September 1, 2022 ACIP Meeting – Evidence to recommendation Framework; COVID-19 Vaccination Guidance

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>> Thank you, everyone. It's 45 minutes after the hour, and we will now reconvene
the ACIP meeting. Next up, we have Dr. Sara
Oliver, who will be speaking on evidence to recommendations
framework for the bivalent COVID-19
vaccine booster doses. Dr. Oliver, if you're ready. >> I am. Thanks so much. Good afternoon. Next slide. Next slide. So you guys are well aware of our
evidence-to-recommendation framework describing
the totality of the information considered
in moving from evidence to ACIP recommendations. Next slide. This is the ETR framework, as
we have seen before; however, I do want to highlight
the equity domain. As you've seen as we've walked
through numerous ETRs to date. We've really had trouble
answering a single question for equity to highlight
the impact of the intervention
on health equity.

So, for the last several months,
we've been engaged with a review of the equity domain and
gathered input and feedback through consultation with
health equity experts and other partners such as the
national medical association, the office of minority
health and health equity. Throughout this process, it's
become clear that consideration of equity is integral to every
aspect of the production, study, authorization, and recommendation
of COVID vaccines. Next slide. The need for a systematic
reliable, and action oriented review of evidence towards enhanced
equity was also made clear, but structural problems
require structural solutions. The adjustment of the
structure is required for meaningful change, and an
adjustment of the ETR framework to enable systematic
reliable review of evidence towards
actionable recommendations to enhance equity may help
facilitate meaningful change. Therefore, for at least
today's presentation, we have proposed a change
to the equity domain. Now as a consideration
across each other ETR domain, we recommend the systematic,
reliable inclusion of data, to speak to the equity
considerations in each domain, both to demonstrate the data
and encourage actions needed to enhance equity as
relevant to each domain.

Therefore, for today, we will
remove the voting question on equity and will
enhance attention to equity across all the other domains. Next slide. This will be an iterative
process that will require feedback
from ACIP and others. We will then take this feedback
and continue with the process for future ETRs, but
this is the ETR framework that we'll walk through today. For each of the domains, we
will address an equity question for that specific domain. Next slide. So then for this
ETR presentation, as you've heard previously,
the EUAs are issued for the bivalent Pfizer
vaccine in those 12 and over and the bivalent Moderna
vaccine for those 18 and over. We'll have votes for
those specific vaccines and age groups specifically,
but we're also asking ACIP to consider the larger question,
does ACIP support the use of updated or bivalent
COVID-19 vaccine booster doses for those individual in age groups already
currently recommended to receive a COVID-19
vaccine booster.

Next slide. On the left are the
current recommendations, where the focus was on
counting does numbers, and those 5 through 49 years
were recommended for three doses and those 50 and over were
recommended for four doses. On the right is overall future
proposed recommendations for individuals recommended
for a primary series and a bivalent booster
dose regardless of the previous booster
doses given. Age and vaccines for this
will be as authorized by FDA and recommended by ACIP and CDC. So this is not necessarily
the recommendations today but where we envision the
future of the program going. We'll hear from Dr. Hill
later today around the details for the schedule, but
I wanted to orient us to the broader discussion that
we hope to have for today. Next slide. Next slide. This figure shows
the daily trends in reported COVID-19 cases. As of August 29th,
there have been over 94 million COVID
cases reported to CDC. Next slide.

We've seen this previously, but this figure shows
the weekly trends in COVID associated
hospitalization rates by age group from COVID-NET. Hospitalization rates peaked for all age groups during
last winter's Omicron wave, and since April hospitalization
rates in older age groups
have increased relative to the other age groups. Next slide. Here, again, we see
the age-adjusted rates for COVID-associated
hospitalizations by vaccination status
among adults. In June, unvaccinated
adults had 4.6 times higher COVID-associated hospitalization
rates compared to those who were vaccinated with
at least one booster. Next slide. And this figure shows
the age-adjusted rates of COVID-associated deaths
by vaccination status. In June, unvaccinated
people ages five and over had eight times higher
COVID-associated death rates compared to those with at
least one booster dose.

Next slide. Then when we focus
in on death rates by vaccination status among
people 50 years and older, we see that in June 2022, people with two booster doses
had 14 times lower risk of dying from COVID compared to
unvaccinated individuals and a three times lower risk
of dying from COVID than people with one booster dose. Next slide. So moving to our vaccination
data, here we see the trends in the cumulative percentage of
the U.S.

Population vaccinated with a primary series
by age group. Persons aged 65 and
over, in the dark orange, have the highest
covering at 92%. Then the coverage
decreases as age decreases with the lowest coverage
among ages five through 11 years
in dark blue at 3%. I'll note that individuals
six months through five years of age are also recommended
to receive a vaccine but aren't yet on this figure. Next slide. Here we see a similar figure
with trends in coverage for first booster
doses by age group. Again, we see the highest
coverage among those 65 and older and the lowest
coverage among persons five through 11. Next slide. And then now we take a
look at trends in coverage for second booster
doses by age group. Again, the highest coverage
is among those 65 and older, but overall only 41% have
completed a second booster. Next slide. So now for the equity
question for this domain. Does the problem impact
all populations equally? Next slide. This slide shows COVID case and
death rates in the U.S. by urban or rural classification. In the recent omicron
surge, the case rate on the left was higher among the
large metro classification while the death rate on the right was
higher in the rural population.

Next slide. You can also see here weekly
cases by race and ethnicity. Throughout the pandemic, we have
seen cases higher among racial and ethnic minority populations. Next slide. This slide also shows
COVID hospitalizations by race and ethnicity. When we look at
hospitalizations, we can also see that hospitalizations
are higher among racial and ethnic minority populations as well although it was
more pronounced earlier in the pandemic. Next slide. Then for COVID-associated
deaths, again, throughout the pandemic, mortality rates have been
higher, again among racial and ethnic minority populations.

Again, they were more pronounced
earlier in the pandemic. Then as highlighted in the box, the recent mortality
rates show less evidence of these disparities. Next slide. So in summary, as of August over 94 million COVID cases
have been reported in the U.S. Since April, hospitalization
rates in older age groups
have increased relative to other age groups. In addition, in June,
during omicron predominance, unvaccinated adults 18 and
older had 4.6 times higher hospitalization rates compared
with those who received at least one booster, and
unvaccinated individuals five and older had an eight
times higher death rate. We know that vaccination rates
are much higher among older adults relative to
the other ages groups. And we know that
people of racial and ethnic minority groups have
been disproportionately burdened by COVID-19 illness,
hospitalization, and death.

Next slide. So the workgroup felt that, yes, COVID is of public
health importance, especially among
populations recommended to receive a booster. Next slide. Now to benefits and harms. Next slide. So first we'll review
the clinical trial data. Then we'll also review other
considerations to emphasize that we're reviewing the
totality of the data able to inform these recommendations. Next slide. This highlights the
available clinical trial data. First for in the Moderna
bivalent booster clinical trial and then from the
Pfizer BioNTech trial, both of which investigate
vaccines comprising an ancestral and BA.1 strains. There's no international
data yet available for bivalent booster and
no clinical trial data for bivalent with BA.4/5 yet. Next slide. So in the Moderna
phase two/three trial, persons were give a 50
microgram bivalent boost, again, which was 25 micrograms each of
ancestral and omicron BA.1 spike as a second booster
vaccine and were compared to those given the ancestral
booster as a second booster. The trial participants
were in adults 18 and over. Four hundred and thirty-seven
participants received a bivalent booster, 377 received
an ancestral booster. The dosing interval
from the first booster to the bivalent was
136 days and 134 days for the ancestral booster, and the median follow
up was 40 to 57 days.

Next slide. Immunogenicity was assessed by
the antibody response on day 29 after the study vaccination. Based on the geometric
mean ratios, comparing the antibody
response in participants that received the
bivalent booster to those that received the
monovalent ancestral vaccine. The bivalent met superiority
criteria for both omicron and ancestral SARS-CoV-2
antibodies. Next slide. The superiority criteria were
also met in participants with or without evidence
of infection on day 29 with the highest geometric
mean titers observed in those with prior infection
on the far right. Next slide. Local reactogenicity with
the bivalent booster, the fourth dose, was similar
to the second and third doses of the ancestral
Moderna vaccine. The most commonly reported
grade three local reaction was redness. Systemic adverse reactions with
the bivalent vaccine were lower than systemic reactions
from second and third doses, and the ancestral vaccine, and the most commonly reported
systemic adverse reaction was fatigue. No grade four events were
reported in the trial. Next slide. This graph shows the
percentage of participants of participants reporting
local systemic, local or systemic reaction
following vaccination with the Moderna
bivalent vaccine. Next slide. There were no serious
adverse events assessed as related to the vaccine.

Two participants experienced
two serious adverse events, one prostate cancer diagnosis
and one traumatic fracture within 28 days of
the booster dose. There were no deaths
or adverse events of special interest
included no cases of myocarditis or pericarditis. In the bivalent booster group, all severe events included
reactogenicity events, and one patient reported
lymphadenopathy. Next slide. Now moving to the Pfizer
BioNTech bivalent booster clinical trial, individuals
received a fourth dose of a 30 microgram bivalent
vaccine comprised of ancestral and an omicron BA.1 strain
and were compared to those that received a fourth
dose of 30 micrograms of the ancestral
monovalent vaccine.

The study evaluated safety and immunogenicity among
participants aged 55 years and over. Three hundred and five
participants received the bivalent omicron vaccine, and 305 received some
monovalent ancestral vaccine. The dosing interval
from the first booster to the second booster
was 6.3 months, and the median followup
was 1.7 to 1.8 months. Next slide. Again, immunogenicity
was assessed by the antibody response
one month after the study vaccination. Based on the geometric
mean ratios, comparing the antibody
response in participants that received the
bivalent booster to those that received the
monovalent ancestral vaccine, the bivalent vaccine
met superiority criteria for omicron antibodies and
noninferiority criteria for ancestral SARS-CoV-2
antibodies.

Next slide. In participant over
55 years of age, local and systemic
reactogenicity with the Pfizer bivalent
vaccine were similar to the prototype vaccine. Four participants reported fever
between 38.9 and 40 Celsius in the vaccine group, and no
grade four events were reported. Next slide. Then these graphs
show the percentage of participants reporting local or systemic reactions
following vaccination with the Pfizer bivalent
booster. Next slide. No adverse events were assessed
as related to the vaccine. There were no life-threatening
adverse events or deaths reported
by participants. No cases of anaphylaxis,
hypersensitivity, myocarditis, pericarditis, appendicitis, or other adverse events
of special interest. In the bivalent booster group, all severe events included
reactogenicity events such as fatigue, chills,
arthralgia, and headache and some mild to moderate events of lymphadenopathy
were also reported.

Next slide. So a summary of the
clinical trial data. A bivalent booster
dose of both Moderna and Pfizer COVID-19 vaccines
increased the immune response in those who've completed
a primary series and a previous booster. Compared with ancestral
booster dose, the bivalent booster doses
demonstrated a superior response to omicron and either a superior or noninferior response
to ancestral. The bivalent booster doses had
a similar reactogenicity profile to the primary series and to
an ancestral booster dose. It should be noted
though that the data from the clinical trials
are limited in size, age, and bivalent booster type. Next slide. So now we'll move to
other considerations. We'll present available data
to assess the potential risk of myocarditis following
a bivalent booster dose. The risk of myocarditis
following a bivalent booster dose is unknown, and
there's limited data from second booster doses of
the current COVID vaccines as its recommended for
adults over 50 years of age.

So we'll review the risk of myocarditis following a
second dose and a primary series and the first booster dose. Next slide. Here we present the
VAERS reporting rates for verified myocarditis
per 1 million mRNA COVID-19 vaccination in the seven
days post vaccination. The rates that exceeded the
estimated background rates of myocarditis in the same
interval are indicated by the peach shading. This is the same
slide that was shown by Dr. Shimabukuro earlier. Next slide. These are the incidents
rates of myocarditis and pericarditis following
primary series and booster dose in another surveillance system,
the Vaccine Safety Datalink, zero to seven days after
Pfizer vaccinations. Next slide. And this is the same data
following primary series and booster dose after
Moderna vaccination. Again, these are the same
slides that were shown in Dr. Shimabukuro's
presentation. Next slide. Then this slide is from
surveillance data in Ontario, Canada, demonstrating their
reporting rates per million doses administered. In the box on the right, we
see the myocarditis rates after dose two and
dose three in males.

You can see that
across all ages, the rates of myocarditis are
lower after a booster dose than after dose two
of the primary series. Next slide. This slide is from the
long-term followup study from myocarditis participants and was previously
presented to ACIP. As a reminder, at least 90 days
after the myocarditis diagnosis, most patients who were
reached reported no impact on their quality of life, and most did not report
missing school or work. And of the healthcare providers
who completed the surveys, indicated that patients
were fully recovered or probably fully recovered. Next slide. So in summary, around
myocarditis and pericarditis, we know that the risk of myocarditis has been
identified after COVID vaccine. This risk is rate and
primarily observe in adolescent and young adult males. Among the VAERS data,
the reporting rates of myocarditis are lower
after a booster dose compared to the primary series.

Among VSD data, the
incidence following dose two of a primary series and a
booster dose are similar, but the case counts are small. Among surveillance data from
Canada indicates that the risk of myocarditis or pericarditis
following the first booster dose appear lower than the risk
following the second dose of the primary series, and this
was observed for both Pfizer and Moderna products
across all age groups. Most individuals
with myocarditis and pericarditis had fully
recovered at followup. And we know that using data
from pre-omicron estimates, the risk of adverse
cardiac outcomes were 1.8 to 5.6 times higher after
SARS-CoV-2 infection than after mRNA COVID
vaccination among males in that 12 to 17-year age group. And we've also discussed
previously at eight weeks that we know an interval — we've discussed previously at
ACIP, we know that an interval of eight weeks between vaccine
doses may further lower the myocarditis risk. Next slide. Then this is from the COVID-19
vaccine safety technical group that closely reviews data from
U.S.

Safety monitoring systems as well as from other sources,
and this is their report. Through August, they had held
64 teleconference meetings. This is their interpretation
of the safety data with a special focus
on myocarditis. Overall, they felt that
for V-Safe the reactions and health impacts were not
higher after a booster dose than after a primary series. Per VAERS, there were
no additional concerns and that the myocarditis
reporting rates were lower after a booster dose
than a primary series.

For VSD, there were
few myocarditis or pericarditis cases
after a booster dose, and the risk estimates
were imprecise. The risk after booster doses
appeared similar to the risk after the primary
series dose too. VAST also reviewed additional
vaccination data in pregnancy, and no safety concerns from any
of the systems that have data on primary series and
the first booster dose. Then as always, VAST
will continue to closely review the
safety data including data after a bivalent vaccine
booster once available. Next slide. So now moving to other
additional considerations. To better understand the impact
of a fall booster rollout, we'll look at projects from the
COVID-19 scenario modelling hub. The scenario modelling hub
is a multi-team effort aimed at creating and modelling
planned scenarios for the mid- to long-term COVID-19 situation.

There are typically five to 10
submissions per scenario round at the national level,
and results are ensembled and summarized by the Hub. Round 14 and 15 planning
scenarios Werner projections COVID-19 burdens there mid-2023
under different booster policies that I'll walk through. Next slide. This slide details the
scenarios for each round. In round 14, the VE with the
bivalent boosters was assumed to be 80% against
symptomatic disease with nonimmune escape streams. The scenario included a targeted
booster campaign in ages 50 and over versus a flu
vaccine-like uptake in ages 18 and over and also looked at no
variant versus a Fall variant x, with a 40% immune escape
and 20% increased severity. Then round 15 was a rapid
round aimed to update round 14 and consider booster dose time.

