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Taking Charge of Your Health


>>Our next session today is on the general recommendations
work group. Dr. Paul Hunter is the work
group chair, and he’s going
to get us started.>>Hi, I’m Paul Hunter. I teach — public
health students at the School of Medicine and Public Health
at the University of Wisconsin, and I consult for the City of
Milwaukee Health Department on communicable disease
and immunization issues. As the work group
of the general — as chair of the general
recommendations work group, I’m here to provide context for Andrew Kroger’s presentation about the recent
and upcoming changes in the best practices
guidelines. The work group meets
monthly to achieve the goals and objectives listed in
the terms of reference. These include revising
the general best practices guidelines for immunizations as
needed, or for some sections, at least every two years. Addressing other general
vaccination issues as needed, including emergent issues
that don’t fit into the terms of reference for other
work groups is also part of what we do. In short, the work group is
a gathering place for people that like making connections
between disparate disciplines in order to come up with
practical interventions that help clinicians
and their patients. Previously known as
general recommendations, the general best practice
guidelines provide expert opinion, and where
available, evidence for issues in clinical practice that
cut across multiple vaccines. The up-to-date version of
the guidelines is available at the ACIP website under
comprehensive recommendations, or directly via the URL
at the top of this slide. As a consultant to public health
nurses who administer thousands of vaccines a year, I find that
the best practice guidelines are where I should’ve gone
first to answer my questions that aren’t answered
by my standing orders. So I encourage you to go
to these guidelines also with difficult questions. In the recent past, sections of
these guidelines were presented for discussion over a series of ACIP meetings
before the entire set of guidelines was voted upon by
ACIP and published in the MMWR. Today, Andrew Kroger will
review recent errata and updates that have been added to the
guidelines on the ACIP website. Dr. Kroger will also present for
discussion the draft addition to the best practices
about healthcare personnel who themselves have precautions
or contraindications, but who may, nonetheless, administer those
vaccines to patients. There are no votes on the
guidelines planned today. I want to thank the non-federal
subject matter experts and liaisons on the work
group listed on this slide for their contributions to updating the best
practice guidelines. Thanks.>>Okay, so thank you. I’m going to do three things. I will give some background into the general best
practice guidelines for newer ACIP members
and the group. I am going to cover
those revisions/errata that have already been
posted to the CDC web page, and then I am going to
discuss a specific topic for discussion by ACIP. And so, to begin
with background — you just saw this image of
our web page, and the website. This still looks the
same, even though the — some of the websites upstream from this page look
a little different. This one looks the same. The general best
practice guidelines for immunizations is an —
is now an online document. It does not exist as an
MMWR document anymore. It is — it is best practice
— best practices of the ACIP, and it is a CDC guideline. So this is how you can
access this information, by clicking the URL at
the top of this slide, and it’ll take you to this page. And then, you may notice
that underneath the bar of comprehensive ACIP
recommendations and guidelines, you can see a link to the general best
practice guidelines. When you click on that, it
brings you to this page, which is the main page — the HTML version of the
general best practice guidelines for immunization. All of the subject headers now
exist as links, as you can see, with the gray banners in
the center of the slide — introduction, methods,
timing, and spacing. Just for clarity, I’ll show
you the rest of them — contraindications and
precautions, preventing and managing adverse reactions,
reporting adverse events after vaccination,
vaccine administration. Storage and handling
of immunobiologics, altered immunocompetence,
special situations, vaccination records,
vaccination programs, and vaccine information sources. So each one of these has a gray
banner that you can click on, and access that individual
HTML file for that section. This product is available
for continuing education. The continuing education is
renewed on a two-year cycle, so we want to make
sure that ACIP is aware of this online document at least
once every two years before we revise the CE. And so, by clicking on that
link, this will take you to all of the registration and continuing education
information. Every word of the general
best practice guidance — or guidelines, I should say — exists not only as
HTML, but as a PDF file. And so, you can see where
you click on the PDF version of that — of the document, and
I’ll make the point that the — there’s a PDF for each of the
individual sub-topics as well. Once you click on the
banner, it’ll take you to a choice of HTML or PDF. And the cover of
the PDF document — it’s a print-friendly
document — looks like this. One of the important — as a transition to talking
about errata and updates, I wanted to show you
where you can find it. It’s just above the block
for continuing education. If you click on this
link, it will bring you to every single update
that has been made to this online document
since April of 2017, barring some punctuation and
other typographical issues. But it’ll take you to
all the other changes. And so, to find this
information, you would click on this link, and it
looks something like this, the list of errata and updates. The entries are indexed by the
date by which they were posted, so the most recent set of updates were made
September 20th, 2018. For each entry, or
update, or errata, you can see that there
is a page number listing. You can see that there’s a link
to its location in the PDF, or a link to the PDF for
that particular section, I should say, as well as a link to that section as
an HTML version. Below that, a listing
for the specific table — table 3-1, you can see that
first listing, and a description of what the change is. So now, I’m going to
kind of run through some of the important ones
that I wanted to make sure that ACIP was aware of. Note that these are
either harmonizations of CDC recommendations,
ACIP recommendations which have already been voted
on, already cleared through CDC. They may be interval issues
that have already been posted to our CDSI immunization
information system registry web page. So these changes have already
been made to the document. So I’m going to index
this discussion by actual disease topic
from this point on, or vaccine topic
from this point on. So the first fix is
pertussis-containing vaccines. We made a clear statement
of the minimum interval between dose three and dose four
of DTaP, which really varies, whether you are looking ahead
to scheduling the next dose or counting a dose that’s
already been administered. We call that prospective
or retrospective. We have a statement that
the grace period can be used for both of these scenarios. It’s a four-day grace period. And so, basically, this is kind
of — for this presentation, I place in red the date in
which this addition was made. This is a — also the way
that CDSI is programmed. Pertussis-containing vaccine
change is that four precautions to DTaP have been removed. These four are no longer
considered to be reasons to withhold the next
dose of DTaP. No risk/benefit indication — or
no risk/benefit should be done. They are no longer precautions. They were considered to be
related to use of wholesale DTP, and not relevant to a
cellular pertussis vaccine. These changes were placed
on the website between July and September of 2018, but
they were actually published in the CDC/ACIP recommendations
back in February of 2018. We did place minimum intervals for serogroup B meningococcal
vaccine on table 3-1 in the timing and
spacing section. This is published on
CDSI business language — the CDSI web page, the business
language for registries. And so now, this also appears in the general best practice
guidelines as of September. I’ll make a point
that, you know, you don’t use minimum
intervals on a routine basis. These intervals, though, are
very important for providers to have in certain circumstances where errors have
already been made. Mix-and-match of brands — you need to have the
minimum intervals. Now they are posted
on the CDC web page, and they’ve been
in CDSI as well. Hepatitis A — there’s two
topics that I’ve changed. I have updated the
dose of immunoglobulin for hepatitis A prophylaxis,
so that’s been updated. I’ve also discussed
with partners in FDA about the fact that, even though
we’ve adjusted the dose of IG, there is no need to
adjust the interval to next subsequent MMR
or varicella vaccine. So that remains the same. We’ve also made a change in the
vaccine administration section to specify that IG and hepatitis
A should be administered in different limbs. This is related,
essentially, to the volume of the immunoglobulin product. There — it joins two
other examples of this, TIG and tetanus-containing
vaccines, and HBIG and hepatitis B vaccines. We added some longstanding
CDC published recommendations for varicella vaccine to
the general best practices. A family history of altered
immunocompetence has been a published contraindication to
varicella vaccine since 2007. It now appears in the
general best practices table. I only have varicella
on this slide, but we’ve also added this
content for MMR vaccine, because it’s also published in the MMR vaccine-specific
recommendations. And then I have a
footnote explaining that the concern here is with
congenital immunodeficiencies, and the noted intervention
is to screen — screen your patients
through histories of first-degree relatives or
use of laboratory evidence of a congenital
immunodeficiency. It is generally presumed that a congenital
immunodeficiency will be detected prior to a decision
to use varicella vaccine or MMR vaccine anyway. The other precaution
is use of aspirin — or the other change is the
precaution, use of aspirin or aspirin-containing products. And so, this is less
a vaccine precaution. It’s more of a recommendation,
in a sense, to avoid giving the
medicine six weeks after the vaccine has
already been given. So that doesn’t really
meet the definition of a vaccine precaution. So that’s a precaution, and then
we’ve also added the precaution regarding receipt of
specific anti-herpes virus, antiviral drugs 24 hours before
vaccination, with the flip that you should avoid use of
the anti-herpes virus drugs for 14 days after vaccination. And then, for zoster
vaccine, we have made a change in the vaccine administration
section of the general best practices. With all the other
vaccines, there is a table in which we list
vaccination injection volume. However, unlike the
other vaccines, for which we allow
administration of additional volume, since
vials are often overfilled, we specifically specify 0.5
cc per the package insert as the volume that should
be injected for zoster — for Shingrix, I should say,
vaccine specifically, RZV. Lastly, as with varicella,
we added the contraindication to LAIV, that antiviral
medications given within the — influence of antiviral
medications in the previous 48 hours is
a contraindication to LAIV. In this circumstance, it’s really not a feasibility
issue, not a precaution. There is an alternate
vaccine that can be used. So those are the changes to
— that are already posted, and you can find all of
these changes either by going to the errata page first,
or just searching for them in the document — in the
online document itself. So now, I want to kind
of, for discussion, present some language that we
would like to share with ACIP. This language will
need to be cleared through CDC before it is
placed on the online document, but we have discussed
this in the work group. We are often asked about
providers who are well aware of the contraindications and
precautions for vaccination, because they’re screening
their patients. But what if the healthcare
personnel have a labeled contraindication or
precaution themselves? Can they still administer
the vaccine? Obviously, they don’t
give it to patients that have these
contraindications and precautions, but can they
— can they give it themselves, given the nature
of various issues that have been presented
in the past? There is no discussion of this
in the general best practices. However, there is a well-known
vaccine-specific recommendation published for LAIV. It arose out of concerns with pregnant healthcare
providers expressing concern about administering LAIV, and to repeat what the
committee already knows, for that recommendation, we say,
“Yes, it can be administered by healthcare personnel
who are pregnant or have any other
contraindications.” There is not thought to be
much environmental spread. There have been few cases of
any type of transmission of LAIV from someone who was
vaccinated to someone who was not vaccinated, and
that’s a little different issue. But it’s a similar
issue to any risk to the healthcare personnel
themselves administering the dose. But can all this be
generalized to vaccines? So we looked at the literature
related to healthcare personnel, risk of adverse reactions based on administration
of the vaccine. And this slide I would’ve —
I should probably tweak this, because these are not really
the potential outcomes. It’s more like the intervention,
withholding the vaccine versus administering
the vaccine, but we requested these — these
articles from CDC library. They searched the
databases MBase, and all Scopus, PsycINFO
and Medline. They came up with 82 unique
articles, and if there’s a typo in the handout — I think I
— that said 20, but it’s — it was actually 82
unique articles were — for which the abstracts
were reviewed. There were two or three of
them that were not in English. Those were not reviewed, but
out of all of these abstracts, only three of them
actually discussed this question specifically. The first was an ACIP MMWR from the 2003 smallpox
vaccination program, which I think you’re — those
— might be well aware of it. Given the low risk of
smallpox disease in 2003, the risk/benefit calculation that was applied
towards vaccinators of vaccinia vaccine — it’s
not the same exact microbe, of course, but it is the
same general topic issue. The risk/benefit calculation
was tipped towards not allowing vaccinators with
contraindications to be allowed to administer the vaccine, and
that was based on inherent risks that the vaccinia
virus posed to persons with underlying conditions and
issues of transmissibility, which we knew of from patients
that had received vaccine, those that had been vaccinated. So there was that article, and then there were two
additional articles. There was the Lyra
article in developments in biological standardization
in 1997, and “Windsor Australian
Veterinary Journal” in 2005. The Lyra article discusses
the risk of vaccinating fish with an inactivated vaccine to
prevent two types of Vibrio, a type of Yersenia,
a type of Aeromonas. So this is vaccination of fish. The other article addressed
the risk of vaccinating sheep to prevent paratuberculosis. Both articles did
focus on needle sticks as the precipitating event which
posed the risk to the provider. The risk in the Lyra article
was an allergic reaction to the vaccine. It was two cases out
of 50 needle sticks. The risk to the provider in the “Windsor” article
was self-inoculation of the infectious agent. So based on this information,
I — we crafted this language, and obviously, the result
of the summary is — seems to be a lack of any additional
targeted direct evidence. So what we said was that “Providers are sometimes
concerned when they have the same
contraindications or precautions as their patients from whom
they withhold or defer vaccine. For administration of
routinely-recommended vaccines, there is no evidence of risk
of exposure of vaccine antigen to the healthcare provider. So conditions in the provider
labeled as contraindications and precautions to a vaccine
antigen are not a reason to withdraw from this function of administering the vaccine
antigen to someone else.” This paragraph will be followed
by another paragraph that says “Historic concerns
about exposure to vaccine antigen are limited
to non-parenteral vaccines in which some degree of environmental exposure
is unavoidable,” and instead of LAIV in red, we’ll have
the footnote for the citation. “Situations in which adverse
reactions from allergy or self-inoculation is likely
due to reduced attenuation of vaccine virus, or
the technical process of administration is complicated
by vaccine recipients that struggle vigorously,
leading to needle-stick injury and reactions due to
allergy or self-inoculation.” So a recommendation in
the first paragraph, followed by the evidence-base
in the second paragraph. And so, with that, I wanted
to leave it to the ACIP to discuss any possible
tweaks to this language. And that’s really
all that I have.>>Great. Thank you.>>Thank you.>>Any questions or comments? Dr. Hunter?>>Could you just move back
to the next-to-the-last slide? Because I think that’s
the pertinent one for us to be discussing. Thanks.>>Dr. Goldman?>>Thank you. Jason Goldman, FACP. I’m wondering if there should
be any comment in there about the obvious statement of using proper universal
precautions, standard technique, to understand that if someone is
using the proper best practices, there’s no chance of infection,
or reaction, or other issue.>>Thank you very much for
that question, because — because I forgot to mention that
this paragraph is going to be in the section on
vaccine administration. There’s a whole section that
discusses proper technique. It starts off with risks of
needle sticks to providers. That’s the — it kind
of leads off with that, and that’s where — and
it — and it follows — it’s followed by this paragraph. Then it gets into a lot of
the, you know, best practices, techniques for vaccine
administration, and with respect to all of the different
routes, the different sites, the different needle lengths. So it’s going to be in
that part of the document.>>Great. Dr. Moore?>>This is a quick
question with respect to the veterinary vaccinology. Will there be a reference
that will send people who have those kinds of concerns
