“Safety Comes First”: FDA Vaccine Advisory Panel’s Dr. Ofer Levy on Rigorous Process Around Vaccine Approval For Kids

Ofer Levy

Female : Welcome to Conversations on Health Care with Mark Masselli and
Margaret Flinter. A show where we speak to the top thought leaders
in health innovation, health policy, care delivery and the great minds
who are shaping the health care of the future.

This week Ma rk and Margaret speak with Dr. Ofer Levy, Director of
the Precision Vaccine Program at Boston Children’s Hospital, and
member of the FDA COVID vaccine advisory panel on the pending
decision on vaccines for younger children and a recent decision to
recommend boosters for older Americans. He discusses the emerging
era, precision science that has been spurred on by the pandemic.

Lori Robertson also checks in, Managing Editor of FactCheck.org looks
at misstatements spoken about health policy in the public domain ,
separating the fake from the facts. We end with a bright idea that’s
improving health and wellbeing in everyday lives. If you have
comments , please email us at [email protected] or find us on
Facebook , Twitter , or wherever you listen to podcast. Now, stay tuned
for our interview with Dr. Ofer Levy h ere on Conversations on Health
Care.

Mark Masselli : We’re speaking today with Dr. Of er Levy, D irector of the Precision
Vaccine Program and D irector of Infec tious Diseases at Boston
Children's Hospital. He's Professor of Pediatrics at Harvard Medical
School and is an associate member of the Broad Institute of MIT and
Harvard.

Margaret Flinter: Dr. Levy is a member of the FDA ’s COVID vaccine advisory panel,
whi ch just issued recommendations for vaccine booster shots for
certain populations. H is team is one of many that's worked on
versions of the COVID - 19 vaccine. Dr. Levy, welcome to Conversations
on H ealth C are.

Dr. Ofer Levy: A pleasure to be here, Margaret t hank you.

Mark Masselli: And Dr. Levy, you serve on the FDA COVID Vaccine Advisory Panel ,
which has been in the news. Your expertise is in that pediatric
immune responses and precision vaccine development. It was looking
like that the 5 to 11 year olds wer e back on track to be approved for
emergency use authorization of the Pfizer vaccine by Halloween. But
some say n ow it may not be until Thanksgiving . M aybe tell our
listeners what the timeline looks like to you on the vaccine
authorization for younger chil dren.

Dr. Ofer Levy: Thank you for that, Mark. This is a very important question. W e face
an unprecedented pandemic. We're very fortunate that the mRNA
and other technologies had mature d to the point that they were
ready to be deployed against this threat. We're fortunate that we
have safe and effective vaccines. Y et, individuals vary in their immune

Ofer Levy

response , in their physiology , a nd we cannot assume that data in one
age group applies exactly the same way to another age group. In fact,
we've seen those dif ferences just in terms of how the infection is
operating. It's hitting the elderly particularly hard, older adults with
higher rates of mortality, etc.

When we convened as an advisory committee recently, we were
asked an initial question by FDA of whether we would recommend a
booster or third dose of the Pfizer mRNA products for individuals 16
years of age and up. T hat first question got voted down by a pretty
large margin. I was one of the votes against. The reason was that,
most of I can't speak for the o ther members , b ut from the
conversation what emerged was, m ost of us felt there was not
enough safety information for the booster dose, particularly in the
younger age groups. T hen after some discussion, we rephrase the
question for 65 years and up and tho se at risk of severe COVID , a nd
that overwhelmingly passed, I think it was by consensus, a 100% vote.

T hen we believe we might get there for younger age groups. But we
need to see the data , a nd the sponsor, I believe will be back in this
case Pfizer with m ore data in younger age groups for safety and
efficacy. T hen we're going to call it as we see it, I can't prejudge any
data I haven't seen yet. I do think it's important for the studies to be
done.

Margaret Flinter: Well, Dr. Levy, you've made the point th at all of us as parents and
health care people know that children are not just little adults, right?
Y ou certainly want to make sure that we have the protocols for
testing and determining safety and efficacy of these vaccines for
younger children. But for our audience, maybe just talk a little bit
besides settling out what's the proper dose . What are the added risk
factors unique to younger children and vaccines the , additional
worries or concerns . What kind of reinsurance s are we looking to be
able to offe r to parents that vaccines will one be effective, but most
of all, that they'll be safe?

