What’s New for the 2016-2017 Flu Season: Recommendations for Children

Moderator: Marcy Friedman

Presenters: Lisa Grohskopf, MD, MPH; Henry H. Bernstein, DO, MHCM, FAAP

Date/Time: October 27, 2016, 2:00 - 3:00 pm ET

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I would now like to turn the call over to Marcy Friedman. You may begin.

Marcy Friedman: Thank you (Kate) and good afternoon. My name is Marcy Friedman and I’m representing the Clinician Outreach and Communication Activity COCA with the Emergency Risk Communication Branch at the Centers for Disease Control and Prevention.

I’m happy to welcome you to today’s COCA call, What’s New for the 2016/2017 Flu Season: Recommendations for Children.

You may participate in today’s presentation by audio only, via webinar, or you may download the slides if you are unable to access the webinar. The PowerPoint slide set and the webinar link can be found on our COCA web page at emergency.cdc.gov/coca. Click on the October 27th COCA call. The slide set is then located under call materials.

Free continuing education is offered for this COCA call. Instructions on how to earn continuing education will be provided at the end of the call.

CDC, our planners, and their spouses and partners wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure that there is no bias.

This presentation may not include any discussion of the unlabeled use of a product or products under investigational use.

At the end of the presentation, you will have the opportunity to ask the presenters questions. On the phone, dialing star 1 will put you in the queue for your question. You may submit questions through the webinar system at any time during the presentation by selecting the Q&A tab at the top of the webinar screen and typing in your question.

Questions are limited to clinicians who have questions about strategies to improve influenza prevention and control in children during the 2016 and 2017 season.

For those who may have media questions, please contact CDC Media Relations at 404 639-3286 or you may email Media@cdc.gov.

If you are a patient, please refer your questions to your healthcare provider.

At the conclusion of today’s session, the participant will be able to describe strategies to prepare for the 2016-2017 influenza season, identify key recommendations in the AAP influenza policy statement, discuss vaccine effectiveness, clarify recommendations related to live, attenuated influenza vaccine, explain the importance of antiviral medications in the control of influenza, discuss flu vaccine in egg allergic children.

Today’s first presenter is Dr. Lisa Grohskopf. Dr. Grohskopf is a Medical Officer and CDC Lead for influenza for the working group on the Advisory Committee on Immunization Practices, ACIP. She is also a subject matter expert for CDC Influenza Vaccination Policy.

Our second presenter is Dr. Henry Bernstein. Dr. Bernstein has 30 years of experience as a general pediatrician in private practice and he is also a Professor of Pediatrics at Hofstra Northwell LIJ School of Medicine. Dr. Bernstein also represents the American Association of Pediatrics, AAP, on the influenza working group of the CDC’s Advisory Committee on Immunization Practices, ACIP.

At this time, please welcome Dr. Lisa Grohskopf.

Lisa Grohskopf: Hi everyone. So I’m going to run through a brief update on what’s new in the ACIP influenza vaccination recommendations for this season 2016-2017. There aren’t many changes but there’s one fairly big one that probably many folks have heard about. Going to move from the title slide onto the second slide, which says ACIP Influenza Statement Overview.

The most recent statement was published in MMWR this past August 26th. The principal changes which we’ll be going over are first the biggest one that the live attenuated influenza is not recommended for use in any population during the 2016-17 season. And we’ll discuss why and how that decision came about.

We also have discussion of some new and recent vaccine licensures, which include Fluad, an adjuvanted vaccine, and Flucelvax Quadrivalent, which is a new quadrivalent version of the cell culture based vaccine that’s been out for several seasons now.

And also we have a couple of minor changes to the egg allergy recommendations.

I’m also going to mention at the end two new product licensures that occurred since publication of the ACIP statement so they’re not discussed in the statement, and those are Afluria Quadrivalent and Flublok Quadrivalent.

So next slide, which is labeled number nine that says change in LAIV recommendations language. This is the language that appears in the ACIP influenza statement concerning LAIV. In light of concerns regarding low effectiveness against Influenza A H1N1 PDMO9 in the United States during the 2013-14 and 2015-16 seasons, for the 2016-17 season ACIP makes the interim recommendation that live attenuated influenza vaccine -- or LAIV4 -- should not be used.

So the Influenza A H1N1 PDMO9 is the pandemic influenza A H1N1 virus that has been among the H1N1 type of influenza viruses the most common circulating one since the 2009 pandemic. It’s still with us. And basically low effectiveness of LAIV was observed for that virus during the 13-14 and 15-16 seasons.

The recommendation that LAIV not be used this season is referred to as interim because we know that over time more data are going to emerge about LAIV and possibly what caused the difficulties during these two seasons. We don’t anticipate at this point that there’s going to be anything that happens that changes the recommendation for this season. So I think it’s safe to assume that for 2016-17 the recommendation will stay as it is.

