its complications during pregnancy.

In terms of newborn and infant benefits, there will be a decreased risk of acquiring influenza in the first six months of life if moms are adequately vaccinated. That decreased risk may be up to 70 percent based on various prospective studies. There's also a decreased risk of influenza related hospitalizations in the first six months of life if mom is adequately vaccinated. Again, that risk reduction may be up to 60 percent based on a recent UK study.

Also, there are improved pregnancy outcomes. Numerous observational studies have evaluated the relationship between influenza vaccination during pregnancy and adverse pregnancy outcomes. Many of these studies were reported after the 2009 H1N1 influenza pandemic. Some of the important variables that have been looked at are the effects on preterm birth, low birth weight, and small gestational age.

To quickly present information from a recent med analysis by Martha Munoz published in The American Journal of Perinatology that maternal vaccination had a modest, consistent decreased effect on the risk of preterm birth and low birth weight. Again, this is based on a med analysis with all of its caveats. It's important to see that the direction is in terms of lowering the risk.

In terms of the recommended tetanus pertussis vaccine, the Tdap vaccine, it's recommended for all pregnant women from 27-36 weeks gestation. It's given with every pregnancy regardless of the prior vaccination history. So, current recommendations, based on efficacy, are to vaccinate in the earlier part of the gestational window, close to the 27 weeks, not the 36 weeks. The recommendation is to link the Tdap to other routine third trimester screenings, such as glucose screenings to facilitate practice implementation.

In terms of the benefits of tetanus pertussis vaccine, it has a significant impact on maternal and neonatal tetanus. There's a decreased risk of acquiring neonatal pertussis with protection up to 90 percent reported from recent UK experience. There's an efficacy in decreasing the severity of pertussis. So, even if the children get sick with pertussis, the disease severity is much less and the efficacy in decreasing pertussis associated hospitalizations and death.

I want to turn things over now to Dr. Munoz to pick up the theme about RSV and how it might become another maternal vaccination.

Flor Munoz, MD: Thank you very much Dr. Sperling. It is my pleasure to discuss with you the topic of RSV. As an infectious disease's practicing pediatrician and also as clinical investigator in maternal immunization, this is certainly one of the areas of highest activity, at this point, regarding research to achieve vaccination for this pathogen.

Let me tell you a little bit about the virus. RSV, respiratory syncytial virus, is actually an RNA virus that is quite simple. It has 11 proteins. The two main types of viruses, RSV-A and RSV-B, are designated based on the type of proteins that they express. However, the ones that are important for us to understand in terms of immunity and developing a vaccine are the F and the G proteins, both of which are in the surface and are depicted in this image as just little colored bulbs. You see how they will be two that are recognized by the immune system. They are essential for the attachment and fusion of the virus into the respiratory cells. But also they are the ones that our immune system recognizes.

Most of the vaccines that are in development will be based on eliciting immunogenicity immune responses to these F and G proteins. RSV is based on the appearance of its cytopathic effect in cell cultures. When it infects respiratory cells, it shows what you see in the top picture, which is the formation of a syncytium. That means there has been disruption of the cell walls and creation of water into sand type of appearance in the respiratory cells. How this translates into pathogenically, if you will, is the presence of respiratory inflammation in the lower respiratory tracts so a peribronchiolar interstitial infiltrate that occurs. That results in mucus trapping and a lot of inflammation in the airways. This is what we see clinically as bronchiolitis.

RSV is actually a mucosally restricted pathogen in those hosts. Therefore, it stays in the upper respiratory tract and it commonly causes upper respiratory infection or illness. However, it is also the most common cause of lower respiratory tract illness or LRTI, which we know as bronchiolitis in young children. Nevertheless, we do see disease occurring frequently in other age groups, including elderly adults and young children.

We know that immunity to RSV is incomplete after primary infections and, therefore, recurrent infections will occur throughout life. However, they tend to be milder. They tend to be more superficial. So, they are faster to recover, except in individuals with chronic medical conditions and, again, the elderly.

