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Protecting Children: Influenza Updates for Clinicians

Moderator:Cynthia Hinton

Presenters:Henry (Hank) Bernstein, DO, MHCM, FAAP, John S. Bradley, MD, FAAP, Alicia Fry, MD, MPH

Date/Time:February 26, 2015 2:00 pm

Welcome and thank you for standing by. At this time, all participants’ lines will remain on a listen-only mode. During the question and answer session, please press star, one on your touchtone telephone.

Today’s conference is being recorded. If you have any objections, you may disconnect at this time.

I would like to turn today’s call over to Ibad Khan. Sir, you may begin.

Dr. Ibad Khan:
Thank you. Hello. I am Ibad Khan and I’m representing the Clinician Outreach and Communication Activity -- COCA -- with the Division of Strategic National Stockpile at the Centers for Disease Control and Prevention. We are delighted to welcome you to today’s COCA webinar, Protecting Children: Influenza Updates for Clinicians.

We are pleased to have with us here today Drs. Hinton, Bernstein, Bradley, and Fry to discuss the current state of flu activity related to children, the importance of continued vaccination despite the mismatch in low vaccine effectiveness, and strategies for using antiviral therapy early to prevent and treat influenza.

At the conclusion of today’s session, the participants will be able to discuss strategies to assist clinicians in caring for children for the remainder of the 2014- 2015 influenza season, identify approaches, and emphasize the value for using antiviral therapy in children, and discuss ways to encourage continued vaccination despite the drifted influenza A H3N2 viruses.

In compliance with continuing education requirements, all planners, presenters, and their spouses or partners must disclose any financial or other associations with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters as well as any use of unlabeled product or products under investigational use.

CDC, our planners, presenters, and their spouses or partners wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. Content will not include any discussion of the unlabeled use of a product or a product under investigational use with the exception of Dr. Bradley’s discussion of the uses of neuraminidase inhibitors that have not been evaluated or reviewed by the FDA and are therefore not included in the package labeling.

Such off-label uses will be noted during the presentation. CDC does not accept commercial support.

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

Additionally, you may email your questions to Coca@ That is C-O-C-A@C-D-C.G-O-V.

Our moderator for this webinar is Dr. Cynthia Hinton. Dr. Hinton is a health scientist with the Children Preparedness Unit in the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention. At this time, please welcome today’s COCA call moderator, Dr. Cynthia Hinton.

Dr. Cynthia Hinton:
Thank you Dr. Khan and thank you everyone for joining us this afternoon. I think we’re in for a very, very interesting session. I’ll introduce each of our presenters to you.

Our first presenter is Dr. Hank Bernstein. Dr. Bernstein is a Professor of Pediatrics at Hofstra North Shore LIJ School of Medicine. He is Associate Editor of the Redbook online and recent member of the Committee on Infectious Diseases of the American Academy of Pediatrics whose responsibility it is to develop and revise guidelines at the AAP for the infectious diseases in children. Dr. Bernstein also represents the AAP on the influenza work group of the CDC’s Advisory Committee on Immunization Practices -- or ACIP.

Our second presenter is Dr. John Bradley. Dr. Bradley is the Director of the Division of Infectious Diseases at Rady Children’s Hospital in San Diego, California. As a member of the AAP Committee on Infectious Diseases, Dr. Bradley was lead author on the AAP policy antivirals for influenza in 2007, which is now incorporated in the annual policy statement for which he provides input for antivirals. Dr. Bradley was selected by the PIDS to participate on the IDSA CDC guideline statement published in 2009 and is currently active in the rewrite of the guidelines as the co-lead for the therapeutic section.

And our final presenter, Dr. Alicia Fry, is the Team Lead of the Influenza Prevention and Control team in the Epidemiology and Prevention branch in the Influenza Division at CDC. Her team is responsible for conducting studies related to vaccines and antiviral agents to inform appropriate vaccine and antiviral use policies to prevent seasonal, avian, and pandemic influenza. Dr. Fry is an infectious disease specialist and is a captain in the US Public Health Service.

Thank you. Dr. Bernstein, I think we are ready to begin with you.

Dr. Hank Bernstein:
Fantastic, thank you. It’s a pleasure to be here. So the take home messages that I hope to convey in my portion of the talk is that influenza H3N2 is the predominant strain, and the majority of them are actually drifted strains. Vaccine effectiveness may vary by match, mismatch of the circulating virus with the vaccine strains, vaccine product, and age of the patient.