to an appropriate resource? Speaking as someone who
vaccinates calves every year for my father’s cattle farm,
I’ve experienced those sorts of needle-stick injuries and didn’t know quite
what to do about that. So, fortunately,
nothing happened.>>Those citations would
be — will be in there. I can look for another
general — I don’t know — I’ll discuss with CDC’s
injection safety folks. I don’t know if they — they probably do branch over
into veterinary vaccinology. I don’t know, but they
may have a website.>>It’s just that people who
are looking for that kind of information may look here,
and it would be great to say, “If you have this experience,
here’s where you should go for more information.”>>Dr. Hahn?>>Yeah, just speaking as
a state health official, we definitely get these calls. You know, in my 20 years, I’ve
never had a provider tell me that they got exposed to a vaccine while they
were vaccinating a human, but veterinarians — and they do
have more challenging patients, maybe. But we do get those regularly,
so that would be really helpful.>>And Ms. Stinchfield?>>Patsy Stinchfield from
NAPNAP. So, thanks, Andrew. One question that I
get is Remicade — moms or clinicians on
drugs like Remicade, and giving rotavirus vaccine. And there really isn’t
anything written about that, but I didn’t see that
in your list here.>>Right, so this is a topic
that we have begun a discussion in the general recommendations
work group. It would fall under
altered immunocompetence, because I think the issue
is, is that immuno — is — for Remicade specifically,
there is a — the package insert
states an interval for — I believe it’s from birth
through six months of age to avoid live vaccines. And CDC does have
a recommendation — I know CDC guidelines
or guidance — I should say guidance — is that
a specialist can be consulted. That’s how we typically
answer that question, because we get that
question a lot. An infectious disease
specialist — when faced with the issue of
rotavirus vaccine, and we wanted to — and we have started
the process of trying to come up with something
general on that topic. We didn’t finish it in
time for this meeting. There is also the
complicating issue of altered immunocompetence. Because the ACIP is in the
process of determining — and CDC is in the process
of determining the working and various partnerships
to come up with some type of harmonized guidance,
and aligning those — that guidance from various
partners, like IDSA, with the CDC ACIP
vaccine-specific guidance. So there’s more to come on
that, and we were not able to fully pursue that issue. But there is CDC
guidance already. I don’t believe it is published,
and I don’t know if that — are there any rotavirus
subject matter experts here now? But it’s not published, but we
always recommend consultation with an infectious
disease specialist to weigh the risks and benefits.>>Yeah, so that’s —
that’s how it comes to me. And so, then, when I go to try
to give them articles or things to look at, there really
isn’t anything published. So that would be really helpful. The Remicade package insert is about the individual getting
Remicade, not the person — so it’s clear you don’t want
to give rotavirus to someone on Remicade, but they’re a
parent who’s giving rotavirus vaccine or in — taking care of a child who’s shedding
rotavirus for weeks. And that’s what their
question is. So something written —
do we need to wear gloves? Do you — you know,
hand-washing, those kinds of things
would be helpful.>>Thank you so much. I think that is something
that we should take back and come back to
the work group with. Dr. Stinchfield? I’m so sorry.>>That’s okay.>>Whitley-Williams>>Whitley-Williams, NMA — along those same lines — and thank you, Patsy,
for bringing that up. But along those same
lines, there are populations in New Jersey that
typically take their one or two-week-old babies back
home to TB-endemic countries, and they purposely take them to get BCG vaccine
while they’re there. So this issue of disease-modifying
drugs is an important one, and certainly should be
considered by the work group. Because it’s devastating
to do that — the mother has been on these
drugs, these medicines.>>Thank you. There will definitely
be more to come over the next year
on this subject. So, Dr. Kimberlin, one last
question.>>Oh, it’s a comment
to follow in this. David Kimberlin,
“Red Book,” AAP. In the 2018 of the “Red Book,”
we added language specifically about that, but a lot
of it is extrapolation from what the anticipated
risk is. The Canadians are
doing some nice work in prospective assessments. We would welcome the opportunity
to work with y’all’s language to make sure that it harmonizes
to the maximal extent possible.>>Great, thank you so much. One more comment from Dr. –>>So some labeled
contraindications or precautions for vaccines, in
particular those related to allergic reactions, have to
do not with the vaccine antigen, but with excipients, or
non-active ingredients. So I’m wondering a little bit
about specifically calling out the vaccine antigen
in this recommendation.>>So the general best
practices has a section on contraindications
and precautions in which every vaccine
— there’s a table, and every vaccine is listed with contraindications
and precautions. And for all vaccines, a — and this is for the
vaccine recipient. This is unrelated to this. This is the vaccine
recipient themselves. If they have a history
of an allergic — of a severe allergic reaction,
e.g. anaphylaxis, to a vaccine or to a vaccine component, that is a contraindication
to the vaccine. So we think that that’s
general enough to cover — and is quite harmonized
with FDA on that — on that — in that respect.>>– yeah, so I think we’re
going to go ahead and move on. It’s really important that we
stick with our schedule today, because we do have a
hard stop this afternoon, and I want to make
sure there’s plenty of time for public comment. But thank you so much. I do know that for these
general guidelines, there are so many
different situations that the group is trying to
address, and Jose’s whispering in my ear multiple other things. And we’ll just make
sure that we — please send me or
Andrew Kroger an e-mail if you have specific
additional feedback or comments, because that’s really
helpful as they’re trying to update these guidance. So we’re going to move
on to the flu session. Dr. Walter?>>Good morning. It’s my pleasure to introduce
today’s influenza session. So these are the members of
our rather large working group. Not listed here is our
fearless CDC work group lead, Lisa Grohskopf. So I just want to
recap what we talked about at our last
ACIP meeting briefly. At the last — June 2018
meeting, we had updates for the 2017-18 influenza
vaccine effectiveness, and we also had a vaccine — influenza vaccine safety
update at that meeting. At that — at the June
meeting, we had a presentation of the SOMNIA study, which
is a multi-national study of narcolepsy following
adjuvanted monovalent pandemic H1N1 influenza vaccines. And then, following that, we
had a presentation from Seqirus on the results of
a study looking at adjuvanted quadrivalent
inactivated flu vaccine in young children. That was followed by a summary of the 2018-19 recommendations
for flu vaccine. Since that time of the meeting, we’ve had continuing
activities in our work group. We meet at least twice a month. We — thanks to Lisa,
largely, and folks at the CDC, publication of the 2018-19 ACIP
influenza vaccine statement occurred in late August. We had presentations
in our work group of the Prevent study looking at
the effectiveness of flu vaccine in preventing hospitalization
among pregnant women, and lastly, we had a
presentation looking at a study of Fluzone quadrivalent
flu vaccine at a .5 mL dose for children age six
through 35 months. So there have been some
changes in labeling information for influenza products. The one change that
happened, I think, that was referenced this
morning in our FDA update was for AFLURIA trivalent
and AFLURIA quadrivalent. This — or, these vaccines
were previously licensed for children five years of
age and older, and in October, the age indication was expended to include children six
months of age and older. Realizing, still,
that the dose volumes for that particular product, for
six through 35 months of age, was .25 mL, and for children —
or children and adults 36 months and older, the .5 mL dose. Note now that there are five
inactivated flu vaccines licensed for children six
through 35 months of age. Most of these products, except
for AFLURIA, are quadrivalent, and there are two
of these products — the GSK products are at
the .5 mL dose currently. The remaining products
are at the .25 mL. This is for the youngest kids,
six through 35 months of age. The dose or — dosing
for persons aged three and older is .5 mL for
all inactivated products. So today’s agenda overview,
what we’re going to be talking about — this is a rather brief
agenda for flu — are two talks. We’ll hear the talk that was — talks that were presented
to the work group, the influenza vaccine
effectiveness, and preventing
influenza-associated hospitalizations
during pregnancy. And that’ll be presented by Dr. Mark Thomson. And then, that’ll be
followed by presentation from Sanofi Pasteur looking at
Fluzone quadrivalent .5 mL dose for children aged six
through 35 months. So, Dr. Thompson?>>Hi, everyone. So I’m presenting on behalf
of the PreventNetwork, and the influenza division,
on the effectiveness of the influenza vaccine in preventing flu
hospitalizations during pregnancy. So as all of you know, pregnant
women are believed to be at increased risk
of severe disease, including hospitalization. This is — was a
prime driver behind WHO making pregnant women
their priority group for influenza vaccination
programs around the world. But so far, less
than half of the WHO member states recommend
influenza vaccinations. A lot of those come with
trimester restrictions. Vaccine is still contraindicated
in many countries, including China, for example, and even in high-income
countries, the vaccine is underutilized. Good news is that, with RCTs
and observational studies, we have growing evidence
that the vaccine is — reduces by about
half the risk of mild to moderately-severe disease. The bad news is that, as WHO
and others have pointed out, it’s the reduction of
risk of severe disease that is most valued by low
and middle-income countries and organizations like
CABI [assumed spelling] and other decision-makers. And this gap is going to be
hard to address with RCTs and existing class
forms, both for ethical and feasibility reasons. So a couple of years ago, we
decided to try to form a network of integrated systems
that can pull together lab and medical records,
and vaccine registries, and we called the
organization Prevent. And I should say the publication
from this just came out a little over a week ago, so I’ll save
you from reading the paper, maybe, and give you a
few bonus tracks, too. And so, we pulled
together actually over two dozen organizations
in these regions and countries. In western Australia, and
Alberta and Ontario, Canada, it was public health
organizations that had the best-integrated
systems. And then, in Israel
and the U.S., it was the integrated
care systems, the Clundeit [assumed
spelling] HMO in Israel, and then Kaiser Permanente
on the west coast that participated with us. And so, all these organizations
went back and looked for records going back
to the 2010-11 season. Most were able to look up
through the 2015-16 season, and together, we had roughly 25
study-seasoned sites to look at. So we started with all these
organizations going back and forming a retrospective
cohort of pregnant women, which was defined by
live or stillbirths, with gestational ages greater
than or equal to 20 weeks, and focused on hospitalizations
with what we called ARFI — so acute respiratory
or febrile illness. So this captures all the
pneumonia, influenza, acute respiratory codes
that we typically look at, but also febrile-only
sepsis-like presentations, and other acute conditions
that have been associated with flu hospitalizations
in adults. And we had to rely
on, of course, clinician-ordered PCR tests. In most of these
organizations, the PCR used in clinical practice had
gone up after the pandemic. There actually was not a lot
of rapid or other tests used in these settings, but those
with that were excluded. And as in a lot of clinical
settings, there’s not a lot of A-subtyping, so what we’ll
focus on today is really VE against all circulating strains. And of course, did
a pretty good job of having good vaccine
capture, but excluded some who we lacked those records, or were vaccinated
close to admission. So as all of you
have heard many, many times about the
test-negative design, which is the
currently-established method for observational
studies of VE — but here, the cases
are your PCR-positives, and your comparison group are
those who are PCR-negative. This is believed to
minimize bias due to access to vaccination and
healthcare-seeking differences. In our study, we adjusted for
site, season, season timing, and the presence of
high-risk conditions. These are the typical
adjustments in this sort of model. They were also associated
with flu positivity and coverage in our sample. There were a number of other
things that were associated with flu positivity and
coverage, but we also looked at, but did not include
in the model, because they didn’t
substantially change the estimate. So starting — so with
just a few exceptions, almost all of these sites
and seasons were able to establish this
cohort year-round. So one of the first things
that jumped out is that, among over two million
pregnancies across all this time, 84% of the pregnancies
overlapped with flu season. So most of this is intuitive
and obvious, but it is striking to see that it’s that large
percentage of pregnancies that are affected by flu
in one way or another. So — but then, from there,
you go down to hospitalizations that occur during flu season. So over 587,000 of those, and
of those, a subset of 19,000, or just 3%, actually had one of these acute respiratory
or febrile illnesses. So — so let’s stay — we’re
going to stay with this — that little sliver there for a
second, and talk about what made up that — those
hospitalizations. So for most of these, the ARFI
diagnosis was not the primary reason the woman was
hospitalized — only 15%. When that happened, about
19% of them were PCR tested, and we found flu in 64%. Not surprisingly, when ARFI
wasn’t the primary driver of the hospitalization,
there was lower testing — so 3%, but here, too, you
have a large percentage — so about half that
were flu-positive. So in these hospitalizations,
67% of them were ARFI-identified at delivery, so — and a third
were not delivery-associated. Again, perhaps not surprisingly,
when ARFI was not associated for delivery, 14% were tested,
and 60% of those were positive. Much less testing if a
delivery was going on, but when it was tested, again,
about half were positive. So I won’t belabor this point,
but any way you looked at it, there were differences in
who was tested and not. But when women — these pregnant
women were tested, we saw a lot of flu, no matter
how you cut it. I’ll return to that
point later, but for now, the VE study focuses
on this subgroup of those 19,000 ARFI
hospitalizations where clinical testing occurred. So that’s only 6%, so
this is a subgroup. And once you collapse
some hospitalizations that were relatively quick
readmissions and treated as the same event, we’re talking
about a little over 1000 events. And all but 25 of those
events are with unique women, so there were a few that were
repeated hospitalizations, but for the most part,
we’ll talk about these as women even though the unit
is actually hospitalizations. So most of these events, these
PCR-tested hospitalizations, were among women under age
35, in their third trimester, who had no high-risk
medical conditions, captured over 598 flu positives. This graphic shows
per-season the — you know, the results
of the testing. The grays are the negatives. The light blues are As. So 83% of the viruses
we’re looking at are As, and then some Bs in yellow
there for a good measure. So H1N1 was prominent in
about half the seasons. H3 was prominent in
over 70% of the seasons. So — and so — looking at the 58% positivity among
these hospitalizations — so flu was more positive — more likely to be positive
in the third trimester if it was a pneumonia
or influenza diagnosis, and if the primary reason
they were there was for ARFI. Influenza was less common when there was a
high-risk medical condition, when there was a pregnancy
complication or delivery. As I’ve already said,
even in these groups, it was still pretty common. And — so across
sites and seasons, about 16% were vaccinated. This varied across
seasons and across sites. Not surprisingly, the USA had
the highest vaccine uptake compared to other sites. And the vaccination
was higher among those with pre-pregnancy
high-risk medical conditions if they delivered in the
hospital, or they were diagnosed with a pregnancy complication,
and lower among those with pneumonia or influenza, or if the ARFI was
the primary diagnosis. So with no further ado, this is
the actual VE table that, again, you guys are used to seeing. So among the influenza
positives, we have 13% vaccinated, among
the influenza negatives, 22%. And so, after you adjust for
the site, season, and timing, and high-risk medical
conditions, that gives us a VE of 40%. And in the paper,
it goes exhaustively through the various
stratifications. So this number varies
by site and season. The U.S. number actually was
higher, so it was actually 55%. And when you take out that
southern hemisphere ’14 and northern hemisphere
’14-’15 season, where typically everybody agrees that was a poor vaccine-match
year, the VE goes up also. But again, in the paper, you’ll
see, really any way you cut it, this overall 40%
number is pretty stable, stable across season timing, by
high-risk medical conditions, by pneumonia, by trimester. It was actually a little — it was actually significantly
higher if the primary reason the
woman was there was for ARFI. So strengths — so
the good news here — we used PCR, had good
vaccine registries. We used the test-negative
design, and the takeaway is, this is, you know, the average
performance of the vaccine across multiple countries,
across a real mixture of seasons with different viruses and
circulations, during years where the vaccine
was a good match, and maybe less of a good match. And it’s similar to actually