The same VE and variant
assumptions were used as round 14 but assumed
booster recommendation with flu-like uptake in 18 and
over, starting in September versus starting in November. Next slide. The round 14 national ensemble
projection intervals showed that regardless of the
presence of a new variant, influenza vaccine-like uptake
in individuals 18 years and older would lead to over 20%
reduction in hospitalizations and over 15% reduction in
death versus a recommendation for individuals aged
50 and over only. Next slide. The round 15 national
projection intervals showed that absent a new variant,
boosters to individuals 18 and over in September
could prevent over 100,000 more
hospitalizations and nearly 10,000
more deaths compared to a booster rollout
in November. Next slide. So we've previously discussed
immune tolerance and concerns for COVID-19 vaccine
booster doses. As a reminder, immune
tolerance is the concern that giving additional doses
of COVID-19 vaccine would lead to lower antibody
levels or a failure to restore antibody
levels to what was seen after a previous dose
or T-cell exhaustion. However, again, we aren't seeing
data at this point to suggest that this is occurring. Bivalent vaccine is able
to improve vaccine titers in individuals without
prior infection and also provided robust
boost in antibody titers for individuals with
prior infection.

As you can see here
on the right, we continue to see
high antibody titers for bivalent vaccine
prior to SARS-CoV — as you can see here on the
right, the high antibody titers that we see for this bivalent
vaccine plus prior infection could lead to slower waning
and prolonged protection against COVID-19
and severe disease. Next slide. We also had discussed
imprinting previously. Imprinting, sometimes known as the original antigenic
sin concerns, is the concern that the initial exposure to one virus strain
primes B cell memory and limits the development
of memory B cells and neutralizing antibodies
against new strains. However, data suggests and improved diverse response
attained with bivalent vaccines. Antibody titers to all SARS-CoV-2
variants tested were higher with the bivalent
vaccine compared to the monovalent
ancestral vaccine.

Next slide. Then we heard from
Dr. Thornburg earlier around antigenic
cartography or ways to map out the antibody responses. Antigenic cartography
uses 2D and 3D maps to viz how closely related
the antibody responses are for different viruses. And example of this
with SARS-CoV-2 is in the figure on the left. Antibody landscapes are
another form of cartography, and they evaluate the diversity
of the immune response. The landscapes are
the things that look like different color
sheets of paper in figures D and E. A flat landscape
is better as it indicates that the response to all
viruses or variants are similar.

When the sheet of paper or
the landscape is sloped, as you can see at the
bottom of panel D, it means that the
responses were very skewed to one particular variant. For this study that
was done by the NIH, they looked at antibody
responses on day 15 after giving a variety of vaccines including several
different bivalent vaccines. For the day 15 antibody
response, which is the top sets of the landscapes, and
especially for those with a history of prior
infection, which is shown in panel E, the bivalent
vaccines with a prototype
+omicron composition, which is the landscape at
the top shown in purple, provided the best robust
response that was diverse and similar across the
different variants. Next slide. So now we'll talk a little
bit about omicron itself and what it means
that we're talking about bivalent omicron
vaccines and a little bit around the differences
between BA.1 and BA.4/5. As we've discussed,
the clinical data from the bivalent vaccines are
primarily obtained using BA.1. Here's a little bit about what
that means and the difference. Compared to the ancestral
virus, which was circulating in early 2020 and
is what is currently in the monovalent vaccines, all omicron sub-lineages have
shared mutations highlighted here in the black arrow.

Many of these mutations are in the receptor binding domain
highlighted in the box with RBD. The receptor binding
domain, as the name implies, is the primary binding
site for antibodies. These mutations contribute
to decreased neutralization and increased transmissibility
for the omicron sub-lineages. So any vaccine that uses any
omicron subvariant would include all of these mutations. Next slide. So what about the
differences between BA.1 and BA.4/5 specifically. First, I want to clarify
why there are two numbers, why we say BA.4 and BA.5. BA.4 and BA.5 are two
different omicron sub-lineages, but the spike protein for
each, which is the focus of the vaccine, is identical.

So what we're talking about in
the vaccine is the spike protein for both BA.4 and BA.5, but it is still just
one single sequence, not two different ones. Then the bar at the top for
BA.1, and then there's the bar at the bottom is BA.4/5. The numbers and letters seen
are areas where they different from the main virus
of comparison. The text you can see on the bottom right
lists all the differences between BA.4 and BA.5. Without this sounding like
an organic chemistry class, the figure highlights
were several of these are in the red arrows. Overall, as you can see,
there are differences, but they fundamentally
are not a completely new or different virus. They actually share most of the same genetic code except
the highlighted red differences. Next slide. So we'll get out of
the chemistry lessons and much more back to
traditional vaccine data.

We fully acknowledge that we're
in a different position now than we were in 2020 or 2021. With the first two, within
the two years of the pandemic, especially the recent
omicron surges we've seen for the past year, many of us have also had a
SARS-CoV-2 infection. We saw on the previous
slides how that impacted the antigenic
landscapes, but now we can look at how that impacts
vaccine effectiveness. This is a study from Qatar
looking at VE with two or three doses of mRNA vaccines
with or without prior infection. The figures are similar, just
looking at Pfizer on the left and Moderna on the
and you can see that in both figures the point
estimate on the far right, the hybrid immunity that's
shown in the orange square, having three dose of the vaccine
and having prior infection, those individuals
were most protected, having a VE of near 80%.

The effectiveness of prior
infection alone was around 50%. Next slide. Then as we saw with
omicron the risk of reinfection fundamentally
changed during omicron surge as well. This study looked at electronic
health records in the U.S. and looked at risk
of reinfection through the calendar months. As you can see, the
figure on the right, as we went into the
omicron surge, the risk of reinfection
significantly increased. Next slide. So today's discussion
is primarily focused on the bivalent mRNA vaccines. We are asking you to consider
the broader program as well. So I wanted to briefly
provide some information on non-mRNA boosters. At this time, the
published data are limited but we'll show what we have. The study looked at a
handful of individuals who received a Novavax primary
series and a booster in teal, highlighted in the
middle, compared to those who received original
monovalent mRNA vaccines in dark blue on the left. Although we don't have any data
to compare what this would look like with the updated
bivalent vaccines, but we can see the responses
overall were fairly similar to what was seen with the
monovalent mRNA vaccines.

Although I will note that
this was only with four or five individuals
in the Novavax group. Next slide. This study then looked at
various booster doses given after being primed with two
doses of a Pfizer vaccine. The study was at a
randomized third trial of various boosters
given 10 to 12 weeks. All booster doses
resulted in an increase in antispike IgG
concentration, but you'll notice that third doses of the
mRNA vaccines resulted in geometric mean
concentrations that were about three times higher
than those observed in the Novavax booster
recipients. And all boosters in the
study showed acceptable side effect profiles. Next slide. So now to the equity
questions for this domain. Next slide. Although the equity question for
this domain is are the desirable and undesirable anticipated
effects demonstrated across all populations equally? This language was very
specifically chosen. First, were they demonstrated
across all populations? Were the persons of diverse race
and ethnic backgrounds included in the clinical trials? Did the demographics
reflect the demographics of the U.S. population? Then are the effects
equally demonstrated? Were the desirable or
undesirable effects evaluated by population groups,
and do they differ in any of those population groups? For all future ETRs, we commit to evaluating the benefit-risk
data through this lens as well.

Next slide. So we'll highlight that this
is the demographic makeup of the Moderna clinical trial
for the bivalent vaccines. It consisted of a smaller
percentage of Hispanic and Latino participants
then that make up the U.S. Census data. Likewise, the trial was
comprised of a larger proportion of white participants
within the U.S. population. Next slide. This is similar data
for the Pfizer trial. And similarly, the Pfizer
trial had less racial and ethnic diversity
than the U.S. population. Additionally, because the trial
was conducted in persons older than 55 years, the median age of the trial participants
was obviously much higher than what is seen in
the U.S. population. Next slide.

So then for results
by race and ethnicity, the Moderna vaccine
bivalent vaccine demonstrated that omicron BA.1 and original
strain neutralizing antibodies after the fourth dose were
comparable across racial groups. In the Pfizer BioNTech trial,
subgroups of participants over 55 in the safety population
generally had similar adverse event profiles from
study vaccination to one month post dose across
various vaccine groups, when evaluated by subgroups
of sex, race, and ethnicity, and overall there were
no meaningful differences between the subgroups
for the omicron variant or the original strain. However, it should be noted that
in both trials the subgroups of race and ethnicity included a
limited number of participants, and so results should be
interpreted with caution. Next slide. So overall, we'll
summarize what data we have to inform the recommendations
as it relates to benefits and harms.

We have experience from using
COVID-19 vaccine mRNA platforms for nearly two years,
over 600 million doses in the United States alone. We have extensive vaccine
effectiveness studies as well as robust post-authorization
safety data across multiple platforms. Clinical human data from bivalent COVID-19
vaccines are available in over 1,700 persons. This includes bivalent
vaccines with both beta and omicron variants and both from manufacturers
and NIH studies. Over 1,400 individuals
received a bivalent vaccine with the omicron
component specifically. Then, as we discussed, there are
subtle differences in mutations between the BA.1 and BA.4/5
spike protein sequences, but overall we don't anticipate
that we would see differences in safety or reactogenicity
of the vaccines based on these limited mutations.

The overall composition
of the vaccine as well as the total antigenic
load are the same as the current booster doses. Then we also reviewed data
from the antigenic cartography and antibody studies as
well as modeling data. Next slide. So here's what we know. COVID-19 vaccines have
a high degree of safety. We know that there are
rare events of myocarditis that have been seen
after the mRNA vaccines in post-authorization studies,
and cases of myocarditis that have been attributed
to the vaccine in the Novavax clinical trials. But we know that they have
a high degree of safety. COVID vaccines also provide
high levels of protection against severe disease. Initially, the COVID vaccines
also provided high levels of protection against
infection and transmission. However, as the virus evolved,
we noted more rapid waning of protection against
asymptomatic and milder disease. We know that COVID booster doses
further increase protection against severe disease. And we know that bivalent
COVID vaccine expand the immune response after vaccination. Vaccines that contain omicron
will improve the antibody response to omicron, and
bivalent vaccines appear to provide a more
diverse response overall, which may actually
improve the immune response to future variants as well.

Next slide. It is important, however, to
acknowledge what we don't know. Right now we don't know
the rates of myocarditis after bivalent COVID-19
vaccines. It's unlikely that the inclusion of omicron would increase
myocarditis rates. What we know that does impact
myocarditis is age and sex of the individual, interval
since previous dose, and potentially dose may be
related, but it's unlikely that the inclusion of
omicron would have an impact. We don't know the
incremental increase in vaccine effectiveness. Antibody titers to currently
circulating variants were higher after bivalent booster dose than with the current
monovalent booster. However, most of the data to
inform recommendations were from that BA.1 bivalent vaccine. The incremental benefit going
from BA.1 to BA.4/5 are unknown. We also don't know the duration of protection for
these vaccines. However, antibody titers
after bivalent vaccine and prior infection were robust. This combination
of prior infection and the bivalent vaccine
may prolong the duration of protection, which could
actually decrease a need for frequent boosters. However, as we all vaccines, the
duration of protection may vary by age and immune status.

Next slide. So in summary of the benefit,
the balance of benefits and risks for these
bivalent vaccines. We know that for both the Modern and the Pfizer BioNTech
vaccines, the bivalent vaccines in increased the immune response for those who've
completed a primary series in previous booster. We saw similar reactogenicity
profiles. We know that the
myocarditis risk is unknown but anticipate a similar
risk to what's seen after the monovalent vaccines. We know that the modelling
projects more hospitalizations and deaths would be averted when booster doses are
recommended broadly for persons 18 and over
compared to those 50 and over and when the booster
campaign would begin in September compared to
beginning in November.

And we also know that
the benefits and harms for the U.S. population are best
assessed when the clinical trial and study populations are
optimally representative of the U.S. population. Next slide. So the workgroup felt that
the substantial desirable anticipated effects
were moderate. Next slide. The undesirable anticipated
effects were small. Next slide. And the balance of those
favored the intervention. Next slide. Now moving to values. Next slide. This slide shows survey data
from an online survey conducted in partnership with the CDC
and the University of Iowa. We've seen results from
this partnership frequently over the course of several ETRs. This survey was conducted
very recently over the month of August and showed that 72%
of eligible respondents said that they definitely or probably
would get an updated booster that protects against omicron. Next slide. Among people who said
that they were unsure about getting a booster,
people both felt that they have enough
protection from their prior dose or that the booster
may not be effective. Next slide. However, when asked why
people would get a booster, preventing them from
spreading to others and preventing severe
disease were the most common.

Next slide. Then as we move into fall. We know that implementation of a COVID booster
program will overlap with the influenza
vaccination season as well. Here we have data around the
co-administration of COVID and flu, and we'll hear more
about the data in trials to look at that, but for this, when
survey recipients were asked if they would be willing to get
a flu shot and the updated COVID at the same time, 63% of
individuals were extremely or somewhat willing to
receive them together. Next slide. So now for the equity
question for this domain, is there important
variability in how patients or populations value
the outcome. Next slide. Booster uptake has
remained relatively steady with those groups with higher
initial vaccine uptake also more likely to have received
their booster dose. This means that older
adults, college graduates, and those with higher
incomes remain the most likely to be both vaccinated with a
primary series and boosted.

There is notable difference
though in the vaccinated versus, in the vaccinated with
the primary series versus boosted status
among adults of Hispanic or Latino ethnicity. Despite a high vaccine uptake
around a third of these adults who say that they've completed
a primary series have not yet received a first booster. Next slide. Then this shows information for why people have not received
a booster, this time shown by race and ethnicity. You can see a higher
proportion of vaccinated but unboosted adults as
Hispanic ethnicity feel that they have enough
protection from prior infection or may have had side
effects from previous doses or could be worried
about missing work from the symptoms post-vaccine. Next slide. So in summary, the value of
this intervention appears high to most of the population. Seventy-two percent of
survey respondents reported that they were likely to
receive an updated booster with the prevention of
spread to others and a change in case severity
appearing to lead as the main reasons
why they would want to get an updated booster.

We also know that nearly two
thirds of adults were willing to receive a COVID vaccine and
a flu shot at the same time. However, we know
receipt of a booster to date demonstrates
persistent vaccine inequity. Adults of older age,
those with college degrees or higher income remain
most likely to be vaccinated with a primary series
and booster. Notably about a third
of Hispanic or Latino ethnicity
adults have not yet received a booster despite
completion of a primary series. Next slide. So the workgroup felt that
the target population felt that the desirable effects
were moderate relative to undesirable effects. Next slide. However, there is probably
important uncertainty or variability. Next slide. So now to acceptability. Next slide. As we think through
the acceptability of bivalent boosters,
we can think through the COVID
vaccination program overall. There have been over 800
million doses delivered to date, over 600 million doses
have been delivered.

Over 90% of the population has
received at least one dose, and over 223 million individuals
have completed a primary series. Next slide. We have a broad network of COVID
vaccine providers including critical pharmacy
providers, federal partners, as well as jurisdictional
providers. Next slide. Then for the equity question
for this domain, is it, is the intervention
equally acceptable across all populations. Next slide. So taking a look at the
percentage of the population with a completed COVID
vaccine primary series by race and ethnicity over time. As shown here, Asian, American
Indian, and Alaskan Native, Native Hawaiian or other Pacific
Islander population have the highest percentage among
those who are fully vaccinated or have complete
a primary series, whereas the black populations
have the lowest vaccination to date. Next slide. Next slide.

