Next week the FDA meets to discuss Pfizer’s request for Emergency Use Authorization of Comirnaty in children ages 5 to 11 years.  Comirnaty is the official name of Pfizer’s vaccine to provide protection from Covid-19.  Glad this is written communication, because I haven’t a clue how to pronounce Comirnaty.  Should the FDA approve the vaccine for emergency use, the CDC is meeting to discuss the recommendations for usage.  Preordering of the vaccine is currently underway pending the CDC recommendations.  Are you cool with that?  Should you be?  Hope you like math, cause this one is gonna hurt if you don’t.

Managed two references to Simon and Garfunkel in the header for today’s blog.  The bridge in the photo is the 59th Street Bridge, and hence the brief live cut of the 59th Street Bridge song from Carnegie Hall above.  Not to diss another great tune, check out a live version of Bridge Over Troubled Water from Miami University (in Ohio) here.

Rationale Behind Vaccinating Children Against Covid-19

There are two major reasons to vaccinate children against Covid-19.  One is to protect the child themselves.  The other is to protect the adults around them.   These are both great reasons, and provided it is safe to vaccinate children against Covid-19, I am all for it.  So, is it safe?

What Risk Do Children Face From Covid-19?

Children are clearly at far lower risk from serious disease from Covid-19 than adults.  Far lower risk relative to adults does not however mean they are a completely insulated bunch.  There have been 637 fatalities attributed to Covid-19 in children (as of 10/21 per the CDC).  Compare that to the  slightly more than 720,000 adult fatalities during that same time.  While there is some convoluted common core way to arrive at the relative risk, I’ll spare you.  Roughly 1,000 adults die from Covid-19 for every child fatality.

But 637 deaths in children from a single cause is not trivial.  I sought to find the total number of childhood deaths (in the same age bracket) during the same time period, and failed.  To give a crude perspective though, approximately 9,000 children between 5 and 14 years of age die in the US annually.   In addition, roughly 1 out of 2,000 children have been hospitalized to date from Covid-19.  Again, not trivial.

Some Chili Peppers for you today.  “Under the Bridge” live from Slane Castle, Ireland.

What Do We Know About Comirnaty in Children Ages 5 to 11?

Pfizer issued a press release regarding the data of their trials in children ages 5 to 11 years near the end of September.  What they found is that these children demonstrated “a robust neutralizing antibody response” with a “favorable safety profile”.  The trial enrolled 2,268 children, 1517 of which were to receive two doses of a pediatric version of the Comirnaty vaccine, and 751 who were to receive placebo vaccine.*

This past Friday, Pfizer followed up that press release with an 81 page document detailing the study design and results.   In that release, the “robust neutralizing antibody response” was further detailed along with data demonstrating that the vaccine protected against over 90% of infections from Covid-19.  Will be delving into why those results are fair statements shortly.  Common side effects were also detailed (nice graphs beginning on page 30).  The usual suspects were involved: redness, swelling, and pain at the injection side; fevers, fatigue, headaches, chills, vomiting, diarrhea, muscle pain, and joint pain.  Other than experiencing increased pain at the injection site, all other endpoints previously listed were less common in children as compared with adolescents.  Rare side effects are not addressed by this study and this will be addressed separately.  It was noted that there were zero cases of myocarditis in the study group.

Where is the data on preventing hospitalizations?  Deaths?  Don’t see it?  Wonder why?  Bet you do.   Spoiler alert, you may get irritated by the answer.**  It has to do with the trial being a “bridging study.”  Will be discussing that in the next section.  Has anyone seen the bridge? Where is that confounded bridge?

*Dose is 10 micrograms rather than the 30 micrograms used in adults.  Don’t fret, the pediatric version still has a full complement of microchips and sterilizing agents.  Placebo group also received standard dose of chips and sterilizers.

**Please note “may,” not should.  This is about managing expectations and keeping things in context.

Remember Shakti?  I bet most of you don’t.  Live cut above called “Bridge of Sighs”.  Some may recognize the guitarist (John McLaughlin) from prior posts.