recent meta-analyses looking at VE against hospital — flu hospitalizations with
working-age adults in general. So limits — obviously, when
you’re doing clinical testing, there are lots of caveats
with that, and obviously, we’d love to have this data for
low and middle-income countries. And there’s limits to the
generalizability of that. I will say, when you limit — you know, the issue here is
threshold of care, and severity, and our study — when you
limited it to ICU admissions — so by any yardstick,
a severe event — the VE was very similar. So — and then, lots of caveats about any time you pull a VE
analysis, and were not able to look at A subtyping or the
virus match or mismatch numbers. And then, registries — also
imperfect, but typically, we’re not as concerned
about that, as long as it’s not
systematically-related to case status. So again, 40% — we think this
is a pretty conservative number, looking forward at
what we would expect of the vaccine in
the next 10 years. It’s also consistent with other
studies that have come out, perhaps lower than
the Malawi RCT, close to the South
Africa RCT, very similar to the study CDC did with
Kaiser Northern California and Kaiser Northwest
looking against symptomatic but non-hospitalized flu
with PCR several years ago. So that’s reassuring,
and, you know, the hope is this actually
gives us additional rationale for material vaccination
programs around the world. And the final point
being that — and hopefully, others
will pick up and — where we left off here,
but is the substantial, perhaps hidden burden
here, that over half of the flu we’re finding was
not the typical PNI diagnoses. It’s a lot of flu
with deliveries. I know absolutely nothing about
pregnancy, but can imagine that, all things being equal, it’d
probably be good not to have flu when you’re having to deliver. And finally, want to thank all
the experts and many players that were involved in
putting this together. Thank you.>>Great. Thank you so much. Do we have any questions
about the study before –>>Yeah, hi. Mark, great presentation. Two questions — I didn’t know
whether you mentioned early deliveries, and the relationship
to early deliveries. And do you have any information on prior vaccination
in prior seasons?>>Yeah, hi, Peter. So we are looking
at birth outcomes, and are going to publish that. Not — nothing really
super-striking from it so far. We did not have prior
vaccination data consistently across these sites, and it is
definitely true that in some of those seasons, it would’ve
been good to have that data, because it modified VE
in ambulatory studies. So that’s — that is
another limitation, yes.>>– great. Any other questions? Thank you so much. Oh, sorry, Dr. Neuzil.>>Okay. Kathy Neuzil, IDSA. I was just going to comment. Beautiful study. You’re right. These are the data that
we need, and if we look at the MODI [assumed spelling]
study for example, we saw — we reduced influenza in
pregnant women by about 50%, but we also had an impact
on pneumonia in infants. So if we’re really looking
at the totality here, you’ve presented part of it.>>Yes.>>But there is also protection
afforded to the infant against severe disease.>>Yes, excellent point.>>Thank you. Okay, we’re going to move
on to the next session. I’m so sorry.>>Oh, okay.>>Sorry. Dr. Monica Mercer,
please?>>All right, good
morning, everyone. It’s my pleasure to be here, to share with you results
from our GRC88 study. And this is a study that —
the purpose of the study was to characterize the safety and
immunogenicity of the .5 mL dose of Fluzone quadrivalent
vaccine in children aged three to 35 months of age,
compared to the .25 mL dose that had already been
licensed in this age group. As you are aware, children
are at increased risk — Children are at increased
risk of influenza and illness, and influenza-related
hospitalizations. And for more than 30 years,
influenza vaccines for children under the age of three
have contained a half-dose of antigen — so that’s
been 7.5 micrograms of hemagglutinin per strain
— to reduce the risk of fever or febrile convulsions
that were associated with earlier whole-virus
vaccines. But with the introduction of the
split-virus influenza vaccines, which are less reactogenic,
we’ve most likely eliminated that need to use a reduced
dose in this young age group. And recent studies
have actually shown us that a full dose can be used in
children under the age of three without increased risk of fever or other systemic
injection-site reactions. These studies have also
demonstrated that a full dose of free vaccine did
induce immune responses that were generally higher
than those that were seen with the half-dose, and
without materially impacting on the safety of the vaccine. So accordingly, full-dose
influenza vaccine is now recommended for children six
months through 35 months of age by health authorities in
Canada, in the United Kingdom, in Finland, and more recently,
in the U.S. With that said, the aim of GCR88 was to describe
the safety and immunogenicity of a full dose of Fluzone
quadrivalent vaccine compared to a half-dose of the
vaccine in children six through 35 months of age. The primary objective of the
study was to assess the safety of the full dose, which was
done by comparing the rate of any fever — so that was
defined as a temperature of greater than 100.4 — in subjects who received the
.5 mL dose of Fluzone vaccine to those receiving the .25
mL dose during the seven days following vaccination. The secondary objective of
the study was to evaluate for immunogenicity, and so that
was comparing the full dose to the half dose, and immunogenicity
comparisons were based on geometric mean titer ratios and seroconversion
rate differences. So the study was a phase IV
randomized, observer-blinded, two-arm, multi-center
study, which was conducted in the U.S. The targeted
children — subjects were 2190 children aged
six through 35 months of age to be enrolled, and
they were enrolled — following enrollment, we
used an automated system to randomize them 1:1 to
either receiving a half dose, which was designated as
group one, or a full dose, designated as group two. Enrollment was also
stratified by age, so that approximately half
of the subjects were age six through 23 months of age, and
then the other half were 24 through to 35 months of age. We also had a subset
of subjects, 1600, who were randomly
selected to participate in the immunogenicity
assessment. The investigators, the study
site personnel, the sponsors, and the subjects were blinded
to their group assignment. Only the study staff who were
actually administering the vaccines were unblinded, and
they did not get involved in capturing any safety data. In the next two slides, I
will describe the safety data, and how we got sera
on these patients. So for subjects who were
receiving one dose of vaccine — so that was per ACIP guidance —
they would come in at visit one, were consented, and if
they were randomized to the immunogenicity subset, they were then —
the blood was drawn. They were then vaccinated
with their designated dose of vaccine, and for 20
minutes, were observed for any immediate reactions. The subjects were then — the parents or guardians
were then given a diary card so that the children
could then be evaluated for the next seven days
for solicited reactions. So along with the diary card, they also received a digital
thermometer and a ruler, and that was so that they could
record daily temperatures. They could measure
any local reactions, and they could also record in
the diary card any medications that were given for
adverse reactions, any healthcare provider
contact, or any hospitalization. So that could all be captured. The parents or guardians
were contacted on day eight to remind them to make sure that
the diary cards were filled in, and then, at the 28-day
visit, which was visit two, they would return
with the diary cards. During that time, also, any unsolicited adverse
events were captured, and serious adverse
events were captured for the duration of the trial. And this is — this
is for subjects who received two
doses of vaccine. So it’s a very similar
format, same procedure for each of the vaccinations. If we just go then
to visit three, which was 28 days following
the second vaccination, at that point, the
second blood was drawn. So the study was conducted
between September of 2016 through until March of 2017. Due to lower-than-expected
recruitment, 1950 participants were enrolled in the study instead
of the planned 2190. However, the study remained
sufficiently powered for both the primary and
the secondary objectives. The participants were
randomly assigned in nearly-equal proportions — so for the half dose
or the full dose. There were three participants
that were randomized in the half-dose
group and six — I’m sorry, I think I’ve got
that the wrong way round. Six in the half-dose group, and
three in the full-dose group who were randomized, but
did not receive a vaccine. So that left a total
of 1941 subjects in the safety analysis
set, and about 3/4 of those subjects
were randomized to the immunogenicity subset. 715 participants were in the
half-dose group, and 745 were in the full-dose group for
that immunogenicity subset. The study was completed by
90% of the participants, and the most common reasons for participant discontinuation
was a voluntary withdrawal not due to an adverse event or
noncompliance with the protocol. There were no participants
that discontinued the study for an adverse event or a
serious adverse condition that was related to vaccination. At enrollment, there was
also nearly equal proportions of males and females
included within the full and the half-dose
groups, and the mean age of the participants was
the same between the half and the full-dose groups. And subject distribution by race
and ethnic origin was similar between the two vaccine groups. So here, we see the most
important outcome of the study, which — that being
the outcome associated with the primary objective,
which was to compare the rate of any fever following
the .5 mL dose — so that’s the full dose
— to the half dose. And the fever rate — excuse me
— for the half dose was 11%, and that for the
full dose was 12%. In order to demonstrate
non-inferiority between the two vaccine
groups, the upper limit of the two-sided 95%
confidence interval in fever rates had
to be less than 5%. And so, if you draw your —
if I can draw your attention to the green box, you will see
the difference in rate of fever for the full dose minus the
half dose of vaccine was .84%, with the upper limit of the
confidence interval being 3.8, meeting therefore the
pre-specified criteria for non-inferiority. In terms of safety parameters, the solicited injection-site
reactions were captured. They consisted of injection site
tenderness, erythema or redness, and swelling, and tenderness was
the most frequent injection-site reaction in both the half-dose
and the full-dose groups. Proportions of participants
reporting solicited injection-site reactions
were similar between full and half dose, and
in most participants, solicited reactions were grade
I or grade II in intensity, and they resolved
within three days. The rates of grade III
reactions, which are indicated in orange, were generally
similar to the full and the half dose,
and there we saw that the most common grade III
solicited site reaction was also tenderness. In addition to fever, the other
solicited injection site — I’m sorry, did that
not progress? There we go. I’m sorry — reactions
consisted of irritability, abnormal crying, drowsiness, loss of appetite,
fever, and vomiting. And rates of these
reactions were, again, similar between both groups. Similar to what we observed for the solicited
injection-site reaction — site reactions, most systemic
reactions were also of a grade I or grade II intensity,
and they also resolved within approximately three days. The most common grade III
solicited reactions were irritability and
abnormal crying, and grade III fever was reported
for .6% of the participants who received the half
dose, and 1.2% for those who received the
full dose of vaccine. With regards to immediate
unsolicited adverse events — so those are what occurred
within the first 20 minutes after vaccination — there
were two in group one — so that’s for the half dose — and there were no
subjects in group two. Overall, the unsolicited adverse
events trended slightly higher in group one subjects than
they did in group two, and there were almost even
numbers in both groups that experienced at least one
unsolicited adverse reaction after vaccination. And for that, the most
commonly-reported adverse reaction for group one was
diarrhea, cough, and rhinorrhea, and in group two,
cough and rhinorrhea. No subjects discontinued
the study due to an unsolicited
adverse reaction. There were two subjects in
group one who discontinued due to other adverse events,
and one subject in group one that discontinued due to a serious adverse
event of pneumonia. There were no subject
discontinuations in group two, and none of the discontinuations
were associated with or related to vaccination. There were a total of five
subjects in each group that reported an SAE
throughout the study. One of those was considered
related to the study vaccine. That was a case of chronic
urticaria in group one. The event was also
considered an adverse event of special interest, but
there were no deaths reported in the study. Now, moving on to the
immunogenicity assessment — this graph represents the
post-vaccination GMTs, or geometric mean
titers in subjects who received the .5 mL dose
of Fluzone quadrivalent, which is represented by the
orange bars, versus those who received the half dose, which is represented
by the blue bars. For all four strains,
the .5 mL dose or full dose induced
higher GMTs compared to what we see for
the .25 mL dose. Non-inferiority with respect
to GMTs was considered to be demonstrated
if the lower limit of the two-sided 95%
confidence interval of the GMT ratio was
greater than 0.667 for each of the four virus strains. And so, if you look
at the table, you’ll see that this was
met for all four strains. Comparing seroconversion
rates induced by the half dose compared to —
I mean the full dose, I’m sorry, compared to the half dose, we see that the full
dose induced responses that were slightly higher than
those observed by the half dose. And for non-inferiority with
respect to seroconversion rates, those are considered
demonstrated for all four strains
if the lower bound of the 95% confidence
interval around the difference between the full dose minus
the half dose was greater than negative 10%. And here, you can see that
the non-inferiority criteria with respect to seroconversion
rates was met for all four strains. So in conclusion, study GRC88
affirmed that a full dose of Fluzone quadrivalent has a
safety profile that is similar to that of a half dose, and
may be more immunogenic. A note of these findings
is that they are consistent with other studies that
have looked at safety and immunogenicity of a full
dose versus a half dose, and Sanofi Pasteur has submitted
a supplementary biologics license application to the FDA
to permit use of the 0.5 mL dose of Fluzone quadrivalent vaccine in children six months
of age and older. The age, then, and
the action date for that application
is in Q1 of 2018. And just some safety
information around the vaccine, and also the indications. And so, with that, I thank you,
and if there are any questions, I’d be happy to answer them.>>Great. Thank you so much. We’ll start with Dr. Atmar.>>I have a couple of questions. One, for the non-white
participants, there were about 25% — do you
have that broken down further into black African-American,
Asian, other groups?>>We actually don’t
have that broken down. I’ve not — well, we do,
but I don’t have that — we don’t have substantial
numbers in that. The way we did our analysis
was either white or non-white.>>And you — for the
immunogenicity analysis, you showed non-inferiority
analysis. Did you also do a
superiority analysis?>>So thank you for that. So we did not perform
a statistical — we did not formally
statistically do testing for superiority, because it
was a non-inferiority study. But we had — we — to
answer that question, we looked at what we — if we
had to use the same criteria that we used for our
high-dose study, which looked at the lower bound of the
two-sided confidence interval, in which then the GMT ratios had
to be greater than 1.5 for two of the strains, then we did not
meet superiority for this study.>>Thank you. Dr. Walter?>>Yes, you report on fever
in the first seven days, and the difference in —
between the two groups. Did you take a look
at the first two days when you would expect most fever
and look at that separately?>>Yes, we did, and
we did see more fever in the first three days.>>And was it different
between the two groups, the first three days?>>So it was — when
we looked at that, we did see more reactions
in the younger cohort that received the .5 mL dose.>>Great. Any other questions? Thank you so much.>>Thank you.>>I think we will move on to — we have a couple of
short work group updates, the first one being to
introduce — oh, I’m so sorry. Was there one more
question in the back? I’m sorry, Dr. Schaffner.>>Yeah, so thank you very much. Bill Schnaffner,
National Foundation for Infectious Diseases. Before we leave influenza, I’d
just like to tell my colleagues that the National Foundation
for Infectious Diseases, in addition to — in
collaboration with a number of professional societies and
colleagues, has issued a call to action, reinforcing the
importance of immunizing people with chronic medical conditions. Obviously, we’re all in favor
of immunizing everyone older than six months of age,
but these are people who get the more
severe complications. We brought in a number of these. They’ve been distributed,
I’m glad to say, so we invite you all who
would like to look at this to visit the NFID website. Thank you very much.>>Thank you for that update. Anything else before we move on? Okay, we’re going
to introduce — Dr. Frey is going to introduce a new work
group that’s getting started.>>I believe it’s
still good morning. I’m going to take the next
few moments to introduce you to the newly-formed
rabies working group, and I will tell you a
little bit about our charge. The members of this
working group are myself and Dr. José Romero. Our CDC leads include
Jesse Blanton and Agam Rao. The representative from the
division of global migration and quarantine is
Kristina Angelo, and the immunization safety office
representative is Pedro Moro. You can see we have multiple