As it pertains to booster
vaccination trends by race and ethnicity, multiracial and Asian populations have the
highest percent among those who received their
first booster dose, and second booster dose
receipt is higher again among multiracial populations relative to other radical
and ethnic groups. Next slide. We see that there have also
been disparities by population for those who've
completed a primary series by county urbanicity with those
enlarged metro areas having a higher vaccination than
those in rural populations. Next slide. Then we'll also see that
vaccination rates vary by both race and ethnicity
and disability status.

On the left, on the far left, you can see that vaccination
rates for those assessed as having different abilities
with vision, hearing, mobility, or cognition have lower
vaccination rates. You can see how this varies
by race and ethnicity as well. Next slide. We've shown throughout
ETRs before that a provider's recommendation
remains very important to COVID vaccine acceptance, and this importance appears
highest among individuals who are over 65, black, retired
or with incomes under 30,000. This indicates that
the potential for healthcare providers to
increase the acceptability of these bivalent vaccines through communications
with their providers.

Next slide. So, in summary, we know that
over 800 million does doses of COVID vaccines
have been delivered across a wide network
of vaccine providers. However, significant
disparities and completion of the primary series
and receipt of booster doses still
persist by race and ethnicity, urbanicity, and differences
in abilities including vision, hearing, mobility,
and cognition. However, it's important
to note that the detection of the disparities does
not necessarily explain the disparities. Differences in acceptability
can be what contributes to the disparities, but
as we heard frequently through listening sessions, when we were revising the
equity domain, we heard caution against explaining all
disparities as vaccine hesitancy or low acceptability, when
there may be other drivers also present. Differences in access may
contribute to these disparities as many others may as well. Identifying and understanding
these and other drivers in equity is a critical step
towards closing these equity gaps, and we have
further work to do here.

In the meantime, we
know healthcare provider recommendations are important
and continue to appear to increase the acceptability of COVID vaccination
particularly among adults who are black, over
the age of 65, retired, and of lower income. Next slide. So the workgroup felt that the
vaccine is probably acceptable to key stakeholders. Next slide. So now moving to feasibility. Next slide. Here we see trends in
completed primary series and first boosters for persons
aged five through 11 in purple, 12 through 17 in orange,
and 18 to 49 in blue, and you can see the primary
series is the darker shade of those colors, whereas the
first booster receipt is a lighter shade.

For most individuals, ages
five through 49 years, you can see that it's
been six months or more since their last
COVID vaccine dose. Next slide. Here we see the trends in
completed primary series, first and second boosters, for
persons aged 50 to 64 years in orange and then
65 or over in blue. While many have received
a second booster in the past six months, you
can see comparatively few have received a dose in
the past eight weeks. You can also tell that overall
the numbers have declined with each of the
booster recommendations as we've progressed. Next slide. This actually shows that
based, that in September, based on the total number
of persons eligible, which includes those who've
completed a primary series but not received a COVID
vaccine in the past two months, consist with the language in the EUA is almost 210 million
individuals while the number ineligible, which would be
those who had a vaccine does in the past two months is
less than five million. Next slide. Overall, the U.S. government
has purchased approximately 171 million bivalent mRNA vaccine
booster doses for the fall and beyond with the options to purchase additional
doses as needed.

Based on this, there
will be a sufficient and finite supply
of these vaccines. We do not anticipate limited
supply settings overall. However, jurisdictions have
been given considerations for selecting sites to
receive the initial doses based on ability to rapidly
use the vaccine. These considerations were in the operational planning
guide provided to jurisdictions with a link at the bottom, and
they include location and access to a range of populations to
ensure equitable distributions. The ability the reach those
at highest risk of COVID, the ability to handle the
large product shipments, and the ability to
administer the vaccines. Next slide. We'll hear more from Dr.
Hall in the next portion of the presentation around
these details, but overall, the bivalent vaccines
have the same storage and handling parameters
as the monovalent vaccines that they're used to handling. However, both manufacturers
bivalent vaccines will have gray label borders but different
injection volumes, and again, Dr. Hall has pictures with much
better details, but I'll note that the monovalent
and bivalent labels for the Pfizer vaccine have
identical cap and label colors. For Moderna, the bivalent
vaccine will be distinct from the adult monovalent
dose but may look similar to the product for
ages six through 11.

Next slide. And for the equity question
for this domain, is it feasible to implement across
all population? Next slide. Again, we looked at
data from the data from the data tracker
demonstrating persistent racial and ethnic disparities
and receipt of the first booster among
those who are eligible. We previously reviewed the
survey data demonstrating that about a third
of adults of Hispanic or Latino ethnicity have
completed a primary series but not received a booster.

Here in the data tracker,
we see that those 12 and up who are eligible for a first
booster, over half of those of Hispanic or Latino
ethnicity had not received it, and in fact, more than half
of eligible populations of many populations, the
American Indian, Alaskan Native, black, Native Hawaiian, and Pacific Island populations
have also not received their first booster. Next slide. In summary, use of the bivalent
COVID vaccines appears feasible but with some important
limitations. Over 200 million
people will be eligible for these bivalent vaccines. Most are at least six months out from their last
COVID vaccine does. CDC has provided an
operational planning guide for jurisdictions
preparation, and as noted, there will be a sufficient
but finite supply of these bivalent vaccines. Some aspects of these vaccines
will be easy for implementation, but vials and labeling may
require additional education. And importantly,
significant racial and ethnic disparities
persist and receipt of a booster suggesting that the
intervention may not be equally feasible to implement
across all populations.

Next slide. So the workgroup
felt the feasibility that it was probably yes
feasible to implement. Next slide. Moving to resource use. Next slide. This study is preprint and it evaluated COVID
attributable disease and direct medical costs
that could be averted by a booster program under
two potential scenarios. On the left is with
coverage similar to influenza vaccination
rates, and on the right is if we achieved broader
coverage of 80%. They estimate that an early
fall booster vaccination program that reaches coverage
similar to the 2020 and 2021 influenza season
could prevent up to $62 in direct medical cost, and
this would further increase with broader coverage
of the vaccines. So this shows that data in a graphical format
comparing the cost that could be saved
compared to their estimate of the vaccination cost. Note this isn't a peer review
publication quite yet or a model that CDC has conducted,
but it includes data of possible estimates of a cost-benefit scenario
using their model estimates.

Next slide. Then for the equity question for
this domain is the intervention of a reasonable and efficient
allocation of resources across all population. Next slide. Note that cost effectiveness
data are not yet available for most demographic subgroups,
but there is one study that was available
for older adults, looked at the cost effectiveness
of the first booster dose of the Pfizer BioNTech
vaccine, administered six months after the second dose,
among adults 65 and over from a healthcare
system perspective. Compared to a two-dose primary
series but without a booster, the booster strategy in
100,000 older adults resulted in a net monetary
benefit of over $3 million and at 3.7 quality adjusted
life years over 180 days.

Noting that the cost
effectiveness of the boosters is
highly sensitive to the population
incidence of COVID and the vaccine effectiveness,
the study estimated that offering COVID boosters
to adults 65 and over in the U.S. was likely
to be cost effective. Next slide. So overall a fall
vaccination campaign that expands eligibility
for booster and moves to reach people could avert
a surge of hospitalizations and deaths that would result
in substantial savings and direct medical costs. Next slide. So the workgroup felt that the
bivalent vaccines probably, yes, were reasonable and efficient
allocation of resources. Next slide. In summary. Next slide. So this slide looks like a lot,
but I'm just trying to walk through the compositions of the
updated or bivalent vaccines on the right compared
to the current or monovalent vaccines
on the left. So the current Moderna
vaccine, there's 50 micrograms of the ancestral strain.

For the current monovalent
Pfizer vaccine, there's 30 micrograms
of the ancestral strain. Then on the right the updated or bivalent Moderna vaccine
contains 25 micrograms of the ancestral
strain and 25 micrograms of the spike protein
from omicron BA.4/5. For Pfizer, it's 15
micrograms of ancestral and 15 micrograms of BA.4/5. But note that overall the
bivalent vaccines have the same total antigen amount as the
monovalent vaccines just with the additional
omicron composition. Next slide. So the summary of the data
that was presented in ETR show that the current monovalent
COVID vaccines have dramatically reduced COVID hospitalizations
and death. However, we know that as
the virus has evolved, declines in neutralizing
antibodies and declines in vaccine effectiveness
have been noted as well as more rapid waning
from the vaccines.

Inclusion of a second
SARS-CoV-2 variant in the vaccine broadens
the antibody response. Omicron-specific bivalent
vaccines were studied in over 1,400 individuals, and omicron-specific
bivalent vaccine resulted in higher antibody titers for
omicron variants, higher titers for other SARS-CoV-2 variants,
and titers that were as high or higher for ancestral
SARS-CoV-2, and we know that broad uptake, the COVID vaccine booster doses
early this fall could prevent over 100,000 hospitalizations
compared to a later or more limited rollout and may
even save billions of dollars of direct medical costs. Next slide. So to avoid — I
know that was a lot. What we're going to do
right now is walk through, I've finished the evidence to recommendation
framework, the data. So congratulations, we
made it to the end of that. We'll break it up
just a little bit. So right now we're going to
break for clarifying questions on data presented to ETR.

Then I will turn it over to
Dr. Hall and Dr. Twentyman as they walk us through
the clinical considerations for the bivalent
vaccines if ACIP votes to recommend them today. After that, we'll break
for clarifying questions on the clinical considerations. Then you'll get me back for an encore discussing the
overall workgroup interpretation of the data, and we'll
open it up for discussion of possible recommendations. So, with that, I'll
turn it over to Dr. Lee for clarifying questions on ETR. Thanks. >> Thank you, Dr. Oliver. That was terrific, and we
really appreciate the break and the ability to
ask some questions.

I'll open it up to
my colleagues to see if there are any questions
about the ETR domains. Ms. McNally. Thank you, Dr. Oliver, for a
really informative presentation. I'm going to state in
advance that I don't know if this question is
more appropriate here or for the workgroup
interpretation. But I would like to try and see if anyone can answer
the question of whether the strain
alteration change, whether it changes the vaccine
safety risk/benefit analysis. >> Yeah. Thanks. I'm happy to kind of summarize
the current understanding. So as we walked through
the differences between, so we have extensive safety data
on overall the mRNA platform and use of the monovalent
mRNA vaccines. Then we have safety data
from over 1,400 individuals who received a bivalent
omicron vaccine, and there were no safety
concerns raised there. We know that the
differences between BA.1 and BA.4/5 are enough to impact
some of the antibody titers, which is why FDA chose to
ask for the BA.4/5 vaccine, but we do not anticipate that those amino acid
substitutions would overall change the safety or overall,
you know, benefit-risk balance.

What we do know is we don't
know the incremental benefits that would be going from
the BA.1 to the BA.4/5, but given the experience,
the experts that have weighed in on this, we do not
anticipate that the safety or reactogenicity of the
vaccines would be different with the BA.1 vaccine versus
the BA.4/5 containing vaccine. Thanks. >> Thank you. >> Thank you. Dr. Poehling? >> I too want to say
thank you for presenting so much information clearly, and I really appreciated
how equity was reviewed with each part of the
domains and thought that was highly effective. Can you go back to the
area where we were looking at modeling, and we had
two different approaches. And I just need to review,
if you could help me review that data, it would
be really helpful. Thank you.

>> Absolutely. I know it goes by fast. I will also say, I'll
walk through a little bit, and then we have some
of our individuals who actually did the modelling. So I'll see if they have
anything else to add. So there have been many rounds
as the virus has evolved. There was round 14 that kind
of looked like a 2 by 2 table. So they looked at, for vaccines,
if we went with 50 and over only or 18 and over, then they
also looked at no new variants or kind of a new variant and those four possible
permutations. Then round 15 said we're going to have the same no
variant versus variant. But the vaccine assumptions
are going to change. Instead of going with age,
we're going to look at time. So it's — we're going
to assume everyone 18 and older is recommended, but
what if we went from rolling it out in September versus
rolling it out in November? Then next slide.

This is, as you can see,
there's kind of the four boxes. So there's the four
permutations, and we're highlighting what was
kind of the most relevant here, which was while we may not be
able to control the variant, we can control the age of
the vaccine recommendations and so a broader uptake leads to more hospitalizations
and deaths averted. I'll go ahead and
just go to slide 15. I may turn it over to
Dr. Lesler if he would like to — but one more slide. Or sorry, just round 15. And then this also shows
that in round 15 — oh. [ Inaudible Comment ] Yes, no, whatever. Yes. That this was then
again looking at kind of the early rolling out vaccine
in September versus rolling it out in November, and we saw that
there was more hospitalizations and deaths that could be
averted by early rollout. But that is a way
oversimplification. So I see if Dr. Wallace and Dr.
Lesler are on, so I'll turn it over to them if they
want to explain further.

Justin, are you — >> Yeah. I'm here. Can you hear me? >> We can. Yeah, so I think that
was a good summary. You know, round 15,
ignoring the potential impact of a new variant. Round 14 was really looking at
this contrast between, you know, something that looked like
earlier booster rounds versus this idea that we could
achieve annual flu-like vaccine coverage in those 18 and
hold, and we defined this as, you know, project a substantial
impact of that in that round. Now, that round was done in
early June, so, you know, or based on data up to
early June, so the amount of data we had there about
exactly what the impact of BA.5 would be and how
things might progress as we entered the fall was
less than the second round. So there is a change
between the two rounds both in exactly how much data we
have and in the, you know, in what we're looking at. So going into round 15, round
15 was really a kind of a redux of around 14 with, you know,
the idea of we're going to do everything the same
except we're going to look at, you know, based on input
from a variety of folks, we're going to like
zero in on this 18 or older flu-like
uptake scenario and see how big an
impact timing has.

It does, in September, you know, a September flu-like campaign
prevents more deaths than, deaths and hospitalizations
that the November one. And we did see, as shown here,
you know, an impact of that. You know, but that's not the
only difference, because, of course, here we have
a lot more data to fit. So you'll notice these
confidence intervals, and to explain these figures, the darkest is a 50%
projection interval. The next darkest is an
80% projection interval. The next darkest is 90,
and the next darkest is 95. You'll notice those have gotten
narrower, which is largely because we have more
data at this point. So hopefully that's clarifying. >> Thank you. Dr. Long? >> It's about the same
thing, but I don't know that it would be helpful
for me to understand rounds.

I just — or exactly what this, what we're looking
at, 552 means. It would look like you
anticipate in January of 2023 we're going to
have a whole lot of cases. Is that what that looks like? >> So that right column
is under the assumption of a hypothetical immune escape
variant, what we call variance. So if this variant x
starts entering the country in the late fall, you
know, has the variant — >> Thank you. >> That variant is assumed to have 40% immune escape
including to the vaccine. So, of course, we see — >> I see. >> Some probability
of a big way there. >> Okay. >> The left side is the
no new variant scenario. >> I see. Then did that, does — what I'm trying to understand
is this advantage of September because you think making it an
influenza-like recommendation in September will immunize more
people or because you think that the omicron 4/5 going on
right now is still robust enough to get a lot of people sick
and dead or in the hospital.

>> It's that second. It's that the — >> It's the second. >> Yeah. So in the
two scenarios, we're assuming the
exact same uptake, so the exact same
[inaudible] in round 15. >> Okay.
>> This is for round 15. >> Yeah. >> So in round 15, were
assuming the exact same uptake in the early, what we're
calling the early booster and the late booster scenarios. It's just the timing
that's different. >> And it's because
there's still omicron going on now for [inaudible]. >> Yeah, and some of the
models, it's not most of the models assume this,
you know, after the booster, seasonal effects and immunological waning could
allow additional cases to occur in the fall, particularly,
you know, potentially a reasonably
high number of them.