Dr. Ofer Levy: Well, I think the message to parents and to all Americans is that we
have to let the process take its course. We have a good process In the
United State s through the Food and Drug Administration or FDA, the
sponsors whether they are Pfizer, M o derna, J&J or other companies
that have Coronavirus vaccines submit data to the FDA . Pfizer has
announced that they have generated data in children 5 to 11 years of
age . T hey believe those data indicate safety and efficacy in that age
group. That's welcome news. But we need to take an independent
stance, we have to see those data and review them. Vaccines you give
to h ealthy p eople, so they've got to be safe , safety c omes first. We
don't presume because it's safe in one age group that it's safe in
another. W e're going to take a very careful eye to the data, we have

Ofer Levy

to let the process take its course.

It's a good process. It's a public deliberation, the members of the
c ommittee are not allowed to meet in closed session . W e're not even
allowed to email each other about the topic. Everything we transact ,
any information we discuss is in public and on the record, and there's
public commentary phase as well, for any American of any point of
view, to express themselves , so w e believe that's a good process. I
look forward to a very open and frank conversation with FDA and with
the sponsor, and we will have to come to the best decision based on
the information available.

Even wh en a vaccine is authorized or approved , we continue to keep
an eye on safety. We have surveillance systems, the FDA, the Centers
for Disease Control, or CDC have safety surveillance. Some of you may
know the V - Safe a pp, when you got [ inaudible 00:06:32] yo u could
opt in on your iPhone, and you answer surveys about say so if any
signals are detected, we have seen entire programs shut down
making the news right with a J & J has presented, shut down even with
very rare cases. I believe the public should look at all of that and say
the system is working. We're taking safety very seriously.

Mark Masselli: I want to pull the thread on the process a n d the system, wondering if
at some point there'll be a retrospective look at what do we do in a
global pandemic . I thin k you're absolutely right. The very sta id process
the FDA has been a great one , served us well in our country. But as
you think about lethality and transmissibility being much greater, do
you think that there is a different process that the FDA might consi der
as it looks out into the future , b ecause we certainly have to prep for
these types of global pandemics to continue . What's your sense about
that retrospective analysis that what's your own view on it?

Dr. Ofer Levy: Well, that's a complex question. I m ean, you know, we want to be
rigorous, and we want to put safety first , a nd we want a system that
can respond efficiently to challenging circumstances like a pandemic ,
t hat's the whole basis of the authorization, right . T he authorization is
short of a full approval, and moved forward pretty rapidly . I f that was
a standard approval process, that would have taken a lot longer , so
we went with about two to three months of follow up data for the
safety, reasoning at that point that the pandemic was killing a lo t of
people , a nd that to the extent that vaccines have side effects, they're
reported in the first days and weeks after a shot . T here are no
medically proven side effects that mysteriously arise many months
later, or years later, after a vaccine just in ge neral looking at all
vaccines. T hat was the basis for deciding on two to three months of
follow up safety data.

Beyond that, once the sponsor submits the data to FDA, FDA
understandably need some time to look at it. These are complex

Ofer Levy

datasets, they have to be looked at statistically, and then that has to
be packaged for the advisory committee, etc. A re there steps there
that could be even faster? I don't know, maybe. But we've got to keep
safety first , so we've got to keep the integrity of the process. If w e
push it too hard, then we have cutting corners, and that that would
not be wise in my mind b ecause the public wants to know we're
taking the safety very seriously. I f we make a mistake, that can have
very negative consequences, not just during the curren t pandemic,
but just in the general confidence in the vaccine enterprise. T he
calculus around this is delicate, and I think the system has done a
pretty good job under the circumstances.