We should all be continuing to give any licensed and age appropriate influenza vaccine that’s available. We should never delay anticipating a specific product and healthy children ages two through eight years may be immunized with either IIV or LAIV. There is no preference for one over the other.

Influenza is a common and serious public health problem, as we all know, contributing significantly to patient morbidity and mortality and creating a financial burden on healthcare systems. You can see the notable impact of influenza each year in comparison with other vaccine-preventable diseases on this slide.

Influenza’s responsible for an average of 50 to 60 million infections annually, resulting in 25 million healthcare visits, hundreds of thousands of hospitalizations, and thousands of deaths each year.

This figure shows the weekly percentage of outpatient visits for influenza-like illness from the US outpatient ILI surveillance network. As of just two days ago, the national baseline level of 2% had been exceeded for 13 weeks during this influenza season. The peak percentage of outpatient visits for ILI is 6%, and that occurred around Christmas week.

Among children hospitalized with laboratory confirmed influenza, almost half -- 40% -- did not have any known underlying condition. Of those with underlying medical conditions, about a third had asthma while one in eight had a neurologic disorder, were immune suppressed, or obese.

There have been 86 laboratory confirmed influenza associated pediatric deaths reported this flu season so far. For comparison, during the 2013-2014 season, 70 pediatric deaths were reported by the same week. By the end of that season last year, 109 pediatric deaths were reported for the entire season.

This table highlights the hospitalizations and deaths each flu season for the past ten years. Notice in the second column that the predominant strain varies from year to year. Last year was almost all H1N1 while this year is mostly H3N2. H3N2 seasons tend to take a bigger toll on children – more deaths and more hospitalizations. Note in the last two columns that the rate of hospitalizations for children under five years always exceeds the rate of children five to 17 years of age each year.

As everyone knows, both trivalent and quadrivalent influenza vaccines are available for the 2014-2015 influenza season. The quadrivalent vaccines contain the same three strains as the trivalent vaccines plus the additional B strain of the opposite lineage. All strains in the vaccines are unchanged from those included in last season’s vaccine.

Influenza is amazingly unpredictable. There have only been five seasons in the past 29 years that have not required a change in vaccine strains from the previous season. This is one of those influenza seasons.

Because the flu virus changes from year to year, annual vaccination against flu is necessary. Even when the vaccine strains stay the same as they did this year, vaccination is recommended because immunity tends to wane by about 50% after six months. The American Academy of Pediatrics recommends that all people including all children and adolescents six months of age and older receive the flu vaccine each year.

Infants younger than six months of age are too young to be immunized with influenza vaccine, so cocooning -- which means vaccinating everyone around an infant -- makes sense. Children nine years of age and older need only one dose. This dosing algorithm highlights that many children six months through eight years of age will actually only need one dose this season unless this is the very first time they are receiving the flu vaccine.

Healthy children ages two through eight years of age may be immunized with either IIV or LAIV. Vaccinations should not be delayed to obtain a specific product. In the absence of data demonstrating consistent greater relative effectiveness of the current quadrivalent formulation of LAIV, preference for LAIV over IIV is no longer warranted.

Using the grade framework, the CDC Advisory Committee on Immunization Practices systematically reviewed the evidence pertaining to the efficacy of LAIV and IIV for healthy children. In this large study, almost 8000 children six months through 59 months of age were randomly assigned in a one to one ratio to receive either trivalent LAIV or trivalent IIV. There were 55% fewer cases of culture confirmed influenza in the live attenuated vaccine group in comparison with the inactivated group.

Similarly, this randomized control trial of over 2000 children six months through 71 months of age documented 53% fewer cases of influenza in LAIV in comparison with IIV recipients.

Quadrivalent LAIV did not perform as well as expected based upon the observations in these earlier randomized trials. Analysis of data from three observational studies of LAIV for the 2013-2014 season - the first season in which LAIV 4, the quadrivalent preparation, was available -- revealed no effectiveness of LAIV 4 against pandemic H1N1 among children two through 17 years of age.

In the absence of data demonstrating consistent greater relative effectiveness of the current quadrivalent formulation of LAIV, preference for LAIV over IIV is no longer warranted. Influenza vaccine effectiveness will continue to be reviewed for future seasons.

This cartoon says that I hate it when we’re not sure we’re inoculating against the right strain of flu virus. That’s something that we all feel and as mentioned earlier most of the H3N2 strains circulating this year are, in fact, drifted strains.