>> So that was my last question. You in this model, you
assumed no early waning, like three months, four months. Because what if we — I mean it
looks as if omicron is falling, and what if we did transition
to a seasonal or a new variant in January and the
vaccine immunity only lasts for three months, four months. That would be a bad choice. >> So, right. So I can dig into
that a little bit. That is something that came
up, and so, one thing I say is, you know, it's important
to remember about the scenario modeling
how this is a multiteam effort. So we're really bringing
together information from five, from in this case at the national level
five different teams, so we have more teams at
the various state level.

Those teams were, all of those
teams had to have some level of immune waning in their
model, but they were free to within certain
parameters have the speed of that immune waning be based
upon their best interpretation of past data. So some teams had relatively
rapid immunological waning that, you know was closure
to, you know, the four, three to four month range,
and some had longer waning. You do see in a couple
of scenarios, in a couple of scenarios,
that — or sorry, for a couple of
the models, that because of that you do see exactly the
phenomena that you're saying, that the, that you see a
little bit more hospitalization in the early booster scenario than the late booster
scenario in that later wave. But for any of the models, you
know, but overall, the majority of the models did not show
that, and even those that did, it tended to be, it tended to
be offset by the benefit you get from the earlier
boosting overall. So that's all to say this
was something that, you know, was covered by the
space of models, the effect you're seeing
does exist to some extent, but you know, because
we're not waned — I think partially because
we're not waning to zero, the net effect being
projected by most of the models was
still more benefit — you know, benefitted earlier
boosters versus later even with that effect in there.

>> Thank you so much. Very helpful. >> Thank you. Dr. Sanchez. Last question, and we'll
move to the next section. >> Thank you. First of all, I just
wanted to make a comment. I think on your slide 80, just
to defend my Hispanic heritage, when you said that, when you
comment about a third of adults of Hispanic, Latino ethnicity,
and I'm glad you say Latino, not Latinx, they're fully
vaccinated for COVID-19 but haven't received their
booster yet, actually I think by current definition,
they are fully vaccinated. They are correct, but they
may not be up to date. That's a minor comment. I just, I'm just, you know, struggling with a
recommendation — I understand that we
need better vaccines, whether it's a messenger RNA, whether it's some
other platform, but we need better vaccines
because obviously we're still, you know, we're still
having a lot of covid despite vaccination.

Even though it has been
extremely helpful and protection against severe disease,
there's no question about that. But I'm struggling with making
a recommendation for a vaccine, bivalent vaccine, and I fully
support the need for such, but to make a recommendation
for a vaccine that has not been
studied in humans, at least I'm not
seeing the data, I know there's ongoing studies, we're going to make a
recommendation for 18 and over, and you know, and then the
other ones, you know, I just, I'm just very, I just
want to bring that up.

But yes, bivalent vaccine, you
know, the BA.1 has been studied, but that's not the vaccine
were going to be recommending. And so, I just want to
bring that up as a concern. And, I guess, I'll [inaudible]. >> Thank you, Dr. Sanchez. Dr. Daley, really last comment. >> Okay. Well, I think I
would like to then either now or later come back to the
sort of fundamental point that Dr. Sanchez is raising, but
we can also do that after ICC if you feel like
that would work, after clinical considerations
if you feel like it's a better time. >> You know, I think
it's okay to address now. We're going to get back
to this when we get to the full discussion. I think this is actually, but
it feels like that would be for the last section after
clinical considerations, and maybe we can talk about
that together as a group. So, I imagine, there's
multiple individuals that have diversity [inaudible]. But yeah, let's do that. Okay. >> Okay. I'll put my hand down.

Yeah, thanks. >> Thank you. So, let's move onto clinical
considerations at this point. Dr. Hall, would you
be able to put up your slides and
lead us through? >> All right. Thank you. So I'll be sharing
anticipated updates to the interim clinical
consideration for COVID-19 vaccines contingent on a recommendation
for these vaccines. Next slide. So yesterday, Moderna and
Pfizer bivalent vaccines were authorized, Modern for use
in people ages 18 years and older Pfizer for use in
people ages 12 years and older. These vaccines were
authorized for use as a single booster dose
administered at least two months after either completion
of primary vaccination with any authorized or approved
monovalent COVID-19 vaccine or receipt of the most recent
booster dose with any authorized or approved monovalent
COVID-19 vaccine. Next slide. Along with the authoritarian
of bivalent vaccines for ages 12 years and
older for the booster, monovalent mRNA COVID-19
vaccines are no longer authorized — [ Inaudible Comment ] Are no longer authorized
as booster doses for individuals ages
12 years and older. This means that monovalent
booster doses can no longer be given to people ages
12 years and older, even if the person had not
previously received a monovalent booster dose.

Next slide. So with this new authorization
for an updated bivalent booster at a high level,
everyone ages 12 years and older is recommended to receive one age-appropriate
bivalent mRNA booster dose after completion
of any FDA-approved or authorized monovalent
primary series or last monovalent booster does. So this means people cannot
get a bivalent booster without first completing
a primary series. Homologous and heterologous
boosters are allowed as long as they are age appropriate, meaning only Pfizer bivalent
can be given to people ages 12 through 17 but either Moderna
or Pfizer bivalent can be given to people ages 18
years and older.

There is no preference. At this time, there are
no changes to schedules for children ages six
months through 11 years. Next slide. So, again, the bivalent booster
recommendation replaces previous booster recommendations for
people ages 12 years and older. This means that now everyone
ages five years and older, who are eligible for a
booster dose are only eligible for one booster dose. People ages 5 through 11 who
received Pfizer are eligible for one monovalent booster dose
currently, and people 12 years and older, one bivalent
booster dose. Next slide. If you perceive this as a
big change to dose counting, you are right our
recommendations are simplified. We are changing the way we're
thinking about these vaccines from dose counting monovalent
boosters to one bivalent booster for everyone eligible.

So this table just
reinforces that regardless of whether you had zero, one,
or two monovalent boosters, one bivalent booster is
now recommended next. So, since some people may
have already had three, four, or even five doses for those
who are immunocompromised and had a second
booster already, we want to emphasize
we're no longer looking at total number of doses. If eligible, meaning age 12
and older, have completed at least the primary
series and are two months out from the last dose, a bivalent booster should not
be denied based on the number of total doses the
person has received.

Next slide. Shown on this slide is a visual
of what the revised schedule for people who are
not moderately or severely immunocompromised
would look like. The schedule is going
to look a bit different as it has been significantly
simplified. So starting at this top row for
people ages 12 years and older, you're recommended to receive a
primary series, either Moderna, Novavax, or Pfizer
is recommended, and then this would be following by an age-appropriate bivalent
booster dose at least two months or eight weeks after
completion of the primary series or most recent monovalent
booster.

As shown in this arrow, the bivalent booster is
now recommended regardless of how many previous monovalent
boosters were received. In certain limited situations,
Janssen can be used followed by bivalent booster at
least two months later. Next slide. Now the campus schedule for
people who are moderately or severely immunocompromised. The primary series
is not changing. This remains the same. Again, Moderna, Novavax,
or Pfizer are recommended. So for Moderna and Pfizer,
this is three doses. For Novavax, this is two, and the bivalent recommendation
is the same for everyone, one bivalent booster
dose at least two months after completion of
the primary series or most recent previous
monovalent booster does. Again, Janssen is only
used in limited situations for those 18 years and older. Those who got a Janssen primary
dose get an additional mRNA followed by a bivalent booster.

Now, I'll hand it
over to Dr. Twentyman to talk more supplementing
the schedule for people who are immunocompromised
the Evusheld. >> Thank you so much, Dr. Hall. This simplification of recommendations is a great
opportunity to look closely at the spectrum of resources we
have available to protect people with moderate to
severe immunocompromise. Therefore, in addition to the
potential new recommendation to receive an updated bivalent
booster, we're discussing today, let's also look at
existing recommendations for pre-exposure prophylaxis,
which can be used in complement to our COVID-19 vaccines to protect our immunocompromised
population. Next slide please. Pre-exposure prophylaxis
refers to a medication that is given before exposure
to an infectious disease to protect an individual
against that disease. The pre-exposure prophylaxis
Evusheld is recommended for those ages 12 and up who
weight at least 40 kilograms or 88 pounds with moderate to
severe immunocompromise due to a medical condition
or receipt of certain immunosuppressing
treatments. Examples of such
medical conditions or treatments are included in the Evusheld emergency use
authorization fact sheets, on CDC's website,
and are similar to those previously
leading to eligibility for multiple boosters.

Evusheld is also recommended to
be given to those who are unable to receive COVID-19
vaccines due to a history of severe adverse reaction
to a COVID-19 vaccine or one of its components. Next slide please. Tixagevimab and cilgavimab
or Evusheld is a combination of two long-acting human
monoclonal antibodies derived from B cells donated by
convalescent patients after SARS-CoV-2 infection. The FDA issued an emergency
use authoritarian for use of Evusheld for preexposure
prophylaxis in December of '21, revised the EUA to increase
the dose to 300 milligrams of each monoclonal antibody
in February of 2022, and revised the fact sheet
for healthcare providers to recommend Evusheld be
administered every six months in June of 2022.

Evusheld must be prescribed
by a healthcare provider. Doses can found through the U.S.
government therapeutic locator tool on Astra's website
linked here. As of last month, there is also
a new ordering pathway available through the HHS health partner
order portal or HPOP such that in addition to the
larger orders available through the HPOP
distribution process, providers who aren't
participating in that process can now
order up to three doses through the small volume
orders portal linked here.

Next slide please. Use of Evusheld is
evidence based. In a randomized clinical
trial Evusheld had efficacy for the prevention of COVID-19 and in multiple other studies
including real-world data. Evusheld was observed
to have efficacy against severe COVID-19 outcomes
including during this period of omicron variant predominance. Additionally, in vitro studies
show that Evusheld is predicted to work against BA.4/5. Next slide please. Despite the protection
that Evusheld can provide, most people we immunocompromise in the U.S. have not
actually received Evusheld. Among the almost 7
million individuals with immunocompromise,
a very small percentage or about 5% have actually
received doses of Evusheld.

This is not an issue of supply. Current Evusheld supply
far exceeds demand, and more than 390,00 doses
are already distributed and available for use today. Evusheld is distributed by
the U.S. government at no cost to participants although
some locations of administration may have an
associated administration fee. Next slide please. Here we illustrate how use
of monoclonal antibodies for pre-exposure prophylaxis
can complement receipt of COVID-19 vaccines for
optimal protection of those with immunocompromise. Specifically, after any
dose of COVID-19 vaccine, and individual should wait two
weeks before receiving Evusheld. After Evusheld, there
is no minimum interval to the next COVID-19 vaccine
either within a primary series or if receiving a booster dose. Evusheld is recommended to be
administered every six months and individuals should consult with their physician
for a prescription. Next slide please. CDC is in the process of
updating several webpages to make this information
more widely available.

Updated content for healthcare
providers will include descriptions of patient
eligibility and detailed Evusheld
administration guidance as well as those links to options
for ordering Evusheld as were shown earlier. Updated content for the general
public will include additional information about how to know
if you're eligible for Evusheld as well as the dose
finder shown earlier. Updated language within our
interim clinical considerations for use of authorized and approved COVID-19 vaccines
will clearly describe how use of Evusheld complements
COVID-19 vaccination to optimally protect
people with moderate to severe immunocompromise.

Thanks very much and then
back to you, Dr. Hall. >> Thank you, Dr. Twentyman. Next slide please. Now, I'll dive into specifics
on timing considerations for bivalent boosters. Next slide. Our current timing guidance
for vaccination in persons with current or prior SARS-CoV-2
infection also applies to bivalent boosters. If a person has current or
prior SARS-CoV-2 infection, at a minimum, vaccination
should be deferred at least until recovery from acute
illness and criteria to discontinue isolation
have been met.

This is the minimum. Additionally, these people may
consider delaying vaccination longer by three months from
symptom onset or positive test if infection was symptomatic. Individual factors such as risk
of COVID-19 severe disease, community-level or
characteristics of the predominant strain
should be taken into account when determining whether to delay getting a COVID-19
vaccine after infection. Next slide. With new bivalent vaccines, co-administration
guidance has not changed. Routine administration of
all age-appropriate doses of vaccines simultaneously is
recommended as best practice for people for whom no
specific contraindications exist at the time of the
healthcare visit. I'll note that orthopox virus
vaccine does not follow the same routine guidance, and
further information on that very specific
situation can be found in CDC's interim
clinical considerations. Extensive experience with non-COVID-19 vaccines has
demonstrated that immunogenicity and adverse event profiles
are generally similar when vaccines are
administered simultaneously as when they are
administered along. Therefore, providers
should offer all vaccines for which a person is
eligible at the same visit.

Next slide. With both influenza and
COVID-19 vaccine campaigns, we received a lot of questions
about co-administration of these vaccines specifically. Providers should offer
influenza and COVID-19 vaccines at the same visit if eligible. This includes adjuvanted or
high-dose influenza vaccines, but the recommendation
in this case is to administer in separate limbs. With both influenza and
SARS-CoV-2 circulating, getting both vaccines is
important for prevention of severe disease,
hospitalization, and death. Getting both vaccines at the
same visit increases the chance that a person will be up to
date with their vaccination. Next slide. Studies looking at
co-administration have shown that immunogenicity is
similar between those who received co-administered
COVID-19 vaccine and seasonal influenza
vaccine and those who received these
vaccines separately. We know many people have
received simultaneous vaccination with influenza
vaccine last season. 9.4% of [inaudible] participants
reported simultaneous vaccination with an
mRNA COVID-19 vaccine and seasonal influenza vaccine. 8.7% of persons enrolled in the Vaccine Safety
Datalink received simultaneous vaccination with
a COVID-19 booster and seasonal influenza
vaccine during the '21/'22 influenza season. Next slide. Finally, this slide
summarizes studies to date on reactogenicity of
co-administered COVID-19 vaccine and seasonal influenza vaccine. This chart shows the
percent difference in participants reporting
reactogenicity between COVID-19 and influenza vaccine
versus COVID-19 alone.

On the left axis is listed which vaccines were
co-administered including any seasonal influenza vaccine,
adjuvanted, cell-based, recombinant, and high-dose
influenza vaccines. In the chart, systemic
reactions are shown in green and local in blue. To the left of the zero
are the differences in which more reactogenicity
was observed with COVID-19 vaccines alone,
and to the right are differences in which more reactogenicity
was observed with COVID-19 and influenza vaccine
co-administration.

Generally COVID-19
vaccines administered with seasonal influenza
vaccine showed similar or only slightly
higher reactogenicity and no specific safety
concerns were identified. Next slide. And this just states the
conclusion I just mentioned. Next slide. So in terms of best practices
for multiple injections, we recommend to label each
syringe with the name and dosage of the vaccine, lot number,
initials of preparer, and beyond use time
if applicable. Administer each vaccine in
a different injection site and separate injection
sites by one inch or more. And finally, administer the
COVID-19 vaccine and vaccines that may be more likely
to cause a local reaction in different limbs if possible. I mentioned this earlier, an
example would be adjuvanted or high-dose influenza
vaccine and COVID-19 vaccines. Next slide. Now take a look at the
bivalent products in comparison to the current monovalent
products. Starting with Pfizer,
monovalent and bivalent cap and border label colors
will be identical.

They are both gray. Most characteristics are the
same, authorized for 12 years and older, 30 micrograms. The injection volume
is 0.3 milliliters. Dilution is not required for these specific products
although other Pfizer products require dilution, and they
have the same beyond use of 12 hours and the
same storage. The differences shaded in gray on this chart are the
composition, monovalent and bivalent, and
the type of dose. The monovalent is
primary series, and the bivalent
is booster doses. Next slide. Can you go back one slide? So here are the labels. So, on the left is
the monovalent. On the right is the bivalent. They are almost identical
aside from on the right in the red box the name is
different, and that is about it. So this is something to
be aware of for errors. We're going to be having
education on strategies to prevent admin errors so that
we can try to reduce errors and provide our offices.