liaison representatives, and also subject matter
experts, and we are thrilled to have them, and look very
much forward to working with these individuals. Our purpose and goals are to
provide a forum for discussion to update the 2008 and
2010 ACIP recommendations on human rabies prevention. The members will review
new and existing data, and also provide
individual input on topics that may inform changes
in these recommendations. Our first meeting was held
October the 16th, 2018. I want to just give you a little
bit of information about rabies and also mention what our
work has been in the past on the working — in the
rabies working groups. So rabies is an acute and
fatal encephalomyelitis, but it is preventable. Greater than 200,000 persons
in the U.S. are exposed to rabies-suspect
animals every year. Over 30,000 persons receive
post-exposure prophylaxis every year. Rabies PEP is safe
and efficacious, but the costs are high. The ACIP recommendations were
comprehensively updated in 2008, and the PEP schedule
was updated in 2010. In the interim, however,
there is new data, and the World Health
Organization has updated its recommendations. Whoops. So here, we have a
draft of our terms of reference. We are going to review the
epidemiology and burden of rabies exposures
and PEP administration in the United States. We will review the
evidence-based recommendations regarding use of rabies vaccines and immunoglobulin products
among various populations for topics including the
pre-exposure prophylaxis schedule, the route of vaccine
administration, the amount and location of rabies immune
globulin, and also the timing of serologic monitoring. We also review efficacy,
immunogenicity, safety, cost effectiveness,
route, and location of vaccine administration,
and vaccination schedules for rabies vaccines for pre
and post-exposure prophylaxis. And also, we will review
rabies exposure risk for the general population, and by occupational
recreational groups. We will evaluate the
effectiveness and cost to adhere to current assessment guidelines and ACIP serologic
monitoring recommendations. We also plan to review
evidence generated for new recommendations of
the World Health Organization and identify where additional
evidence generation may be necessary to inform
recommendations. And finally, we would like
to identify areas in need of further research
informing future vaccine and immune globulin
recommendations. This is our timeline. As you can see, we are
beginning phase III. The scope of work
has been determined. The systematic reviews
are being gathered. The working group has just met,
and we hope to, during 2019 and hopefully early 2020, be able to begin presenting
the information to the ACIP for their review, and
finalize any recommendations, and have a vote in 2020
or 2021 — early ’21. So in the way of
acknowledgements, I would like to recognize
the CDC technical work group and subject matters experts. Thank you.>>Thank you so much. We have one more brief update from the meningococcal
work group. Dr. Stephens?>>Hi.>>Thank you. I want to quickly
update activities of the meningococcal work group. The terms of reference
have been updated to focus on specific policy questions. The issue of men B
vaccine booster doses for persons aged greater
than or equal to 10 years at increased risk for
meningococcal disease, and men B vaccine in children
age less than 10 years at increased risk for meningococcal
disease upon licensure of men B vaccines
in this age group. Activities of the work
group include review of available safety,
immunogenicity, persistence of antibody
protection, and effectiveness data
for men B, men A, C, W, Y, and future pentavalent
ABCWY vaccines. There is a — a activity
including development of an updated meningococcal
vaccines ACIP recommendation and report, and the
group is also — continues to review
the epidemiology of meningococcal disease,
and identify areas in need of future research
to inform potential vaccine recommendations. We have been reviewing
new data — new available data on men B
vaccines, antibody persistence, and response to a booster
dose, and also safety and immunogenicity
of men B vaccines in children aged 10
— less than 10 years. In addition, reviewing
and grading evidence for booster doses
of men B vaccines for persons at increased risk. Upcoming activities are
a — in February of 2019, a review of data and
grade evaluations on men B vaccine booster
dose, and in June of — anticipated in June
of 2019, full session on men B booster doses
in persons aged greater than 10 years at increased
risk for meningococcal disease. And in mid-2019, publication of consolidated ACIP
recommendations, and report on meningococcal
vaccines, both men A, C, W, Y, as well as men B. I want to
thank the working group members who are listed here, in
particular two ACIP — other ACIP members, Kelly Moore and Hank Bernstein, and appreciate the leadership
of Sara and the CDC team in this working group activity. So with that, I thank you.>>Thank you. We’re going to move on
to the pertussis session. Dr. Bernstein will be telling
us about this new work group.>>Thank you. We are in the home
stretch [laughter]. So I — there’s a new
pertussis vaccines work group that has been convened,
and this work group’s terms of interest — reference
are to consider the evidence for recommendations that
would allow any tetanus and diphtheria toxoid-containing
vaccine — that’s TD or Tdap — to be used for the decennial
TD booster in adults, and also as tetanus prophylaxis
as-needed for wound management. The issues being considered by this newly-convened ACIP
pertussis work group will first look at the previous ACIP work
group work that was discussed about repeated Tdap
vaccinations in 2013 and 2014 and published in MMWR in 2018. We’ll also look at and recognize that the current Tdap
products are currently licensed for single-use, and this new
pertussis vaccine work group that has been convened
is going to look at potential FDA label changes and additional programmatic
changes. The agenda for today’s
pertussis section — first, our fearless CDC leader,
Fiona Havers, will review the background, the
current ACIP recommendations, as well as the previous
ACIP consideration for Tdap revaccination. We’ll then have two
of the companies that make the two Tdap
products present safety and immunogenicity, and then
we’ll have a discussion. The question specifically that
we’re hoping the ACIP members and others can help us with is, “Should the current
recommendation that non-pregnant adults receive
a single lifetime dose of Tdap and TD boosters every
10 years be changed to allow any TD-containing
vaccine — that’s Tdap or TD — to be used for the decennial
TD booster in adults?” And then, the second
question is, “Should any TD-containing
vaccine, Tdap or TD, be allowed for use for
tetanus prophylaxis in the setting of
wound management?” And of course, I want to
thank the multiple members of this group, including
Dr. Hunter as a fellow ACIP member,
multiple experts as liaisons and invited consultants, Fiona
Havers as our fearless leader, as I mentioned, and of course, always need to acknowledge
these active participants. Thank you.>>Thank you, Dr. Bernstein,
for that introduction. Today, I’m going to discuss
pertussis epidemiology, the vaccines available for
protection against diphtheria, tetanus, and pertussis in
adults and adolescents, which include Tdap and TD, and current ACIP recommendations
for these vaccines. I’m also going to
review the discussions that the previous pertussis
vaccines work group in ACIP had on repeat Tdap vaccinations,
and the rationale for revisiting this issue now. This slide shows
the number of cases of pertussis reported
from 1922 to 2017. The graph shows the declining
cases after the introduction of diphtheria, tetanus, and
wholesale pertussis vaccines for children in the 1940s,
indicated by the DTP arrow. Note that overall, there
are far fewer cases reported after vaccines were introduced
than in the pre-vaccine era. However, there has
been an increase in reported cases
in recent decades. This slide shows in more
detail this recent increase in pertussis cases in
the last several decades, and also shows the
introduction of new vaccines. Acellular pertussis
vaccines, indicated by DTaP, were phased in in the 1990s to replace the whole sale
vaccines previously used in the childhood series. The adolescent and adult DTaP
booster was introduced in 2005. The number of cases
peaked in 2012 when we had over 48,000 cases
reported in the U.S., the largest number
in over 55 years. Pertussis has historically
had a large annual variations in the number of
cases, but a number of factors are likely
driving the overall resurgence of pertussis seen in the
past several decades, which is occurring despite
high vaccination coverage in children and adolescents. I will discuss coverage and
the reasons for the increase in pertussis in more
detail later in the talk. To protect adolescent and adults
against tetanus, diphtheria, and pertussis, there are two
formulations of Tdap licensed for use in the U.S.,
Adacel and Boostrix. These two products
contain either four — three or four pertussis antigens
in different quantities, as well as diphtheria
and tetanus toxoids. The details are shown
here for your reference, but note that these
are currently licensed for a single use only. In addition, there are
two licensed tetanus and diphtheria toxoid-containing
vaccines, or TD vaccines, Tenivac and a generic TD vaccine
manufactured by MassBiologics. ACIP currently recommends that
all non-pregnant adolescents and adults, age 11 years and
older, receive a single dose of Tdap, preferably
at age 11 to 12 years. To ensure continued protection
against tetanus and diphtheria, booster doses of TD are
recommended every 10 years. The single Tdap dose can
replace a decennial TD booster, but the dose of Tdap,
when indicated, should be administered
regardless of the interval since the last tetanus or diphtheria toxoid-containing
vaccine. TD may also be recommended
for tetanus prophylaxis in the setting of
wound management if a tetanus toxoid-containing
vaccine has not been administered in the
last five years. In order to prevent
infant pertussis, pregnant women are
recommended to receive a dose of Tdap during every
pregnancy, irrespective of the patient’s prior history
of receiving the vaccine, and regardless of the interval since prior vaccination
with TD or Tdap. Note that this is an
off-label recommendation. Pertussis vaccination coverage in the U.S. is variable
by age group. There has been sustained
high coverage with pertussis vaccinations
among children, shown in the yellow
and green lines. With Tdap in adolescence,
shown in blue, there have been substantial
increases in coverage following
the 2005 recommendation, with the most recent survey
showing nearly 90% coverage. Coverage for Tdap in adults
is more difficult to measure, but in general, the Tdap
vaccination program has not been as successful in
achieving high coverage, and coverage is lower
than for adolescents. This slide shows the timeframe
for some of the discussions of repeat Tdap vaccination
after it was licensed in 2005. In addition to the discussion of Tdap vaccination during
every pregnancy in 2012, the ACIP pertussis vaccines
work group previously considered repeat Tdap vaccination for
the general population in 2013, and for healthcare workers and other at-risk
populations in 2014. Many aspects of repeat
vaccination were previously discussed by the work group, and their conclusions
were presented to ACIP. These aspects included
the changing epidemiology of pertussis, Tdap vaccine
effectiveness and duration of protection, immunogenicity, safety of repeat
Tdap vaccination, the potential impact on
overall disease burden, and economic impact. I am now going to
summarize the conclusions of the previous work group
and ACIP on these topics. The previous work group
concluded that the increase in pertussis cases seen in recent decades was
likely multifactorial. Improved diagnosis
and reporting, as well as possible changes
in circulating strains of pertussis, likely
contributed, but there was also evidence
that waning of protection from acellular vaccines
contributed to the rise in pertussis cases. Changes in the age distribution of reported cases raised
concerns about the durability of protection from the childhood
series and Tdap for those primed with only acellular vaccines. For example, in 2012, emergence of disease among
adolescents aged 13 and 14, many of whom did receive Tdap,
emphasized the importance of better understanding the
effectiveness and duration of Tdap protection,
especially among children primed with acellular pertussis
vaccines. The work group also examined
multiple vaccine effectiveness, or VE studies, done on Tdap,
many of which are listed at the bottom of this slide, and most of which were
done in adolescents. The work group concluded that
in observational studies, Tdap vaccine effectiveness
is generally high, approximately 75%
within the first year, but it waned substantially
in two to four years. This VE data was consistent with
changing pertussis epidemiology. The work group also reviewed
data on immunogenicity, both for initial
Tdap vaccination and for repeat Tdap doses. Immunogenicity studies
demonstrated that, for pertussis antibodies,
after an initial Tdap dose, there is a rapid decline
during the first year, with a gradual decline
afterwards. After 10 years, the
concentration of pertussis antibodies,
while higher than pre-vaccination levels,
had declined substantially, and were close to
pre-vaccination levels. Of note, for pertussis, we
know that antibody contributes to protection, but there are no
well-established antibody levels which correlate absolutely
with protection. However, the rapid decline in
antibody levels was consistent with the epidemiologic and VE
data that indicated rapid waning of immunity, and
a short duration of protection conferred by Tdap. Studies that examined
a second Tdap dose, including those listed on
the bottom of the slide that were reviewed by the
previous ACIP work group, indicate that the immune
response is similar to the first dose in cohorts
boosted after five or 10 years after first Tdap dose, compared with naive groups
receiving an initial Tdap. For tetanus and diphtheria, there was a robust
antibody response that was comparable
to TD vaccination. The work group reviewed
safety of a second Tdap dose in the same trials of
repeat Tdap vaccination. They noted that the
majority of local and systemic adverse events
were mild to moderate, and self-limited, and
were generally comparable to those after a first Tdap. Among the few serious
adverse events reported, none were determined
to be related to the receipt of
the second Tdap. Safety profiles were
comparable at the five and 10-year intervals. In addition, the previous
work group concluded that while there was
evidence of direct protection, it is unclear what impacts
Tdap has on herd immunity and preventing pertussis
transmission. For people vaccinated with
acellular pertussis vaccines, symptoms are not as severe, and they are presumably
less likely to transmit. However, given evidence from
animal models and the lack of strong epidemiologic data
indicating a herd effect, the work group concluded that Tdap had potentially
limited impact on disease transmission
and herd immunity. In addition, they reviewed data
examining the economic impact of repeat Tdap vaccination on an adolescent cohort
at ages 16 and 21. Given the higher cost of Tdap
compared to TD, they concluded that repeat vaccination with
Tdap would not be cost effective under the assumptions in this
model, and that the reduction in disease burden would likely
be limited with a second Tdap. So in summary, after examining
the available evidence, the work group in 2013
and 2014 concluded that the increased number
of cases of pertussis seen in the last several decades
was likely to continue, although we will likely
see annual variation in the number of cases. Also, while Tdap
had high initial VE, there was substantial
waning of protection within two to four years. The ACIP work group also
concluded that a second dose of Tdap was safe
and immunogenic, but that any reduction of
disease burden resulting from repeating Tdap doses would
likely be limited, and that, given that Tdap is
more expensive than TD, the certain strategies were
unlikely to be cost effective. Overall, the work
group concluded that the data did not
support the recommendation for a second dose of
Tdap, particularly given that any recommendation at that
time for more than one dose of Tdap would have
been an off-label use. So, why are we revisiting
this issue now, and why do we have a
newly-convened work group? So one of the reasons
for the timing of convening the
new work group is that there has been
an application for an FDA label change to
remove the single-use language from one Tdap product. The FDA has accepted
the application, and the review is expected to
be complete by January 2019. There are several more reasons
for revisiting this issue. There have now been several
additional studies on safety and immunogenicity of
repeat vaccinations. We are also seeing
that multiple doses of Tdap are increasingly common. One large retrospective
review identified persons who had received Tdap, and
then later received a dose of another TD-containing
vaccine, either TD or Tdap. It found that the vast majority of those patients had
received a second dose of Tdap, and only 11% had received TD. This fits with anecdotal
evidence that many emergency
departments, clinics, and hospitals are no
longer stocking TD, and only have Tdap available. Allowing Tdap to be used
for the decennial booster or wound prophylaxis would
potentially be easier for providers. So the questions that
we would like ACIP to address going forward is —
as per our terms of reference and what we’ll be looking at in
this new work group, is that — is whether or not
the recommendation for a single lifetime
dose of Tdap, followed by TD boosters
every 10 years, be changed to allow either
Tdap or TD to be used for the decennial TD
booster in adults, or for tetanus prophylaxis in
the setting of wound management. So after our next
two presentations, we would like to hear from
ACIP if there are other — if there are specific
data that they would like to see presented, or if
they have specific options or other recommendations that
the work group should address to help inform this discussion. So, thank you.>>Thank you. So, we have Dr. Greenberg from Sanofi Pasteur presenting.>>Good afternoon,
and thank you to Drs. Bernstein and Havers
for allowing me to give the update repeat