For the 2013-2014 season, LAIV showed very low vaccine effectiveness in two through 18 year olds. Early estimates for the 2014-2015 season -- and this is just preliminary data -- suggest low effectiveness of influenza vaccine against circulating viruses, mainly H3N2.

The most recent data for the 2014-2015 season shows vaccine effectiveness for IIV to be around 22% and for LAIV to be -18% in two to 18 year olds. Again, this is very preliminary data but it appears that LAIV 4 does not offer greater protection than IIV for these viruses.

Over the past 30 years, influenza activity was often at its peak between January and March. 75 to 80% of disease generally happens during these three months. The greatest activity may be in February, but notice there may still be influenza activity as far out as April and May.

This calendar is to remind all of us to offer flu vaccine throughout the year until the vaccine expiration date, which is June 30, marking the end of the influenza season. As I mentioned earlier, influenza is unpredictable. There can be more than one disease peak in a given community and international travel may result in potential exposure to influenza throughout the year.

In 2014-2015, according to preliminary data from the National Immunization Survey, the estimated national coverage among children six months to 17 years is currently 42%, a slight increase from last year’s preliminary estimate coverage of 41%. Estimated coverage among children was highest in younger children and was lower in older age groups. Estimated coverage was highest in children six months to four years at 50% and lowest among children 13 to 17 years at 32%. So there is room for improvement.

This line graph shows age-specific influenza vaccination coverage rates over these recent five influenza seasons. Full coverage is defined as one or two doses, depending on the child’s vaccination history. As you can see, there is notable room for improvement in children of all ages.

According to data from the early 2014-2015 influenza season, the most common place of vaccination among both adults at 33% and children at 63% were in doctor’s offices. These results are similar to results from the same time period last season.

All of the influenza diagnostic tests vary by method, availability, processing time, sensitivity, and cost. These different factors can help in making the best clinical judgment for the use of diagnostic tests. Some of the more rapid tests have lower sensitivity, which must be kept in mind in the clinical setting. A negative test does not mean a patient does not necessarily not have the flu.

You’ll notice on this slide that those tests with higher sensitivity take much longer to process and cost more. This will be touched on more by Dr. Bradley when we talk about the use of neuraminidase inhibitors in the clinical setting.

So I hope that I’ve conveyed to you that influenza H3N2 is the predominant strain this season so far and a majority, actually, are drifted strains. Vaccine effectiveness may vary by the match, mismatch of circulating virus with vaccine strains, by vaccine products, and by the age of the patient.

We should still continue giving any licensed and age-appropriate influenza vaccine available and never delay for a specific product. Healthy children ages two through eight years of age may be immunized with either IIV or LAIV. There is no preference for one formulation over the other.

Thank you.

Dr. Cynthia Hinton:
Thank you very much Dr. Bernstein. And now I’d like to turn it over to Dr. John Bradley.

Dr. John Bradley:
Thank you very much. My role in this particular webinar is to talk about antivirals. Dr. Bernstein certainly has done a wonderful job setting up information on immunization and some of the tests that we have, but what I’d like to do is to specifically talk about where we think antivirals can produce the greatest impact on outcomes for both morbidity and mortality in children.

The sources of information for those who take care of kids with influenza come from a number of different places. The American Academy of Pediatrics published guidance each year that Dr. Bernstein is the lead author on and contains information from all of the different specialties, everyone that has a stake in treatment of influenza, and the CDC. And I’ll show you the cover page of that particular publication in just a moment.

The CDC has information on antivirals online and as was mentioned at the very beginning, the IDSA Peds IV Society guidelines in which the CDC participates for influenza just came out before the pandemic hit a few years ago and are currently in revision. So, all of the literature on treatment, the types of studies, the quality of studies, the populations treated will all be part of that assessment when it comes out towards the end of this year.

This is the policy statement that I mentioned that Dr. Bernstein is the lead author on, and I’ve taken the opportunity here to highlight the small area about antivirals. Since it’s very clear that prevention is always preferable to treatment, and our overarching suggestion is that pediatricians should promptly identify clinical influenza infection to enable rapid antiviral treatment when indicated to reduce morbidity and mortality.

