(light music)

- Well, hello, everyone,

and welcome to the AMR Exchange Series.

Thank you for joining.

Today, we have a stellar panel

of Infectious Disease and
Epidemiologist experts

to talk about vaccines

and their potential impact
on antimicrobial resistance.

My name is Tony Fiore.

I'm an Infectious Disease Specialist,

formerly worked at CDC, and
now, an independent consultant,

working part-time at HilleVax,

which is a vaccine company that's working

on a norovirus vaccine
in the early stages.

I have no conflicts of interest to report.

I want to – 

I want to also provide
you a quick overview

of the AMR Exchange Series
and what its purpose is.

The main purpose is to provide
important and new research

to the field describing how
antimicrobial resistance

can be reduced, prevented,

and reduce the spread of
antimicrobial resistance,

and our panelists are
typically asked to provide

some examples of research that's important

and that people who are
listening to the webinar

need to know about,

particularly focusing
on what we're learning,

and what works, and
emphasizing the examples

of collaborations across
sectors in healthcare,

the environment, animal health,

and the public health community.

You just saw the poll pop up there.

Thanks for participating in that.

- Okay, so we have four panelists today.

Dr. Kristin Andrejko is an Epidemiologist

for the Respiratory Diseases Branch

in the Division of Bacterial Diseases

in the National Center for Immunization

and Respiratory Diseases at the U.S. CDC.

Yonatan Grad, our second panelist,
is an Associate Professor

at the Harvard T.H. Chan
School of Public Health.

Shelley Magill is the
Deputy Chief for Science

in the Epidemiology, Research, 
and Innovations Branch

in the Division of
Healthcare Quality Promotion.

It's where I used to work, in fact,

in the National Center of
Emerging and Zoonotic Diseases

at, again, at the U.S. CDC.

And finally, Ramanan
Laxminarayan is the Founder

and Director of the One Health Trust.

I'm going to start to set the stage

for our panelist discussions
to give a general overview

of the issue from a
national, global perspective

and mention a few specific examples

that we might not otherwise
have time to discuss.

If you could advance the
slide, please, Shayla.

Thanks, I mentioned no
conflicts of interest to report,

and I gave you my current affiliation.

Next slide, please.

Here is the typical verbiage that we have

in the front of most of
our presentations saying

that this is not officially endorsed

by the Centers for Disease
Control and Prevention,

or Department of Health
and Human Services.

Next slide, thank you very much.

Okay, so just starting off,

the threat of antibiotic resistance

in the United States is enormous.

In the 2019 "Threat Report," (AR Threats Report)

the most recent one that we have,

it was estimated that
there were 2.8, sorry,

2.9 million infections related

to antibiotic-resistant
bacteria and fungi,

and about 36,000 deaths.

This most recent "Threat
Report" also listed

some new threats,

including five urgent
threats, two new threats,

and three threats to watch for.

We'll talk about many of those today,

although not all of them.

During the pandemic, some of
the progress that was shown,

if you could just go back, sorry,

some of the progress that was shown

with trends trending
down in many of these,

in many of these antibiotic
resistance threats

was interrupted by the many

problems with providing health care

and access to health care
during the pandemic.

I think you'll hear from
Shelley a little bit

about what these impacts were.

So if anything, for many of these threats,

progress has been stalled,

or sometimes even to some extent reversed.

So that's a very concerning issue.

As bad as this is in the United States,

globally, it's even worse.

The most recent estimate

from Murray, et al. in a
recent "Lancet" article was

5 million AMR-associated deaths annually,

including 1.27 million deaths

that were directly attributable to AMR.

You can see this is an
enormous global problem,

and it's projected to get much worse

over the next several decades

unless we aggressively seek
interventions right now.

You'll notice that in places

you'll see the term
antibiotic resistance, or AR,

and other places, you'll see AMR,

which is antimicrobial resistance.