vaccination with Adacel from our recently-completed
study. The rationale for conducting
this study are as follows. As previously noted,
antibody concentrations to pertussis antigens wane
during the years following Tdap vaccination. Similarly, protection against
pertussis wanes over time, resulting in an increased
risk of infection. Revaccination would
potentially boost protection against pertussis and the
other antigens contained in the vaccine, tetanus
and diphtheria. However, Adacel vaccine
is currently indicated for only a single dose. Under various scenarios,
Tdap may be more appropriate, even when the history of a
prior vaccination is unclear. Examples include persons who,
one, need tetanus prophylaxis for wound management, two, are
exposed in a pertussis outbreak, or three, are caring for or
living with a young infant. By way of background, in Canada
and many other countries, Adacel — the Adacel label
includes revaccination at five to 10-year intervals to
boost immunity to tetanus, diphtheria, and pertussis. In the U.S., Adacel vaccine is
only approved as a single dose in persons 10 through
64 years of age. For our revaccination study, two cohorts of individuals
were recruited. First, in the U.S., we
enrolled individuals who received Adacel vaccine in our pivotal pre-licensure
phase III clinical trial, TD506, which was conducted
in 2001-2002. Second, in Canada, we
enrolled individuals in specific provinces where Adacel vaccine was
routinely administered to adolescents in school-based
programs beginning in 2000. The primary goals of
this study were, one, to characterize the safety and
immunogenicity of Adacel vaccine when administered eight to 12
years after the first dose, and two, to generate
data to support revision of the U.S. licensed indication
to include repeat vaccination. This was an observer-blinded,
randomized, multi-center study with goals as already stated. The U.S. cohort received
their first dose of Adacel vaccine eight to 12
years previously in study TD506, and they were 21 through
64 years of age at the time of enrollment in
the current study. The Canadian cohort
consisted of individuals who also received
their first dose eight to 12 years previously, and
were 18 through 24 years of age at the time of enrollment
in the current study. The participants were randomized
3:1 to receive either Adacel or TD vaccine, with
nearly 1000 subjects in the first group planned, and about 333 subjects
planned in the TD group. Adacel and TD vaccines
that were used in this study have the same
quantities of diphtheria and tetanus toxoids, as shown in
the first two rows of the table, and Adacel vaccine additionally
contains a pertussis toxoid, filamentous hemagglutinin,
pertactin, and fimbriae types two and
three, shown together as Fim, with the concentrations
shown here. The primary objectives
of this study were, one, to compare the seroprotection
rates to tetanus and diphtheria toxoids induced
by Adacel versus TD vaccine. To compare the booster
response rates to tetanus and diphtheria toxoids
induced by Adacel versus TD. To compare pertussis geometric
mean antibody concentrations induced by Adacel vaccine
versus those induced by three or four doses of Daptacel
vaccine in historical trials. And four, to compare booster — pertussis booster response rates
following Adacel vaccine induced by the first dose of Adacel
among similarly-aged adults in TD506. So blood samples were collected
before vaccination on day one, and again 28 days
after vaccination. Participants were observed for
immediate reactions occurring within the first 20
minutes after vaccination. Solicited adverse events were
pre-specified on diary cards that were completed
by the participants for seven days after
vaccination. Unsolicited adverse events
included any other health issue occurring within 28
days post-vaccination. And finally, serious
adverse events, primarily hospitalizations,
were monitored for six months post-vaccination. Approximately 2/3 of the
participants were female. The mean age was about 29 years. Approximately 95% of the
participants were white, and nearly all were
not Hispanic or Latino, and all of the demographic data
were similar in the two groups. Now on to the study results. First, safety — grade I, II,
and III, or mild, moderate, and severe injection
site reactions are shown in this slide with the color
coding shown in the legend there at the top of the slide. Pain was the most
commonly-reported solicited injection site reaction. There were a few participants
who reported swelling or erythema at the
injection site. Each of these reactions
occurred at similar rates between the Adacel
and TD vaccine groups, and most of the reactions were
grade I or II in intensity. Among the solicited
reactions, myalgia, headache, and malaise were reported
at modest frequencies. Fever was reported infrequently. As the injection site reactions, each of these systemic reactions
occurred at similar rates between the Adacel
and TD vaccine groups, and most reactions were
grade I or II in intensity. There were no immediate
reactions reported. Unsolicited adverse events
were reported at similar rates in each of the two
vaccine groups. A total of nine serious
adverse events were reported, eight in the Adacel group and
one in the TD vaccine group, and these occurred 25 to
149 days post-vaccination, and all were considered
unrelated to vaccination. And there were no
deaths in this study. So switching now to the primary
immunogenicity results — seroprotection rates were
greater than 99% to both tetanus and diphtheria toxoids
in both vaccine groups. Adacel vaccine met the
non-inferiority criteria for this endpoint
for both antigens, as shown in the far
right column. The booster response
rates to tetanus was 74.5% in the Adacel group, and
81.6% in the TD group. The difference for this endpoint
for the two vaccines was 7.1%, and the lower bound of the 95%
confidence interval was minus 12%, which did not meet the
non-inferiority criterion, requiring that the lower bound
be greater than a negative 10%. The booster response rate
to diphtheria was similar in the two vaccine groups, and Adacel met the
non-inferiority criterion for diphtheria. Now on to the pertussis
results — Adacel vaccine induced geometric
mean antibody concentrations to each pertussis antigen
that was similar to or two to five times greater than
the GMCs induced by three or four doses of Daptacel
in the historical studies. Therefore, Adacel met the
non-inferiority criterion for GMC responses to
each pertussis antigen. Adacel vaccine induced booster
response rates to PT and FHA that were similar to the expected rates
in this age group. However, Adacel induced
booster response rates to Fim and pertactin that were lower
than the expected rates, with the lower bounds of the confidence
intervals not meeting the pre-specified criterion. Therefore, Adacel met the
non-inferiority criterion for PT and FHA, but not for
pertactin and Fim. In summary, Adacel
induced tetanus and diphtheria seroprotection
rates that were non-inferior
to TD vaccine. Adacel induced booster
response rate to diphtheria that was non-inferior to
TD, and the non-inferiority for the tetanus booster
response was not achieved. However, it should
be noted that 100% of Adacel recipients achieved
seroprotection antibody concentrations to tetanus, and Adacel vaccine induced
a robust anti-tetanus GMC of about 10 international
units per mL, representing an 8.6-fold
increase pre to post-vaccination. Therefore, the lack of meeting
the non-inferiority criterion for the booster response rate
should not impact clinical protection against tetanus. Adacel induced GMCs to
all pertussis antigens that were non-inferior to
those induced by Daptacel in historical studies, and Adacel induced non-inferior
booster response rates to PT and FHA compared to
the expected rates. Adacel induced booster response
rates to pertactin and Fim that did not meet
non-inferiority criterion. However, pre-vaccination
pertactin and Fim antibody concentrations
were five to 10-fold higher than those in the historical
comparison study, TD506, and therefore clearly
more difficult to induce a four-fold
rise in antibody. In addition, Adacel
vaccine met the pertactin and Fim non-inferiority
criterion for post-vaccination GMCs,
and the GMCs were two to three-fold higher in
the Adacel group compared to the historical Daptacel data. And finally, Adacel vaccine
induced five to six-fold rises of pertactin and Fim
antibody compared from pre to post-vaccination. Therefore, the missed
non-inferiority results should not impact clinical
protection against pertussis. With regard to safety, the most
frequently-reported solicited injection site reactions was
pain, with minimal swelling and erythema, and the most
frequently-reported solicited systemic reactions were
myalgia, headache, and malaise. The majority of injection site and systemic reactions were
a grade I or II in intensity, and all SAEs were considered
unrelated to vaccination. So just a few final thoughts
regarding the results of this study —
these results indicate that Adacel vaccine should
be safe and effective when administered eight to 12 years following a
prior Adacel vaccination. Data from other studies that
I’ve not reviewed today suggest that the safety is there as well for even shorter
revaccination intervals. And Sanofi Pasteur is
seeking approval from the FDA for repeat vaccination
of Adacel vaccine. It’s not infrequent that we are
asked by healthcare providers if Tdap vaccination is
acceptable when caring for patients who
do not remember, and for whom there may be no
documentation whether a prior dose of Tdap was received. Under various scenarios
such as wound management, individuals exposed to
a pertussis outbreak, people who are directly
caring for or living with young infants. If the FDA approves repeat
vaccination of Adacel vaccine, we hope that efficiencies
can be gained by not having to stock both Adacel or Tdap
vaccine and TD vaccines. Thank you. Thanks for your attention.>>Thank you very much. Some questions specifically
about this presentation — Dr. Atmar?>>Thank you, David. Was there — what was
the seroprotection rates pre-vaccination in the groups,
and were there differences in the geometric
mean concentrations between the groups at baseline?>>So for the –>>For tetanus, I’m sorry. For tetanus.>>– for — okay. So for tetanus, pre-vaccination
seroprotection rates at a .01 international unit
per mL, and .1 were 100% in both groups, and at 1
international unit per mL or greater, they were
in the 92, 93% range, and similar between
the two groups. And then, were you also asking about post-vaccination,
or just the pre?>>No, I was ask
— just asking — I was asking both about what
the seroprotection rates were, and what the geometric
mean concentrations were, whether there were differences.>>Yeah, the GMCs
were also similar between the two groups
pre-vaccination, yep.>>Thank you.>>Mm-hmm.>>So correct me if I’m wrong. After the first dose of Adacel,
you still get a reduction in the seroprotective rate. When you give every booster,
you get the same reduction. So what is there that shows us that the second dose will
help us have some more effect after a repeated dose?>>Yes, in the responses, as
you noted, to the second dose, does increase by anywhere from
five to 10-fold the antibody to tetanus, diphtheria,
and the pertussis antigens.>>But is there some –>>Right, and in –>>– you know, introduction
that you have, that we notice the first dose. So if that happens again,
what — you know, what –>>– right, and we do not
have at this time persistence after the second dose. So that’s an area of interest. If it does decline
at a similar rate — and I don’t know if that’s
the case, but if it does, then I think that one would
expect similar protection and waning immunity
and protection. I think the primary
point for me is that, with the single-dose indication,
and the current recommendations, what faces healthcare providers,
and what we receive as feedback, is they have patients for whom
they don’t know which vaccine or if a Tdap vaccine had
been given previously. And they feel a bit
cornered, because they would like to administer the Tdap
they have in their refrigerator, and yet, with the
single-dose indication, and there not being
any suggestion that another dose can be given,
and that it would be safe, they — they really
— they’re perplexed. They don’t know what to do, because they might
not have TD available, and they only have
Tdap in stock.>>So I think that’s a good
advantage to doing that, but it doesn’t take
away — if we do — or could we have the data to see if it will have the
same rapid decline that you have after
the first dose? I mean, it’s good to know
that if you have Tdap, you could use it, but
we want to know also — does it actually offer any
advantage, repeating this dose?>>Yes. Yes, so just
the — just the — the knowledge that it
would be safe, I think, would reassure many
healthcare providers.>>I’m sorry, could I just
ask that you specify — are there specific studies being
either undertaken or planned to look at antibody levels? That’s what you’re
asking, right? So I understand it’s
an area of interest, but can you just clarify whether
that data will be available for ACIP to consider as
they consider this issue?>>So with regard, for
example, to persistence of antibody, duration
of antibody?>>Against pertussis,
specifically.>>Against pertussis
— well, we — we appreciate the ACIP comments,
and we’ll definitely take that back, and see if we can
bring these subjects back for a repeat vaccination. I can tell you that,
among the many people who received the
first dose of Adacel, it was extremely difficult
to find them 10 years later. So we’ll certainly look for opportunities
to bring them back.>>Dr. Hunter?>>So I have a question about
tetanus levels of antibodies that are lower when you
do the Tdap, correct, than they are with TD?>>The quantity of
antigen in the vaccine?>>No, the antibody response.>>So the antibody
response to tetanus — so the booster response
— I’m sorry, yes. The — yeah, the booster
response rate was a little lower in the Tdap vaccine group.>>So do you have
any data and a model to project whether 10 years
later you’re still going to have enough tetanus antibody
so that you wouldn’t have to shorten the interval
of the revaccination?>>Yeah, so thanks — thank
you for that question. So while it’s true that the
booster response rate was different in the two groups, the geometric mean concentration
was clearly many-fold higher than the pre-vaccination level. And pre-vaccination of that
second dose, seroprotection — seroprotective levels of
tetanus antibody were at 100%. So while a — while the boost
is measured by a four-fold rise, was a little bit lower in
that Tdap vaccine group, the GMCs were as high in
the Tdap as the TD group, and I would expect there, 10
years later, to still have, you know, at or nearly
100% persistence.>>Thank you. Any other questions? Okay, I think if you’re
okay, we’ll go ahead and move on to the next talk. Dr. Leonard Silverstein, please?>>Good afternoon. I’m Leonard Silverstein from GSK’s clinical
and medical affairs. I want to thank the ACIP
and the CDC for inviting GSK to present our two Boostrix
revaccination studies, studies 009 and study 012. Boostrix study 009 and 012
were revaccination studies in which subjects who previously
received either Adacel or Boostrix nine or 10 years
previously were revaccinated with Boostrix. And these studies were done to
show that Boostrix could be used for the decennial
immunization dose of TD, and also to help inform policy. Over the next 15 minutes, I would like to show
you the diphtheria and tetanus seroprotection
rates, the pertussis antigen GMCs, the booster response
endpoints, and also safety data. Turning to the first
study, Boostrix study 009 — Boostrix study 009
was a continuation of Boostrix study 007, which was
conducted in 19 to 64-year-olds. Both studies were conducted
in the United States. Boostrix study 007, shown
on the righthand side of this schematic, was the
study which was the basis or indication for Boostrix
in 19 to 64-year-olds. In Boostrix study 007,
subjects were randomized to receive either
Boostrix or Adacel, and then persistence was
assessed at years one, three, five, and then subjects were
brought back in year nine for persistence and also for revaccination,
but with Boostrix. So the Adacel subjects
received Boostrix. The Boostrix subjects
received Boostrix, and also a control
group was added that had not previously received
either Boostrix or Adacel. Shown here are the
co-primary objectives that I’ll be sharing with you. They are D and T
seroprotection rates, pertussis antigen GMC
ratios, booster responses for all the antigens after
a second booster dose, or a first booster dose, and
also persistence of D and T at years one, three,
five, and nine. Shown here on this slide are
the secondary objectives. Included amongst the secondary
objectives is the safety endpoint that I will show you. With respect to the
study population, as shown in this slide, I’d like to just spend
one moment referring to how I will denoted
each of the groups. Tdap B, B for Boostrix,
denotes the subjects who received Boostrix
initially at year zero, and then Boostrix
again at year nine. Tdap A, for Adacel, denotes the
subjects who received Adacel at year zero, and then
received Boostrix at year nine, and the control group is as
I discussed a moment ago. I’d like to turn to the first
endpoint, which was achieved. Diphtheria and tetanus
seroprotection rates for revaccination with Boostrix
were non-inferior to vaccination with a first dose of Boostrix. In the Tdap B and
the Tdap A columns, as shown in orange boxes, over 99% of subjects achieved
seroprotection at a rate of .1, and shown in the blue boxes are that the non-inferiority
criteria were achieved. Turning to PT/FHA revaccination
GMCs, they were non-inferior to Infanrix GMCs in the infant
household efficacy study. And I’d like just to
spend a moment to explain that there’s no immunogenicity
level for pertussis antigens that correlates with protection. So efficacy of acellular
vaccines can be assessed by comparing post-vaccination
antibody levels in this study to those observed in a
population where both efficacy and antibody levels are known, and where the same pertussis
antigens were used to vaccinate. This is a regulatory-accepted
method of inferring pertussis
seroprotection. So in this study, the PT, FHA, and PRN immunogenicity
was compared to the immunogenicity
achieved by infants who received three
doses of Infanrix in the German household
efficacy study. And Infanrix contains the