But this is something that the ACIP is going to continue to evaluate as more data come out.

Next slide, number ten -- Change in LAIV Recommendations History is the title of this one. Just want to give you in this slide and the next one a little bit of historical perspective on what’s happened with ACIP and LAIV over the last few years.

Way way back, going to the beginning, LAIV was licensed in 2003 in the United States. It was initially licensed for people 5 years through 49 years and then a couple of years after licensure that was expanded to 2 through 49 years of age.

There were a couple of early randomized comparative trials at LAIV versus inactivated influenza vaccine or IIV. These were conducted prior to the 2009 pandemic. Two of the larger ones were done during the 2002-03 and 04-05 seasons. And these demonstrated superior efficacy of LAIV as compared to inactivated vaccine among younger children -- those in the neighborhood of about six years and under.

The consideration of this data led ACIP to express a preference for LAIV for healthy two through eight year olds for the 14-15 season.

Subsequent to that vote, as the 14-15 season was getting underway, surveillance data for the 13-14 season was completed and analysis revealed that there was no effectiveness of LAIV against H1N1 PDMO9. Again, that’s the pandemic influenza H1N1 virus.

Now, 13-14 was an interesting season in that it was the first H1N1 predominant season we had since the 2009 pandemic. The most common influenza A viruses in humans are H1N1 viruses and H3N2 viruses. And after the initial phase of the H1N1 pandemic in 2009-10, subsequent seasons were H3N2 predominant seasons. So we didn’t have another H1N1 predominant season until 13-14.

Now, while the LAIV was not effective against H1N1 PDMO9, inactivated vaccines were. So there was a pronounced difference in efficacy between the two. It was hoped that LAIV might be more effective against H3N2 even in the setting of drifted H3N2 -- that is H3N2 viruses that had mutated and changed from the virus whatever H3N2 virus was projected to be in the vaccine. So no change was made immediately to the recommendations during the 14-15 season. We had an H3N2 predominant season. And that virus was mostly drifted virus that did not match well with the vaccine virus.

There had been two earlier studies that indicated that LAIV was better than inactivated vaccine against drifted H3N2 and it was hoped that would hold out for 14-15 but it was not the case for the 14-15 season. Both LAIV and inactivated vaccine performed sub-optimally during the 14-15 season.

After reviewing these data in February 2015 ACIP did not renew the preferential recommendation for LAIV for the 15-16 season, which is the one we just finished.

Next slide, number 11. Following up on this, ACIP again reviewed seasonal LAIV and inactivated vaccine effectiveness data in June 2016, and this was for the 15-16 season. This data came from three different US observational studies, as was also the case during the 13-14 season. These data came from the US Flu VE Network, which is a CDC sponsored study from Medimmune and also from the US Department of Defense.

And these data were viewed again in 2016. Of note to the point estimates for effectiveness vary among the different studies. They are studies that are relatively similar in design, or what we call test negative case control designs. They’re not randomized trials.

Looking at all influenza A and B, the Flu VE Network had 3% V not statistically significant. Medimmune data 46% that was statistically significant and the Department of Defense 53% that was statistically significant.

Looking at VE against influenza A H1N1 PDMO9 specifically, however, again we see some variability in the point estimates -- minus 21% 50% and 15%. However, none of the estimates were statistically significant.

After reviewing these data, the ACIP expressed concern regarding the low VE against H1N1 PDMO9 and that led to the recommendation that LAIV not be recommended for use during 2016-17.

Next slide, number 12. So the next three slides are some data from US Flu VE Network that were shown at the (Tune) ACIP meeting. These are LAIV in inactivated vaccine effectiveness data specifically for children aged 2-17 years. We see any flu on the far left then H1N1 PDMO9 then the 2Bs. Yamagata and Victoria are the two separate B lineages.

Within each blue box, outlined box, the dot and point estimate on the left are LAIV and one on the right is inactivated vaccine. And what we see overall is consistently low and statistically insignificant effectiveness, whether it’s for any flu or for the H1N1 PDMO9 or the Bs of LAIV, whereas we have relatively high and statistically significant effectiveness for the inactivated vaccine.

Slide number 13, the next slide. These are the same data except this time we’re looking at just two through eight-year-olds. This is the age group that was the subject of the preferential recommendation that had been expressed for the 14-15 season. We see similarly low VE for LAIV.

And the next slide we have the 9-17-year-olds, number 14, slide number 14 where we have a bit better efficacy or effectiveness for the older kids but still not statistically significant. And again, the effectiveness of IIV is higher and statistically significant. That bears out across the age groups.

So the next slide, number 15, these show data from the Flu VE Network for a total of six seasons, from 2010-11 through 2015-16. I’m going to hit next slide again. Marcy, if you can hit next slide again, that should put a red box around some of those data -- the three columns to the left.