For the purposes of this discussion,

even though those are
slightly different terms

in terms of the impact of vaccines on AMR,

we can continue, we can consider them

to be the same for this discussion.

When you hear me use
those different terms,

it's because those are
the terms that were used

in the sources that I've cited.

Thanks, next slide, please.

So in the U.S., the national action plans

for combating antibiotic-resistant 
bacteria have been,

many have been, mostly focused

on developing new antibiotics
and new diagnostics

and new surveillance systems.

But even, but in the most recent,

and even in the one before that,

the U.S. government was clear
that vaccines played a role,

that we needed all the tools we could

to reduce the spread of
antibiotic resistance.

And here, I've quoted Objective 3.3,

which says, "Facilitate
development of vaccines

to prevent bacterial and fungal infections

with known rates of resistance,

and augment existing
post-licensure evaluation systems."

We'll hear a bit about that second part,

the post-licensure evaluation
systems, as we go on.

Thanks, next slide, please.

So the WHO also has recognized
vaccination as another tool

that's important to combat
antimicrobial resistance.

You can, you can see from these
sort of five pillars

on the left here, the
approaches to contain AMR,

vaccines are specifically highlighted.

I put a little red arrow there,

in case it's a little
hard to find on the slide.

From the vaccine side of things,

the vaccination experts
and the vaccination funders

are also recognizing the importance

of linking their work
with containing AMR. And Gavi,

which is the primary
funder of much vaccine use

in the low- and middle-income countries

for vaccine use for
children, has now added this

under the rubric of 
global health security

and specifically calling
out AMR as one of the things

that they think about
when they're, when they're discussing

which vaccine to invest
in in which country.

That reduction of AMR is
an important consideration.

Thanks, next slide, please.

The World Health Organization
also has begun to think about

how we better leverage vaccines

for use against AMR and AMU.

AMU is antimicrobial use, by the way.

They had three important objectives

of some recent guidance
that I've screenshot

on the left there.

The first is expanding
use of licensed vaccines

to maximize impact.

The second is developing new vaccines

that contribute to prevention and control,

and the third, and very important one,

is expanding and sharing knowledge

of what the vaccine impact is on AMR,

so, so funders, and countries,
and public health programs

can fully recognize that

vaccines can have an impact in AMR,

and are important to include
when they're thinking about

reducing the development and the spread

of AMR in their countries.

We'll hear more about
national action plans

from Ramanan a little bit later.

Thanks, next slide, please.

So how do vaccines reduce AMR?

This, on the left, again,
this is a slide I've borrowed

from the World Health Organization.

There's five main categories

that they can prevent infections,

then help reduce AMR.

The first is that vaccines
prevent infections

with both drug-susceptible

and antimicrobial-resistant pathogens,

and the reason for this
is that the immunity

that's engendered by vaccines is,

these antibodies are
attacking different areas

of the organism, typically,
usually surface proteins,

compared to the mechanisms
of antibiotic resistance.

And so, even resistant
organisms are susceptible

to prevention with the use of vaccines.

The second important category is that

vaccines reduce secondary infection.

So, a person who develops

a vaccine-preventable disease

can sometimes develop
a secondary infection,

and that includes infections
with AMR pathogens.

There's also the important
concept that vaccines prevent

both individuals and
communities from getting sick,

and that's often referred to,
the communities part of it,

often referred to as herd immunity

in the sense that people
who are not vaccinated,

who didn't respond to vaccine,
or who can't be vaccinated

due to age, or underlying
conditions also benefit us

if there's less circulation
of a pathogen in a community.

If you don't get sick,
you don't use antibiotics.

That's pretty obvious, the fourth one,

and then finally, suppressing
resistance of evolution

and decreasing transmission

of these antibiotic-resistant
pathogens is important.

If the pathogens are not seeing,

being exposed to antibiotics,
because there's less use,

they're less likely to develop resistance,

and this is also depicted in, if you like,

that sort of visual in this
flow chart here on the right,

essentially the same
thing that I've just said.