same antigens as Boostrix. As shown in the orange boxes
on the slide, the subjects in this study achieved at least
a 1.5-fold higher GMC level for pertussis antigens
than the infants did in the infant household
efficacy study, and also, as shown in the blue boxes, non-inferiority criteria
were achieved. Before I show the booster
response endpoints, I’d like just to make a — spend a moment to review
what the criteria were. So for diphtheria and tetanus,
if the pre-vaccination was less than .1, there had to be
at least a .4 increase. If the pre-vaccination titer
was at least .1, there had to be at least a four-fold
increase, and depending upon, for the pertussis antigens, what
the pre-vaccination level was, there had to be an
either two-fold or at least four-fold
increase in GMCs. This slide shows the
booster response rates for Boostrix study 009. Non-inferiority criteria
were met for Tdap B and for FHA in the Tdap A group. What I’m going to do
on the next few slides, because of limitation of time —
I’m going to make several points about the Tdap B group. The same — the results for Tdap
A were similar in what I’m going to show right now, but due
to limitations of time, I’ll just show Tdap
B. If you take a look at the righthanded
slide, which is — these are the seroprotection
rates that I showed you after vaccination, and
the seroprotection rates for both D and T were over 99%. And if we turn to the righthand
side, where I show the increase in GMC from pre to
post-vaccination, it’s at least, for D and T, a 4.7-fold rise. And if we take a look at
the pertussis antigens, the pertussis antigens
had at least a 5.9-fold from pre to post-vaccination. The colors indicate
which antigen it is. Turning to safety — the solicited local and general
adverse events for the Tdap B and the Tdap A group were
higher than the group that received its
first dose of Boostrix. However, the grade III AEs, which are those little
hatched boxes within each symptom
area, were very low. Similar between groups, and
ranged between zero and 1.6%. I’d now like to turn
to Boostrix study 012. So Boostrix study 012
was a continuation of Boostrix study 01. 01 was conducted in
10 to 18-year-olds. This was a study
in which three lots of Boostrix were compared to TD. Both 01 and 012 were
conducted in the United States. 01 was the basis of our
licensure for Boostrix in this age range, licensure
that we received in 2005. The subjects in 01 were
brought back at 10 years. Those who received Boostrix in the first study
received Boostrix in 012. Those who received TD
received their first dose of Boostrix in 012. Shown here are the study
— is the study population, also how we denote the groups. The TD group is the
group that got TD at year zero, Boostrix
at year 10. Tdap — Boostrix at year
zero, and at year 10. We had planned to enroll 500
subjects, but we were only able to get back 165 subjects. But a sensitivity analysis
of persistence was done, and there was no apparent
bias based on the dropout. In terms of co-primary
endpoints, again, D and T seroprotection
rates, and also GMC ratios, and as secondary objectives,
the booster response, and also a safety endpoint. So turning to the results — diphtheria and tetanus
seroprotection rates for revaccination with Boostrix
were non-inferior to vaccination with the first dose of Boostrix. As you can see on the
slide in the orange boxes, seroprotection rates were
100%, and the blue boxes show that the non-inferiority
criteria were met. Turning to the pertussis
GMCs, the GMC ratio that I discussed previously — in this study, the GMCs were
non-inferior to the GMCs in the infant household study, similarly to what we
saw in Boostrix 009. The GMCs, shown in
orange on this slide, were at least two-fold or
greater higher than the GMCs in the infant household study, and also the GMC non-inferiority
criteria were achieved, as shown in the blue boxes. With respect to booster
response rates, non-inferiority criteria
were not met, but I’d also like to show you again what I
showed for Boostrix study 009. Percent seroprotection at
the level of .1 was 100%, and the GMC fold-rise from
pre to post-booster was at least three-fold
or higher for D and T. And if we take a look
at the GMC fold-rise for the pertussis antigens, it
was at least a 6.5-fold rise from pre to post-vaccination. And with respect to safety,
the percent of subjects with solicited local and general
adverse events was higher for the group that received
two doses of Boostrix compared to the group that received
its first dose of Boostrix. And, as you can also see in
the pink boxes, the incidence of grade III symptoms
were extremely low, and were similar
between the groups. So in summary, Boostrix
study 009 and 012 were revaccination
studies in which subjects previously
vaccinated with either Boostrix or Adacel were revaccinated
at either nine or 10 years with Boostrix. Both studies met primary
endpoints of diphtheria and tetanus seroprotection
rates, and pertussis antigen GMC
ratios, and as I explained, that is an accepted method of inferring pertussis
seroprotection. Booster endpoints were missed. Over 99% of subjects
had diphtheria and tetanus seroprotection
rates above .1, but if we look at a seroprotection rate
for D and T 10-fold higher, a seroprotection rate of 1,
over 91% subjects achieved that higher seroprotection rate. And in terms of pertussis
antigen GMCs, there was at least
a 5.9-fold increase from pre to post-vaccination. Local and general safety
symptoms were generally higher after dose two than dose
one, and as we discussed, grade III symptoms were similar
after dose one and dose two. So in conclusion, Boostrix,
when administered to adults 19 to 73 years of age,
nine to 10 years after previous vaccination, is
immunogenic and well-tolerated. Thank you very much, and I’d
be happy to answer questions.>>Dr. Messonnier?>>Yeah, I’m just going to ask the same question
I asked Dr. Friedlander. What studies do you have
planned, or can you provide data to ACIP around the duration
of the immunogenicity of the pertussis components?>>After the second
booster dose?>>After the second
booster dose.>>It’s something we’ll have
to take back and discuss.>>Ms. Hayes?>>Carol Hayes, the American
College of Nurse Midwives. I have a question for both
GSK and Sanofi Pasteur. It’s the same question for both. I’m very excited that
you have new data. I would like to know, when you
submit your data to the FDA, do you have any intention
of presenting data on safety in pregnancy, that this
vaccine is safe in pregnancy? And will you be submitting that
to the FDA, so we can remove that language from
the package insert?>>That is something that we
are considering for the future.>>Thank you. And my next question –>>We are intending — we are — GSK is intending to submit
an SBLA for inclusion of the revaccination
data in our label.>>– thank you. And my next question is, do you
have any intention on the future to create a pertussis-only
vaccine? Pregnant women everywhere
would love you if you did.>>Okay, so what I can say is –>>I would love you if you did.>>– so what I —
what we can say now is that GSK is evaluating the need
for a new pertussis vaccine in light of the observed
epidemiologic dynamics of pertussis. The different options that
could lead to improvement of a current pertussis
vaccine are under evaluation. So everything is
under evaluation.>>Thank you.>>Thank you. Dr. Greenberg, would
you like to respond to that question as well?>>Yes. David Greenberg,
Sanofi Pasteur. For the pregnancy indication or
language, we’re working with FDA on updating the label,
along with this submission for the revaccination, based on the newer FDA
guidance on pregnancy. And as far as a single
pertussis antigen, or a single pertussis vaccine,
that is something that is under consideration, and
we’ll have to get back to you on determination of that.>>Thank you.>>Thank you. Any other questions? I believe — oh, sorry,
Dr. Lee?>>Mostly just because it
went by really quickly, and I might’ve missed it. Could you go back
to slide 12, please?>>Sure. Let me go back. Oh, thank you.>>Oh, wow. That was fast.>>Yes.>>So I just wanted to
make sure I understood. So I understand that there’s an
increase pre-Tdap be to post, but it looks like
there’s also an increase in the control group. Is that –>>In the what group?>>– is that pre-control
versus post-control?>>Yes.>>So the difference between
the two — are they significant, and why did it go up
in the control group? Am I reading that correctly?>>Yes, you are. So one thing is — let me look
at the question another way, because it’s a very
good question. The two groups, in terms of their baseline GMCs,
are not comparable. If you look at the
GMCs over here, there is a multi-fold difference
between where the group that had already received a
dose of Boostrix or a dose of Adacel — in this case,
it’s a dose of Boostrix. You can see how much higher
— eight-two versus five-four, 42 versus 26, 63 versus 17.8. So that when we were looking
at a booster response, we’re not comparing
groups that are equal. The group that received one dose of Boostrix has a higher
starting point than the group that never received a dose of
Boostrix, or a dose of any Tdap. So immunologically, it
is harder to be able to achieve the multi-fold
booster response criteria that we set for ourselves
in these clinical studies.>>And is the increase
in the controls related to background exposure?>>Yes.>>Okay.>>Probably.>>Okay.>>That’s probably all the cases
of pertussis we can’t prevent.>>Dr. Greenberg, would you
like to respond as well?>>Dr. Leonard, from GSK. Just so we can just
clarify a bit more on this, the control group is receiving
Tdap for the very first time. So they will have a — it’s showing the control is
having a response to Tdap.>>Thank you.>>You’re welcome.>>Sorry about that,
Dr. Greenberg.>>Okay, well, I believe Dr.
Havers has a few more slides, unless we have any
other questions. No? Any more?>>I don’t have actually
any more additional slides, but we would like — we have
a few minutes, I believe, to ask the ACIP members
what they would like to be hearing
in future sessions. As we mentioned previously, this
is a newly convened work group, and these are the issues
that we’re going to be — we will be addressing. But are there specific questions
or specific data that ACIP would like presented at
future meetings, and are there other
specific policy options or other considerations that the
work group should be addressing? So we would — if you
— I’m opening up the — if you have any questions for
me, based on my presentation, or if you have specific
issues that you would like to see addressed
at future discussions, that would be helpful.>>Thank you. Dr. Hunter?>>I’d just like to
second the pregnancy and pertussis-only information.>>Pregnancy and pertussis-only
information, okay.>>Dr. Goldman?>>Thank you. So also very supportive
of having the Tdap in whichever company at the
10-year to replace the TD. From a private practice
perspective, the purchasing cost between TD and Tdap is
negligible, so information for the ACIP as far as what
it would cost to purchase in the private sector
would not make much of a difference between the two. And I think it’s
just much easier to give Tdap every 10 years.>>Thank you. Ms. Cinchfield?>>Yeah, Patsy Cinchfield,
NAPNAP. I’m always curious on
vaccines in the pipeline, so ending the manufacturer
presentations with what’s on the horizon would be helpful.>>Okay, thank you. Dr. Stephens?>>Just some additional
information — there was this — the issue of strains, and the
strain variability has been, and continues to be, an issue,
and updating us on where that stands would be helpful.>>Okay. Specifically, it
would be helpful for us to hear if there is — I presented data from the previous ACIP work
group and the various topics that they had gone
over specifically to address the Tdap — whether
or not Tdap should be allowed to replace the decennial
TD booster. So if there are aspects I hear
— some issues about pricing or concerns, but if there
are specific areas related to our terms of reference,
we’d be interested in hearing what you would most like to hear presented
at the next meeting.>>Dr. Moore?>>It was — thank
you, Kelly Moore. It was very helpful to see the
information on a second dose. If there are any available
data on the responses to multiple repeat
doses of Tdap, that might also be helpful. I don’t know if there are any
available, but if there are, seeing if there’s a
diminishing return, or if there’s any other things
that you wouldn’t expect to see after just a single booster dose as presented here,
that would be great.>>Okay, thank you.>>Dr. Hunter?>>I would want to know whether
allowing repeat Tdaps is going to actually increase the uptake
of Tdap in general in adults for the first dose, because
people aren’t worrying about whether they
had it before, and you’ve actually
documented it. And if so, if there’s any
projections on if that — if you can project
at all whether that would have any
effect on epidemiology.>>Okay.>>Thank you. Dr. Amar?>>So you told us the previous
consideration in term — from an economic analysis
was that it didn’t look like it was cost effective
to prevent pertussis. But here, I mean,
we’re hearing that, in terms of the availability of
the vaccine in private practice, or in different healthcare
settings affects the ability to deliver it, and potentially
does not really change the cost, at least to the practitioner. Some economic analysis
on what the impact of the change might be
would be useful, also.>>Okay. And we have an analysis
underway now that that’s — likely could be presented
at a future ACIP meeting. Okay.>>Dr. Frey?>>I would be interested to
know if there has been a look at tolerance to these antigens, and if that significantly
affects any of the three antigens
in the vaccine. And how often do we anticipate
that this vaccine will be given in anyone’s given lifetime?>>That’s an excellent point. Okay.>>Dr. Lee?>>Thank you. I would love it if we’d be
able to take a look at whether or not there’s any disparities,
in terms of epidemiology, vaccine coverage, and then also
just getting an understanding of the populations that
are included in the — any trials that are done.>>Okay.>>Dr. Stevens?>>I just finished
international travel. I went to my travel clinic, and
they recommended Tdap as opposed to TD for my 10-year booster,
so I think that the issue of travelers would
be something also to consider in this discussion.>>Travelers, okay.>>Great.>>Well, those are
very many useful — those are many useful
suggestions, and we really appreciate
the feedback. And we’ll be — we’ll be talking
as a — with the work group, and forming the agenda for
the next couple of meetings, but we certainly appreciate
your feedback for this session, so thank you very much.>>Sorry, one more question. Dr. Hayes — Ms. Hayes?>>Yes, Carol Hayes with
ACNM. One of the things that Caroline Bridges and I had worked on was whether or not certain
states are covering Tdap in adults. It’s an unknown question that no
one seems to be able to answer. Most states have expanded
Medicaid, but not all states. And so, do we have
any new data on states that are not covering
Tdap in adults, which would affect
pregnant women on Medicaid? And if Caroline Bridges
could snap that data out of the ethos,
we would love it.>>Great. Thank you so much. So it is five after 1:00. We would — this is
the end of the sessions for today prior to
public comment. I would like to propose that we
take a five-minute break before public comment to give
people a chance to stand up. That will still give
us plenty of time. The meeting does have a fast
— hard stop at 1:45, and so, if you guys could quickly take
a break and be back here at 1:10 to start public comment,
that would be excellent. Thank you. Okay, everyone, please
take your seats. I want to make sure we
have the full 30 minutes for public comment. So a couple of announcements
before we have public comment — first of all, I just
— I really want to extend our sincere gratitude
to all the members of the public who attended and provided
comment at this meeting. I know several of you
traveled really far, and we really do
appreciate that. We do have a considerable
number of individuals signed up right now for public comment, and we do have a
hard stop at 1:45. Unfortunately, some of the ACIP
members have planes to catch. So to ensure we have time
to hear as many individuals as possible, we would really
appreciate your limiting your comments to three minutes. This will allow us to
get through everybody, and to make sure that everyone
has an opportunity to be heard. So we can go ahead and get
started, and if you would like for me to signal
you when you’re about three minutes,
I can do that. I will just — I’ll actually
hold up a three for you guys, so that you guys know
you’re at three minutes. So I’m going to go ahead
and announce the order, and please come up in order. So the first is Destiny
Maynard, and then Hillary — excuse me, then Elijah
Mendoza-Bunch, then Hillary Simpson, Russell
Meyers, Laiar De la Vega, Erin Osbin, Laura Seminelli,
Brandi Vaughn, Tia Severino, Susan Corrigan,
Jamie Lynn Juarez. So if — Destiny, are you ready?>>Yeah.>>Great, thank you.>>Hello, everyone. My name is Destiny Maynard,
and this is our son, Christopher Bunch, born
December 5th, 2003. I’m here to help
spread awareness, to plea to the people
who call the shots. Christopher was not your
average son or child. He was — he was special,
not just to us, but to anyone who was ever fortunate
enough to meet him. He was such a leader, and
so compassionate to life. He was an honor-roll
student with a GPA of 3.9. He also loved playing
baseball and football. Christopher, along with his
best friends and girlfriend, were beginning new journeys
in their lives — high school. They all had such high
expectations for this year — first dance, meeting new people, and as Christopher would
say, better lunches. But all that changed for Christopher on
August 14th, 2018. His friends attended
high school games that he should have been at,
and playing in, but wasn’t. His girlfriend attended her
first high school Homecoming dance without Christopher, all
because on June 29th, 2018, I trusted my son’s doctor — my
son’s doctor’s persistent advice about the HPV vaccination. This is a preventable — or,
“This is a preventative,” he told me, “and I will be
giving it to my children.” God, do I wish I knew
then what I know now. By July 20th, Christopher
was complaining of headaches. By July 31st, a sore throat and
headaches, and by August 6th, Christopher was very ill and
vomiting at football practice. On July 8th, we went