Next slide. So for Moderna, I'll
highlight two different vials in comparison to the bivalent. The one for the older age
group, ages 12 years and older, and then the one with the
most similar appearance, and that's actually
for ages 6 through 11. Next slide. So first the monovalent product
authorized for ages 12 years and old is fairly
visually distinct from the bivalent
product authorized for ages 18 years and older. The monovalent is
in a red-capped vial with a light blue
labeled border color, and this is now only
authorized for primary doses. Comparatively the bivalent
product for booster doses in people 18 years and older is
in a vial with a dark blue cap and a gray labeled border. Again, the injection
volume is the same, the same beyond use date of 12
hours, and the same storage. Next slide. So here are the labels of the
two products I just highlighted. As you can see, they're
much more visually distinct. The bivalent booster is clearly
labeled booster doses only in all caps, and there
are different colors on these labels.

Next slide. So the vial that looks the
most similar is actually the monovalent product
authorized for primary doses in people ages six
through 11 years. This vial also uses
a dark blue cap, and the visual distinction
is the purple label border. Next slide. Here's a look at
the label comparing. So both say booster
dose only in all caps. However, of note, the
monovalent vial authorized for primary doses in ages six through 11 is not
authorized for booster doses. He main distinction is the name
of the vaccine and the color of the border and the background for the booster dose is only
text, purple versus grad. So this is also something
to keep an eye out for and implement strategies
to prevent errors. Next slide. And finally, CDC continues
to encourage people to stay up to date with their
COVID-19 vaccines. Staying up to date
keeps people current with the COVID-19
vaccine recommendations. With new recommendations
people are up to date if they have completed
a primary series and received the most recent
booster dose recommended for them by CDC.

Next slide. And now we'll break
for questions. >> Thank you, Dr. Hall. Ms. McNally. >> Thank you. I'm thinking about recent
infections, and I just want to clarify whether there is
data to answer the question of whether prior recurrent
infections plus vaccination with the bivalent
vaccine has any indication of increased myocarditis. Thank you. >> Elisha, this is Tom. Do you want me to take that one? >> Sure I was going to say no, but I did not have a
more detailed answer. >> Okay. Yeah. I mean I don't, I don't
think we have any information on the bivalent booster dose,
but we do know that individuals who have a recent
COVID infection and then are vaccinated for COVID can experience
increased reactogenicity events.

But we don't have any
evidence that that places them at increased risk
for myocarditis. >> Okay. Dr. Shimabukuro. Can you clarify whether we're
talking about a timeframe that is less than 90 days or
more, like recent infection just after 90 days when you say that? >> I don't have the exact
timeframe off the top of my head, but there's
actually a couple of studies, which aren't published yet.

One looks in V-Safe data, and
it looks at, it looks at people who report having a vaccination, and I'm not sure how they
define it, but I suspect its on the order of, you know,
within several months, but based on that
information, you know, self-reported reactogenicity
appears to be, and that's things like systemic reactogenicity
fever, fatigue, muscle aches, that type of thing, is
reported with higher frequency if you've had a recent
infection, but again, there's no evidence or
there's a lack of evidence that that places you at
increased risk for myocarditis. >> Okay. That's helpful. I have one followup
question since we have you. Can you confirm for us that
the CDC and the workgroup and whether that's VAST or the COVID workgroup will
be following the international safety data for this
particular vaccine? I would defer to maybe Dr.
Oliver about the U.S.

Vaccines versus the international
new booster vaccinations. I'm not sure about the
formulations for those, but I will stay that
we regularly consult with our public health
and regulatory colleagues, international colleagues
to exchange information and to better keep on
top of the safety data. So the answer is yes. >> And I'm happy
— this is Sara, for the COVID workgroup as well. Yes, we will collaborate. There are [inaudible], which is
the things like ACIP that are across the globe and with other
safety agencies to look at, any available safety data for bivalent vaccines whether
it's the BA.1 vaccine that's used in some countries in Europe
and potentially Canada as well as the BA.4/5 vaccine if
that's used internationally as well, yeah, thanks.

>> Thank you. >> Thank you. And we have Dr. Deeks on if she
wants to raise their hand later and make any comments,
that would be great. I don't want to put her
on the spot in the moment. We'll move to Dr. Poehling. >> Thank you. My big question and to outline
it a little bit more before I ask it is really about the
switch immediately from bivalent to monovalent boosters. And here's the thought
process behind my question so that we can have
a robust discussion. The data reviewed today
highlight great benefits of booster dose on preventing
hospitalization and death, and this data includes
the monovalent vaccine. We have also reviewed and
discussed disparities. In this discussion we
noted that that factors like access may contribute
to those disparities. It was implied in the discussion that there will be sufficient
supply to replace monovalent with bivalent booster dose.

My concern is that this
information differs what we're receiving locally that our
initial supply will be small. And so, could you please clarify
what the anticipated supply distribution is and how
we can make sure not to exacerbate disparities. Thank you. >> Hey. This is Sara Meier. So thank you for that comment. I guess what I'd like to say
is, you know, we've been working through all of our estimated
channels for making sure that this bivalent
booster vaccine is accessible nationwide. We have hundreds of thousands
of doses beginning delivered around the country today, and by
the end of the holiday weekend, millions of doses
will be in the field with more arriving every day. So we anticipate that we will,
you know, quickly be able to have, you know, and authorized available
booster product out there over the next couple of days,
but then to your longer-question about how can we make sure
that we have, you know, sufficient supply, access,
and ensuring equity, we will be distributing this
vaccine to tens of thousands of sites across the country.

You know, the vast
majority of people will be within a five-mile radius
of a COVID-19 vaccine site, and we've been working
for years now to make sure that we have equitable
access including efforts to make sure the
vaccine is available for high-risk populations
including long-term care facility residents and also
in areas that serve people who may be at higher risk
because of their race or ethnicity and
underlying conditions, how we've been working with
many partners for years now to build those networks to
ensure that we can continue to have equitable
access for this vaccine. So I hope that helps
to answer the question. >> It does, except I
worry about our children because the vast majority
of children get vaccinated in the primary care setting, and I hope that has been
an important component of what has been included
in this thought process. Thank you. >> Thank you. I see Dr. Deeks has
raised her hand. Oh, sorry, go ahead, Dr. Mara, do you want to add any
additional comments. >> Well, I don't need to, but
I was just going to acknowledge that comment and just say
that, yes, and as we think about bivalent booster
authorizations potentially in the future moving down in
the age groups, we'll continue to really on our strong
network of providers.

Again, most VFC, you
know, a large number of VFC providers
also participate in the COVID-19 program. We do have a pretty robust
network of pediatric providers that are participating, and
we would anticipate continuing to leverage all these
partnerships for pediatric vaccines as well. >> Yeah, just, sorry to jump in,
but just to augment that issue, I mean this is why
I've been so worried about the labeling issue, because it's impairing
our ability to actually deliver
vaccines without fear of causing any adverse effects. We are, you know, kind
of partitioning out sort of the way we think about
those doses in order to make sure we give it in the
safest and most reliable way.

But it would just be
a lot easier if some of these labeling issues
got fixed, to be honest. Dr. Deeks. >> Okay. Thank you very much. Yeah, we had licensed
the bivalent, Moderna bivalent BA.1 was
licensed today in Canada and NACI recommendations
were also released today. Similar to the U.S., we are
approaching the fall booster as a fall booster and
stopping dose counting. So recommending that individuals
receive a fall booster regardless of previous
number of booster doses. Unlike the U.S., our ancestral
products remain licensed, and because there is a
concern of potential supply at least initially, our
recommendations were that unauthorized dose of a bivalent vaccine should
be offered as a booster dose, but if the bivalent
omicron-containing vaccine isn't readily available, an original or ancestral vaccine
should be offered.

And then our timing is a
recommendation for six months as opposed to, I think,
what you're talking about, which is two months, but
noting that it can be decreased to a minimum of three months if epidemiologic
conditions warrant it. And then we have given an
off-label, NACI does a lot of off-label recommendations, so we have given an
off-label recommendation for bivalent Moderna for
adolescents 12 to 17 years of age but only those
adolescents with moderately to severely immunocompromising
conditions or who have a biologic or social
risk factor that puts them at place of high risk
for severe outcomes given that there are no data for
Moderna in this age group. So it was only authorized
in Canada, as I said, to 18. Pfizer is not yet authorized, so we don't have NACI
recommendations for them. Thanks. >> Yeah, no, that
thank you very much. And, you know, Dr. Deeks is
my counterpart in Canada, so just for clarification.

Ms. Bahta. >> Thank you. I think I need a
little clarification. When you have been going through
the scenarios for bivalent versus monovalent for
kids versus adults, and my question is,
right now though, the one monovalent
booster is recommended. Now, are we assuming that
will change once we have an authorized product,
a bivalent product? >> And so right now the only
monovalent that can be used for a booster dose is the Pfizer
product for people ages five through 11 years who received
a Pfizer primary series. That's essentially the
only small population that the monovalent booster dose
would still be recommended in, and we would anticipate
to respond when and if FDA authorizes a bivalent
for the younger age group to then make applicable
recommendations afterwards. >> Thank you, Dr. Hall. >> Thank you, Dr. Cineas. >> Thank you. I share the concerns of Dr.
Lee regarding the labeling of these vaccines, and
give that Pfizer monovalent and bivalent look very similar. In fact in our system, the
monovalent is to be ordered in Epic as the [inaudible] and
now we'll have two [inaudible]. What happens, what is the
clinical recommendation when a patient receives
inadvertently a bivalent vaccine instead of a monovalent as
part of their primary series, what will be the
guidance on that, because I do see the
scenario happening.

So if I, I'm going to do
both scenarios just in case. So if for Pfizer gray
label, it's a monovalent, is administered instead of
a bivalent for the booster, in general, the recommendation
is going to be do not repeat the dose. Vice versa, if a bivalent is
administered instead off a monovalent, for a
primary dose, again, we're going to say do
not repeat the dose. >> Thank you. >> Thank you. Dr. Kotton. >> Thank you very
much for your emphasis on encouraging Evusheld. I think it's a really
important options, especially for the
most immunocompromised and most vulnerable.

Could I ask you to comment
on there's a lot of confusion and a lot of people
are making up rules about when they should
get vaccine and when they should
be getting Evusheld. And it's pretty clear
in the Evusheld EUA that people should
not get vaccines for two weeks afterwards. But can you comment, you
or anyone else on the call, comment as to whether there's
actually a immunologic impact by getting Evusheld as far as decreasing response
to vaccination. And maybe you could go
back to the Evusheld slides and just put that, put up
the interval recommendation. >> Slide 129 please. Thank you so much, Dr. Kotton. There it is excellent. So to review the schedule,
it is true that Evusheld UA, emergency use authorization,
Evusheld needs to be given at least two weeks after any
dose of any COVID-19 vaccine. However, after Evusheld,
there is no minimum interval to the next COVID-19 vaccine,
and we did want to underscore that today because you
may be quite correct that there is a misunderstanding
of in which direction that
two weeks works. I hope that is helpful.

Thank you. >> Yes. Thanks very much for
providing the clarity here. >> Thank you, Dr. Bell? >> Thank you. I likely missed this but could
you review what the clinical considerations are going
to say about the interval between the last does and the
booster dose not for people who were known to
previous have COVID. Is it saying two months. Is it saying at least
two months. How are you going
to deal with that? Okay. So for people who did
not have a recent infection, I think if I'm understanding you
correctly, from the last dose that interval is going
to align with the EUA? >> Okay.

That was my question. Has anybody been
giving any thought to providing any additional data
around that with respect to, you know, effectiveness
of the booster dose with a longer interval,
other considerations, anything like that,
are you planning to add any additional verbiage,
or are you just planning to leave it like that. As you can tell, I
feel a little bit, I think it would be unfortunate if ppl interpreted the two
months, at least two months since it seems to me there's
at least some suggestion that waiting is perhaps
would improve performance of the vaccine. >> Do you think — Dr. Bell —
since this is more around kind of the authoritarian and the
vote, so I mean I think the EUA, what is kind of authorized
is this at least two months, there was slides in, slides
that did kind of break down where people were, so
you can see that for most of the population, less than 50
years of age, it is merely all of that population less
than 50 years has been at least six months since
our last vaccine dose. So I think there's both the kind of what is the earliest
interval legally allowed by the authorization,
and I think, you know, it would be important that
we'll get into the three — as we kind of walk through
what the votes may be, but that the CDC recommendations and ACIP recommendations mirror
what is in the EUA, however, acknowledging that for
most of these individuals, it's been at least six months
since our last vaccine dose.

We know that that's different
for those 50 and over, where there are some individuals
who have had a second booster in that kind of six-month
timeframe. That's also the population
that may be at the highest risk of severe outcome, if they
have a COVID infection. So I think the decision,
you know, there's the minimal
interval that is authorized with the two months, and
then I think the decision for when exactly to get this
booster for when exactly to get this booster dose, and we
can talk about this as we move into the recommendations
as well. But can be informed by
personal circumstances when you recently had COVID,
when your last vaccine was, what your age and kind of individual risk
factors for COVID are. You know, and so,
and what your kind of upcoming risk activities
may be, if you're going to be, you know, traveling or
in a congregate setting in the future.

So I think there's a lot of
kind of personal experience that can go into when
exactly it's given the dose. The legally, you know, minimum
interval is that two months, and then for most
of this population, 5 to 50 years they're
well beyond that at least six months
from their last dose. >> Okay. Thank you. I understand that from a
practical perspective this isn't really, you know, it's not
going to be a big problem for most people, and I also
understand what the EUA says, but I do think it's
something that would be nice to at least provide
some, as you say, some context for individuals. >> Thank you, Dr.

Loehr. >> Thank you for this
wonderful presentation. I've got two comments. The first is an area
for ongoing research. My awareness of immunocompromised people
has been raised by Dr. Kotton, and I have been paying attention
to the data, which suggests that they are simply not
responding to the dose as well and that they might need
more than just three doses. And so, I would encourage
people to be aware that this booster
dose might be great, but it might not be enough
for immunocompromised people, and we might have to
revisit that down the road. My second comment is it
is incredibly confusing, and it took me literally
15 minutes while I was on this call trying to find
comparisons of all the doses and vials and who can use it
for what, and I would encourage that this somehow get delineated
with pictures for everybody so they can see what vial is
being used for what situation. I finally found it on
the CDC without pictures. It was pretty helpful, but I
encouraged [inaudible] the CDC to put it out with pictures. Thank you. >> And I'm not sure if the
manufacturers are still here and can comment, but I believe
there are some wall charts that have pictures on
them that are available from those websites, and we just
essentially did not re-create the wheel since they were
already available, but if you're on the line to confirm if those
have been updated for bivalents.

>> Dr. Lee just put
a link in there, so I'll go looking some
more on the internet and see what I can find. Thank you. >> Yeah, sorry. Just so folks know, the AIP has
put a really nice vaccine dosing quick reference guide after
the last round of approvals for pediatric vaccines. I am hoping that something
similar could exist for this 12 and older
population. Let's go to Dr. Sanchez, and then I see four
additional hands raised. I'm just to ask that we
go with quick questions and quick answers
so that we can get to the additional discussion.