Margaret Flinter: Well, I agree. I have to say I can't think of a sin gle day since March of
2020. When COVID vaccine , COVID testing wasn't on the front page of
the newspaper , s o the whole country has had kind of an education in
how this whole pandemic has unfolded and our strategies to control
it . C ertainly when the FDA Vac cine Advisory Panel issued a ruling on
COVID vaccine boosters for the general public and recommending
boosters for people 65 a nd over and those with underlying health
conditions. They rejected a booster for the general population ,
recommend it for people 6 5 a nd over and those with underlying
health conditions, but the CDC, which also overrode some of the
recommendations and expanded the categories of those to be eligible
for a booster shot . T ell us more about the science that led to that
decision. A l so, fro m your point of view, the likelihood we'll see a
change to those recommendations as more data comes in ?

Dr. Ofer Levy: Well, you know, we are still learning how these vaccines are
protecting occurrence COVID, they do. T hey protect best as against
hospitali zation and mortality, even against the Delta variant and other
variants s o that's the good news. T hat's why everybody should get
immunized. V accines vary in their durability, how long does that
immune response last in a way that's protected? W e're still le arning
as a global biomedical community, the duration of protection after
these vaccines . B ut there's some data to suggest that there's some
waning of immunity , a nd that's to be expected to some extent .

T he antibodies diminish over time, we think the antib odies are
important for protection. There may also be T cell immunity, cellular
immunity against the virus , so w e're still defining all of that. But
there's some evidence that they come down not unexpectedly, the
antibodies with time. T here was some eviden ce from the data in the
US and in Israel, that with increasing time since immunization, you
have an increased risk of infection. Now, that's complicated to sort
out, because at the same time the variants change. W as it due to the
antibody coming down , o r w as it due to the new delta or some
combination? That's a little hard to tease apart. But the bottom line is,
there was the impression, particularly in those who are older people

Ofer Levy

with weak immune systems, that a booster benefit would outweigh
any risks know n for the booster .

As you get into younger and younger age groups, the risk of severe
outcomes drops and the amount of safety data around a booster is
less , s o therefore the risk benefit now didn't seem as compelling. But
we are agnostic for the future. In other words, there was likely going
to be more data collected, and sponsors whether it's Pfizer , M o derna,
J & J will be bringing those data to FDA and FDA will determine when
it's time for us to sit and look and say, h ey, maybe it's time to go
down now, to lower age groups. That's perfectly possible , c ertainly
what the state of Israel has done.

Mark Masselli: We're speaking today with Dr. Ofer Levy, Director of the Precision
Vaccine Program , Director of Infectious Disease at Boston Children's
Hospital. He se rves on the FDA COVID Vaccine Advisory Panel . Dr.
Levy, when the pandemic struck, there were already other vaccine
studies underway based on the mRNA technology and your own team
began working upon this much earlier, working with Dr. Peter Hotez,
who we've had on our show who developed a vaccine to address the
SARS outbreak and which I think really set the stage for developing a
COVID vaccine far more quickly . I wonder if you could just talk about
that trajectory and why it matters when talking about how sw iftly
these vaccines were created, because it was over a longer period of
time, at least the platform that was used.

Dr. Ofer Levy: Correct. A lot of these are technologies that have matured over the
years. You highlight the leadership f rom Dr. Peter Hotez and Maria
Botta zzi a n d the group at Baylor, they had worked on the earlier
version of SARS. T hen of course, as that epidemic dissipated, there
was less interest in funding in moving that work forward. But their
work was seminal years ago and allowed us to get out of the gate.
They provided us very valuable spike protein antigen to work on . Ou r
group here at Boston Children's Hospital, I direct the Precision
Vaccines Program . W e're bringing precision medicine principles to
vaccinology. How do we understand the immune system varying with
age? H ow do we build vaccines that are tailored to a particular
susceptible population ? R ight off the bat, we started to collaborate
with Keater [PH] and others to develop a vaccine that would not
require freezing that was hig hly active in the elderly .

Our group has strengthened adjuvants . A djuvants are molecules that
boosted immune response. T hese are like rocket fuel for the immune
system. T hese molecules you can add to a vaccine to get the vaccine
to work better, possibly ev en a single shot protection, high levels of
antibody. I t turns out that different age groups respond differently to
these immune enhancing molecules, these adjuvants. W e modeled
human elderly responses outside the body. We had members of my

Ofer Levy

synagogue in Ca mbridge come in and donate blood, older individuals
60 , 70 , 80 years old at the height of the pandemic coming in bravely
and donating blood so we could test it outside the body and find the
best adjuvant for that age group , and then test it in elderly mice and
showed that this vaccine that we created was at least as effective as
the Pfizer vaccine.