Bridge Over Trouble Waters


“A bridging study is defined as a study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the population in the new region. A bridging study for efficacy could provide additional pharmacokinetic information in the population of the new region. When no bridging study is needed to provide clinical data for efficacy, a pharmacokinetic study in the new region may be considered as a bridging study.”

Dude, English.  Do You Speak It?

Yes, and I am fluent in sarcasm too.

In plain English, as it applies to the issue at hand, the Pfizer study compares the level of neutralizing antibodies produced from a subset of this group of 2,268 children ages 5 to 11 years with those of the original larger trials in older individuals; using that as a proxy for the real end points which are protection from infections, hospitalizations and deaths caused by Covid-19.  The assumption is that if the levels of antibodies produced are equivalent between the groups, the level of protection from infections, hospitalizations, and death will be equivalent as well.  If you ever saw Under Siege 2, you know what assumption is……

Yoo Hoo!  What About the Safety Thing?

What, you don’t like to just take the statement “favorable safety profile” as sufficient?  What the heck is favorable anyways?  In the case of a bridging study, it means that nothing appeared to be less safe based on the data collected in the small sample size.  We are back to that assumption thing.  Did you see the body?  Funny thing is, I can’t remember a damn thing from that movie other than the one line.  Sorry Steven Seagal.

Tweaking Yet? Let’s Digest a Bit

So now that I probably have your attention for a few more minutes, let’s take one step back, and understand what exactly Pfizer is applying for, what more needs to be addressed, and what decisions each of us needs to make with the data in hand.  We have an issue in this country with delivering information.  Much of the uproar about premature approval is because there is a lack of understanding of exactly what is going on.  Again, we need to appropriately manage our expectations.

Pfizer is applying for Emergency Usage Authorization for the 5 to 11 year age group.  It is not a full approval.  It is understood that there is work to be done.  They used a bridging study to collect enough data to demonstrate based on past experience that this vaccine will work as intended in the expanded age bracket and without catastrophic results.  Granted catastrophic can be interpreted many ways.

The next step if the Emergency Usage Authorization is approved by the FDA is that the CDC recommends that it may be offered to children in the general population.  Generally speaking if the FDA grants it, the CDC will recommend it.  If, and when, the vaccine is administered to the children in that bracket, continued monitoring for side effects and efficacy (how well it works) will occur.  The concern is for rarer side effects.  The next section will address some of the math behind it.  Suffice it to say, the bridging study would not suffice to address increased or decreased frequency of say…..myocarditis, which occurs in roughly 1 in 50,000 adolescents who take the vaccine.  And lest I leave you hanging on that too long….the risk of myocarditis is much higher in adolescents who get Covid-19 and hence the vaccine is still the better choice despite the risk.  Also keep in mind nearly all the cases of myocarditis in both cases resolve completely.

A week without something Dead?  Hell no!  “The William Tell Bridge” leading into “The Eleven” from Hartford, CT last month.  Happy belated birthday Bobby and John (both on October 16th)!!!   Listen close to the rhythm of “The Eleven.”  It is 11/12 timing and peculiar in rock.  Tap out 1-2-3, 1-2-3, 1-2-3, 1-2, then repeat for 8 minutes.

Sharpen Your Pencils

This is the section that is gonna either excite you, bore you, or baffle you.  The first subsection will discuss the general concepts underlying selecting a sample size for a study.  The subsequent subsections will go through scenarios addressing specific questions.  Those subsections will be summarized in the conclusions.   So, if you are apt to be bored or baffled with calculations, there is always the scroll option….

What Factors Into Selecting a Study Size

There are three major factors that enter into the selection of sample size in any trial. The first relates to expected rates of the measured outcome both on an absolute and relative level between study groups.  The other two relate to how much confidence you want in your answer when the study is complete.