In a typical RSV season, which seasonality is very similar to that of the flu in that we see it in the winter time in the Northern Hemisphere but we do have a longer period of circulation of RSV typically between October and March every year, depending on where you are, during those seasons, we usually see both RSV A and B circulating commonly.

Then, again, as I mentioned before, we know that upon infection, there is a neutralizing antibody that is virus specific usually to the F and G proteins that protects against severe lower respiratory tract illness though they may not protect completely against a new infection. We know that either infection induced or antibody that comes from the mother through the placenta or if it's passively administered, as we will see in a moment, through the administration of monoclonal antibodies, one can have protection against RSV.

I'm going to talk a little bit about the impact of RSV disease in children in the United States and throughout the world by showing you some data. We know that RSV is the most important respiratory pathogen in infants and young children, again, because it tends to have seasonality and a very prolonged circulation compared to influenza. For example, it is known that nearly all children, so 100 percent of babies, will be infected with RSV at least once by the age of two years.

Again, the majority of these infections will be upper respiratory tract. But you can see that one-third or so of those primary infections will result in bronchiolitis and lower respiratory tract symptoms. Of those, two to three percent of children who are infected will require hospitalization. This also varies in different places but it is a very fair recent estimate. However, in countries where there is good access to care, like the United States, mortality is relatively infrequent but it's not negligible.

Here is some data from Dr. Caren Hall, published in The New England Journal in 2009, that talks about, again, one of the outcomes. This infection rates focusing on children less than five years of age in the United States. What you can see here, when you look at the number of infections, this is infection rate by a thousand children.

The younger children, those under five months of age and those under one year of age, tend to have the highest rates in terms of hospitalization, in this case, 16.9 per thousand versus 5.1 per thousand in the first year of age. It decreases quite a bit after that, in the second year of age. It's the same thing for emergency department visits and visits to the practitioner in pediatrics will be much higher in the first six months and the first year of life compared to children who are older.

Another way of looking at the impact of RSV is looking at hospitalization. This particular study was prior to the use of Synagis, a monoclonal antibody, for passive prevention of RSV. It actually informed that particular intervention in that it demonstrated, again, that there are certain factors that put babies at risk for RSV.

In this case, we have the group of less than five month olds and we have RSV hospitalizations per thousand. You see that clearly, when you look at the very highest bar, which is in green, those are babies with what we used to call BPD and we call now chronic lung disease of prematurity and that in the first six months of life but also in the second so first year of life all together the babies with chronic lung disease of prematurity would have the highest hospitalization rate.

The second group after them would be those with a congenital heart disease that would be usually hemodynamically unstable heart disease. The third group you have there, compared to the normal, the normal is in purple, but the third group overall together would be those babies who are premature. You have here babies that are preemies, from less than 28 weeks, or less than 32 weeks, or 33-35 weeks who are the older ones here. Certainly, again, the first few months of life would be the highest risk. In general, this information served, again, to inform the utilization of monoclonal antibody to prevent RSV, particularly in premature babies and those with heart disease and chronic lung disease.

More recent data, this is as of 2014. We continue to see now looking at average RSV hospitalization rates in children less than 24 months after utilization of the monoclonal antibody prevention that we still continue to have RSV hospitalization at a rate in all infants that is about five per thousand. However, when you break it down, depending on their gestational age, you see that it remains relatively between five and six, even including the preemies, until you get down to those less than 29 weeks gestation where you see the highest risk hospitalization rate of 19 per thousand. So, for those who are very premature, it is still recommended to continue to use the passive monoclonal antibody.

Another way to look at the impact of RSV is to look at fatalities. As I mentioned, that is less prominent in countries like the United States. This particular report looked at compiled data from 1996-2009 with 36 studies looking at hospitalization and what would be reasons for fatalities. You see that for otherwise healthy children the fatality rate is relatively low, less than one percent. When you start including items or risk factors like prematurity, it could be up as high as six percent. Certainly, chronic lung disease and congenital heart disease are the highest rates. We also understand that if children do require intensive care and other supportive interventions, like extracorporeal membrane oxygenation device, then the risk for fatality is much higher.