So if you look at the three boxes to the left, actually the ones that don’t have the red box around them, these are prior to the 13-14 season. We see relatively comparable effectiveness overall for kids 2-17 years for the two different vaccines.

Then when you move from the 13-14 season forward, we see differences. Now, the 14-15 season, again that was a predominant H3N2 season with a drift so one might expect neither vaccine to perform well -- and neither did. But we look at the 13-14 season and the 15-16 season, which were H1N1 predominant seasons, and we see the low VE for LAIV. So something has changed as we went from the earlier three seasons to the later three seasons.

One thing that changed -- and this is what the arrows that span the bottoms of those boxes refer to. There’s an arrow on the three left ones that says LAIV 3 and then there’s LAIV 4 in the right hand three columns. One thing that changed in 13-14 is that there was a wholesale switch from the trivalent LAIV to the quadrivalent LAIV. Everything prior to 13-14 was trivalent. Then we had quadrivalent. That’s the vaccine that has two different Bs in it.

One possibility that has been put forth for why the change in LAIV performance is we now have a quadrivalent vaccine. Perhaps addition of that extra B is responsible for some interference, and particularly affects the H1N1 virus. That’s one possibility.

Another thing that happened over time and is reflected particularly with 13-14 -- because again 13-14 was the first H1N1 predominant season we had since pandemic -- if you compare 13-14 with that period early on after LAIV’s licensure where there were those comparative trials that I mentioned earlier that showed that LAIV worked better than IIV for very young children, one difference that occurred from then until 13-14 is the fact that we had the pandemic. And maybe it’s something specific either about the H1N PDMO9 virus or that virus that is used in the vaccine to cover for H1N1 PDMO9.

A third thing that’s happened since early days after LAIV approval in more recent seasons is that coverage of influenza vaccine among children is higher than it was. Prior to the 2004-05 season, we didn’t have a routine recommendation in place for vaccination of healthy children. And that was something that was phased in through the period of roughly 2003-04 with the very youngest kids and then older aged groups getting phased in by about 2008 where the first recommendations for routine vaccination of all children through 17 years of age or 6 months through 17 years of age I should say, regardless of their health status, came in.

So another possibility that’s been expressed is maybe with repeated vaccination, LAIV doesn’t work as well. It is a live virus vaccine. It has to multiply in order to work well. Maybe as we get older and there’s more antibody onboard, it just can’t function as well as it did in somebody who’s relatively vaccine-naïve.

We already knew from prior to pandemic that comparative trials of LAIV and IIV among adults didn’t have the same results as kids by and large among adults. Whereas in kids LAIV was better by and large among adults, the two vaccines perform about the same or inactivated vaccine is better. So that sort of would fit with that logic.

The bottom line is we really don’t know yet completely what is causing this issue. Those are three potential possibilities. There are I’m sure going to be more data and more information coming out about this subject over the course of the year.

Next slide, number 16. Moving onto the next topic, new vaccines for 16-17. The ones that were approved as of the publication of the flu statement in August were Fluad -- which is an MF59 adjuvanted trivalent inactivated influenza vaccine. It’s a standard dose vaccine. Has the same amount of hemagglutinin as other inactivated standard dose vaccines. It just also has MF59, which is an adjuvant intended to provide a stronger immune response.

Currently this is indicated only for people age 65 and older. It’s (immunogenetically) non-inferior to a licensed comparator IIV in preclinical trials. And a Canadian observational study noticed improved effectiveness of it compared with an unadjuvanted inactivated vaccine among 65 and older adults.

This vaccine’s not licensed for children in the US. We may see that in the future but at least for right now, it is not for the pediatric population.

The over one is Flucelvax Quadrivalent, which is going to replace the trivalent formulation of Flucelvax for the 16-17 season. The trivalent formulation’s been out roughly since 13-14. That one initially actually was only licensed for people 18 and over. With the approval of Flucelvax Quadrivalent formulation, both the quadrivalent and actually the previous trivalent form have licensure for four years and older.

That being said, we’re anticipating only the quadrivalent is going to be available this year and not the trivalent.

This vaccine has a vaccine virus that instead of being propagated in eggs during production of the vaccine, it’s propagated in canine kidney cells. The starting virus at least as of this season is initially passaged in eggs -- the virus that goes to the manufacturer to make the vaccine -- but once they get it, propagation occurs in kidney cells. So you know, while it can’t be said to be certain to be 100% egg free, it likely has a far lower amount of egg protein than other inactivated vaccines that are propagated in eggs.

Two more recent licensures that have occurred since the publication of the ACIP -- this is slide 17 -- Afluria Quadrivalent, which is a standard dose quadrivalent inactivated influenza vaccine. This is the quadrivalent formulation of Afluria trivalent, which has been out for many seasons. Currently even though Afluria trivalent is licensed for five years and older, the quadrivalent formulation at present is only licensed for 18 years and older. So basically at this point only adults.