The problems with influenza this year have to do with the fact that the strains are not - the strains that are circulating are not well matched with the strains that are in the vaccine. So we have children who’ve been fully immunized who are coming into the hospital and we had the occasion to treat a ten month old who was on positive pressure ventilation with intravenous zanamivir because he was not able to tolerate oseltamivir. The child did well eventually, but it underscored the fact that the vaccines are not always effective.

Both CDC and Academy of Pediatrics recommend early treatment of influenza disease with antivirals and the CDC tracks susceptibility of circulating strains so that we actually know in real time whether there’s a problem with resistance in the community. And so far, the stains that have been tested by the CDC form this year are all susceptible to the currently available neuraminidase inhibitors.

The target population for treatment are those that high risk of complications of influenza and the references which document these high risk populations are all nicely placed in the AAP guidance document. We are not recommending that everyone with influenza -- especially otherwise healthy children with average disease -- get treated with antivirals. We’re only recommending that those who are at high risk of complications or those with particularly severe illness be treated.

So a summary of those at high risk of complications are those children under two years of age, particularly under six months of age because they don’t have the benefit of being able to be immunized; those with underlying comorbid conditions which prevent them from dealing with the pulmonary inflammation and GI tract inflammation that comes with influenza -- so underlying respiratory, chronic lung diseases, cardiovascular problems; neurologic injury where a child can’t handle secretions well; seizure disorder. All of these kids are at increased risk of complications.

Children who are receiving immunosuppression and, even though we try to immunize these kids, many of them may not have an appropriate immune response to the vaccine.

Pregnant or post-partum women, older children, adolescents certainly were highlighted during the pandemic to be at increased risk of complications. Native American populations and those who are morbidly obese also have a greater risk of complications.

Now, the treatment should be offered to - this is a suggestion. Obviously, clinical judgment is important for anyone who is managing a child with influenza, but we believe -- and this is in the statement -- that influenza of any severity in kids at high risk of complications that I just listed on the previous slide should be offered treatment.

And any child hospitalized with presumed influenza, regardless of influenza immunization status or whether the onset of illness occurred greater than 48 hours before admission -- and I’ll explain the 48 hours issue in just a moment - the original studies that led to approval of the drug were in otherwise healthy children in outpatient populations.

Both Roche and GlaxoSmithKline did very nice, well controlled studies and they picked the 48 hour time point of symptoms of influenza so that they would get these kids earlier in the infection and have a greater chance to show impact of antiviral therapy, which of course would lead to approval by the FDA and their ability to market the drugs.

So the prospective randomized comparative trials were in these healthy outpatients, but unfortunately those that are sicker or those that are at risk for complications were never treated in a prospective randomized comparative study by either of these companies. The FDA of course approves drugs based on information that’s provided to them by the companies. The FDA doesn’t itself search the literature, review published studies, and come up with new recommendations. They rely on industry to supply information to them for changing the package label.

For these children who are hospitalized with presumed influenza, we assume that these are kids that are sicker than those that were originally studied. And this is a marker for severity of disease. These kids have pneumonia, problems with oxygenation, vomiting, diarrhea, and problems with hydration particularly in the younger infants. So these are kids that are sick enough to be admitted. They have not yet turned the corner and we believe that these are kids who should receive therapy.

Now, for those otherwise healthy children, again, we’re not recommending for every child with influenza. But for those with moderate to severe disease who have not yet turned the corner – these are kids who are getting sicker and I the judgment of the clinician evaluating them may progress in their disease and ultimately need hospitalization.

Every study that’s been done acknowledges that the greatest impact on outcomes occurs with early treatment. But again, during the pandemic, initially with adults and subsequently with children, for hospitalized patients who have had symptoms for more than 48 hours, antiviral therapy has been shown to produce better outcomes.

Of course, these are generally retrospective data and not well controlled. And I think everyone agrees that we wish we had prospective controlled data, but the data that are published do suggest that if you’re hospitalized and even if you’ve had symptoms more than 48 hours, you can still benefit from treatment.

When someone sees a child in an office or clinic, there’s no way that you can predict during the first 24 to 48 hours whether they’re the ones who will turn the corner within a day or two – which of course is the majority of children -- or whether the child you’re evaluating is going to be one of the more severe ones on the tail of that Gaussian distribution where a few percent of kids always have more severe disease for whatever reason. We wish we could predict which kids were going to deteriorate. That’s a dilemma that all of us have and I have no easy answer for you on that issue.