Here's another comparison of two studies that, again, points out mortality of RSV this time comparing it with influenza, just to give you a little bit of a reference. Again, you see here the incidents of mortality in the different age groups. For example, in this initial study, it is, again, babies under one year of age that have the highest incidents of mortality associated with these infections. I just wanted to point out that it not only is higher in infants under one, and that is consistent with both of these publications, but it is higher in RSV compared to influenza in both of the publications. Therefore, again, the impact of RSV is relatively high at all levels in the United States.

Few data exists in the rest of the world but there is at least one publication by Nair, et al. in Lancet 2010 that estimated the global burden of RSV disease in children under five years of age and concluded in general that RSV is indeed an important cause of death after pneumococcal pneumonia and Haemophilus influenzae type b pneumonia throughout the world. It is certainly a major global pathogen.

throughout the world. Therefore, in the developing world where most of the RSV infection occurs is where you also will have the majority of deaths occurring associated with RSV. These are important considerations for vaccination.

What do we know about RSV in pregnant women? This is also another very important area of research because women are susceptible to RSV like all of us are in the sense that all adults would have a risk of acquiring RSV since we do have incomplete immunity. However, we do not look for it often as a pathogen, especially in the context of pregnancy.

In some studies that have started to look at this, particularly in the United States, I am citing data from one of our epidemiologic studies here in the Houston area where we looked at women coming for routine prenatal care during the winter season. They were enrolled in the study whether they had respiratory symptoms or not. This could be any type of respiratory symptom. We tested them for multiple viruses.

Two things were interesting. One was that about two-thirds of women do develop some type of respiratory illness during the winter season as part of their routine prenatal care. That might not have been the main visit why they were there but they did report some respiratory illness. Among those, approximately ten percent of pregnant women with respiratory illness had RSV. So, it is found. What we need to understand is what it causes.

There is at least one report that I'll show you in a little bit more detail in a moment by Wheeler, et al. where there have been some severe cases of lower respiratory tract illness associated with RSV in pregnant women. However, we understand that the majority of the disease is probably mild. We think though that in some cases RSV in pregnant women could affect outcomes of pregnancy because it can result in fever, respiratory distress, need for hospitalization, and even induction of labor. It is likely that although it is less severe than influenza it's probably more significant than a virus like rhinovirus which causes the common cold when it occurs in pregnancy.

This is some data. I don't expect you to see all the details but to show you out of the ambulatory pregnant women study that I just described to you in Houston we had these cases, six cases of women who had documented RSV of a duration that could go from one week, even up to four weeks of symptoms. These were young mothers who had a gestational age that varied from 15 weeks of gestation to term, 39 weeks, and that presented and were tested by us anywhere between one and even 25 days after the onset of symptoms.

The majority, as you can see, had congestion, sneezing, and cough, which is very common. In one case where this person had more symptoms, including wheezing, we believe that there was a chance of a secondary infection as well. In this case, there were no significant outcomes or adverse events to the delivery or to pregnancy.

However, in the study by Wheeler, et al. that was published November 2015, this came from the experience at Duke, you see that they describe three cases. These are all pregnant young women, again, 32-34 weeks of gestation at the time of infection. Infection was documented by PCRs. In one case it was only RSV. In the other cases it was co-infection with H1N1 flu virus or with base strep. You can see that they had lower respiratory tract illness. One woman had bronchitis and pneumonia. The second one had pneumonia and one just had upper respiratory infection.

The most severe case was this 26 year old with first pregnancy at 33 weeks of gestation who had bronchitis and pneumonia and actually required hospitalization for two weeks with mechanical ventilation and even delivery by C-section at 34 weeks of this baby because of the maternal illness. This woman eventually recovered and did receive broad antibiotics because there was also a concern of another infection although that was not proven. The woman recovered.

You can see how there are important risk factors to consider, like asthma or having been a smoker and, in this case, also, exposure to young children with respiratory symptoms, which is very important for RSV. The second case was also a little interesting in that there was this 27 year old woman at 34 weeks of gestation developed preterm labor and delivery after one day of mechanical ventilation, not as severe as case one. Again, I would like to just point out that these are case reports that when identified RSV could potentially be a cause of severe lower respiratory tract infection. But it is expected that the majority of RSV cases in pregnancy are going to be mild. More data is coming and more investigators are looking at this particular question.