There may be some potential for confusion here because to our knowledge there are some lots of Afluria quadrivalent vaccine that have been released. The trivalent also already had lots released. So both the trivalent and quadrivalent may be out this season, although I’m guessing not a lot of the quadrivalent.

This may make for some confusion, mainly because the trivalent as I said it’s licensed for five years and older. This however is the vaccine that was associated with the febrile seizures and febrile reactions in Australia during Australia’s 2010 season. And as a result of that, Afluria Trivalent is recommended by ACIP even though the licensure says five and up is only recommended for nine years and older.

So on the one hand, that’s the recommendation for the trivalent. Currently the quadrivalent is only licensed for 18 and up. So some potential for confusion there to be aware of.

The other recent licensure is Flublok Quadrivalent, which is the recombinant vaccine. Flublok Trivalent has been out roughly since the 13-14 season. The quadrivalent has now been licensed - it’s only licensed for 18 and older, so not for the pediatric population. We don’t anticipate that it’s going to be available for this season. Probably won’t be out until the 17-18 season.

Next slide, number 18. The last little topic to cover is change to the egg allergy language. Since the 2011-12 season, the ACIP recs have taken a stratified approach to egg allergic folks. Mild egg allergy being folks that have had only hives as a reaction to egg, and more severe allergy being essentially any other symptom.

We still have that stratification but some other things have been relaxed. One is that the 30-minute recommended post-vaccination observation period for egg allergic persons has been removed. The guidance still does discuss the fact that according to the general recommendations on immunization -- which is another ACIP document that applies for all vaccines -- there is a statement in there about providers should consider a 15-minute observation period for all patients regardless of allergy history, particularly adolescents with any vaccine to avoid injury due to syncope if the person syncopes, but that’s not something that’s specific to egg allergy.

Egg allergic persons, regardless of severity of allergy to egg -- whether it was more severe, less severe -- can receive any licensed recommended vaccine that’s otherwise appropriate. That could be inactivated influenza vaccine or recombinant vaccine. However, important to note that RIV, the recombinant vaccine is not currently licensed for people under 18 years old.

The only other caveat that remains for those with more severe egg allergy over time, this language for the more severe egg allergic folks, has sort of resolved from get referral to an allergist first to get referral to somebody who’s knowledgeable in allergy first. The language now says the selected vaccine for these folks should be administered in an in-patient or out-patient medical setting and supervised by a healthcare provider who’s able to recognize and manage severe allergic conditions.

Last slide I think is number 19. This is the egg allergy algorithm. I just wanted to mention that it’s no longer in the ACIP recs. However, for folks that want it, it is available on the CDC web pages and the link to that is there.

And I just want to acknowledge the folks in our division and also the ACIP Influenza Workgroup. And that is all I have. Thank you.

Marcy Friedman: All right. Thank you so much, Dr. Grohskopf. Next we would like to introduce Dr. Henry Bernstein. Go ahead, Dr. Bernstein.

Henry Bernstein: Great. Thank you very much. It’s an honor to be here talking about something so important as the prevention and treatment of influenza.

So this first slide is a slide that highlights five different studies that give the percent reduction and outcomes for healthcare personnel receiving influenza vaccine. And it’s important for us to understand that all healthcare personnel should receive the influenza vaccine each and every year.

And as you see here from these CDC data that were published in a recent MMWR, these are the flu vaccine coverage in healthcare personnel in the United States last flu season 2015-2016. What you see on the left hand side is the overall rate for coverage was at 79%. The middle bar is 97% and that bar reflects a requirement for healthcare personnel to receive the flu vaccine.

On the right hand side, no matter what different strategies are used in voluntary programs, none of them as you can see achieve the same rate as when it’s made mandatory for healthcare personnel.

The American Academy of Pediatrics released its latest recommendations for mandatory flu vaccine for all healthcare personnel in 2015. And it is recommended for various healthcare settings including pediatricians’ offices and healthcare settings -- not just hospitals.

So over the next several minutes, what I hope to cover is a little bit of the epidemiology, some of which we heard from Dr. Grohskopf, talk about the vaccine effectiveness to emphasize also what Dr. Grohskopf shared with us, mention about egg allergy again, review the recommendations for the prevention and control of influenza for this coming 2016-2017 season and also to remind us that although vaccine is the number one preventive measure we have, we also should be using and considering treatment with oseltamivir in certain circumstances.

We all know that influenza causes an immense amount of morbidity and mortality in any given season. As you can see here, 50-60 million infections and illnesses occur prompting 25 million physician visits, hundreds of thousands of hospitalizations, and an average of anywhere from 3,000 to 48,000 deaths per year. On average around 100 of those are pediatric aged patients under the age of 18.