Regarding rates of measured outcome, if the absolute rate of an endpoint is low (i.e.: rare), one would have to study a larger group to find any such endpoints, never mind find a difference in treatment group.  Think of this as the needle in the haystack problem.  The opposite is the case for common expected outcomes, where a smaller sample suffices.  The second aspect regarding expected rates of measured outcomes is the relative difference between the study groups.  If one expects a dramatic difference, a smaller study is required.  Again, the opposite is true as well – subtle differences between study groups require larger studies.

In the Pfizer trial, the primary outcome studied was level of neutralizing antibody response to vaccination.  They were seeking to see these levels equivalent between the groups.  The rationale here is that everyone will have an antibody level and that is easily measured.  Furthermore, they were seeking to ensure there was at most a subtle difference in antibody levels generated between the two groups as a proxy for the endpoints of actual protection from severe disease.

The second and third factors relate to what margin of error you are comfortable with.  One of these factors is known as the “alpha” level of the study.  Most studies use a level of 0.05.  This represents the rate of finding a result in error.  Stated perhaps more clearly, a 0.05 alpha level means that there is a 5% rate of “the results could simply be due to chance.”  The other factor is known as the “power” of the study.  The factor indicates the likelihood of finding a true difference if in fact it does exist.  There is significant debate among the medical community as to what this value should be.  Classically, a value of 80% as been used, though many have argued for use of 90% or even 95%.

For the purposes of subsequent discussions, I used an online calculator to run some scenarios as it pertains to Covid-19 vaccination.  Now that you understand the concepts, feel free to double check my math.  And of course, have fun changing the parameters to see the effects.  You can access the online calculator here.

Did the Study Demonstrate It’s Primary Objective?

The answer is yes.  The neutralizing antibody responses for children ages 5 to 11 years was comparable with that of the older adolescent population in the study previously conducted.  The data was compared using Student’s t-test, which is the appropriate test to do such.

As previously stated, neutralizing antibody responses is being used as a proxy for what we really care about, protection from severe illness (hospitalizations and deaths).  These endpoints are not addressed in the study before the FDA at this time.

If you were curious as to whether the sample size was appropriate for the measurement, it comes down to retrospectively creating expectations since we already know the data.  The average antibody level produced in adolescents was 1146 +/- 101.  The study found the level produced in children 5 to 11 years to be 1197.  Plugging those numbers into the calculator (one study group, continuous means, alpha of 0.05, and power of 80%) shows that you would only require a sample size of 31.  This aspect of the Pfizer trial had more than 250 children in each group.  The sample size selected was therefore sufficiently selected for its purpose.

A full Crosby, Stills, Nash, and Young concert from the Bridge School Benefit

What About The Data on Efficacy of the Vaccine Against Infection?

While not the primary endpoint of the study, data was presented on the efficacy of the vaccine as defined by comparing the number of cases of Covid-19 occurring more than 7 days after the second dose in the vaccinated group with that of the placebo group.  They found an over 90% reduction in risk among the vaccinated group for getting Covid-19 during the study.  If you look at the data, you will see 3 cases in the vaccinated and 16 in the placebo.  You have to take into account there are more children in the vaccinated arm of the study when comparing risk (1450 vs 736 that completed trial).  Based on the size of the study and the alpha value selected, the real reduction may be has high as 98% or as low as 68% (this is your “confidence interval”).  If the vaccine is safe, a 68% reduction  of risk as a worst case scenario would still be a nice result.   Refer to page 60 of the release if hunting to look at these numbers.

As before, if you were curious as to whether the sample size was appropriate for the measurement, it comes down to retrospectively creating expectations since we already know the data.  The percentage of children in the placebo control group who became infected with Covid-19 was 2.174% (16 of 736).  The percentage of children in the vaccinated group who became infected was 0.2% (3 of 1450).  Plugging those numbers into the calculator (two independent study groups, dichotomous endpoint, alpha of 0.05, and power of 80%, enrollment ratio of 2) shows that you would only require a sample size of 936 (312 placebo and 624 vaccinated).  This aspect of the Pfizer trial had significantly more children than required in each group.  The sample size selected was therefore sufficiently selected for its purpose.

What Study Size Would I Use to Assess Halving the Rates of Hospitalizations and Deaths?