Let me just talk to you about prevention strategies because this is where we would like to focus in terms of what are current options and future options. We don't have a licensed vaccine for RSV either for children or adults at this time. We rely on passive antibody administration at this time with RSV specific IgG, which is a monoclonal antibody that has been licensed since 1998. It reduces mortality and severity of RSV disease. It's very effective.

As per current recommendations, it's restricted to use in preterm infants less than 29 weeks of gestation and infants also with chronic lung disease of prematurity or those with congenital heart disease that is hemodynamically significant. It does require monthly administration. It's costly. A lot of infants – those who are more than 29 weeks of gestation, including term babies that get RSV – are excluded from this intervention.

Why don't we have an RSV vaccine for children? There are many reasons. The primary target population, which is as we've seen with the epidemiology that I presented to you, are the very young, those under five months of age usually, who actually don't have the ability to respond very well to vaccinations without the need of multiple vaccinations. We also have a maternal antibody that is present that could actually interfere with the uptake of a vaccine. In addition to that, we have incomplete immunity to natural RSV infection. That is particularly true in the young babies.

Babies also have the historical burden of having had in the 1960s a formal and an activated RSV vaccine that was given to very young infants that then went on to develop RSV infection. Some had enhanced or severe pulmonary disease and death. That actually hindered the development of an RSV vaccine for children for a long time. We also don't have adequate models to challenge in the laboratory to test for RSV infection at a very young age. So, the bottom line is that this combination of factors has not allowed us to have an RSV vaccine that works. In reality, we need a vaccine that stimulates a better immunity than even the natural infection to be able to protect young babies.

We know, for example – these are established facts – if you do have maternal RSV specific antibodies, that will result in protection of the neonate. In multiple studies this has been shown so I'm giving you here a list of different studies that have been published over the last three decades where when you have infection in children, those who did not develop disease that was significant actually had higher RSV antibody titers that were passively transferred from the mother compared to those who did develop RSV disease whose titers were lower. That is a known fact.

The rationale then for protecting infants against RSV through maternal immunization is that during those first months of life, when those babies are at highest risk for infection, the reduced incidence of RSV disease will actually correlate very well with those higher concentrations of RSV specific maternally derived antibody in the cord blood. We have also the experience of the passive IgG, the Palivizumab (through Synagis®) that is given to reduce the incidence of severe disease in the premature.

We also know through several studies that the transfer of RSV specific IgGs through the placenta from the mother to the infant is very efficient because IgG is transferred preferentially through an active receptor based model where you have higher concentration actually on the fetal side. That actually makes us think more of maternal versus infant immunization because of the challenges that we have already described for infant immunization.

If we had a vaccine for pregnant women against RSV, we really are looking at a vaccine that would be focused mostly on preventing infant death and hospitalization. This will be vaccinating the mother with the goal of protecting the infant. We also would want to think of a vaccine that could prevent or reduce the severity or lower respiratory tract illness in the babies and also potentially delay the onset of that first RSV infection in infants.

If we are able to do that, if the babies do not get their first RSV infection until their lungs are a little bit larger and they have been able to grow, they will be able to resist that infection better and not have as much of a severe outcome as opposed to when they're very young and their lungs are still very susceptible. We also hope that vaccinating pregnant women would limit the transmission of this virus through the community and also, particularly, the community of mothers and young babies who are susceptible.

Other indirect benefits from preventing RSV in early life would be reducing secondary complications in the baby. We know we can have bacterial infections that come after that cause pneumonia or otitis media. We would reduce potentially the use of antibiotics in those babies. There is a lot of discussion currently regarding the association between respiratory infections, respiratory viruses, and wheezing and how that could be translated in the future into risk for asthma or recurring wheezing.

There is a particular interest as well in reducing this first episode of wheezing and also the recurrence in the future, which could potentially be done if we prevent RSV infection. In the end, though, the main goal will be that is also a platform that helps us improve maternal and pregnancy outcomes in the future once we learn more about the effects of RSV in pregnant women.