As I’ve mentioned, the original FDA- approved clinical trial for oseltamivir in pediatric outpatients specified no more than 48 hours of illness. And no additional efficacy data from Roche or GlaxoSmithKline have been presented to FDA, so the package insert - package label still says 48 hours. I’m sorry that the formatting of this slide may not allow you to see the “hours” word at the bottom of the slide. But the package label says “approved for children with symptoms less than 48 hours.”

And there’s another statement that they have; not that the drug doesn’t work if you start with symptoms greater than 48 hours, but that the efficacy of oseltamivir has not been established in those who have symptoms for greater than 48 hours. So the FDA has no secret information that says it won’t work. They just say that they’ve not evaluated it, which is a standard for the FDA.

The tests that diagnose influenza were nicely discussed by Dr. Bernstein. A rapid influenza antigen diagnostic test does not exclude influenza but, of course, if you are going to send out a much more sophisticated, costly test and it takes a couple of days to get the answer back, then you’ve lost your window of opportunity of maximum effectiveness of the antiviral. And for those reasons, if you really think it’s influenza, we believe that you should go ahead and treat even if the diagnostic test -- the rapid one -- does not indicate influenza.

One other thing that showed up on the original studies is that if you treated children with oseltamivir, you reduce the risk of otitis media. Subsequent studies have also suggested you decrease the risk of a subsequent bacterial pneumonia. However, we are not recommending that antibiotics be routinely given to anyone with influenza. I think that would be horrible.

Certainly, the benefit for a very few patients would probably not be worth the risk of toxicity in the development of resistance. But I just wanted to share that there are prospectively collected data which suggest that you can reduce the risk of bacterial infections if you treat early with antivirals.

In the AAP guidance, we have table three which gives all of the information on the doses that one needs to use to treat all of the different age groups, with both oseltamivir and zanamivir. And based on information from some early studies that were supported by the NICHD that David Kimberlin was involved with, we have some data on pharmacokinetics, safety, and efficacy on a small number of neonates including premature neonates. And dosing recommendations are given for influenza in this population as well.

Just want to mention that there’s no national shortage of oseltamivir; that local shortages may occur, especially if a pharmacy runs out of suspension formulation. But again, during the pandemic when there were shortages, there were nice studies to document that if you crushed a tablet and suspended it in a sucrose-containing solution, that the absorption of oseltamivir in children was equivalent to the regular pediatric suspension.

So the package label - every package label gives instruction for this extemporaneous suspension that you can make from the capsules. So every child should be able to have access to a suspension whether it’s in the package as the standard pediatric suspension or whether it’s an extemporaneously compounded suspension.

For infants who can’t tolerate oral, as I mentioned at the very beginning, there are two antivirals that are available for those who need them for children. peramivir is an FDA-approved product, but there are very limited data on pharmacokinetics in children. Zanamivir has completed their pediatric intravenous studies and pharmacokinetic data, safety and efficacy data are currently being presented to the FDA for approval. But at the moment you can get Zanamivir IV for compassionate use from GlaxoSmithKline.

So in summary, antiviral treatment should be started as soon as possible after illness onset for all of those hospitalized or in a high risk population. Consider treatment for otherwise healthy kids with more severe infection caused by either documented or highly suspected influenza, even after 48 hours of symptoms, clearly recognizing that the earlier treatment is better.

Thank you very much.

Dr. Cynthia Hinton:
Thank you Dr. Bradley. And now I would like to turn it over to our final presenter, Dr. Alicia Fry.

Dr. Alicia Fry:
Thanks. I’m just going to give a brief overview of the ACIP meeting today. And I apologize I don’t have any slides to share.

So ACIP is normally a two-day meeting, but it was shortened to a one-day meeting due to weather in Atlanta. Today an update of the interim B vaccine effectiveness estimates was presented and there was a vote on the flu recommendations. So I’m just going to quickly go through them, and you’ve seen a preview of these data or similar data from Dr. Bernstein. So I won’t spend too much time on it.

We have a network of five academic sites that participate in our US flu vaccine effectiveness -- or VE -- network. And we were able to - we’ve been enrolling patients since mid-November and we pooled all our data through the end of January. And so I have a little bit - some updated numbers compared to some of the numbers that Dr. Bernstein presented.

So we had 1600 flu cases and among those, 94% were H3N2 infections. And this year was a unique year for us because we were actually able to genetically characterize more than 700 of those H3N2 viruses. Among the viruses that were characterized, 85% were from genetic groups that are low reactors to the current 2014-15 vaccine; and 15% of the H3’s were in genetic groups that are vaccine-like. So it was an unfortunate year for us as far as what’s circulating.