As aforementioned, hospitalizations and deaths in children are far rarer occurrences, and therefore will require larger studies to demonstrate.  How large?  While in some ways a masochist, I had zero desire to do these calculations long hand.  Again, here is the link to the online calculator used to arrive at the numbers to be presented.  For these calculations, select the “One study group” option with “Dichotomous” endpoints.  I used the 0.05 alpha level and 80% power.  Again feel free to mess around with these as it pertains to your comfort level.

Without further ado, let’s run some numbers to get a grasp of how large a sample size is required to assess rates of hospitalization.  At present there have been roughly 70,000 hospitalizations of children due to Covid-19.  There are roughly 75 million children in the country.  Using those numbers, 0.093% of children in this country have been hospitalized due to Covid-19.  To run a necessary sample size, we need to make an estimate of how well we expect the vaccine to work.  If for example, we anticipate that it will only protect against half the infections (i.e.: 0.0465% of vaccinated children would still become infected with Covid-19), a trial of 28,056 children is required.  If, however, we anticipate it to work as it has in other age bands, anticipating a 90% reduction in cases (0.0093%) may be a better number to plug in.  In that case, only 6,753 children need to be enrolled to assess whether the vaccine worked as expected.  In a nutshell, the better you expect the vaccine to work, the smaller the trial needed to assess, but this study is not of sufficient size to assess the endpoint of hospitalizations.

To assess vaccine efficacy at preventing death in children would, by extension of what we saw above, require far larger studies still.  Using similar anticipated benefits, if only a 50% reduction in risk of death is expected, just over three million children would need to be enrolled in the study.  This is clearly not a realistic study to conduct.  That number remains unreasonable for a trial even at 90% anticipated benefit in risk reduction as that would still require 720,000 children be enrolled.

What Study Size Would I Use to Assess Ensuring Myocarditis is Not Occurring More Frequently Among The Youngin’s?

As the young children are not at high inherent risk from infection, it is critical to ensure their risk reward ratio remains favorable to take the vaccine when accounting for side effects. Using similar strategy as before, let’s apply our “plugging and chugging” skills as it pertains to assessing for side effects.

Since myocarditis was the most concerning of the side effects noted to date in the adolescent population, we will perform some sample calculations to decide how large a study would be needed to ensure we are not increasing the risk in the younger population as we compare them with the adolescents.  You can then use this same strategy to go have fun with any side effect that is of concern to you as you calculate your own levels of tolerance.  For these calculations, use the “One study group” design with “dichotomous” endpoint (I left the alpha at 0.05 and power at 80%).

Currently about 1 in 50,000 adolescents develop myocarditis after receiving the Pfizer vaccine.  That is 0.002% of the vaccinated population.  If one wants to ensure that that rate is less than 1 in 25,000 children (i.e.: more frequent than adolescents by a factor of 2), one would need to enroll 496,173 children in the study.  If one wanted to ensure that the rate was less than 1 in 10,000 (i.e.: more frequent than adolescents by a factor of 5), one needs to enroll a more manageable 46,123 children to address the concern.

Working backwards, if you wanted to know what the current study was able to detect based on its size, the answer is a 1 in 1428 risk of myocarditis (or 0.07% of children receiving the vaccine).  While Pfizer trial reported no cases of myocarditis among the 5 to 11 year children, it was not designed to assess for this outcome. 

“London Bridge” by Bread.

End Musings

Conclusions That We Can Make From The Trial

There are a couple of conclusions that are appropriate to make from the Pfizer trial in the younger children.  First, the younger children do in fact generate an effective neutralizing antibody response to the vaccine using a smaller dose when compared with adolescents.  Second, younger children appear to receive similar benefit as other age groups with respect to protection from infection post vaccination against Covid-19.  Without getting too much more in the weeds, while the neutralizing antibodies are measured in this study, there are other aspects of immune response such as cellular immunity that are not measured and do contribute to infection prevention.  The antibody response is used as a proxy for the other endpoints.