to the local ER, where we were transferred to the Iowa City Children’s
Hospital on August 9th. On August 10th, from a
regular room to the PICU, because Christopher’s condition
was rapidly deteriorating. On August 11th, the
most terrifying thing that I have ever witnessed
in my entire life — Christopher stopped
breathing on his own. On August 12th, the swelling
in Christopher’s brain was so severe, the only
option they had to potentially save my son’s
life was to perform a craniotomy on the right side of his skull. Unfortunately for Christopher
and our family, the damage was so severe that he was
pronounced brain dead. On August 14th, his
father and I had to make the decision no parent
should ever have to make, to unhook our baby that we
had raised from life support. We will never get to
kiss our boy again, or hear his voice tell
us how much he loves us. He will never graduate
from high school. He will never get married, and
he will never have children. That has all been taken from us. You voted on October 25th, 2011 to offer the
Gardasil shot to boys. How does it feel knowing
that your vote killed my son? I also have a letter that Christopher’s
neurologist wrote to us. “In many cases, the patient
received a vaccination shortly before the onset of the disease,
thus strongly suggesting that this immune-medicated
disease is triggered by vaccinations in
at least some cases. Furthermore, the human
papilloma virus vaccine has been specifically implicated in
several published reports. Christopher received
a vaccination against HPV one month
before the onset of ADEM. Therefore, strong consideration
must be given to the notation that the HPV vaccination
triggered the ADEM in this case.” Thank you.>>Thank you. [ Applause ]>>Mr. Bunch, are you –>>Yes?>>– are you speaking as well? Okay.>>My name is Elijah Bunch. As you just seen, we was up
here with my son’s mother, and it’s affected us terribly. There was so much I wanted to
say, but his mother and I kind of compiled stuff together
in a short period of time. And I wanted to ask you guys, seeing that this is
being broadcast live, and I’m not as smart as
a lot of people here — but I want to get some
words out for my son. If I could invite somebody
to come up here and kind of help me speak just a minute
or so, would that be okay?>>Sure.>>Brandi, would you come
up and help me, please? Thank you.>>We were told that we
might run out of time today, and I wanted to go into
some of the science that they had just spoken about. So as she mentioned, and as
the neurologist mentioned in his comment, in his
letter, there are multiple — dozens of studies linking
Gardasil particularly, but the HPV vaccine in general
to ADEM, and multiple paralysis, autoimmune-mediated diseases. I have 50 studies right
here, and I tried to get them in the hands of the working
group, but I was not told that that was a possibility. This is just a selection of
over hundreds of studies, case reports, but also
epidemiological studies and metaanalysis showing that there are serious health
issues following the HPV vaccination, not just in
the U.S., but all over. So, in fact, you know, there’s
60,000 adverse reaction reports to VAERS, again, regarding the
HPV vaccine in the 12 years — 12 years it’s been
on the market. There have been 432 deaths, not even including
Christopher Bunch’s, because his is not
included in the numbers yet. If this was a pharmaceutical
drug, would it still be on the market? You know, I would love an
answer to that question. I know you guys don’t
answer public comments, but Christopher Bunch should
never have been sacrificed as a test subject on a vaccine that hasn’t been tested
properly, and has shown so many adverse events. So in 2010, the HHS decided that Harvard Medical School
should do a report on whether or not VAERS was being
used, and according to that Harvard Medical
School study, fewer than 1% of vaccine reactions
are ever reported. So this is Harvard
Medical School. This is not us. This is not Christopher
Bunch’s parents, okay? We’re giving you the information that pharmaceutical companies
are not, and we may not be able to stand up there and
present in a PowerPoint, which I would love
to do one day. But this information
needs to be looked at by every single
member on the committee. So if you use this estimate from
Harvard Medical School report that was funded by the HHS,
that would mean thousands — thousands of children have
died after this vaccine, and millions — millions
have been possibly injured. And yet, this vaccine
is still on the market, and the newest version,
Gardasil 9, has twice as much of the aluminum adjuvant which
is in most of these studies as the antigen that’s
triggering the autoimmune-mediated diseases. Twice as much aluminum,
and twice as much of the virus, as well. So I’m going to speak later on
whether it even causes that, but thank you, Elijah,
for giving me that time, because he wanted me to help
him go over the science, to show you this is not
just their personal opinion.>>Thank you all so much
for giving us a minute, and hearing our story. Thank you.>>Thank you, Mr. Bunch,
and thank you, Ms. Maynard, for sharing your story with us. Next, Ms. Hillary Simpson?>>Good afternoon. My name is Hillary Simpson. I am the founder of a
nonprofit called Crazy Mothers. We work at spreading vaccine
injury and recovery awareness, because that’s the crazy thing. If you catch your child’s
vaccine injury early enough, you can recover them. You can heal them without the
use of a single pharmaceutical. But enough about me. We’re here to talk
about you, and really, I just have a couple
of quick questions. The first question is, who? Who in here thinks it’s okay to
recommend 72 doses of vaccines to children without doing a
single cumulative safety study? Who in here thinks that
it’s okay to refuse to do a vaccinated versus
unvaccinated safety study so that we might truly be
able to assess the advantages and disadvantages
of vaccination? And who in here thinks
that it’s okay that 54% of our children are suffering
from a chronic illness, and one out of 36 of those
children will be diagnosed with autism? My second question is, what? What are you, as the
committee working with the regulatory
agencies tasked with protecting the
public’s health — what are you going to do about the vaccine-induced
autism epidemic, and the vaccine-induced
autoimmune epidemic this country’s currently
experiencing? What are you going to
do about the generation of children that we have lost? How? How are you
going to continue to explain away those autism
rates as they go from one out of 36 to one out of 25, one
out of 15, and eventually one out of two, which will
be by the year 2032, according to
Dr. Stephanie Suniff, if the numbers continue
to increase at the rate they’re
currently at? How are you going to
persuade those mothers, having children 15, 20
years down the road, when the vaccine
injury epidemic is so blatantly obvious it
becomes impossible to ignore? And lastly, when? When are you going to start
listening to the hundreds of thousands of parents
screaming from the rooftops that these vaccines injured
or killed their children? When are you going to start
actively working towards a resolution for this
massive problem? And when are you going to
stop hiding behind the — we don’t know why our children
are so chronically ill. We don’t know why we’re
experiencing an autism epidemic. We don’t know why. Because we do. Us crazy mothers know, and
we’re healing our children — biomedical treatments,
holistic modalities, naturopathic medicine. We’re healing our
babies, and if that — if that makes us
crazy, so be it. Like I said, let us know when. Thank you.>>Thank you. Russell Meyers?>>Hi, I’m Dr. Russell Meyers,
National Health Federation. Ladies and gentlemen,
we have a problem. Clearly, there’s
been a disconnect between trusted health officials
and those people that you serve. You say that vaccines
are safe, effective. We believe you. We receive them, and
when we get injured, we are ultimately ignored and told there’s zero
science backing the claims. Needs to be addressed
somewhat properly. It is unclear to me what
scientific evidence you have been reading to make the
claims that vaccines are safe, considering the — that even the
father of modern-day vaccines, who literally wrote the book on
vaccines, can’t defend the — this medical procedure’s safety under oath during his
deposition earlier this year. But further than that,
seeing the extreme lack of proper evidence
presented in this room today and yesterday is
quite terrifying. All these safety studies
using the word placebo, when in reality, it’s an
adjuvant-containing placebo, or in some cases, like
the HPV ones over here, it was a straight shot
of aluminium hydroxide. It’s misleading,
to say the least. This speaks volumes for lack
of knowledge that is known and in this area, no
matter how much one says that vaccines are safe. According to the Supreme Court, they are unavoidably
unsafe by design defects. Your vaccine safety
studies comparing those who get fewer vaccines to those who get more vaccines is
obviously flawed, and at worst, criminal, considering
the dire consequences. Your epidemiological
studies have not held up to scientific
scrutiny, and have — worse, have been shown to
be revised multiple times to get the designed results. Not only losing faith
with the people, but losing your reputation
in the process, especially when we see the
CDC testifying in Congress, blatantly unaware of any vaccine
peer-reviewed studies showing how much damage they do cause. This looks more of a political
issue than a scientific one. The biological studies, the
mechanism of action studies of vaccine adjuvants,
and ingredients such as aluminum
hydroxide, aborted human DNA, are clear that not only do
vaccine adjuvants cause damage, it’s just a matter of how much. Many of these ingredients have
even been found to be neurotoxic at parts per billion by
themselves, but when added to the vaccine at
1200 micrograms, suddenly becomes safe. There’s a large gap, as far
as I see it, of understanding, or a problem extrapolating the
evidence from basic science to the clinical science realm. Now, I understand that
there will be pushback seen under the umbrella
of public health, but this is at the
expense of taking lives and giving debilitating
injuries, like paralysis, encephalitis, myelitis, death,
all without informed consent. CDC and doctors telling
the parent that the only real side effect
of a vaccine is the redness and pain at the injection
site whilst death and lowered consciousness is
listed is not informed consent. You have not done a
good enough job to show that these things are safe. The majority of those opposed
to vaccines all believed in vaccines until their child
or themselves were injured at the moment of injection,
and would have wished at least to have been informed
of the risk akin to surgery risks before
they get the surgery. Before they sacrificed,
you know, to the medical community then — which the medical
community disregards and ridicules after performing. It concerns me from what
I’ve seen from this panel and from conversations I’ve had
here from top vaccinologists that most people here
cannot comprehend any idea on how vaccines can
even cause damage. The science is clearly
not settled, and from what I’ve seen today,
not even looked at properly. Let’s do this right this
time, not have like another [inaudible] study incident, where meetings are held in
private to go over the problem that simply won’t go away. Thank you very much.>>Thank you. Ms. Laiar De la Vega?>>Hi, Lyra, yes. My name’s Lyra De la Vega. I am here representing also
the National Health Federation. I don’t have a vaccine-injured
child. I don’t have any children,
actually, and it’s — in an environment like
this, it scares me out of having children, because
I don’t want anything like this to transpire with my
child that’s happened to many of these families. But I’m here to represent
NHF, and I’m 100% against vaccinations,
just so that you’re aware. As of the beginning of October, the National Vaccine Injury
Compensation Program has paid out about $3.9 billion. I don’t know how many of
you are aware of that. I don’t know what you
all are aware of much, but that was created
in the 1980s. And this number continues
to go up. The fact of the matter is that if safety reporting was
done properly and truthfully, we would be paying
out in the trillions, financially crippling
our nation even more. And I say that because
there’s merely a 1%, as Brandi Vaughn said, there’s
reported vaccine adverse events, So — and I say we, because
it’s common knowledge that — amongst attendees like myself, that pharmaceutical
companies are liability-free, which is criminal, and these
vaccine injury payouts are compliments of the
taxpayers now, and have been for
quite some time. Now, my comments on VAERS, the Vaccine Adverse
Event Reporting System — I’m here representing the
oldest health organization in the world, and we
have very deep concerns about your scientific
data related to vaccine safety
and effectiveness. Sorry. The mere fact that
VAERS even exists indicates that you all have
admittedly acknowledged that adverse events do occur,
and we know that they exist because we’ve paid in the
billions, like I pointed out. And since there is a risk for
adverse events, my belief is that there must be
choice as to whether or not we want to
take that gamble. And I say gamble because
everybody’s chemical makeup is completely different, and
if you guys don’t know that, none of us should be here, and
we should really be freaking out and going back to the drawing
board, which we should be doing. Now, with regard to VAERS, when this panel uses VAERS
post-market adverse reaction surveillance, it sounds and seems very formal
and matter-of-fact. But when VAERS is
actually used by us, it’s basically a random
free-for-all for those that are even aware of it, and the masses are
not aware of VAERS. And that is very dangerous. Now, since you’re all taking
all of these situations as matter-of-fact
post-marketing surveillance, I don’t understand this —
that this is usable data, especially because only
1% are even reported. So to say that these
assessments are way off are a gross understatement. But at this point,
I’m just going to — I want to urge you all —
I’m imploring you, if I can, to please place urgency on
VAERS for what it’s meant to be, to receive proper data. And also in making — I want to
make it an absolute requirement for health officials to have
a vaccine adverse event safety conversation with the
recipients of vaccinations, as it is their right to be aware of what horrible
things can come to them. Recipients of vaccinations
must be informed on what to do and who to contact, so that all of you can finally use
close-to-factual data when making such important
decisions for people of our country that are
indoctrinated to trust you. You guys couldn’t even determine
yesterday what ultimately the definition of homelessness
even was. What kind of data
are we working with? I mean, you voted
yes to vaccines. You’re voting — you’re voting
with data that’s incomplete. It’s not a fair assessment. We have no business
being here right now. As far as I’m concerned, not
only is the science not settled, it hasn’t even been conducted. I feel like I traveled across
the country from California only to watch a biased panel go through the motions,
and we’re at the CDC. I’m not a singular
individual speaking out against vaccinations. This happens to be
a movement now, and one that’s growing
rapidly and exponentially, and not because we love
or even like each other, but because you’re creating more
of us every single time you vote in favor of implementing more
questionable vaccinations. Thank you.>>Thank you. Laura Seminelli? And I just want to remind
people to please try to keep under the three minutes, so
that we can listen to everyone.>>I’m a little shorter
than she is. I’ll try to talk fast. I don’t come here
with any degree. I come here as the public. I live locally. You are our one and all. I’m going to start with a
quote by William Wilberforce, and he stated, “You can
choose to look away, but you can never say
you don’t know again.” I just retired from a
local hospital here. No one believes in
the flu shots. My colleagues — I didn’t,
because the efficacy — and I won’t give you data. You created the data. Ten percent one year, 18%
the next, 40% at best. The flu medicine you inject — you gave to our children
from two to eight years for almost four years
— it never worked, 3%. Oh, well. You know, I worked in
a hospital where my colleagues, doctors, and nurses, and medical
assistants, and patient care and lab — we didn’t
believe in the flu shot. We were probably at 40%,
and then came your mandates. And then came your
recommendations. So you know what? For four years before I retired,
I put a mask on 12-hour shifts. It wasn’t easy to breathe, but that’s how much I didn’t
believe in your efficacy. My colleagues didn’t
believe in it either, but some of them couldn’t
wear that mask for 12 hours. So in the beginning, they said,
“I’m just getting the shot. I can’t wear the mask.” But in the truth — the
public’s truth, my observation, which is the first step
in scientific theory — they didn’t believe
in your shot. This year, I retired. I’m grateful for that,
because my soul was sick at what I saw go on. That flu shot was crazy. At first, it was 10%. How can you do data? Which 10 got the
shot out of 100? Then it was 30, and then
you get up here today and make new implications on
our children, and combined four. Really? You govern
globally and this country. I’m glad I’m retired now,
because now I can talk to you. Because you know what? While I worked, I couldn’t, because if I did,
conflict of interest. I would’ve lost my job. That’s truth. A lot of my colleagues
did lose their jobs. I was one of the few
hospitals in this city that allowed us to mask. I can name five hospitals
that don’t. Goodbye, pink slip, no flu shot. How did I survive 20 years and never get the flu
in that environment? ER, high volume. Was I not on the front lines? Every flu case, 300 people a day
— every flu case, it was me. I never had the flu. You know why? I knew how to wash my hands. I knew how to take
vitamin D. I knew how to take out [inaudible]. I don’t approve of
your flu shot. Now you have pharmacists
giving it. You bribe us with cards at
Target, and you tell us, “This is free, and
it’s everywhere. And get it, get it, get it.” They’re scare tactics,
and you should be ashamed. And then, I will end, because I
do want my colleagues — my — the other moms that know what
the CDC doesn’t do for us. Robert F. Kennedy, Jr.