This is only the clinical
considerations section. Thank you. >> One question. With Evusheld, has
it been looked at for IV administration at all? I note that [inaudible]
it's IM, but I would imagine that that question may come up. >> Thank you, Dr. Sanchez. Do we have either of
our representatives from the AstraZeneca
sponsor on the phone, please? >> This is Kevin
Cope [phonetic]. Can you hear me? >> Yes, we can. Thank you. >> So, Evusheld was
studied intravenously in first in human study. In the treatment studies
in [inaudible], sorry, in active two and active three,
they were also studied IV, and the active three data is
currently published online. >> So it can be IV or IM? The picture just says IM.

It's not authorized for that use
in the EUA, but the data exists in the active three publication,
which is in the public domain. The formulation that was
used is not different. >> Thank you. And in another comment,
thank you on that, I really like the
movement towards a, almost like a yearly
booster type thing. I do like the, you know,
despite my misgivings, as I've mentioned
previously, I like the fact that we're moving towards
just like a booster dose, and I think that's
going to be helpful. I do want to thank though
Dr. Bell's comments, though because although
most individuals who maybe getting it
soon, if it is approved or recommended may
already be six months out, we're going to be seeing
people who may have only been, you know, a couple months
out from their last one, and I do want to echo Dr.
Bell's comments that it appears that waiting a little bit longer than that may improve the
immunogenicity plus have less potential for side
effects [inaudible].

And I think that's all. Thank you. >> Thank you, Dr. Sanchez. Ms. Rock [phonetic]. >> Thank you, representing AIM. I'll try and be fast. Back to the labeling. We're also concerned. Today was the first time I
actually heard the rationale behind the why, right, why
they're labeled how they are, and I think sharing
that more broadly with immunization programs and providers could
help alleviated some of the frustration while we
also tackle it from a training and education perspective. And then I'm wondering
if you can speak to the expectations regarding
providers having to document in advertent monovalent
boosters, having been given since yesterday, as vaccine
administration in VAERS and considerations for any
increase wastage we might expect to see with that
removal of authorization.

>> So that would be
considered reportable vaccine administration error. Tom, please correct me if
I'm wrong, but I believe that would be a reportable
vaccine administration error to VAERS. >> What is the actual, so what
is the actual practice again? Can you just describe that? >> It's a monovalent. >> As somebody who
— oh, go ahead. If a monovalent was
administered incorrectly, now that it's not authorized
as a booster dose intended to be the bivalent
or vice versa, if the bivalent was administered
as the primary series, which also, it is
not authorized for. >> Yes, that would be a
vaccination error, and I believe that vaccination errors are
a reporting requirement. >> Thank you. Dr. Hahn. I'm sorry, just for
clarification, Dr. Shimabukuro, you mean reporting
requirements of VAERS, correct? Yes, to VAERS. >> Thank you. >> Dr. Hahn? >> Yeah, thank you. Can you hear me okay? >> We can, thank you. >> Okay. Great. Yeah, I just have
a quick comment.

State and local health
departments are in the throes of putting on large
monkeypox or, you know, orthopox virus vaccination
clinics targeting in many cases young males. Right now, the Jynneos vaccine
clinical consideration say, and I quote, "People,
particularly adolescent or young adult males might
consider waiting four weeks after orthopox vaccination
before receiving Moderna, Novavax, or Pfizer COVID vaccine because of concerns
about myocarditis." I didn't hear, and
sorry if I missed it, but in the clinical
considerations presentation I didn't hear anything about
monkeypox vaccines, and in light of the fact that we are
trying to ramp up efforts, I would just ask that those
recommendations be harmonized to make sure that the
message is the same.

We had a large one coming up,
a large pride event in a week, and I'm not sure right now. We're going to have people
offering monkeypox, flu, and COVID, and now I'm not sure
whether they should be doing them simultaneously. So if that could be
addressed, I'd be very grateful. Thank you. >> Yes. The COVID interim
clinical considerations do match the monkeypox ones. Apologies, I did not highlight
that specific situation on today's presentation,
but it is in the text. >> Thank you.

>> Thank you. Dr. Duchin. >> Thank you. I would just like to remind
folks that achieving optimal and equitable vaccination
coverage requires more than just vaccination
doses, vaccine doses. Your state and local health
department colleagues are now in their third years as
well as our clinicians are in the third year of COVID
pandemic response as well as trying to respond
to monkeypox outbreak and vaccination campaigns on top of other local infectious
disease outbreaks. Many areas are also grappling with climate related
health emergencies like heat, flooding, wildfires. And the work of achieving
optimal vaccination coverage and equitable vaccination
coverage requires significant investment in building
relationships with community partners,
empowering community partners, and developing trust, and that
trust requires consistency, and that consistency
and the adequacy of the response overall
requires funding. We have not received
additional COVID funding. We have not received
any monkeypox funding, and we are very much
running on fumes after such a long
outbreak response that is being now multitasked with all the other overlaid
responses by the same staff and healthcare providers.

So I do want to put this
information front and center for funding the necessary
response at every level, not
just the vaccine. Thank you. >> Thank you, Dr. Duchin. Dr. [inaudible] quick question. >> Yes, I wanted, I'm
still very concerned about, and this tag teams beautifully
with Dr. Duchin's comment that by saying we're going to
do a massive switch on one day, and then, if you inadvertently
administer monovalent vaccine, which looks really similar to
some of the others, now you have to need to submit
a VAERS report. If we're trying to,
the opportunity is to increase booster
doses overall, and there's a huge
opportunity, and it seems like we might be making this
much harder than it should be. Thank you. >> Thank you. Is it okay, Dr. Oliver, to
move onto your presentation. I'm happy to leave time
for additional comments or responses, but perhaps
at the end, if that's okay? >> Absolutely. Okay. So just to summarize
the overall workgroup interpretations, as Dr. Daley
mentioned at the beginning of the day, the workgroup has
met frequently over the course of the last several
months to review data that would inform
these recommendations.

In addition, the workgroup has
had broad policy discussions around the use of the updated
bivalent COVID-19 vaccines for people in age groups
currently recommended for booster doses. Again, as a reminder based on
the current FDA authorizations, the recommendations
would be for the — the current recommendations
would be for Pfizer BioNTech
COVID-19 vaccine, bivalent for individuals
ages 12 years and older, and the Moderna vaccine bivalent for individuals 18
years and older. However, we expect that
additional authoritarians for other ages and
vaccines may follow over the next several
weeks to months. The workgroup discussed that the
current population recommended for these boosters
is very heterogenous. Many in the United States
have had omicron infection over the past nine months. In addition, individuals
recommended for the bivalent COVID-19
booster doses may have previously received a primary
series only, one booster dose, or for the population 50 and over immunocompromised
two booster doses. The workgroup also noted
that the balance of benefits and risks for individuals may
vary by age, by previous receipt of booster, or by recent
SARS-CoV-2 infection. And there are uncertainties
around the incremental benefit for some individuals including
those with recent infection or recurrent vaccine receipt.

Next slide. And the workgroup also
discussed recommendations in the setting of
prior infection. We know overall that COVID-19
vaccines are recommended even for those who have received,
who have had prior infection. We also know that the rates of reinfection increased
during omicron period. Bivalent COVID-19
vaccines in the setting of prior SARS-CoV-2 infection, some of which called
hybrid immunity, results in the highest antibody
titers, and encouragingly, these high and diverse titers
may result in a longer duration of protection and increased need for frequent COVID-19
vaccine booster doses. We also know that studies
have shown that increased time between infection and
vaccination may result in an improved immune
response to vaccination. Those with recent SARS-CoV-2
infection may consider delaying the vaccine does by three months from symptom onset
or positive test. Next slide. Then the workgroup also
discussed that time since most recent vaccine
dose may be more important than total cumulative
number of doses. We also fully acknowledge
that there will be a time of transition as the
recommendations move from counting dose
number to optimal timing of the vaccination campaigns.

And we very clearly
know and have learned for the last two years that
vaccine recommendations that are simple and easy to
communicate are important. The workgroup also discussed that if SARS-CoV-2
becomes seasonal virus, and annual vaccine program
could be an effective strategy for the future. So all of this highlights
that there's a distinct effort to simplify vaccine
recommendations through a transition to what
could be a more sustainable and long-term COVID
vaccination program. Next slide. I also just briefly want to
highlight the new framework for the equity data
we used today. Next slide. And a key important part of the
discussion through equity is that equity isn't
a yes/no question but requires considerations
for implementation but requires considerations
for implementation.

Discussions on the workgroup
also identified several of these implementation
considerations, some of which have
been discussed already, ensuring supply, ordering,
and provider readiness through an equitable
distribution of the vaccine. Next slide. Communications is also integral
for equitable implementation, creating COVID communication
plans that understand existing data
around attitudes and perceptions for COVID vaccines and
adjusts actions accordingly, leveraging trusted partners to
deliver the vaccines as well as trusted messengers
to communicate with a broad population. Next slide. So the workgroup
reviewed the totality of the data presented today,
and while acknowledging some, and so as a reminder,
this was the summary of the workgroup
judgements for ETR. Next slide. Then as they reviewed
the totality of the data presented today
and acknowledging uncertainties around aspects of the data, they felt that the desirable
consequences probably or clearly outweighed the
undesirable consequences. Next slide. And the workgroup
proposed to ACIP to recommend the intervention. Next slide. So then the question to
ACIP will turn it back over to you guys, is
should the updated or bivalent vaccines
be recommended for persons already recommended to receive a vaccine
booster dose broadly, very specifically pointing out
the votes for today would be for the Moderna vaccine
in 18 and over and the Pfizer vaccine
in ages 12 and over.

Thanks. >> Thank you so much,
Dr. Oliver. We can now proceed with
a robust discussion. Oh, apologies, robust discussion
of the question that's put on the table, should updated/bivalent
vaccines be recommended for persons already recommended to receive a COVID-19
vaccine booster dose. And actually, I don't
see any hands raised. I was going to actually
call back on Dr. Daley, if you're able to maybe
provide some thought and comments on your
perspective. >> Oh, yeah. Thanks so much. I mean, you know, this is in
direct response to or thoughts about the comment that Dr.
Sanchez made, and I think for me that comment about, you
know, lacking clinical data for bivalent BA.4/5, that is
to me one of the most important and fundamental sort of
considerations and questions for us to discuss today,
and I guess my thoughts about that are as follows. You know, I think, and it's
something I really struggled with as well, but you
know, in the abstract, if not in a pandemic with
90,000 cases a day or something, I think it would have been
better to have clinical data from a bivalent BA.4/5 vaccine, but I would highlight
a couple points.

I mean the FDA considered that
issue very carefully and met with their advisory committee,
VRBPAC, and made the decision that they felt it was safe
and appropriate and important to extrapolate data from
bivalent BA.1 vaccines to this decision, and then they
made their UA authorization yesterday based on that. So I think if we were to
ask what would be the harm in waiting for clinical data
from a BA.4/5 bivalent vaccine that the idea would
be to me at least and my understanding is we would
need to wait until November or December to start
a vaccination campaign and then based on the
modelling that we saw, there would be a cost to that,
and that cost might be somewhere in the range of 9,700 deaths
and 1,000, or excuse me, 137,000 hospitalizations
potentially averted. So I think that is the
tension that I feel for sure, but I think I am reassured
about several aspects of the bivalent vaccines. You know, I find
it quite reassuring that the immune response
in general to the bivalent vaccines
really does seem more diverse, and I'm hopeful that
it'll protect against additional variants.

And then there's also sort of
a practical aspect to it too, for me, which is that given the
decisions that the FDA has made, we're now in the position
where we have millions of doses of a bivalent vaccine that
are ready and available, and I think they're going
to be an effective tool for disease prevention this
fall and into the winter. So even though I also
struggle with the exact issue that Dr. Sanchez raised, those
are my thoughts about why I feel like there is, again, this is
going to be an important tool to prevent additional disease.

Over. >> Thank you, Dr. Daley. Dr. Brooks. >> Yes, thank you. And my comments address the
same issue that was there that Dr. Sanchez raised. I mean first of all, and I wish
I had the slides in front of me, but the BA.1, which had
clinical [inaudible] BA.1, that had clinical data, showed
activity against BA.4/5. Theoretically I had thought
that might be a vaccine that we would consider
for recommendation. The other side of that
is that, you know, these are relief
type immunobridging, and that has been done
with vaccines for decades. But I really do struggle
with a vaccine that has no clinical data
that's reported for humans, for those who will be
actually receiving the vaccine. Overall, you know, I'm just,
I have an issue with that, and keep looking back on
the BA.1 bivalent vaccine and thinking perhaps that
might have been a way to go.

>> Thank you, Dr. Brooks. Dr. Long. >> Yes, I agree with Dr.
Sanchez and Dr. Daley. I come down on the side, I
think, of Dr. Daley mainly because we would have
not much expectation that this vaccine would
be clinically inferior to what we're already giving and
because it has the potential, I think, to decrease
hospitalizations and even deaths. So I think I will reluctantly
come down on that side and know that we don't usually
have much information, too much clinical information
for sure for efficacy when we are thinking about
changing influenza vaccines when it is the same scaffolding, part of the same roof we're
just putting in, you know, some dormers and windows. That's one thing. The [inaudible] thing I would
say is that I'm with Dr. Bell and others that I don't think,
even though most people would be at least six months out,
I don't think we want to give the message
that this is a two month after your primary
series or booster vaccine, and on one side, you said
you may want to delay it for three months, I
would give the feeling that usually this is six
months after your primary or your last booster, which
it will be for most anyhow, and that there would be
reasons that you might want to give it sooner, as
soon as two months, that is that you haven't had a
booster for some time and you're in some risk category or that
I really do want to delay in people who have been recently
infected for three months.

And I'll tell you why that is. It's not only because
what Dr. Oliver says, which I think is true, is that if you wait a little
more time you get a better immunologic response. I am really concerned that
there are an awful lot of people who have very recently
had omicron infection. We are now going to recommend
this for the group that is at risk for myopericarditis,
and we clinicians know that those few patients
who got myopericarditis, the adolescent boys who got
it after their first dose, if we looked hard and
we did serologic tests, we found that they had been
infected, symptomatically or asymptomatically in the
short time before and then with the added comment
of Dr. Fink that it looks like you got your second
dose in less than eight weeks after your first dose, you're
more likely to get pericarditis.

So I want to do no harm, so Iike
all the things that you said about the three months might be
a better, there might be reasons to do sooner and
later, and as early as two months could be
justified, but in people who have infection, I would
like that to be three months, and I would like the idea to be
that this booster is six months, and the very last thing,
which is all grammar, is although we know you're
talking about boosters even on this slide that's before us, you want to say currently
authorized by FDA for booster doses include
because I think people are going to start misunderstanding
and wanting to give these as primary. That's all from Sara. >> Thank you, Dr.
Long, and thank you for picking up on that as well. Ms. Bahta. >> Thank you.

I have some similar
hesitations about moving forward with the recommendations for which we have no
human clinical data. I'm reassured by the
neutralizing antibody data that have been done for
BA.4/5, and I'm also reassured by the hundreds of millions of
doses that we've been given. I think that we're being
asked to take a leap into a whole new
dimension [inaudible] with COVID vaccination
and that's going to be a much more routine cycle
of vaccination and I think that the data that we've had
presented is very reassuring, and so it would incline
me to support that recommendation
in front of us. But I do want to make
sure that the concerns that I have are voiced. That's all. Thank you. >> Thank you. Dr. Poehling. >> Yeah. So first I
want to say thank you for framing this
question broadly, and I do like this approach. I also agree that in the
conversations and looking at the clinical data we have,
how it compared to interval data and using that as a bridging,
does answer a lot of questions for me and that the modeling
data shows a clearly waiting until November is a cost
and 137,000 hospitalizations and over 9,700 deaths.