Conclusions That We Cannot Make From The Trial

There are some conclusions that we cannot make from the current trial.  First, we cannot assume there will be a decrease in hospitalizations or deaths in vaccinated children.  Based on the reduction in numbers infected, it is reasonable to expect such, but not provable based on the study size involved.  As we saw when running numbers, to actually run a trial to demonstrate reduction in deaths in children would not be feasible.

Second, we cannot draw significant conclusions about side effects of the vaccine as it pertains to the rarer complications.  What was seen in the trial regarding side effects was essentially what we have come to know and love from getting vaccinated.  Fevers, aches, fatigue, yada yada.  Whether rates of myocarditis seen in older adolescents are lesser or greater in the younger age group is indeterminate from this current trial.

Did The Study Achieve It’s Goals?

Yes, the study achieved its goals.

The study sought to demonstrate that children were going to respond to the vaccine and to ascertain the dosing to accomplish the generation of similar titers of neutralizing antibodies as a proxy for protection from infection and serious disease outcomes.  The study did look at short term protection for acquiring infection and again the results were similar to other age groups.

This study showed no new common side effects of concern.  This study was not designed to address the rarer side effects.

This study again is is for the purpose of evaluation by the FDA for Emergency Use Authorization.  Notice the words Emergency Use.  This is not seeking a final approval.

With that in mind, what are your goals?  That is the question we will all likely be facing in a couple of weeks.

Off the Bridges and Walls album, this John Lennon tune features Elton John. “Whatever Gets You Through The Night.”  Kinda like the conclusions that will follow. 

I Hate Math, What Should I Do Doc?

You need to do some soul searching and address the risks in your own home from getting Covid-19 and how much risk you feel you can tolerate from your actions to prevent Covid-19 from entering.

For example, if you have your grandparents or immune compromised individuals living with you, you likely have higher concerns of your 6 year old who goes to school, dance classes, and other potential germ infested locales bringing some goodies home to harm others.  If you are a 29 year old single mother who has been vaccinated with no others in the home other than that 6 year old germ wick, you may have a lower level of concern.

Once Emergency Use Authorization occurs, there will undoubtedly be many rushing out to get the vaccine for their young children.  Some based on concern for their child themselves.  Some out of concern of what that infected child can spread to others.  There may even be a few who do it for the purpose of a bandaid and making a TikTok of the event.  Within a couple of months, all the questions regarding rare side effects will be addressed based on the “early adopters” experience.

Perhaps the best way to view this is that we live in a very crazy time period of a pandemic, and there is risk out there.  Emergency Use Authorization is to permit a vaccine which appears safe and effective to be selected for use by those who want it before complete vetting due to that unusual risk.  The “early adopters” are essentially those that are willing to participate in a clinical trial where more than typical vetting has already been done and there are known benefits already identified.

If you are asking me if I think we should immediately go vaccinate every young child based on the trial at hand, the answer is no.  Nor is that what Emergency Use Authorization is intended to suggest.  You may receive a very different message in the media and from others.  By the same token, I do not think it is a poor choice for many to elect for their young child to receive the vaccine based on their relative risk factors.  The downside risk is likely quite low.  Given a couple of months, the full picture will be known and more definitive direction will be possible.

Sometimes it’s hard being an adult that has to make decisions for your children.  Hope this article at least gives some perspective as to what you need to contemplate.  As always, speak with your physician if you have questions and are trying to navigate through your decision making process!  And here’s hoping this vaccine is fully safe and effective for all.  I am hoping that when kids mask up next Halloween it will represent an unusual event to see a mask on their faces!

Post authored by Jason Halegoua PhD, MD, MBA, FAAP.  Jason is the founder of Peds First Pediatrics in 2009, and has been a practicing general pediatrician since completing residency at Schneider Children’s Hospital in 2004.  In addition to earning his medical degree from the Medical College of Pennsylvania, Jason earned a PhD in Molecular Pathobiology for his work contributing to the understanding of the genetic regulation of immune responses to murine leukemia viruses from Hahnemann University in Philadelphia and an MBA in Finance from Hofstra University.