— he fights for us. He does. He goes, and
goes to court for us, for our kids that suffered. I’m looking around. Some of you are my age, and
if I’m mistaken, I apologize. But I’m in a generation
where I got seven shots. Twenty-six years later,
my daughter got 10. Her son got probably 60. My new grandson’s
expected to get 72, and I just watched you add more. I’m appalled. My grand — Robert Kennedy,
Jr., you know what he says? His family started
Special Olympics. There were no autistic kids. He says that, “Where are the
40-year-olds wearing diapers with helmets on at the mall?” If you misdiagnosed them
— if you missed them — because you say they’re not
vaccines, that they missed them. Where were the special
ed classes when people of my generation —
there weren’t any, because they didn’t exist. That’s what he says. Do you know — and it’s truth, but you know what’s
going to happen? I have a 10-year-old grandson,
and I don’t care what you say, that the autism and
vaccines don’t exist. It does, because I watched
a perfectly healthy, beautiful two-year-old
get those shots, and become a severe
autistic child. And guess what? He will be 40, walking
in the mall with a diaper on and a helmet. Thank you for the
studies that you don’t do.>>Thank you. Ms. — Ms. Brandi Vaughn?>>Hi. So a little bit earlier,
I gave you the statistics on the VAERS results
for Gardasil. I’m going to talk a
little bit more about it, and about the science,
about what’s going on here. It’s clear that this
vaccine, Gardasil, is harming more children
at epidemic proportions. So what are the benefits? Why would you add it
to the adult schedule? I mean, the science
is slowly showing — does HPV even cause cancer? There was a great study out
of the University of Berkeley by a well-known professor,
Peter Duesberg, that showed cervical carcinomas
are not caused by the HPV virus. It is a passenger
virus, a latent virus. We all have latent
viruses in our body. Because it’s in a carcinoma
does not mean it caused it. So, quoting him, he says, “Since
there is no scientific evidence that it will do anything
else” — HPV — “will do anything else than
occasionally cause warts, which will be eliminated
by the immune system, there is absolutely no need for
vaccination against this virus.” His basis for this perspective
was an in-depth study that he did in 2013 with
colleagues from University of California Berkeley,
and it was published in “Molecular Cytogenetics”
under the title “Individual Karyotypes at the
Origins of Cervical Carcinomas.” He is one of the leading
experts on cervical carcinomas in the world, and the study
states there is no direct functional evidence that
cervical carcinomas depend on the latent papilloma
virus viral sequences. So not only does evidence show
that HPV is not the real cause of cervical cancer,
newly-released cancer data — cervical cancer data
out of countries that implemented the
HPV vaccination at — more heavily than the U.S. —
so the UK, Norway, and Sweden — are all showing increased
rates of cervical cancer in the population that was
vaccinated, up to 90% in the UK. This is not happening in
the older populations. I have the numbers, and
I have the research here. So, in Norway, before
the HPV vaccination, cervical cancer rates
had fallen sharply, but since widespread HPV
vaccination campaign in 2009, cervical cancer rates have
increased and nearly doubled — doubled between 2004
and 2015 — doubled. The rate continues
to trend upwards. We’re looking at a vaccine that
is actually causing an increase in cervical cancer rates. So, what happened in the UK? The youngest group age reported for cervical cancer
rates that’s tracked by the government, 20 to 24. The change before and after
the HPV vaccination campaign, which covered 90% of
the — of girls began — it’s shocking, and this should
cause every single one of you to rethink this push
to have girls and boys, like poor Christopher,
vaccinated for HPV. So between 2002 and
2009, in the UK, the last year before the
vaccination campaign started, cervical cancer incidence
decreased 40% in girls age 20 to 24. It decreased 40% before
the vaccination campaign, in the six years directly
before the campaign. In 2009, the year the
vaccination school campaign achieved 80% coverage
rate for girls 12 to 18, the incidence decreased —
it slows, and then stagnates. So it was going down,
and then it stagnates. By year 2011, cervical
cancer begins to increase in girls age 20 to 24 only,
not in older populations. These are the girls –>>Excuse me, I am so
sorry, but I’m going to have to ask you to wrap up.>>– this trend is so
pronounced, between 2012 and 2015, cervical cancer rates
increased 45% in the population that received the
vaccine — increased 45%. Older women did not
show an increase. So, how did it happen? I’ll be brief.>>Please.>>This 2012 study by Dr.
Lee, published in “Journal of Inorganic Biochemistry,”
shows the mechanism of action, the HPV gene binding to the particulate aluminum
adjuvant in the HPV vaccine. So it’s taking aluminum
to the reproductive area, because HPV is a
reproductive virus, and it is possibly the
mechanism of action that is creating the increase
in cervical cancer risk. So when you vote to add
this to the adult schedule, you are voting to increase
cervical cancer in this country for a vaccine that is causing
widespread side effects, and has never been proven to
reduce cervical cancer rates, not even proven to
reduce one case.>>Thank you so much. We really appreciate it.>>So please, vote no to
add it to the schedule, and please do the studies
and pull this off the market. Thank you.>>So we only have a few more
minutes for public comment. I would really like to
know if there’s anybody who hasn’t spoken yet who
we would like to hear from. Have all three of you
spoken in the past?>>I will be brief.>>Okay, thank you.>>I said quite a
bit yesterday, so –>>Great. And Ms. –>>Oh, okay. Oh.>>Hi, I’m here as a
member of the public. I’m also an engineer with
my master’s in engineering, and I’ve been here
over the past two days, just observing the
studies and looking at the work that you’re doing. And I’ve seen a lot of
competent scientists, and a lot of wonderful
physicians who are doing great, but I did have a couple of
concerns that I wanted to raise. The first concern is that the
studies I’ve seen are very linear in nature. You’re giving the — the
subjects are given the vaccine, and then immediately measured
to see how much their auto — how much their immunity
increases. My concern with this
is that you’re assuming that these vaccines don’t
have consequences later on down the road. I would really like to see
you direct more money towards studies that look at the long-term
consequences of these vaccines. My second concern
is prioritization. As I’ve sat here, I’ve
seen that you looked at Japanese encephalitis
that affects people that go to the Philippines for
over a month, and — while in our country
we have children that their autoimmunity is
being damaged by the day. And I hope that you
will reprioritize. Thank you very much.>>Thank you so much. Ms. Severino?>>Thank you. I said a lot yesterday, so I’m
going to make this very brief. I have two lists
to read you, okay? I want to start with a quote
by Dr. William Thompson, who is still employed
here at the CDC. I’m sure you all know who he is. Dr. Thompson said,
“Here’s the deal. The CDC — they’re paralyzed. The whole system is paralyzed, and the whole branch
is paralyzed. And it’s becoming
more paralyzed. There’s less and less being done as the place is coming
to a grinding halt.” He was referring to autism. Autism seems to be paralyzing
the CDC, and he should know. So I just want to read
you a quick list here. These are the theories
of autism causation. Started off, it was
refrigerator moms. That was a good one. Then there’s the genetics,
better diagnosis, toxins, but not from vaccines. This one’s good. Advanced paternal age — okay. Wireless exposure, rubella
in pregnancy, biological, encephalitis, untreated
PKU, pesticides, herbicides, heavy metals, but not the
ones in vaccines, viruses — again, not the ones in vaccines. Bacteria — but not the
ones from the vaccines. Low oxygen at birth, chemical — just not the ones
in the vaccines. Prematurity at birth,
but hey, go ahead and vaccinate your premature
baby at the same schedule as if they were born full-term. That’s a good one. Neonatal exposure to
environmental toxins, but not the ones in the vaccines
that you give to pregnant women. Phthalates exposure in pregnancy
— oh, living in cities, higher-income parents. Basically, anything
but the vaccines. And I’m here representing
a lot of families who could not be
here, as you know. And you met, yesterday,
my friend, Priscilla, and her husband, Will, who
lost their daughter, Willow, after her four-month vaccines. So I have a list of deaths
— deaths from vaccines, because yesterday, we heard from
Paul Offit and his friend about
the lovely lady who started the meningitis
B vaccine campaign, which seems to be
kind of like — it kind of makes me think
you guys are copying — like, they’re copying
the anti-vaxxers, but never mind that. Nobody likes to see a child die from a disease or
anything, okay? I wouldn’t wish meningitis
on anybody. I certainly wouldn’t
wish a death on — from meningitis on anybody,
but because this baby died, all kids have to have
the meningitis B vaccine. That’s interesting. So let’s talk about it. Daniel Ramirez went for his kindergarten
shots, and died. Ryan Lavrie had his DTP vaccine and died. Rose Haashad the HPV vaccine and died. Nicholas Katone had the DTaP in his infant vaccines and died. Marshall Thomas had the flu shot and died. Zara Shiel — and I’m probably not saying
that last name right — went for her 16-month
vaccines — dead. Holly Stavola had the MMR — dead. Kyle Dale-Mowry at three months, dead from his routine
infant vaccines. Kelly Michelle Hall, at two months, DTP — dead. Colton Barrett had the HPV vaccine because the doctor told him
he would be protecting his future wife. Athlete, paralyzed, on a
respirator, committed suicide because he couldn’t
go on that way. Eric Pine had the DTP vaccine. He suffered over 100
seizures before he died at 22. His father spends
countless hours online trying to spread the story
of his son’s death. And finally, Mason Bundy, who when he was four
months old, was told — his mother was told by a doctor,
“If you don’t get this vaccine, you are signing his
death certificate.” Yeah, less than a week later, they were signing his
death certificate. He would’ve turned
eight on Monday. If I had given my
son the full barrage of the CDC recommended
schedule — because I told you, he’s had four, single-dose,
spaced-out vaccines. If I had given him
all of the vaccines, in the way that they are
routinely administered to infants, he would
be on this list. He certainly wouldn’t be sitting
here today, and if he was alive, he would be so severe
that there’s no way that I could be sitting here, listening to you,
and talking to you. Please, any death of
any child is tragic, but you cannot ignore
these deaths anymore. They are just as
important as a baby who dies from whooping cough, meningitis, or any other vaccine-preventable
disease, okay? Thank you very much.>>I’d like to point out –>>Thank you.>>– that the committee
needs a timer. I’ve been to thousands of
hearings and committee meetings, and there’s usually a timer.>>Thank you for that feedback.>>So are you going to end this,
or are we going to be allowed to finish our public comment?>>I did say that we
had to end this at 1:45. Is there anybody who has not
had the opportunity to speak, who has signed up
for public comment? I have Susan Corrigan and
Jamie Lynn Juarez, and then –>>And we spoke. And I also suggest cameras, because we have Dr. Paul Offit on camera shooting himself
in the head while a mother of a very sick child, who
was giving public comment was mocking, and that’s not okay.>>– thank you. So we have one final just —
I think we, unfortunately, have to end public comment. Everybody who has come and has
had an opportunity to speak. Is that correct?>>Yesterday, I wasn’t
able to read my comment because of just being
a little overwhelmed. Mine’s about 13 sentences.>>Please go ahead. Thank you.>>Okay, I will go quickly. Thank you. Susan Corrigan, Seattle,
Washington. FDA recently approved Gardasil
9 for men and women 27 to 45, so the age range recommended for this vaccine now
spans nine to 45. FDA’s decision to expand to
older adults is concerning, given that FDA originally
refused to approve Gardasil for this age because there
was insufficient evidence of the vaccine’s effectiveness. In the older women, FDA
also noted increased risk of non-vaccine-type
related CIN2 or greater, but Merck erases
disease enhancement risk in the long-term followup
by vaccinating the controls, and then comparing those
originally vaccinated versus later-vaccinated women. Please see page eight of the recent FDA approval
document showing how Merck and FDA compared only vaccinated against vaccinated
to mask any risk. Additionally, in another
Gardasil trial of 16 to 26-year-olds,
the FDA recognized that the vaccine actually
increased the risk of women developing
vaccine-type-related CIN2-3 or worse by 44.6% if a woman
had been previously exposed to vaccine-related HPV types,
and currently had an infection with vaccine-related type. Based on these disease
enhancement signals, we are extremely concerned
that this new recommendation for older adults, as more
likely to have HPV exposure, will increase a woman’s
risk for cervical disease, and perhaps even
cancer from both vaccine and non-vaccine HPV types. While this data should’ve
been supported — should have supported
doctors screening for HPV infection before
vaccinating to reduce risk, the American College
of Obstetricians and Gynecologists
instead actively discourages pre-screening. Moreover, FDA approved Gardasil
9 for men aged 27 to 45 based on inferred efficacy for women
and an incredibly small study in men, which is insufficient
to recommend a blanket approval for all men in this age
range in the United States. An immediate investigation is
warranted, as we do not believe that the FDA examined this issue
with close-enough scrutiny. Thank you.>>Thank you so much. Okay, I believe that is all, and the meeting is
officially adjourned. Thank you all for being able to stay the extra
couple of minutes –>>And I’m ashamed
of our military.>>– comment, and we will
see you all in February. Thank you.

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