Here are some prospects. Thinking, again, about what is happening now for an RSV vaccine. It would not be only a vaccine for the United States. It would be a vaccine geared to protecting infants worldwide because this is a global problem. The reason this is feasible and being considered at this point is because we know that maternal immunization in and of itself is an accepted strategy to prevent maternal and infant disease in the world.

The best examples are tetanus with maternal and neonatal tetanus elimination programs and also the use of influenza vaccine and pertussis, which is being implemented in some countries at this point. In addition to that, there is a very active development of RSV vaccines for pregnant women that is happening in the industry with most interest for vaccines directed to pregnant women or the protection of infants although, as you will see, there are also vaccines being prepared for children.

There is tremendous support from regulatory agencies in the United States, the FDA, and others, the EMA in Europe for the ability to establish a path for licensure of those first vaccines that will be indicated for pregnant women. This will be the first time that vaccines will be, hopefully, having a specific indication for pregnancy, yet again, with the goal of protecting infants and hopefully also protecting the mothers.

This also has been feasible because of the support of funders. One of the largest is the Bill and Melinda Gates Foundation, who is really helping understand RSV disease burden throughout the world but also supporting the development of these vaccines. Clinical trials are underway, as we will see in a moment, to look at safety and efficacy but also supporting different aspects of vaccine implementation, which are going to be critical.

This is not for you to read. This is just a table to show you the active pipeline that we have in terms of RSV vaccine development. This is actually a figure that is put together by Path who does a lot of the work that the Bill and Melinda Gates Foundation supports but it doesn't reflect only their vaccines. Obviously, all of these, as you can see, we have different types of vaccines as listed here.

There are different models, live vaccines, whole inactivated, particle based, subunit, nucleic acid, gene based vector vaccines. Here at the very bottom is the immune prophylaxis approach where you have so much going on in the preclinical area right now that you can see many vaccines are potentially coming in the future. Some are in phase one clinical trials, phase two clinical trials, and there is currently actually a phase three clinical trial of RSV vaccine in pregnancy that is ongoing looking at this particular indication. This is also true for the monoclonal antibodies. It's also true for the infant vaccine.

Let me just tell you about two studies very briefly. We completed a study many years ago of a PFP2 subunit vaccine here in the Houston area where we have healthy pregnant women that receive the vaccination at 30-34 weeks of gestation. We looked at safety as well as the effect of the antibody on different cytokines as well as immunogenicity endpoints looking at efficiency of transplacental transport antibodies and also persistence of antibodies in the babies in breast milk.

Why I want you to know about this study is because the vaccine actually was never developed further than this particular trial in pregnancy. Although we did have a very nice response, 95 percent had a rise of IgG after vaccination compared to six percent of those who received a placebo, unfortunately, only ten percent of the women who received the vaccine had neutralizing antibodies which is what you need for the adequate protection against RSV. So, it was not a potent vaccine enough to develop.

What was interesting, and you can see it in this figure, is that compared to placebo women who received the vaccine were able to have higher cored antibody titers to the RSV which is really the goal that one would expect to have with an RSV vaccination bringing up those that are at the lowest level so that each baby is born with the highest concentrations at birth. So, importantly, again, we demonstrated that there was efficient transplacental passage. We demonstrated that we could measure the antibody in the breast milk and that persisted up to six months. There was no concern for enhanced RSV disease in the babies. The babies did have higher antibody levels and controls up to six months of age. So, it was a proof on concept.

More recently, the phase two study of the RSV F post-fusion protein nanoparticle vaccine, that is actually aluminum ajuvanted, has been completed in the United States in 2014-2015. This was also a small study of 50 pregnant women 18-39 years of age who had uncomplicated pregnancies who received their dose between 33-35 weeks of gestation. Safety was assessed as well as immunogenicity.

Similarly, I have to report to you, as you've seen probably in some of these presentations, that the mothers responded well. The transplacental passage was adequate. The infants did receive immune antibodies for several weeks in the first few weeks of life. This actually has led to the phase three clinical trial that has already started and is underway and for which we expect to have data in the next couple of years regarding the safety and efficacy of this RSV vaccine in pregnant women.