N ow a company is advancing a similar concept with these same
adjuvants in India. I think the company's called B iological E and they
work with Peter Hotez a n d the ir group. I t's been a very powerful
collaboration . W e recently released o ur data, and it's under review at
a nice journal. W e're very proud of our team's work , a nd we thank all
of our collaborators around that. This pandemic really, in many ways
brought ou t the best in people working together across academia,
industry and government to accelerate vaccine development, and we
need those vaccines because right now, across the globe, there's a
shortage of vaccines. I n Africa, for example, only 1 to 2% of the
po pulation has been immunized. It's a moral outrage. T here's a lot of
work to be done. How can we develop vaccines that give single shot
protection that are safe and effective, easy to transport , a nd this is
really a challenge.

Margaret Flinter: Certainly on e of the great frustrations in the midst of this has been
addressing the issue of vaccine hesitancy or vaccine flat out
resistance, despite all the evidence of how well vaccines work . W e
have dec ades of history and hundreds and thousands, millions of lives
across the globe that have been saved. But just recently, it seems
we're making some progress, perhaps with previously resistant
populations.

I wonder what your thoughts are, it seems part of it, as we read about
in New York City, where municipal employer s or businesses are
mandating it, that may be one thing that's pushing people to get the
vaccine. But I'm also reading that it's really the Delta V ariant that
people have heard enough now about how dangerous it is, really to all
ages, that that may finally be the knowledge that is overcoming some
of this resistance. What are you seeing in the data around the country
or just what you're hearing from the people that you're working with
about overcoming this hesitancy and resistance?

Dr. Ofer Levy: W hen we con vene as an vaccine Advisory Committee, there's a public
commentary phase . T ogether with a colleague of mine, Elisa
Weitzman we systematically analyzed all the public commentary
around the mRNA, vaccines Pfizer and M o derna. As you might
imagine, we have Ame ricans of all points of view weighing in , pro - v ax,
anti - v ax, in between vaccine hesitant, and that was very instructive.
We published that work recently. N ow we're looking at the
commentary around the booster dose meeting. As Americans learn

Ofer Levy

more and more about the virus and the vaccines, attitudes evolve.
More people are coming forward to endorse immunization. I know
that in a range of communities uptake has increased, including in the
African - American community, we welcome that news. Y et still, there
are people for a range of reasons who are vaccine hesitant or
resistant.

In some cases, information helps. In other cases, people have made
up their mind and they have a certain stance and a certain belief. You
know, we have a large heterogeneous country with a lot of different
points of view. But we have to continue this respectful
communication. The vaccines are , yes for ourselves, our loved ones,
but for our entire community, for getting our economy back on its
feet, getting the schools reopened a nd getting back to some
semblance of normality here .

Mark Masselli: Dr. Levy, we were recently talking about th e silver lining of this
pandemic experience with your Harvard colleague, Dr. Michael Mina.
W e really talked about the acceleration of scientific discovery s purred
by the urgency of the pandemic. T he idea that we can vaccinate
against emerging infectious pathogens is, is one thing, but the idea
that vaccines could prevent cancer or HIV, even opioid addiction
seems like futuristic fantasy . B ut actually, there a re people like
yourself who are working hard on many of these , y ou're doing it at
the Precision Vaccine Program . W hat excites you most about the
potential to improve human health with the science that's unfolding
right now?

Dr. Ofer Levy: Well, as our coll eague Stanley Plotkin, who's widely renowned as the
godfather of vaccinology says it is hard to overstate the beneficial
impact of immunization across the globe. P arents used to be afraid to
let their kids swim in the public pool, they were going to get po lio . T he
last time any of us were worried about that. People were dying of
smallpox. When was the last time when you traveled anywhere you
were worried about that?

Vaccines are a victim of their own success, and we need to realize
that . Yes, each new vacci ne has to be scrutinized for safety, we have
to have the process we talked about . B ut in the big picture other than
clean drinking water , vaccines are by far the most important
biomedical intervention known to humans. T his in many ways is
ushering in a new golden era of immunization, where we can develop
vaccines that are more precise, that are safer, more effective, and
against a range of indications.