Next slide, please.

So, vaccines against
viruses are also important,

and even though we won't
talk much about that today

after this slide, it's
an important concept

that is not maybe obvious
on the face of it.

Patients are often given
antibiotics for viral illnesses,

which drives antibiotic
use and resistance,

and of course, we know
that things like penicillin

and azithromycin don't help viruses,

but for many people, when they get sick,

we don't know what caused their illness.

Think of respiratory
diseases, for example.

You call your doctor, you go
to the urgent care clinic.

They're not sure what it is.

We don't have the diagnostics available

to really determine it, and
people will get antibiotics

that they don't need.

Obviously, better diagnostics
would help with this,

but so would vaccines.

If we prevent those viral illnesses,

then you wouldn't be going to the clinic

and getting those antibiotics.

And there are some real life
recent examples of this,

and Ramanan was involved in this work

that I'm going to cite right now.

You see the two maps of the
U.S. on the right there.

Map A shows the amount of
influenza vaccine coverage,

and the darker orange has higher coverage

of influenza vaccine for that state,

and there is a surprising amount
of variation state to state

of flu vaccine coverage.

The second map shows the
amount of antibiotics used,

and the lighter green shows
that that state uses per capita

less antibiotics than states
that are depicted darker.

You can sort of use the
eyeball test to visually see

that there is at least some correlation

between higher influenza vaccine coverage

and lower antibiotic use,

and this was statistically
correlated also.

The second example I'm showing
down on the far lower right

on my screen there is

the very exciting new respiratory
syncytial virus (RSV) vaccine.

This was just recently approved by FDA

for use in pregnant women. In this study,

the pregnant women were
given the RSV vaccine.

These antibodies are then
transferred to their babies.

The babies have some relative protection,

and actually quite good
protection, against RSV

in the first few months of life.

As you can see here, in
addition to preventing RSV,

it also reduced the amount
of antimicrobial prescribing

that those babies required.

And even though those look
like pretty modest reductions,

and they are from a
percentage point of view,

these viruses are so
common that this ultimately

would result in many thousands,

or tens of thousands fewer
antibiotic courses given

to children born to
women who are vaccinated

with RSV vaccine.

Just approved by the FDA last week,

and we hope to hear from CDC on this

sometime in the next few weeks,

probably at the ACIP (Advisory Committee on Immunization Practices) meeting in October.

The second thing I wanted
to mention about viruses

and vaccines are that
viral infections can lead

to secondary bacterial infections

that end up requiring antibiotics,

and one example is invasive
Staph aureus infections

after influenza.

Another is severe group A strep (group A streptococcus)
infections after varicella.

Next slide, please.

Something else we won't
talk about much today,

but it's been the topic of several

of the Antimicrobial Exchange
discussions in the past is

this One Health concept,

where combating antimicrobial
resistance is important

across multiple sectors,
not just in people,

but also in animals,

and also, but also use in the environment.

So, it's important to recognize
that not only do vaccines

for animals prevent the
infections in animals,

but they also prevent people
from getting those infections,

and also reduce the amount of antibiotics

that are put into the environment

used to treat those animals.

Next slide, please.

And so, just to wrap this up,

I think I've had a
couple bullet points here

that are ones that I often say

when I talk about this.

So, vaccines must be developed

and provided to our patients,

but they have to be also
accepted by the public,

and they have to be
supported by our policymakers

in order to be effective.

A vaccine that doesn't go into a person

or an animal is not a
vaccine that's going to work.

Coverage is too low for many
current vaccines in the U.S.,

and we even lost some
ground around the pandemic.

We hope to recover that
in the next year or two.

We also have new vaccines
coming down the pipeline

that we hope to get good
coverage in as soon as- quickly-

as soon as possible.

Surveillance systems, such
as those that are led by CDC

and state and local governments,
have to be supported

and improved to monitor
the vaccine uptake,

effectiveness, and safety, and
you'll hear more about that

from Shelley in a bit.