When we look at selected underlying medical conditions that resulted in hospitalization last season, in pediatrics, asthma, neurologic disorders, and cardiovascular disease are the top three medical conditions that put children at higher risk for needing to be hospitalized.

But I also want to point out at the bottom of your screen you’ll notice that 50% of the hospitalized children were healthy. So that suggests that the influenza vaccine, as you know, is a universal recommendation and should be given to everyone, not just those with chronic medical conditions that perhaps put them at risk for complications from influenza.

These are the vaccination rates for adults last season in the 2015-2016 season in comparison to the previous year 2014-2015. If you start in the upper left hand corner, you can see that the rate for adults 18-64 years of age is only around 36%. And then when we look at adults greater 65 and older, it’s up to 63% but again those rates are down in comparison with the previous season.

I mentioned earlier that healthcare personnel are doing great and they’re up to 79% although requirements make it even higher.

And then on the lower left hand corner, you’ll see that pregnant women are at 50%. And we really need to be sure that we earmark pregnant women because not only do we want to protect them, but we also want to provide antibodies to their newborn babies.

And remember that there are 4 million births a year in this country, so targeting pregnant women is very important.

Now let’s look a little bit at the pediatric deaths and hospitalizations by season and predominant strain. So when we look here at the red bar, you can see that the average number of deaths does vary from season to season. And it depends upon which of the influenza strains is predominant during that particular year.

You’ll see in the last five years that the number of deaths in the pediatric population under 18 has ranged between 37 and 171. And then when we look at hospitalizations in the last two columns, you will notice over the last ten years that all children under the age of five have a much higher rate of hospitalization than children 5-17 years of age.

This season as Dr. Grohskopf mentioned the 2016-2017 seasonal influenza vaccine strains, that two of the strains in the trivalent vaccine have changed and the quadrivalent has the same strains as the trivalent one plus an additional B strain.

As was also mentioned, it’s important to recognize that the LAIV4 -- the quadrivalent intranasal product -- should not be used in any setting during the 2016-2017 season, as the interim recommendation of both the CDC and the AAP is harmonized with that particular recommendation.

Now, historically Dr. Grohskopf also mentioned that early on when the LAIV intranasal product was a trivalent product, in this particular study by Ashkenazi and colleagues, LAIV3 had a consistently fewer episodes of culture-confirmed influenza in comparison with the inactivated shot.

And similarly when we look at Belshe and colleagues’ study going back to 2007, we also see again that the proportion of children with influenza was higher in those that received the influenza vaccine by injection in comparison to those that received the live attenuated trivalent intranasal product.

Now, it’s also been mentioned that something has gone differently with the intranasal product. Well it turns out that in the last three years, there was a shift between the LAIV3 on your left hand side -- sort of like the Coke Classic -- and then we went to LAIV4 -- which is like the New Coke.

And as you saw in some of those other slides -- and I will highlight the important elements of those -- you can see that there’s been a problem with the shift to the LAIV4 quadrivalent intranasal product.

It was mentioned that perhaps there’s some increased susceptibility to thermal degradation of the H1N1 vaccine strain or the addition of the 4th strain into the intranasal product may be causing some interference with the trivalent product. The mention that all children have received vaccine before or the recommendation has been that all children receive vaccine each and every year, which may in fact be impacting the response that’s appreciated.

Remember that the LAIV intranasal products -- whether trivalent or quadrivalent -- sprayed up the nose requires viral replication within the nose. And perhaps previous antibody within patients may in fact be impacting the production of protection.

There also could be waning protection during the season from when the vaccine is administered to later in the season. And then there was also the suggestion that the company that produces the intranasal product switched their manufacturing plant with the introduction of the LAIV4 quadrivalent product and perhaps the manufacturing process is contributing to the low vaccine effectiveness.

When one looks at the overall vaccine effectiveness of LAIV4 versus IIV in children 2 through 17 years of age for the last three seasons, you’ll notice that the LAIV4 confidence intervals all cross zero, which means that there was no significant vaccine effectiveness in any of the last three years in any of the ages overall in 2-17, even when broken down between 2-8 year olds and 9-17 year olds.

If you look at the right hand column, which is the vaccine effectiveness for the last three years with the IIV3 or IIV4 products, you can see that indeed the IIV3/IIV4 injectable products outperform the LAIV4 products in all three years and in all age groups within the pediatric age range.

So in summary as you can see from this Norman Rockwell picture that LAIV4 seems to have struck out. Three strikes and you’re out.

This next timeline reviews this history and summarizes it again. The left hand side when we had LAIV3 and it seemed to outperform the injectable product. And then a shift to LAIV4 where in fact the injectable product outperformed the LAIV4.

What’s next for LAIV4? As Dr. Grohskopf mentioned, we certainly would love for the product to be effective because indeed there are many people that are needle phobic and would much prefer spraying a vaccine up their nose. And so data are being collected and evaluated and we do hope that an intranasal product becomes available for future influenza seasons.