Infectious diseases , yes , we need better influenza vaccines . V accine
against HIV , w e're working in collabo ration with the HIV vaccine trials
network on that and also against opioid overdose such as F entanyl .
O ver a 100 Americans a day are dying of opioid overdose. The

Ofer Levy

C oronavirus pandemic has worsened to the opioid epidemic, and we
are funded by NIH NI AI D to d evelop a vaccine that would induce
antibodies against F entanyl. This would be a vaccine given to people
who have substance use disorder. Not to the general population, but
they're at risk in a moment of weakness taking a speedy drug that
might be cut with F entanyl. But if they're immunized, they have
antibodies in their blood , it binds the F entanyl doesn't let it get to the
brain where it suppresses respiration and causes death.

It's a multiyear project that will culminate in a phase one clinical trial.
Dav id Dowling of the precision vaccines program, and I are the PIs a nd
we collaborate with my wife, Dr. Sharon Levy, who directs the
substance use program here at Boston Children's . V ery
multidisciplinary work. W e are enthused and excited by the potential
of these vaccines.

Mark Masselli: W e're watching the FDA authorization for M o derna vaccine and J&J , I
think a lot of people want to know, can they mix these booster shots,
such as J & J recipient, a booster of M o derna or Pfizer? I know that
hasn't fully been ve tted yet, but what's your sense of what we might
see about blending vaccines ?

Dr. Ofer Levy: H ypothetically, it might be very good, you might have additional
boosting of immunity, but we need data. As you intimate , we
welcome the studies that are ongoing. T here are some studies looking
at that , a nd we look forward to the data. But it is an interesting
concept, it may be helpful.

I also want to add another thing, and this might not have come across
in some of the other discussions. It is not that we had any concerning
safety signal about the boosters, it was just the absence of general
data. It's not like we saw a bad signal. I just want the public aware of
that.

Mark Masselli: M aybe the size of clinical trials probably vary, but people are worried
about the size of those clinical trials for the 5 to 11 year olds . H ow big
do those need to be , b ecause the public may not understand the
complication of registering people for clinical trials and setting that
up . What is the standard size for building confidence?

D r. Ofer Levy: This is a very good question. It's a question of power of statistical
power. And that relates to what are the main endpoints of the study ?
If the endpoint is the basic safety parameters, and the ability to
induce an antibody response that we think is protective, it's possible
that a couple of thousand i ndividuals may be sufficient. It also
depends a little bit on how big the differences we detect ar e . On the
other hand if one is trying to detect less common events, one might
need a larger stud y. T hose are some general principles , y eah.

Ofer Levy

Mark Masselli: Great. Thank you and your wife for all the work that you're doing .

Margaret Flinter: Incredible, incredible.

Mark Masselli: Sounds like family --- yeah, very impressive.

Dr. Ofer Levy: Thank you.

M argaret Flinter: We've been speaking today with Dr. Ofer Levy, D irector of the
Precision Vaccines Program at Boston Children's Hospital, and he also
serves on the FDA COVID Vaccine Advisory Panel . Learn more about
his exciting work by going to children's h ospital.org/researchers /Ofer
Levy or follow him on Twitter @L evy _O or @ PREC V accines. Dr. Levy,
we thank you for your curiosity, your tenacious commitment to
uncovering the secrets of immunity and for joining us today on
C onversations on H ealth C are.

Dr. Of er Levy: Take care and thank you, Mark and Margaret.

[Music]

Mark Masselli: At C onversations o n H ealth C are, we want our audience to be truly in
the know when it comes to the facts about health care reform and
policy . Lori Robertson is an award winning jou rnalist and Managing
Editor of F act C heck.org, a nonpartisan, nonprofit consumer advocate
for voters that aim to reduce the level of deception in US politics. L ori ,
what have you got for us this week ?

Lori Robertson: In early September, President Joe Biden announced a plan for
vaccination mandates for some employers, the specifics haven't been
determined yet, but misleading claims about which employers will be
exempt have been circulating online . O ne viral version of the claim list
11 businesses, government branches or federal agencies as being
“ exempt .” T hat list includes a mixture of entities that are actually
covered under the mandates, some that are not covered, and some
that might be covered, but it's unclear without more guidance about
the directives.