We also had 95 cases who were infected with influenza B and eight-seven of those 95 were B Yamagata, which is the lineage that is in both the trivalent and the quadrivalent vaccine this year. And so I’m going to just quickly tell you some of the updated estimates for the vaccine effectiveness.

For H3N2 for all ages, the overall vaccine effectiveness was 18% and the 95% confidence intervals ranged from six to 29. We could stratify the H3N2 cases by age groups and the point estimates were all similar. But once we stratified by the age groups, none of the confident - all of the confidence intervals overlapped zero. So that is all significant. That is all consistent with a point estimate that could include zero.

Our point estimate for our influenza B was 45% with a 95% confidence interval of 14 to 65%. So it looks like the vaccine works better against influenza B and we are still seeing influenza B circulating and really maybe even increasing numbers of influenza B. and so that’s good news that at least the vaccine is moderately effective against influenza B.

Now we were able to use the large number of data from our sequencing to provide really for the first time ever genetic group-specific vaccine effectiveness estimates. When we looked at the H3N2 viruses that were in the genetic groups that were vaccine-like, the vaccine effectiveness was 49% and the 95% confidence intervals ranged from 18 to 69.

When we looked at the H3N2 viruses that were in the genetic groups that were low reactors and the predominant genetic group circulating in the United States, the vaccine effectiveness was 15% and the 95% confidence intervals ranged from minus five to 30. So the confidence intervals equaled - included zero, so we can’t exclude that the vaccine effectiveness was zero or null for those low reactors this year.

So this - often when we have - in many of our seasons, we have different influenza viruses circulating, not just one predominant virus. And if we do have vaccine mismatches, we often aren’t so unlucky to have so much mismatched virus. But this year was really an unusual year for us in that we had an overwhelming majority of drifted viruses that are actually circulating. And those viruses that were not drifted or - and influenza B actually had much better vaccine effectiveness.

So the other data that was presented were the H3N2 specific vaccine effectiveness estimates for LAIV and IIV for children aged two to 17 years of age. And as you saw in the preview from Dr. Bernstein, the point estimate for LAIV was minus 24 with the confidence intervals ranging from minus 74 to eleven. So the 95% confidence intervals included zero, which is consistent with no effectiveness.

The IIV point estimate -- and this is for all ages two to 17 -- was 18% and the confidence intervals ranged from minus seven to 37%. So again, the confidence intervals cross zero and are consistent with a vaccine effectiveness that may include zero.

When we stratified by children age two to eight, we had similar point estimates; but as you might imagine, the confidence intervals became even larger because we had even smaller numbers.

Now MedImmune shared results of a study that is taking place concurrently with CDC. Their study is very similar to CDC. It’s a test-negative design similar to CDC. They do have more specific case definition. Their case definition includes fever where CDC’s does not include fever. You don’t have to have fever to be enrolled. They also had more information on confounders.

So the MedImmune point estimates for H3N2 for LAIV were 16% with a 95% confidence interval of minus 33 to 47. And the point estimate for IIV was 33% with a confidence interval from one to 54. So, again, when you look at both the CDC network data and the MedImmune data, there’s really no evidence for better protection for LAIV compared with IIV for this year. And both of the vaccines did not work well against the predominant H3N2 circulating viruses.

And then finally, I’d like to tell you that - how ACIP voted today. The committee members voted to continue to recommend that all persons six months and older be vaccinated annually against influenza. And also, the ACIP members did not renew the 2014-15 preference for using LAIV instead of IIV for healthy children aged two through eight years of age.

Instead, the decision was not to have a preferential recommendation but that either IIV or LAIV could be given to children aged two to eight years of age depending on which vaccine was available with no preference. That would be recommendations that are consistent with the AAP recommendations that Dr. Bernstein presented earlier.

And that’s all I have. So thank you.

Dr. Cynthia Hinton:
Alright, thank you Dr. Fry for giving us some hot-off-the-press information from the advisory committee. And on that note, I would like to turn it back over to Dr. Khan who can lead us into the question and answer part of this meeting.

Dr. Ibad Khan:
Thank you Drs. Hinton, Bernstein, Bradley, and Fry for providing our COCA audience with such a wealth of information. We will now open up the lines for questions and answer session. Also remember you can submit questions through the webinar system.