This leads us to the American Academy of Pediatrics recommendations for the prevention and control of influenza in children for this season. Again, everyone six months of age and older should get the flu shot this season. Notice that it is a flu shot and not a flu vaccine, since the intranasal product is not recommended.

We do recommend that the vaccine be offered throughout the entire year. It should start as soon as it’s available in your community, and ideally it would be in this particular month (October). But if not, certainly offer it in any of the other months. Remember that 80% of the peak influenza activity happens in January, February, and March so there is certainly time for children to receive their vaccine and some children, as we’ll talk about in a moment, will need two doses. And so this gives adequate time for children who require two doses to receive two doses and be adequately protected.

When we look at children, it’s a universal recommendation but there are special populations that we want to be sure to reach. Of course, all children, and as was mentioned earlier, children under the age of five are more likely to be hospitalized with influenza in comparison to children 5-17 years of age. So we want to make sure that children are reached and get influenza vaccine each and every year.

We mentioned healthcare personnel because they are in contact with lots of individuals, particularly those that are at risk for complications from influenza. We know that many -- 3/4 of kids -- are in childcare settings and that there are grandparents and daycare providers and special programs that children are participating in and it’s important for all household contacts and anyone that’s in contact with all high risk children, and especially those children that are under the age of five, that they receive their flu vaccine as well.

And then again we mentioned about pregnant women, how important it is for them to receive the vaccine -- not only to protect themselves, but as you can in this study by Zaman and colleagues where mothers received the flu vaccine during pregnancy, what was monitored was how many cases of influenza were identified in their offspring once their kids were delivered in the first six months of life.

And as you can see, those mothers who received vaccine, their newborns were much less likely to develop influenza in comparison to a control group of pregnant women who did not receive influenza vaccine.

This is now moving to the number of doses that are needed. So we like Dr. Seuss and we can see that there should be one dose versus two doses. And determining that is a simple algorithm. And basically what it is is that if any child from six months through eight years of age, if they’ve received two doses of influenza vaccine at any time in their life prior to July 1st of 2016, then they only need one dose.

If they have not ever received two doses of influenza vaccine prior to July 1, 2016, then they need two doses and the two doses should be given at a minimum of four weeks apart.

Some people have asked if those previous receipt of influenza vaccine doses included LAIV4, does that mean that they should not be included in this algorithm? That is not the case. It doesn’t matter whether they received intranasal product or injectable flu vaccine in the past. The LAIV4 is still expected to have primed a child’s immune system despite the recent evidence of poor effectiveness.

When we also think about egg allergy, the evidence really has been driving, as Dr. Grohskopf mentioned, the recommendation that we don’t need to worry about egg allergy like we used to. There are now 28 studies in over 4,300 egg allergic subjects. And you’ll notice that more than 650 of those subjects actually had severe allergies. And there were no serious allergic reactions -- that’s respiratory distress or hypotension -- noted in these over 4,300 subjects who received the influenza vaccine.

So the data suggest that we don’t need to worry about egg allergy the way we have in the past. It can be received in a pediatrician’s office or family doctor’s office or health center. As you know, anybody that administers vaccines needs to be prepared should there be any allergic reaction.

Dr. Grohskopf also mentioned how the waiting period has changed. In egg allergic children, we used to recommend 30 minutes to be sure that there was no severe allergic reaction associated with it. But as you can see in this particular study of 33 children who had vaccine-triggered anaphylaxis, you can see that a majority of cases actually occurred after 30 minutes.

And so at this point, the recommendation is to follow the general recommendations of the CDC, that we wait 15 minutes. Primarily that’s associated with teenagers and the concern for syncope.

So in summary, the AAP policy recommendations are that all children with egg allergies can receive the influenza vaccine with no special precautions other than those recommended for routine vaccines.

And so I now want to shift gears. Influenza vaccine is the number one preventive measure that we can use. And we know that influenza the virus itself is incredibly unpredictable, so it is important for us to also recognize that we do have an antiviral medication that can be quite useful in treating children who have influenza.

And as you can see here, the adamantanes are resistant and have been resistant for a number of years now, so they are not recommended. But the neuraminidase inhibitors -- Tamiflu, Relenza, and Rapivab -- are available and should be used in appropriate settings.

The American Academy of Pediatrics recommends that treatment be offered as soon as possible to children who are hospitalized for presumed influenza or have severe complicated or progressive illness felt to be attributed to influenza.

It also should be offered to children as soon as possible for any child with influenza of any severity who is at high risk for complications.

Treatment should be considered for clinical influenza if any healthy child has presumed influenza, especially those children and family members who have siblings at home under six months of age -- since children under six months of age cannot receive the flu vaccine -- or there are children under five years of age at home, or those of any age at home who have high risk conditions.