Let me finish by talking to you about some of the major considerations in terms of implementation. Once we have these vaccines, which we are very hopeful, we need to think about implementing these vaccinations throughout many countries in the world. It is important then to understand the burden of disease both in mothers and in infants, especially in high resource versus low and middle income country settings so that we know what the impact of the vaccination would be.

It is important to make sure and understand the safety profile of the vaccine, both in the mother and in the infant. Know that for these types of vaccines going to pregnant women, the infant vaccine enhancement of disease is not a consideration because we are not exposing that infant to the vaccine, other than the mother and IgG.

We also need to understand background obstetric events so knowing, for example, rates of these sections or rates of other events, so that we have a better understanding of how we are preventing or potentially altering those in the context of administration of a vaccine to pregnant women and have very clear efficacy endpoints, as we mentioned, as to whether we want to decrease severe lower respiratory tract illness, hospitalization, death, or all.

In addition to that, the system will have to have a diagnosis as surveillance of RSV disease, also of adverse events following immunization. The potential approaches would be that, again, we don't know how this will happen but that potentially pregnant women would require an annual RSV vaccination, usually given the third trimester. It could be given at the same time as an influenza vaccine or other vaccines, such as Tdap.

Finally, in terms of the other prevention strategies that are in place, we will need to consider, as you see here, that even having a maternal vaccine available might not actually allow us to not use existing prevention strategies. For example, giving a maternal vaccination will not necessarily protect the very young premature babies because we do need to have enough time for those antibodies to pass from the mother to the infant. Premature babies will not benefit from that.

Having monoclonal antibodies that are given to infants is still going to be necessary for some of these preterm babies. Having a monoclonal antibody that has longer duration and fewer doses needed to be administered during the season would be advantageous. That is an area of current research where phase two and three clinical trials are on their way looking at this possibility.

Infant vaccination also remains a possibility. What you see is that phase two and three clinical trials are on their way for vaccines that could be given in the first six months of life or it could be given to toddlers in the 6-23 months of age range. When we talk about the strategy in the end, when we consider the fact that RSV in the first two years of life is particularly severe but maternal immunization could only protect in the early part of that, we could think of a strategy when you have a maternal followed by an infant vaccination. That infant vaccination could be given in the first six months of life or you could have a maternal vaccine then followed by a toddler vaccination if the vaccine is actually able to protect those babies for a longer period of time.

I will pass the microphone to Dr. Sperling to give you some parting conclusions and thoughts about how to proceed. Thank you.

Rhoda Sperling, MD: Thank you, Dr. Munoz, for a fun and wonderful presentation. I wanted to make some concluding remarks as we are in the era of advancing maternal immunizations for the prevention of infant RSV and other diseases.

RSV is the first vaccine that's undergoing evaluation specifically for pregnancy indication. We will be requiring a non-live virus vaccine formulation. It's likely going to be utilizing some type of Atrovent, probably aluminum Atrovent. Aluminum Atrovent is already commonly used in other vaccines.

Adults are prime from previous infections and so the vaccine will boost the maternal antibody concentrations that serum and breast milk antibodies will contribute to the infant protection. The administration in the second to third trimester is projected for both optimal safety and efficacy, in addition to the existing platform for prenatal vaccination with influenza and Tdap. So, there is more to come as we go from bench to bedside.

I also want to make some concluding remarks about advancing maternal immunization in general. Disease prevention through maternal vaccination is a very important strategy that will help both mothers and babies thrive. Designing and conducting vaccine clinical trials that rigorously assess both safety and efficacy are necessary for regulatory approval. How we coordinate how these vaccines fit into the broader toolkit of antepartum and newborn care is important and will be a challenge and opportunity for the Ob-Gyn community.

My last comment is not necessarily a conclusion from this presentation but acknowledging the issues about vaccine hesitancy and the importance of addressing both patient and provider education gaps so that misconceptions about, for example, the diseases and how important they are, that they are serious and life threatening. Misconceptions about vaccine safety, misconceptions for how vaccines get approved, and concerns about implementation of vaccine administration during routine prenatal care get addressed up front with obstetric and other care providers so there are really no misconceptions as these vaccines get rolled out. Hopefully, RSV will be the next vaccine that we will be adding to our armamentarium.