Thank you. At this time if you would like to ask a question over the audio, please press star, one on your touchtone telephone. You will be prompted to record your name in order to be introduced. Once again, please press star, one on your touchtone telephone and please record your name.

I’m currently showing no questions over the audio.

Dr. Ibad Khan:
While we are waiting for questions from the audio, I have a question form the webinar system that I would like to pose to our presenters. The question is -- why simply offer influenza vaccine and antivirals rather than strongly recommend?

Dr. John Bradley:
Ibad, may I take a stab at answering that question? This is John Bradley.

Dr. Ibad Khan:
Yes, sir.

Dr. John Bradley:
There - whenever a recommendation is made -- at least for antivirals -- we like clinical judgment to be part of that decision. And for any particular child, their underlying conditions, how sick they are, the severity of the illness, other medicines they may have that have side effects, their ability to tolerate antivirals -- all of these go together to balance the risks and benefits of therapy.

So for antivirals, we don’t want to say “must.” We want to say that we believe that for children who meet this criteria it should be offered. So if it allows clinicians to use their judgment and - in some situations where there’s a high risk child, there may be extenuating circumstances for that child where treatment would not be appropriate. So it’s all in how the words are put together and acknowledging that these are recommendations only for all children with influenza or who are at risk of influenza, and that we don’t pretend to be all-conclusive for 100% of the children out there.

Dr. Ibad Khan:
Thank you Dr. Bradley for your elaboration in acknowledging the nuances. Operator, do we have any questions on the line?

Dr. Hank Bernstein:
This is Hank Bernstein. I just wanted to add we absolutely recommend - strongly recommend or whatever description that people feel comfortable with. We absolutely recommend influenza vaccine for everyone six months of age and older unless there’s a contraindication to the vaccine. So it isn’t a consideration. It is a firm recommendation. Obviously, there’s no way to literally make it mandatory, although the American Academy of Pediatrics is supportive of mandatory influenza vaccine for all healthcare personnel.

Dr. Alicia Fry:
Yes, and this is Dr. Fry. The advisory committee for immunization practices recommends vaccination for all persons six months and older unless there’s an obvious contraindication similar to what Dr. Bernstein said.

Dr. John Bradley:
Yes, this is Dr. Bradley. I didn’t want to assume that I wasn’t recommending immunization. And my comments should be taken as insight into antiviral therapy only.

Dr. Ibad Khan:
Thank you very much. Operator, do we have a question on the line?

At this time I am showing no questions over the audio.

Dr. Ibad Khan:
I would like to ask another question that we have received through the webinar system to our presenters. The question states, “What progress is being made towards development of influenza vaccines that target conserved virus epitopes resulting in a vaccine that won’t need to be changed annually?”

Dr. Alicia Fry:
This is Dr. Fry. I can take that, although I welcome the other speakers to chime in if they would like to. There is quite a bit of research ongoing to develop a - what we call a universal flu vaccine. But at this time, it’s - first of all, let me tell you it’s not easy at all. These viruses change very frequently and so identifying a conserved part of the virus that actually generates a protective immune response is difficult.

But there are many groups who are working on it right now. There’s a lot of government money that is going into this type of research, but I’m afraid to say we’re a couple years off from being close to a vaccine that would - a universal vaccine that you would only have to get once.

Dr. Ibad Khan:
Thank you. Operator, do we have any questions on the line?

Please hold a moment. We have a question from (Brandon Ermer). Your line is open.

(Brandon Ermer):
Thank you and please disregard the question I typed in through the webinar. My question is - so I understand the theories of why LAIV was not effective against H1N1 in the 2013-14 season, but do we have any insight on why LAIV was not effective against H3N2 this season? Because it’s my understanding prior studies show that you get superior protection with LAIV even in mismatched years.

Dr. Alicia Fry:
This is Dr. Fry and I’ll take a stab at that as well. So I would remember that neither vaccine worked against the drifted viruses. So it’s neither the inactivated nor the LAIV worked. So that’s the first thing you need to remember.

And we actually were all hoping that we might see better protection from the LAIV than the inactivated vaccine and we didn’t see it. So I think you - it’s hard to directly compare with some of the earlier studies because the criteria for what made one virus mismatched has changed over time and it’s a little bit hard to go back and put all the pieces together so that we can have a direct comparison.