When we look at the studies around the use of oseltamivir treatment, everyone knows and seems to remember that if the onset of symptoms was less than 48 hours, then it’s appropriate to begin oseltamivir. But a number of people have opted not to treat when it’s beyond 48 hours. And I just wanted to briefly review the studies that led to that recommendation and the importance of the use of neuraminidase inhibitors.

As you can see here, the original study was done -- a prospective controlled study in an outpatient setting. And when they do a study like this, they need to have specific criteria for when you enroll study subjects. And in this case, they arbitrarily set that at 48 hours. It could’ve been 24. It could’ve been 72. But in this case, this prospective controlled trial set enrollment at 48 hours.

But I would to also like to point out the right side of the screen where there have been retrospective, uncontrolled studies of hospitalized patients dosumenting the benefits of the use of neuraminidase inhibitors in reducing morbidity and mortality.

Here’s a couple examples of antiviral treatment. And on your left hand side, Whitley and colleagues studied the use of oseltamivir and compared it with the use of placebo. And as you can see, the duration of symptoms was reduced by 36 hours -- a day and a half -- in those that were treated with oseltamivir. And almost two days earlier, subjects were able to return to normal activity.

On the right hand side of the same screen Hedrick and colleagues also studied but this was the use of inhaled Zanamivir in comparison with placebo. And as you can see, the time to resolution of symptoms was improved in those who were treated with Zanamivir by more than one day.

This is another study that looked at the use of neuraminidase inhibitors and its impact on mortality in children, using California surveillance data. And the key message here is that the neuraminidase inhibitors definitely work, but as you can see, early treatment resulted in decreased mortality, particularly under 48 hours. But there is still utility in using neuraminidase inhibitors in those who have influenza, even if it’s been beyond the 48 hours.

Now, the Cochrane Collaboration published a review of neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. And this was published in April of 2014. As many people know, the Cochrane Collaboration values first and foremost randomized controlled trials.

But as you can see here -- and this is from Dr. Traenor in Rochester -- that was just published a couple weeks ago, he describes the three different study designs that we’re talking about. And at the top of the screen you can see randomized control trial, which are favored by the Cochrane Collaboration.

Although I can mention in the middle graph, you can see the observational cohort analysis and there have been multiple observational trials that have been studied -- more than a dozen in adults and more than a half dozen in children. And these observational trials have demonstrated that there is significant improvement with the use of neuraminidase inhibitors in people who receive neuraminidase inhibitors when they have presumed influenza.

The bottom graph is a test negative control that Dr. Grohskopf mentioned. And these are the types of studies that are used in looking at vaccine effectiveness. So you look at an illness cohort that has been exposed to influenza. You test them and compare the group that tests positive for influenza versus the group that tests negative. And then you look at their vaccine history and you look at how well influenza disease was prevented.

So this commentary in the Infectious Disease Society of America supports the use of influenza antiviral treatment as does the American Academy of Pediatrics. It is true that there are no placebo-controlled, randomized control trials available for the use of neuraminidase inhibitors of hospitalized influenza patients.

And it’s challenging actually to undertake randomized control trials when you’re looking at outcomes such as severe morbidity and mortality. So the fact that there are multiple observational studies consistently reporting clinically meaningful benefits of neuraminidase inhibitor treatment really enhances and emphasizes the value in you using neuraminidase inhibitors for the treatment of influenza.

So in summary, we’ve studied the epidemiology of influenza in the past seasons and have noted the vaccine effectiveness trials that have been studied and emphasized that LAIV4 should not be used during this current 2016-2017 season.

Egg allergy is no longer an issue and the vaccine can be administered in pediatricians’ offices and should be prepared to handle any allergic reaction, since we administer multiple vaccines to children each and every day.

These recommendations are available on the AAP website, specifically aapredbook.org, which has these recommendations, recommendations from the CDC, and multiple resources that are available not just for providers but also for the public.

And lastly, we talked about treatment and the importance of neuraminidase inhibitors -- even in children who have received influenza vaccine. As was mentioned before, two seasons ago there was a H3N2 predominant vaccine strain in that particular season, but 80% of those strains did not match the H3N2 strain that was in the vaccine.

So the use of neuraminidase inhibitors, even in children who have received vaccine in that particular season, should still be considered as recommended, particularly those that are hospitalized or at higher risk for complications from influenza.

I thank you for your attention and Dr. Grohskopf and I are more than happy to answer any questions. Thank you.

Marcy Friedman: Thank you, Dr. Bernstein. And thank you to Dr. Grohskopf and Dr. Bernstein once again for providing our audience with such a wealth of information.

We will now open up the lines for the question and answer session. Questions are limited to clinicians who have questions about strategies to improve influenza prevention and control in children during the 2016 and 2017 season.

For those who have media questions, again we ask you to please contact our CDC Media Relations at 404 639-3286. Or you may send an email to media@cdc.gov.