Dr. Munoz, would you like to make any other concluding remarks?

Flor Munoz, MD: Thank you so much. I think that this is very important as a summary in terms of being able to know that as pediatricians like myself, obstetricians like yourself, for this particular project, which is decreasing infant RSV disease and understanding the burden of RSV in pregnant women, we would work together. It is an exciting field. It is something that will continue to open up opportunities to work on maternal immunization. I would like to make sure that we have time for questions from the audience.

Moderator: Absolutely. Thank you, Dr. Sperling and Dr. Munoz. We will now open it up for questions for both of our presenters.

Let me go ahead and read the first question. “Is tracking the diagnosis of bronchiolitis on administrative reimbursement claims from children less than two years a reasonable syndromic case definition of RSV for public health tracking purposes?”

Flor Munoz, MD: This is Flor Munoz. I can try to answer that. The diagnosis of bronchiolitis is obviously not specific but it does reflect pretty well the incidence of RSV in general. As a syndrome, it is important to code it as bronchiolitis. It should be reasonable in terms of public health tracking. There are specific RSV codes and so when known, which is part of the issue is that it's not always known that it is RSV, unless children are tested. That is not necessarily happening routinely everywhere. But if it is known it is important to include RSV bronchiolitis. Otherwise, coding it as bronchiolitis should be appropriate.

Moderator: Thank you, doctor. Our next question, “in terms of infant vaccination, would you be concerned about interference from maternally derived RSV antibodies?”

Flor Munoz, MD: Yes. That is one of the considerations when developing a strategic plan for how to utilize maternal, followed by infant vaccines. At this time, we know that if we have maternal antibody that is induced by the vaccine, based on the phase two and three clinical trials that are ongoing and previous studies, there is actually a relatively rapid decay of the IgG that is vaccine induced.

The half- life is anywhere between 35 and 42 days. It's about six weeks. So, the higher the concentration that is achieved at birth, the longer that antibody will stay in the baby. However, again, the level of protection to the baby depends on a certain amount or threshold of antibody that needs to be present. There's no specific correlate but people talk about a concentration of six to eight logs too to be able to have some protection for the baby.

To answer the question, at this time the most vulnerable are those babies under five months of age or under six months of age for whom, if we achieve a high enough concentration, we should be able to protect them through maternal antibody. But if we bring in a vaccination for young children, we would have to take into consideration that potential interference on when to start that first vaccination dose on the infants. So, it's probably going to be later, not in the second month but even four or six months if we did that, based on the fact that maternal antibody would be the one that will really protect them when we need them to be protected and that the infant vaccination would be mostly for the older children.

Moderator: Thank you, doctor.

Flor Munoz, MD: There was a question asking, “when did we think the vaccine would be licensed?” I wanted to address that. The phase three clinical trials are on their way at this time. The licensure of the vaccine for pregnant women for RSV will depend on the results of that phase three trial. What I can tell you is it's a four to five year clinical trial. It's about halfway through. So, the licensure of these RSV vaccines for pregnant women specifically is not going to be before the next five plus years. We would hope that it's soon but it will take at least another five years.

Moderator: Excellent. Thank you, doctor. This question is for the first presenting doctor. “For premature babies, for instance, an infant delivered at 30 weeks or slightly less, at what age does the doctor suggest the infant be given the RSV infant vaccine, especially if the mother was not given or administered the RSV vaccine at pregnancy?”

Flor Munoz, MD: Let me just clarify that we currently do not have any vaccines available for infants or for mothers. There shouldn't be any babies vaccinated at this time because there are no licensed vaccines for infants or for mothers. All that we discussed today is investigational and its potential planning for the future.

Trying to think about this particular question, if you have, again, an infant that is born prematurely, whether a mother receives the vaccine or not, premature infants are not going to have the advantage of receiving the maternal antibody at optimal levels to protect them enough. We know that the placental passage of antibody really takes off after usually about the 20th week but, most importantly, after 28 weeks or so of gestation.