Demonstrating that vaccines can
have an impact on resistance

is not typically part of
clinical licensure trials,

because they're usually too short,

but they could be built
into them where possible,

but more importantly, built
into post-licensure assessments,

and this will help supporting-

increase support- for vaccine use.

Finally, we just need to
continually seek to develop

new vaccines, improve existing ones,

improve and monitor safety,
demonstrate impact on AMR,

and further build support for
this idea that AMR reduction

and vaccine use are inextricably linked.

So, with that, I think
that was my last slide,

and I think we are ready to-

to go ahead with,

Our next thing here is to
go ahead with questions

specifically to the panelists.

So we're going to start with Kristin.

So Kristin, the pneumococcal
conjugate vaccines,

who are often abbreviated PCV,

and you'll hear that referred
to as she talks about it,

are highly effective in reducing
illnesses and transmission.

Could you share why PCV
is also an important tool

to slow the spread of AMR?

Yeah, sure. Thank you for such a great question.

PCVs have really been a great example

of how vaccines can be an effective tool

to reduce antibiotic resistance,

and antibiotic resistance was
first detected in pneumococcus

in 1963, and as you showed
with the "Threats Report,"

it's now considered a serious
threat in the United States.

And so, these pneumococcal
conjugate vaccines, or PCVs,

are designed to protect
you from many infections

that are caused by the bacteria
Streptococcus pneumoniae,

or pneumococcus, and there
are over 100 known serotypes,

or variations of pneumococcus,

and it can cause a wide
range of clinical illness

ranging from less severe infections,

like a bacterial acute otitis
media, or an ear infection,

to a more severe infection that
can lead to hospitalization

and even to death, like
community-acquired pneumonia,

or meningitis, and
these are all conditions

that necessitate antibiotic use.

So, infections with these
antibiotic-resistant strains

of pneumococci both
complicate your treatment

and increase the cost
of your medical care,

and in the early 2000s,

a sven-valent pneumococcal
conjugate vaccine, or PCV7,

was introduced for routine use

among children in the United States,

and prior to the
introduction of this vaccine,

data from CDC surveillance estimated

that nearly a quarter of
isolates from patients

with invasive pneumococcal disease

were non-susceptible to penicillin.

And so, PCV7 was really
designed to provide protection

against the specific
serotypes that are responsible

for the majority of resistant
invasive pneumococcal disease

at the time.

In fact, five of the seven
serotypes that were included

in PCV7 were responsible for nearly 80%

of penicillin
non-susceptibility at the time.

And once that vaccine was introduced,

there was a sharp reduction
in invasive disease,

especially resistant disease.

So, four years following PCV7 introduction,

there was an 84% decrease

in multidrug-resistant
invasive pneumococcal disease,

and we continue to see rates

of resistant invasive disease drop

with introduction of newer
pneumococcal vaccines

that provide protection
against even more serotypes.

- Thanks, okay, you answered a little bit

of my second question with that,

but maybe if you could give
us some more specificity

about how PCV has been shown to reduce

the threat of antimicrobial-
resistant strains?

- Sure, so think of it this way.

Any resistant infection that
is prevented by vaccination

is a case that reduces the burden

of antibiotic-resistant disease.

If a vaccine prevents
a vaccinated individual

from getting infected
with a resistant strain

in the first place, it
reduces the overall burden

of antibiotic resistance,

it reduces the need
for antibiotic therapy,

and it reduces the likelihood
for a bad clinical outcome.

But there are also other mechanisms

in which PCVs can help reduce the burden

of antibiotic resistance.

Vaccines can have herd
effects, or indirect effects,

in which protection is afforded

not only to the vaccinated individual,

but also to the unvaccinated community,

and a nice example of this effect occurred

following PCV7 introduction in the U.S.

So, in 2000, PCV7 was introduced

in the routine childhood
immunization schedule,

and as expected, introduction
of PCV7 in young children

dramatically reduced the
rate of disease caused

by penicillin non-susceptible strains.