And once again if you are a patient, please refer your questions to your healthcare provider.

When asking a question, please state your organization and also remember you can submit questions through the webinar system.

Operator, do we have any questions coming in from the phone line, please?

Coordinator: As a reminder to ask a question by phone, please press star and then 1. One moment for our first question.

We have a question from (Rachel Wood). Your line is open.

Rachel Wood: Thank you. I was wondering if you can have any comments about the effectiveness of masking for healthcare workers in terms of preventing influenza in their patients.

Henry Bernstein: This is Hank Bernstein. The data - I can only talk about it anecdotally, as there really aren’t data that masking them really makes a significant difference in the clinical setting. I can say from personal experience at our institution unfortunately many of the healthcare personnel who have chosen not to get the vaccine and use the mask don’t use the mask properly.

And so it’s been a problem for us. And there are really not data that compares the vaccine with having the mask on.

Rachel Wood: Thank you.

Marcy Friedman: Okay, thank you. We do have a question that came in from the webinar. And the question is for Dr. Grohskopf. Dr. Grohskopf, it looks like it’s coming in. If you refer to slide 16.

Lisa Grohskopf: Okay.

Marcy Friedman: The question comes from (Gary Goldbaum). And he’s asking what precisely is meant by 60% relative effectiveness of the adjuvant containing vaccine versus the enhanced antigen vaccine.

Lisa Grohskopf: Basically, instead of comparing the two -- one vaccine or the other versus the placebo -- they’re comparing one to the other. And so basically what it means is there’s a 60% relative effectiveness, at least according to this study comparing the adjuvanted and activated vaccine with the unadjuvanted and inactivated vaccine.

We have to be a little cautious in interpreting these kinds of results, mainly because here we have an observational study. It’s not a randomized control trial. And sometimes with randomized control - with observational studies, estimates of the relative risk for getting something or the vaccine efficacy are not going to be what they would be say in an RCT.

This is also a relatively smaller study. I think it was only 282 people.

So I meant to mention also one thing that you may hear about a question you get over the course of time -- particularly now that we have this vaccine that’s approved for 65 and older. And we also have the (Hidos) vaccine that has been out for several seasons now. I believe since 2009. You may have patients who are aware of both vaccines who are 65 and older and want to know which they should get, which is better. And the thing is we really don’t know.

There haven’t been any studies that compared one to the other. There was a (Hidos) vaccine study that showed improved relative efficacy but that was comparing (Hidos) versus another standard dose inactivated vaccine.

So anyone who takes care of adults may get that question. Neither of those vaccines are approved for kids -- just to remind you of that.

Marcy Friedman: Thank you, Dr. Grohskopf. Operator, do we have any other questions coming in from the phone line?

Coordinator: There are no other questions in the queue at this time.

March Friedman: Okay. Thank you. We do have one other question that came in from the webinar. And it looks like due to time restraints, this will be the last question.

The question is what recommendations do you have for clinicians working with parents that may be hesitant to have their child vaccinated?

Henry Bernstein: So that - did you want to say something, Lisa?

Lisa Grohskopf: No. You go first, Hank. That’s great.

Henry Bernstein: So this is obviously an age old question that we are asked. And certainly we have had some very disappointed children who were expecting to get the intranasal influenza vaccine.

I think that probably the best thing to recommend just in the interest of time is to refer to the American Academy of Pediatrics, which has literally just published in the last few months and is available at pediatrics.org, a whole clinical report that has all different strategies for people to use in encouraging and making children and parents feel comfortable about receiving an injection this year.

It’s a vaccine hesitancy clinical report and it goes through vaccine history, the production of vaccine, their effectiveness, and then reviews multiple strategies that we can use as clinicians in making families and children more comfortable in receiving the shot. So I would refer specifically to that.

There are also - I know that the University of Pittsburgh as an example have methods for using local - being able to use topical EMLA or other products in order to numb the area where the injection is going to be placed. And that’s also available. The details of that I’m sure could be posted on the website. They have a plan and it doesn’t take a long time within their practice in order to use this method in comforting children and making the injection itself much less painful.

Marcy Friedman: Thank you so much Dr. Bernstein. Okay. So on behalf of COCA, I would like to everyone for joining us today, with a special thank you to our presenters Dr. Grohskopf and Dr. Bernstein.

We invite you to communicate to our presenters after the webinar. If you have any additional questions for today’s presenters, please email us COCA@cdc.gov. Put October 27 COCA Call in the Subject line of your email and we ensure that your question is forwarded to the presenters for a response.

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The recording of this call and the transcript will be posted to the COCA website at emergency.cdc.gov forward slash coca within the next few days.

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Thank you once again for being a part of today’s COCA webinar. Have a great day.

Coordinator: Thank you. This concludes today’s conference. Thank you for your attendance. You may disconnect at this time.

END