So, if the baby is born early, that end of pregnancy period, which is really the third trimester when you have the highest concentrations of antibody to the infant, are now going to be feasible. Those are, again, the premature babies that would continue to benefit from receiving passive monoclonal antibody today and in the future based on current recommendations.

Moderator: Thank you, doctor. Our next question, “getting women vaccinated against influenza is still a struggle for public health. What can we learn about the flu model so that we can improve vaccine uptake among pregnant women for RSV if or when a vaccine becomes available?”

Rhoda Sperling, MD: This is Dr. Sperling. I would say, education, education, education. I think its public health education, educating providers, educating patients. This webinar is an example of trying to do that where we're talking about an RSV vaccine that's really in late stage development but still years away from being there in clinical use.

It's important that we all start to frame the discussion and talk about maternal benefits, neonatal, newborn infant benefits, and also talk up front about the risks and how the risks were looked at, side effects were looked at, safety was looked at so people have a level of confidence that things were vetted properly before they were introduced into clinical practice.

I'd also be interested in other people's ideas about how we can do a better job because, clearly, these are life-saving interventions. We need to be able to get that information across.

Moderator: Thank you, doctor. Our next question, “in the maternal immunization study that you participated in, how did you address vaccine hesitancy?”

Flor Munoz, MD: Let me tell you a little bit about those because it's different. When you do clinical research to enroll pregnant women to participate in a study compared to the clinical practice, I would wholeheartedly agree with Dr. Sperling in the sense that any vaccine given to pregnant women requires education of the mother, education of the partner, any other family member, but also the provider regarding what it is that our goal is with that vaccination.

We continue to learn more about vaccines in general but vaccines in pregnancy become an important issue because you do have, again, in mind two individuals, the mother and the baby, and you do have a goal. Sometimes, as in influenza, it's primarily the protection of the mother because we understand how severe influenza can be in pregnancy but with additional benefits to the infant, which have been proven and documented, as shown by Dr. Sperling today. We also have, in some cases, the goal, primarily, of protecting the infant. That would be the case of RSV, as we've discussed today. However, the intervention and the platform is the same, which is during prenatal care.

So, how do I use the concerns of vaccine hesitancy for research? For example, we know that a woman who has received and is open to receive her routinely recommended influenza or Tdap vaccine during pregnancy right now is actually more likely to participate in a clinical study because they believe in the cause of the vaccination. But that's not necessarily universal. One would be surprised that sometimes women accept other vaccines and they will not take, for example, the flu vaccine.

It is, again, an effort of education. It is an effort of understanding what the benefits are. That is true for the providers as we understand, again, how safe these interventions are. These vaccines are designed to be safe. They're designed to be given to pregnant women. We have systems in place to assess any adverse events that occur after vaccination or in the case of some of these vaccines, like pertussis, which was introduced and now is given routinely.

After introduction, what are the adverse events that one needs to be looking for? So, there is very active surveillance that, again, hopefully, will reassure both providers and also the patients that are somehow hesitant. They're right to be hesitant in the context of pregnancy. Providing all this information is going to be critical.

Moderator: Thank you very much, doctor. We are coming to the end of our time. Before we wrap up, do either of you have any final thoughts?

Flor Munoz, MD: I can comment very briefly on the fact that although we sound like this is very routine I would like to make sure that the participants know that the field of maternal immunization is extremely active. For the first time in many, many years we have really the prospect of having both RSV and group B strep vaccines become vaccines for pregnancy indication, which is unique and never done before.

Again, everything seems to be aligned from both support and research to the regulatory aspect of this. We expect to see a lot of changes in the coming years in terms of updates that would be available and accessible to both the obstetric and the pediatric population. These will be interventions that have a potential global impact in terms of early life health and maternal health. It's both maternal and infant strategy.

Thank you so much.

Moderator: Wonderful. Thank you very much, again, to today's presenters and attendees. If you have any outstanding questions that are not answered today, please contact ACOG's immunization department at [email protected].

This concludes our program for today. Thank you for joining us. We'll see you next time.