A taskforce is developing guidance on implementing Biden's executive
order requiring federal employees to be vaccinated a nd separately,
the Occupational Safety and Health Administration is tasked with
developing a rule for employers with 100 or more workers that would
require employees to get vaccinated or get tested at least once a
week. We don't yet have those details, but we can explain what we do
know about various federal employees.

Employees at the White House and in agencies within the Department
of H ealth and Human Services are subject to Biden's executive order
requiring vaccination. That means employees at the Centers for
Disease Control and Prevention, the Food and Drug Administration

Ofer Levy

and the National Institute of Allergy and Infectious Diseases ar e
required to be vaccinated. The order doesn't apply to the legislative
or judicial branches. It only applies to executive branch employees .
It's unclear whether the OSHA rule will apply to Congress and the
f ederal courts or to independent agencies such as the US Postal
Service.

Claims circulating on social media also falsely say employees at Pfizer
and M o derna are exempt. Both companies which are responsible for
two of the approved or authorized COVID - 19 vaccines in the US
already require their employees t o be vaccinated. T hat's my fact
check for this week. I'm L ori Robertson, Managing Editor of
F act C heck.org .

Margaret Flinter: FactCheck.org is committed to factual accuracy from the country’s
major political players and is a project of the Annenberg Public Policy
Center at the University of Pennsylvania. If you have a fact that you’d
like checked, email us at chcradio.com, we’ll have FactCheck.org’s Lori
Robertson check it out for you here on Conversations on Health Care.

[Music]

Margaret Flinter: Each week C onversations highlights a bright idea about how to make
wellness a part of our communities and everyday lives. Vaccinations
are considered one of the great public health achievements of the
th
20 century, reducing fatalities from most common and fatal dise ases
st
by up to 99%. But in the 21 century, some of those numbers just
aren't stacking up.

As recently as 2009, only 45% of the nation's preschool aged children
had received all of their recommended vaccinations and boosters.
R esearchers at the Children's Outcome Research Program at
Children's Hospital in Colorado decided to take an in depth look at the
problem.

Dr. Allison Kempe: Primary care practitioners are so overstretched that it's rather
impractical.

Margaret Flinter: Dr. Allison Kempe heads up the C hildren's Outcome Research
Program, and she conducted a study on what would help to generate
better compliance with required vaccinations, which is a goal of the
government's Healthy People 2020 initiative . S he found that when
parents received timely remin ders from their state and local health
departments, parents were much more likely to get the vaccinations
and boosters for their children that they needed.

Dr. Allison Kempe: What our study did was to centralize those eff orts s o it didn't take
away from th e primary care providers, but it helped them to do the
reminder recall for their practices centrally, using a state registry. T his
was much more efficient and much more cost efficient .

Ofer Levy

Margaret Flinter: Her research shows that one reminder message can be g enerated for
an entire population across communities. It takes the onus and the
burden off of the primary care and pediatric practices. Her study
published in the December issue of the American Journal of Public
Health showed that those effects were pretty significant

Dr. Allison Kempe: in a fairly short six month period in the counties where this was done
centrally. About 19% of children who are not up - to - date became up -
to - date, versus about 13% i n the practice based recall states which on
a population lev el within six months is really very powerful.

Margaret Flinter: T he study also suggest that there's a cost savings with a centralized
state or county run database and reminder system both in terms of
the vaccines themselves and reduce medical cost as fewer children
fall ill .

Dr. Allison Kempe: Yo u have one case of influenza haemophilus meningitis can cost tens
of thousands of dollars. The costs are of not preventing these illnesses
are very high .

Margaret: A state health department driven vaccination progra m that assist
private practices in vaccine compliance for their patient population,
improving vaccination rates of young and vulnerable children. Now
that's a bright idea.

[Music]

Mark Masselli: You've been listening to Conversations on Health Care. I'm Ma rk
Masselli.

Margaret Flinter: And I'm Margaret Flinter.

Mark Masselli: Peace and Health

[Music]

Female : Conversations on Health Care is recorded at WESU at Wesleyan
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