So waiting for more
data is not costly. I remain concerned about
saying you can't use monovalent vaccines, and I would really like to understand the
thought process behind that and why we're not taking an
approach more similar to Canada. Thank you. >> Thank you. Dr. Bell. >> Thank you. I want to agree with what
my colleges have been saying and also just on the side
of my discomfort note that the Canadians,
the Europeans, are using a bivalent vaccine
with a BA.1, and it's not clear to me that we have fabulous data about what the incremental
benefit is of using a 4/5 as opposed to BA.1 against this
somewhere discomfort about, you know, recommending a vaccine that we have no clinical
data about. Having said all of that, I
think there are good arguments for going forward with that. The other comment that
I wanted to make is that while I wholeheartedly
embrace this idea of being more routine and, you
know, this, now we're going to have, you know, just maybe
one booster, and that sort of path forward, as Dr.

Wharton
outlined at the very beginning of this meeting, I think
it is important for people to understand that
while we will, you know, we hope that we can go in
that direction and we're all, you know, ready to change
the way we're dealing with this pandemic, I just,
I think it's important to recognize and to say
that things might change. We don't know what the
future is going to hold, and while we would like to be
more routine, it may be that we, you know, have to
continue in this vein, depending on what happens with
the virus and with the pandemic. I just don't want people
to totally get their hopes up when I think we all recognize
that we might not get there as quickly as we would like. >> Thank you, Dr. Bell. I'm going to remain optimistic,
I'm just going to say. Dr. Sanchez. >> [inaudible] so I, my
concern, as others have voiced, but I guess is that we're — so
first of all it's not that I'm against the bivalent vaccines. It makes sense to
have bivalent vaccine.

But however, which bivalent
vaccine are we talking about, and the data that we have on the
V1 is really for 18 and over, for Moderna, and Pfizer,
we have nothing less than 55 years of age. And yet we're going to
make a recommendation for 18, for 12 and over. So I have a concern
for that, and we are, and that is the younger age
group where there are, I mean, myocarditis is the real side
effect, and yes, you know, and so we're then extrapolating
the data that has been seen with the bivalent B1 to
hopefully similar data for the, you know, for the, you
know, the B4 and 5. I'm, so I'm just concerned
about that extrapolation, and because ultimately,
I really don't want to establish a precedence
of recommending a vaccine that we don't have
clinical data on.

And I think, and I am
concerned about that. So that's what I have to say. >> Thank you, Dr. — >> Dr. Lee, this
is Melinda Wharton. Can I make a brief comment? >> Sure, absolutely. >> Okay. I just would like
to remind the committee that every year we use influenza
vaccines that are based on new strains without
clinical studies being done. This is what we do every year. We have well-established
platforms. There are changes made in
the, the particular strains that are included, but overall, the vaccines are incredibly
similar year to year. And in a lot of ways, this
is really analogous to that, and we've had hundreds
of millions of doses of these vaccines used. We've got a lot of
familiarity with the vaccines and their performance, and
what's happening is a change in the particular virus that
the vaccine is targeting that is not a huge one.

And so, I think the
extrapolations that are being made as
well as the preclinical and clinical data
that is contributing to this discussion
really do provide a lot of information upon
which the Food and Drug Administration
bases the authorization, and I see that Dr. Fink has
his hand up, and he may want to add something to that. >> Yeah, Dr. Fink,
please go ahead. >> Thank you. I did want to weigh in on this
discussion on behalf of FDA, and I do appreciate the amount
of discomfort that I'm hearing from committee members who are
being asked to take this leap with the COVID vaccines
that you haven't been asked to make previously with
the COVID vaccines but yet, as Dr. Wharton just reminded us, we do want to on a
regular basis annually with influenza vaccines,
but as Dr. Long mentioned, with her wonderful construction
analogy, these are vaccines that we understand
very well in terms of the original monovalent
vaccine, and we are talking about bivalent vaccines that are
manufactured using the very same process and which contain
the same total amount of RNA and are otherwise the
same except for the fact that they now contain two
mRNA sequences instead of one.

And so, FDA felt very
comfortable with the approach of extrapolating the
safety and effectiveness or rather the known and
potential benefits and risks which underly our
emergency use authorization. Based on the clinical
trial experience with the bivalent vaccine
containing the BA.1, sub-lineage component, which
is also an omicron sub-lineage component we felt similar
enough to BA.4/5 to allow us to make that extrapolation. We recognize that we've
taken a different path than the regulatory authorities
have in Europe and in Canada, but we made our decision based on several factors including
feedback and advice that we got from our vaccines and related
biological products advisory committee meeting in
June as well as data that we had toward the beginning
of the summer including some out of South Africa indicating that neutralizing
antibody responses against BA.4/5 natural
infection appeared to be more cross
reactive than responses against BA.1 infection.

And so for the purposes of
improving protection heading into the fall and winter, the
best we could against the strain that we knew or sorry the
variant and sub-lineage that we knew would
be predominant, we went with the choice
of a BA.4/5 component, and we felt confident in that. I also just want just want to
address briefly the concern about extrapolating
across age groups. Again, we have a tremendous
amount of experience with the monovalent original
vaccines in the age groups in which they're authorized. There are some differences
across various age groups in terms of reactogenicity
profile or immune response, but by and large the experience
and trends are very similar across age groups and even more
so what we're seeing as we move from primary series doses
to booster doses trends in the exact same
direction no matter which age group we're
talking about. And so, for that reason we felt
very comfortable taking data from a specific age group
whether it was adults 18 years of age and older or adults
55 years of age and older and extrapolating
that experience with a bivalent product to authorize another
bivalent product, again, manufactured using the exact
same process to authorize use of that product in
all age groups.

And I think we will be
intending to take that approach for consideration of authorizing
the bivalent vaccines in younger pediatric age
groups once we have a product and manufacturing information
that would allow us to do so. Thank you. >> Thank you, Dr. Fink. I'm just going to jump
in really briefly here and let my colleagues
know that I would like us, if there's any additional
comments I see, Dr.

Long and Ms. McNally, I just
wanted to say a couple of quick things at the end. But we cannot go backwards
[inaudible] so I'm just going to suggest to our committee
members any additional comments, please look ahead, look forward. We have a decision in front
of us that we need to make, and we can't change what is
being put in front of us today. So given all the uncertainties
and the recognition that we have to ensure that that we make the
best possible decision going forward given all the
uncertainties, I'll just ask that we focus the comments
on this decision right now.

Dr. Long. >> Yes. I wonder if Dr. Fink,
would you, can you tell us, I don't remember seeing a
vote on this [inaudible] path. Was there a vote, and
if so, was it unanimous for this authorization? >> No, we did not, we did
not take these authorizations to our VRBPAC. We relied on what we felt
was pretty clear advice that we received at the end
of June and also an approach to extrapolation that
scientifically made sense to us. >> And then my next
question, I'm sorry, Dr. Lee, it is related in reference
to Dr. Sanchez's comments, and asking Dr. Daley and
others on the workgroup, did you consider at this point
only recommending this vaccine for maybe 50 and
older, realizing that's where the main mortality is
right now, and it would not, it would not put at risk the
younger people who are at risk for myopericarditis, who may
have recently been infected and A, not needed,
not benefitted as much as you would think, and two, might be at more risk
for myopericarditis.

Did you consider limiting
this today to 50 and older? >> I don't know what to say. >> Dr. Brooks, I'm sorry. Thank you. If you want answer briefly, Dr.
Daley, I'm happy to allow you to jump in, and then we'll go
to Ms. McNally and Dr. Talbot. >> So, Dr. Long, in
response to your question, we did discuss this at the
workgroup, and still came to the general workgroup
consensus that the workgroup was in favor of this at all ages. Although there were voices that
expressed your sentiment too, and that's sort of trying to
weigh the totality of benefits against the totality
of the risks. And part of that is looking
very carefully at the risk of myocarditis following
what we know about the risk of vaccine-associated
myocarditis following booster doses to date. And so, yes it was
discussed at the workgroup, but the workgroup's
general consensus, again, although there were some who
expressed your thought too or who raised that, but
the general consensus was to make a recommendation
across all ages.

Thank you. >> So Matt, I was
the — it's Keipp. I was the odd voice. So Sara, I have the same thought
as you, because I was looking at risk of hospitalizations
and incremental benefits. And so we had actually
talked about, you know, what if you did everyone
over 50 or even over 40, those who have comorbid
conditions, like immune suppression and
healthcare workers, and then, the concern by the majority
of the workgroup was that then that becomes too complicated, and the recommendations are
already too complicated. So I think that was the concern
that the workgroup is trying to keep it simple so that
actually people were immunized. Does that summarize the — >> Yeah, I mean I think, I think
not just, not just simplicity but also the feeling
that, of some members with benefits would still
outweigh risks at a younger age, but there's more unknown
about the incremental. I think some of this,
Dr. Long, is that we're, we don't have great data about
the incremental benefit of this for say a 25-year-old who's
already had maybe two doses and a booster plus an
infection, for example, that data doesn't exist.

So, I think, I agree with
what Dr. Talbot said other than to also acknowledge
that there's more uncertainty about the magnitude of
the benefits compared to the magnitude of the
risks in younger ages. >> Thank you. Ms. McNally. >> Thank you. I just wanted to
offer some comments for my colleagues to consider. I definitely share in the
concern that there is a desire for more information, but as
I think about our experience with COVID-19 vaccines over
the past several months, it is beyond dispute that
we have gotten really good at data monitoring. And that includes the robust
monitoring systems we have for safety. And there has been a very clear
demonstration of an ability to respond quickly to any issue
that has needed to be addressed. And so, for that reason, I am
comforted by what we're talking about now, and I very much
appreciate the comments from Dr.

Wharton and Dr. Fink. I do remain seriously concerned
about two issues, and I wanted to express those here. The first is avoidable
administration errors because of labeling and
communication and the accuracy of the reporting of those
administration errors, and I think that, I think
about this not as much from the medical
provider perspective, although that is critically
important, but I think about it as the consumer who would
potentially have a family member, a child, a parent
receive an incorrect vaccination at a very critical time. And so I wanted to
raise that point. And the second is, continuing
to voice concern about, concern and appreciation for the fact that this simplified
recommendation, even thought it is
simplified, is indeed a change in a recommendation, and that is
complicated for the [inaudible]. And so I want to advocate that
the CDC continues to have clear and accessible communication
that remains available for consumers and also that
the avenues for consumers to have their voice heard
continues to remain open. Thank you. >> Thank you, Ms. McNally. And I will just add a couple
of additional comments. Dr. Long, I think, I agree — I agree with everything
you have said.

I'm just going to augment
what you said earlier, which I think built upon
the comments of many of our colleagues
who spoke before. Number one, you know, I want to
echo what Dr. Wharton mentioned, and actually I think Dr. Loehr
mentioned at the very beginning which is this approach is very
similar to what we've done for flu, so I don't think this
is an entirely fundamentally new approach that we're looking
at, but I do feel, you know, the same level of, I would
like to have more information, and it would be better to have
more information, but we, again, have this decision
in front of us where we anticipate there will
be a tough winter season ahead, both with flu and with
COVID-19, and I feel our job is to do our best to
protect public health. So given that, and given
the, you know, the potential for early, earlier
administration during this season, to protect a greater
proportion of the population, so I am anticipating
effectiveness, and my concern is about missing opportunities
for protecting many people.

I do think that this
makes sense going forward. I also want to emphasize that
I feel strongly about reducing and mitigating any potential
risks if at all possible, and so I am going
to put out there that my personal preference
is to anchor on three months with a minimum interval
from either infection or a prior vaccine dose. That is what I will recommend
to involves who ask me, but I recognize that there is
an authorization out there.

I just feel like we've seen
benefits and reductions in harms by a longer interval. The third is, I want
to emphasize again that making access and implementation easier
should be a priority. The final thing I want to
mention is, and you know, I really appreciate
Ms. McNally's presence on this committee. We need to create patient safety and clinical consideration
material for a one pager that would help individuals
understand how to maximize the benefit
and minimize their risk, and I do think that
that's possible. I recognize it's challenging, but many patients are going
directly to get vaccines. I always tell people to talk
to a healthcare provider if they have any questions,
and I know that all of our providers are
here and ready to help, and that includes our
pharmacy providers are here and ready to help. I want to be very inclusive. And our public health providers. However, I do think
having more information out there can only help. So that is my plea to
continue to push that front. Thank you. Dr.

Daley? >> Yeah. I wanted
to jump in again after Ms. McNally's comments,
which is just that, you know, I've heard of, to make a
couple comments related, I've heard of parents
who've been very concerned about COVID vaccine safety and
then have decided to vaccinate and then only to be told that they were vaccinated
with a higher dose. And I think, you know, at
some level we run the risk of losing confidence in the
program more broadly the more that that happens, and
even though, fortunately, there hasn't been
serious adverse events that at least have been
reported in that circumstance, I think it's critical and
it's not, it's not just sort of a simple error that you
just sort of move on from for some parents because
then they may not complete the series.

And so I'm going
to borrow a quote from Dr. Oliver's
presentation although it was in a different context,
you know, I think structural problems need
structural solutions, and so, I think we need to look
at structural solutions for vaccine administration
errors, and I think we need to, you know, work with the FDA and with the vaccination
manufacturers to come up with structural solutions that are not just
around education. But then I also think we need to
push for continuing to simplify and simplification may also
mean just fewer presentations. And so I think looking
forward I would hope that we could work
with, again, the FDA and vaccine manufacturers to have fewer different
presentations of different doses for different ages
with different volumes and different dilutions and
different storage, and the fewer of those that we have, as long
as that can be done safely with an effective
vaccine, I think, again, less vaccine administration
errors, but hopefully greater confidence
in the program overall as well.

Thank you. >> Thank you, Dr. Daley. I'm going to ask Dr. Oliver, are there any additional
slides we need to consider? >> No, I have proposed vote
language but no new information. >> I actually would
really appreciate it if you would be willing to put
up the proposed vote language so that we could start
to proceed with the vote, because I see no addition
hands raised in this moment. >> Okay. Because there are
two products authorized — I did not acknowledge people.

Well, maybe there's one more
something I want to say, which is, this is, you
know, an hour's long of EGR presentations plus the
extensive presentations and data to inform that are so,
so much a representative of a fantastic team here. So if I'm speaking, it's only
because I've got excellent, excellent people on my team. So I do want to acknowledge
that. Then I will also acknowledge, because there are two
different products, there are two different
proposed vote languages, and I can read both
of those real fast and then turn it back
over to you, Dr. Lee. So vote one is that
a single dose of the bivalent Pfizer BioNTech
COVID-19 vaccine is recommended for individuals ages 12 years
and older at least two months after receipt of
a primary series or prior monovalent booster dose
under the EUA issued by FDA.

The vote would also include land to repeal its previous
recommendation for administration of
the monovalent vaccine for persons ages 12 and over. This is because that product
is no longer authorized, and so as it is no
longer authorized, we need to replace the
vote legally with moving from the monovalent
to the bivalent. Then the language for the
next vote is very similar, but a single dose of bivalent
Moderna COVID-19 vaccine is recommended for individuals ages
18 and over at least two months after receipt of primary series
or prior monovalent booster dose under the EUA issued by
FDA and would also replace, this recommendation would
replace the monovalent recommendation for 18 and over to mirror what has
happened with the EUAs.

Thanks. >> Thank you. Any clarifying questions
to the wording? And for myself, Dr.
Oliver, just to restate, there is no authorization
that exists anymore for the monovalent vaccine? >> In those age groups. So for the age groups, where
there is a bivalent booster. So Moderna 18 and over, Pfizer
12 and over, for the age groups and products where there
is a bivalent booster, FDA replaced the EUA for the
monovalent with the bivalent. So we are doing the same
or proposing to do the same with the recommendation. The EUAs are still in place
for the Pfizer vaccine for five through 11, because that is
a vaccine, the monovalent, because that is an age groups with which there already
was a booster monovalent recommendation, but does not
yet have a bivalent product. >> We can't hear you, Dr.
Lee, if you're speaking.