So I don’t know for sure if it’s the amount of mismatch, how different the viruses are, or something else. And I can’t - I don’t’ know if we had a different type of year where the mismatch were different changes in the hemagglutinin - if maybe we would reproduce that earlier study or not. I just don’t know but we didn’t see a better effectiveness and we actually don’t know why.

Dr. Hank Bernstein:
This is Hank Bernstein. I’d echo Dr. Fry that just as we’re exploring the lack of effectiveness for the 2013-2014 season with H1N1, the same is happening or will happen as well for the H3N2 and the drifted strains - different hypotheses, whether it’s strain -specific, country-specific, or other elements are being fully explored by the manufacturer, the CDC, and others.

Dr. Ibad Khan:
Thank you very much. Operator, do we have another question on the lien?

At this time, I’m showing no further questions. Once again, if you’d like to ask a question over the audio please press star, one on your touchtone telephone and please record your name.

Dr. Ibad Khan:
Let’s take a question from the webinar system. We’ve talked about the vaccine. Let’s do an antiviral question. This question states, “How do you respond to clinicians who are reluctant to prescribe antivirals due to reported side effects?”

Dr. John Bradley:
This is John Bradley. That’s a very interesting question and we’ve had to unravel the symptoms of influenza which are, of course - can affect virtually every organ system and those that are drug-attributable. And what the FDA has nicely done on the package label is to show you from placebo controlled trials which symptoms are from influenza -- those patients that got placebo – versus those that are oseltamivir-attributable.

So for instance, nausea occurred more often in the oseltamivir group -- about 20% compared to nausea in the placebo group of about 10% to 12%. So there’s a slight drug-attributable side effect and obviously I wish it weren’t nausea because that’s one of the predominant symptoms of influenza.

However, there are other side effects which are of both the disease and treatment, which are more concerning. The psychiatric disorders which occurred and were reported out of Japan caused a lot of concern. And a full investigation by the FDA with collection of additional data suggested that those reported cases actually were much more likely to be a function of the virus itself and perhaps genetic background of response to the virus rather than a drug effect.

So for a while there were cautions about using oseltamivir for fear of neurologic symptoms, and that certainly hits the press and everyone is aware of them. but when the nice detailed study by FDA subsequently came out that said this is not a problem of the drug, those sorts of pieces of information rarely make it to the news, certainly; and will make it in the literature, but not quite as highlighted as adverse events.

So from the standpoint of oseltamivir, there are very few side effects, which I personally think would keep a clinician from prescribing the drug for influenza. For inhaled zanamivir, obviously underlying lung disease in which bronchospasm may be a problem when you inhale the powder would make me worry. But in those children with that underlying problem, oral oseltamivir should be a reasonable option.

Dr. Ibad Khan:
Thank you Dr. Bradley. Operator, do we have any questions on the line?

I’m still showing no questions on the audio.

Dr. Ibad Khan:
Okay, we will take another question form the webinar system. Question states, “Any preference in children for quadrivalent IIV over trivalent IIV?”

Dr. Hank Bernstein:
So this is Hank Bernstein. I - it would make sense, I suspect, to many that quadrivalent would provide more protection than trivalent; although we have seen that LAIV 4 -- the quadrivalent version -- has not necessarily been more effective than the LAIV 3. At this point, a grade analysis has not been done looking - comparing quadrivalent from trivalent. And the supply of quadrivalent for the pediatric age population is not where we would like it to be, although we expect that it will continue to increase.

So with the supply issues and no formal grade analysis, I suspect that we will not make a formal preference for quadrivalent over trivalent until there’s more data available.

Dr. Ibad Khan:
Thank you, sir. Operator, can we check the system for one last question?

I’m still showing no questions over the audio. Once again, if they would like to ask a question please press star, one.

And I’m showing no questions.

Dr. Ibad Khan:
At this time, we would like to stop the Q and A session and remind you that you can always ask your questions through email via That email address is C-O-C-A@C-D-C.G-O-V.

On behalf of COCA, I would like to thank everyone for joining us today with a special thank you to our presenters Drs. Hinton, Bernstein, Bradley, and Fry. WE invite you to communicate to our presenters after the webinar if you have additional questions or comments for today’s presenters. Please email us at Put “February 26 COCA call” in the subject line of your email and we will ensure that your question is forwarded to the presenters for a response. Again, that email address is C-O-C-A-@-C-D-C-.-G-O-V.

Thank you. That does conclude today’s conference call. Thank you for participating and you may disconnect your lines at this time.