Oh, yep. I called on you
Dr. Long, please go ahead. >> I'm sorry, we
couldn't hear you. So, two things on this one. I really think you
need booster in there because people will thing that we're recommending a single
bivalent as part of extension of a primary series or to
complete your vaccination, and so I think, I would put the
booster, I would put the booster after vaccine on the first line. And then the second things
is we're going to stick with two months although
I agree with you, and I feel pretty strongly
that it really should be longer to get maximum benefit and
reduce risk, but were going to leave that to
clinical considerations.

Was that your idea? And here we stick with
at least two months. I think it's the wrong
message, but it is, it would be, you know, one of the
brackets of timing. >> Let me first clarify. Dr. Oliver, is there
any objection to adding the word booster? >> No, we can. It's — the language
specifically clarifies that it's after receipt of
a primary series, but I think for clarification
purposes we can, we'll work on getting
booster added.

Do you want me to say anything
about the interval or — >> Yes, please. I would appreciate that. >> Okay. Yeah, so, I
mean we absolutely, the workgroup talked
about this as well. I think there are
distinct reasons that it is really helpful
for the ACIP recommendations in the current setting
that we we're in for the recommendations
to match the EUA. If ACIP were to vote on a
different recommendation, then that would be different
than the authorized interval, and it would cause
significant confusion and potentially legal issues
with the provider agreements, that there would be
different intervals, recommended by FDA and ACIP.

So that's why we've really
tried to emphasize that we have in clinical considerations
some considerations for longer interval
especially around those who have had prior infection. And that for kind of the
population that is at risk for myocarditis,
nearly every one of those individuals
is six months, if not longer, from
their last dose. I will say that this
is not meant to imply that people need boosters every
two months moving forward. As we said, this is a transition
point for the program. We're moving, hopefully,
forward where we're not kind of counting doses with minimum
intervals but may be able to get on kind of a more
regular schedule.

Fully agree with Dr. Bell that
we have to follow the data, and that could change,
but that's the plan. And so hopefully the future
interval is considerably longer, but this is, if we're
recommending a time-based program that we think
everyone should, who is eligible should go
get this vaccine this fall, the minimum interval is two
months since your last dose, but most people are longer than
that, and it legally is really, needs to be in line with FDA. Thanks. >> Dr. Oliver, was there
any objection to taking out the words "at
least two months." It could just be just "12
and older after receipt of a primary series" with additional clarification
in the wording. [ Inaudible Comments ] >> That it, that it's, the
interval that matches the EUA, I think, is important here. >> I don't quite
understand that, but — I mean I understand
that we would say that at least two
months has to pass, but it would allow us more
flexibility to actually provide that information that's needed
for both clinicians and patients to understand, you know, if they
just had an infection, you know, perhaps more leeway, or
something along those lines.

I just, there's a lot of people
who have had recent infection and I read this as
they should be getting at two months even though
it says at least two months. So this is a legal issue? We cannot change the wording
of the recommendation? >> It is a [inaudible] liability if the ACIP recommendations
are different than the EUA recommendations around specific things
like time intervals. >> Dr. [inaudible]. >> Could I just push this
just a little bit more and ask if we're not making a
different recommendation, if we simply are silent on
the issue of the interval and the recommendation? It's not exactly the same as contradicting the
EAU language of the FDA. Again, we may be, this may
not be very fruitful avenue, but I do wonder if the
lawyers might look a little bit differently on this
specific issue, which is not contradicting
the FDA.

It's just being silent on
the issue in the language of the recommendation. >> This is Melinda Wharton. I appreciate the
concerns about this issue. I will remind you all that there
are very few people who are within two months of
getting a recent dose. We're just not talking about
meeting the people who are in the age groups that
are eligible for this, and realistically,
as this goes forward and moves toward publication
and program implementation. It will have to be in
alignment with the EUA. I certainly appreciate
the concerns though that you all have articulated. I think you absolutely
have expressed concerns about those groups of people
for whom this may be the most, a more important
consideration, and we do have in the clinical considerations
guidance about people with recent infection. And I am sure the conversation
today has increased the visibility and awareness
of those issues, and hopefully people can
make decisions about timing of vaccination accordingly. So, I don't think we can take it
out of the vote, but you know, it's not a, it's
not a requirement for a strict two-month interval.

It's at least two months, and
again, there's very few people who are within two months of
getting vaccinated anyway. >> Dr. Brooks. >> Yes, [inaudible] it will be in the clinical considerations
[inaudible] whatever we want to be in the clinical
considerations, and number two, the words at least, that covers,
that covers us comfortably. If you want to do it
six months or 12 months, we're saying at least
two months. And I believe it's
somewhat aligning with the, whatever the clinical data that we have be it
from humans or mice. So I'm comfortable with
"at least two months," underscoring "at least." >> Okay. Dr. Poehling? >> I wanted to make a motion
to accept the vote language. Thank you. >> Thank you. Dr. Fryhofer [inaudible]. Well, actually before we do
there, sorry, Dr. Fryhofer, I have a motion on the table.

I need to ask for a second. Does anyone want to second
the motion on the table? Ms. McNally. >> I second. >> Thank you. We have a motion on the
table, and it's been seconded. I'll ask — Dr. Fryhofer,
did you want to make a quick comment? >> Yes. Sandra Fryhofer,
American Medical Association, but speaking as a
practicing physician, I think that keeping the
"at least two months" in there is actually
very helpful to practicing physicians. I think this discussion
to me is so reassuring about how carefully the ACIP
members look at these issues, and it also points
out the importance of the clinical considerations,
but to take that out, I think would be
more detrimental to what you're trying to
help with than leaving it in. So I think leaving the at
least two months in there, I hope you do that, and
I hope you vote for this.

>> Thank you, Dr. Fryhofer. Any additional comments from
members, from voting members? I don't see any additional
hands raised. Since there are no hands raised, I'll assume the committee has
no objections to proceeding with a vote, number one here. That is specific to the
Pfizer BioNTech vaccine for individuals 12
years and older. I won't read the whole thing. It is there on the slide. I'll ask the ACIP members if you
would please turn on your video. I will ask you to state
your name, whether — well, I will state your name
and whether you have a conflict of interest, and then your vote. So I'm just going to go in
order of who I see on my screen, and I see Ms.

McNally first. >> Veronica McNally,
no conflict, yes. >> Dr. Daley. >> Matt Daley, not
conflict, yes. >> Thank you. Dr. Talbot. Oh, you're muted, Dr. Talbot. >> Let me think a
little bit longer. >> Okay. We'll come back to you. Dr. Cineas. >> Sybil Cineas,
no conflicts, yes. >> Thank you. Dr. Brooks. >> Oliver Brooks. No comment. Yes. >> To conflicts or no comments? You're muted, Dr. Brooks. Just want to confirm,
no conflicts? >> I'm sorry. Didn't you hear me? Oliver Brooks. No comments. No conflicts. >> Thank you. That's what I was
[inaudible], Dr. Brooks. Thank you. Dr. Chen. >> Wilbur Chen. No conflicts. Yes. >> Thank you. Dr. Sanchez. >> No conflict. No. >> Thank you. Dr. Poehling. >> Kathy Poehling,
no conflict, yes. >> Thank you.

Dr. Bell. >> Beth Bell. No conflicts. Yes. >> Thank you. Dr. Loehr. >> Jamie Loehr. No conflicts. Yes. >> Thank you. Ms. Bahta. >> Lynn Bahta. No conflict. Yes. >> Thank you. Dr. Long. >> Sara Long. No conflict. Yes. >> Thank you. Dr. Kotton. >> Camille Kotton. No conflicts. Yes. >> Dr. Talbot, well,
I'll go before you. This is Grace Lee. No conflicts. Yes, but I still feel strongly
about the three months. I know that's not
really a vote, but. Dr. Talbot. >> I'm struggling. Dr. Talbot. No conflicts. Yes. >> Thank you. I believe we have 13
yeses, and one no. Dr. Wharton. >> That's what I got
as well [inaudible]. >> And the motion passes. Okay. This vote number
one passes. Thank you, everyone. We'll move on to
vote number two. I'm going to try and go in
alphabetical order right now. Thank you. >> Ms. Bahta. >> Lynn Bahta. No conflicts. Yes. >> Oh, I apologize.

I did not ask for a motion,
and Dr. Poehling caught me. Dr. Poehling, would you
like to make a motion. >> Yes, I'll make a motion to accept the language
as its written. >> Thank you. Can I get a second? Ms. Bahta. >> I second the motion. >> Thank you. Thank you so much. Thank you, both of you. It's been moved and seconded
that we accept vote number two, which is focused on the
Moderna COVID-19 vaccine booster for individuals 18
years and older. So, now, we can proceed. Oh, any objections,
any concerns? We'll proceed with
the vote then. We'll start with Ms. Bahta. >> Lynn Bahta. No conflicts. Yes. >> Thank you. Dr. Bell. >> Beth Bell. No conflicts. Yes. >> Thank you. Dr. Brooks. >> Oliver Brooks. No conflicts. Yes. >> Thank you. Dr. Chen. >> Wilbur Chen. No conflicts. Yes. >> Thank you. Dr. Cineas. >> She's saying that her audio
and camera have stopped working.

So maybe give her a moment. Thank you. We'll come back to
you, Dr. Cineas. Dr. Daley. >> Matt Daley. No conflicts. Yes. >> Thank you. Dr. Kotton. >> Camille Kotton. No conflicts. Yes. >> Lee. No conflicts. Yes. Dr. Loehr. >> Jamie Loehr. No conflicts. Yes. >> Thank you. Dr. Long. >> Sara Long. No conflict. Yes. >> Thank you. Ms. McNally. >> [inaudible] McNally. No conflict. Yes. >> Thank you, Dr. Poehling. >> Kathy Poehling. No conflicts. Yes. >> Thank you. Dr. Sanchez. >> Pablo Sanchez. No conflict. >> Thank you. Dr. Talbot. >> Dr. Talbot. No conflict. Yes. >> Thank you. And Dr. Cineas. Are we still having trouble. Dr. Cineas, this is the
one exception I will allow for using the chat. If you are able to
chat in your name, whether you have a conflict,
and whether it's a yes or no, I will take that. Dr. Cineas. No conflict. Yes. Thank you. This is a one-time exception
only for technical difficulties.

So I have 13 yeses and
one no, Dr. Wharton, and vote number two passes. >> Thank you very much, Dr. Lee. That's my count as well. >> Thank you. Dr. Well, we are actually
quickly running out of time because our colleagues at CDC
have a very, very hard stop or the entire audio
will shut down. So I will ask maybe if anybody
wishes to express their opinions about this vote,
anything different or new, and then I'm going to ask
Dr. Oliver, just a couple of the wrap-up questions
before we close the meeting. My warning scared everybody off. I apologize. Any other comments? Okay. You know, I
will ask Dr. — [ Inaudible Comments ] Oh, there we go, Dr. Long, okay. >> Yes, yeah. No I wanted to say that as a
clinician and making a decision for individuals, I would
be on Dr. Sanchez' side And I make this decision for
the best of the most people, considering and hoping that the
advantages will outweigh any risks that we do
not yet anticipate. >> Thank you, Dr. Long. I think we feel similarly.

Dr. Sanchez. >> So I voted no
because I really feel that we need the human
data, and that's really to me really important. It's a new vaccine. It's a new platform. There's a lot of vaccine
hesitancy already. We need the human data. And at the same time, I think
that the vaccine will be, will have similar safety
as we've already seen with the previous vaccines with
messenger RNA, and you know, I personally, I'm in the age
group where I'm at a high risk, and I, you know, I
mean I'm almost sure that I will recessive
it and I will take it.

So I just feel that we really,
that this was a bit premature, and I wish that we
had seen that data. Having said that,
I am comfortable that the vaccine will likely
be safe like the others. >> Thank you, Dr. Sanchez. Dr. Poehling. >> I wanted to say
that I do think that this is a huge step forward in simplifying the
recommendations and hopefully enhancing
coverage. It does put a lot of pressure on
the distribution of the vaccine because we have now switched
from bivalent to monovalent for boosters people 12 and
older, and my sincere hope is that this will be expedient and not impair access
for all who want it. Thank you. >> Thank you. Dr. Brooks. Just two quick statements. First, I really appreciate
Dr. Oliver's synopsis, the ETR showing the beauty
of how important that is and the addition of equity
on each of the line items, because Werner struggled
with equity. And then almost the only
reason I voted yes was because of thinking about
how we do flu vaccines on a yearly basis.

We have data. It doesn't show the new vaccine. We just base it on
the last vaccine. It was the last year that
determination that it's okay. Safety profile was comfortable,
so that was my primary reason for making a difficult
vote in saying yay. >> Thank you so much. Dr. Oliver. I just wanted to confirm, and
I know that you will answer in the affirmative, but I
just want to confirm that all of the discussion and
deliberation will be captured in the clinical considerations
to make sure that it fully reflects
the diverse opinions of this committee in the vote. >> Thanks, yes. Absolutely. The clinical considerations
team is hard at work. We'll do everything we can to
get everything posted as soon as possible, hopefully within the next 24 the
48 hours-ish, but thanks. >> That's always a tall order,
and apologies that you need to get this out so quickly, but we appreciate how much
your team is doing to get all of this commentary in and the
opinions of the committee.

So we really appreciate that. I want to go ahead and proceed
with ending this meeting. So I want to, you know, thank
everybody, all the speakers and our ACIP members
and our ex officio and our liaison members
for your work today. There are a couple of
comments I just want to make at a high level, and I'll turn
it over to Dr. Wharton to see if there's any further business.

You know, the ACIP, I know
on behalf of all of us that we will, we appreciate
all of the input today on the booster recommendations
and, you know, the hope towards simplification
and the hope that, and I will be optimistic,
and I can't remember which of the members
of said this, but we might not be
out of the woods yet. I'm going to remain optimistic
as this becomes a solution that is one that we can
sustain, but as always, I will put in the caveat that
if anything substantive changes about the benefit-risk balance or if there's any new safety
considerations, rest assured that ACIP will most certainly
meet, and I just want to make sure that, you know, the
members of the public are aware that we're continuing to monitor
closely that with this decision, the decision was [inaudible]
as Ms.

McNally mentioned, we have systems and teams
that are continuing to monitor and to meet over time. So I want to, you know, I
recognize the uncertainty. I want to acknowledge, and I
just want to say that despite that I think, you know, we
hopefully made a huge impact in our ability to continue the
weather the pandemic together. Dr. Wharton, do you have any
further comments that you wish to make, or do we have
any further business? >> So there's no
further business, but I would like to thank
the committee as well as all of our speakers and the public
for sticking with us today for this very long meeting.

I do think that this is a big
step forward for simplification, and I hope moving
towards something that is both a more normal
set of vaccine recommendations as well as cadence of changes
to two recommendations. We're clearly not there yet, but I think this is a big step
forward, and I hope we're moving to something simpler
that will not require such frequent changes
going forward. So thank you, all, so much. I'm really grateful for
your help and especially to our committee members
for all the hard work today.

So nothing more, Dr. Lee. >> Thank you. Any other objections to
adjourning today's muting? >> Dr. Lee, one more point. I have been reminded that
some people who were not as on at the very beginning
may not be aware that were are not
meeting tomorrow, but adjourning today is
the end of the meeting. >> I concur. This would be the
end of the meetings. There's no need to
meet tomorrow, and I don't see any
hangs raised, so seeing no objections
I would like to announce that today's ACIP
meeting is now adjourn. Thank you, everybody for your
time and all of your efforts. Take care..

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