But, the rate of invasive
pneumococcal disease

caused by penicillin non-susceptible
strains also decreased

among older children and adults,

a group that would not have yet received

the conjugate vaccine.

So how does this happen?

It's a bit complicated,
but one of the precursors

to pneumococcal disease is colonization,

a phenomenon where the
pneumococcus lives in your nose

and throats without causing disease,

and young children are often
colonized with pneumococcus,

and can transmit the bug to
their family and community.

So, when PCV7 was introduced,

young children stopped carrying

vaccine type strains of pneumococcus,

which interrupted transmission
of these vaccine type strains

between children and
adults, or put another way,

vaccinating children
interrupts transmission

of the resistant vaccine type pneumococci

between children and adults.

So, the vaccine conferred benefits

to not just the vaccinated child,

but also the whole community.

- Thanks so much, Kristin.

Tell us a little bit more
about the progress in creating

and expanding PCV to include
more of these serotypes.

You mentioned there were
over 100 at this point,

including those that are most important

from the perspective of being resistant.

- Sure, so there are a lot

of new pneumococcal conjugate vaccines,

all of which may help
continue to reduce trends

in antibiotic-resistant
pneumococcal disease,

and currently, as you were mentioning,

all those pneumococcal
conjugate vaccines confer

serotype-specific protection,

meaning they provide protection
against pneumococcal disease

caused by the specific
subset, or of serotypes,

or variations of pneumococcus.

So how does it get decided
which of those 100 serotypes are

actually included, or
excluded from the vaccines?

Well, CDC is always
monitoring the serotypes

that are responsible for the majority

of severe resistant disease,

and these are the
serotypes that are included

in the new higher valency
pneumococcal vaccines.

In fact, CDC has been
conducting the epidemiological

and laboratory-based surveillance

of the most severe form of
pneumococcal infections,

invasive pneumococcal
disease, for over 20 years

to help inform these decisions.

So, we can walk through an
example of how, for example,

the serotypes in PCV13 were decided.

The first pneumococcal conjugate
vaccine PCV7 was introduced

for use in young children
in 2000, and 10 years later,

a 13-valent pneumococcal
conjugate vaccine, PCV13,

was introduced, and PCV13
included the seven serotypes

from PCV7 in addition
to five new serotypes.

So how were those five
new serotypes determined?

Well, PCV7 was hugely
successful at reducing

the incidence of resistant disease caused

by the seven serotypes
included in the vaccine,

but there is still a significant
burden of disease caused

by non-vaccine type serotypes,

or serotypes not included in the vaccine,

and there was this one serotype
in particular, serotype 19A.

It wasn't a major contributor to disease

when PCV7 was introduced,
but it emerged over time

as the dominant serotype
causing the majority of disease

in the years following PCV7 introduction.

In fact, following PCV7,
it was causing about one-third

of all resistant invasive
pneumococcal conjugate,

or invasive pneumococcal disease cases.

So, it became important
to include serotype 19A

in updated vaccine
formulations, including PCV13,

and after introduction of PCV13,

only 8% of resistant
disease was caused by 19A.

So PCV13 introduction was really necessary

to target these new
serotypes that were causing

the majority of resistant
invasive pneumococcal disease,

and was quite successful at doing so.

More recently, in 2022 and 2023,

the Advisory Committee on
Immunization Practices,

ACIP, voted to recommend use

of the 15 and 20-valent
pneumococcal conjugate vaccine,

which now expands
coverage of these vaccines

to 15 and 20 serotypes,

and while there's been no
dominant serotype that's emerged

causing resistant disease
following PCV13 introduction,

it's still expected that
the additional serotypes

that are included in 15 and 20 may prevent

up to 30% of all non-susceptible disease.

So, there's still certainly
a lot of potential

for these higher valency vaccines

to continue to reduce these
trends in resistant disease.

- Okay, thanks.

One more question now before
we turn to the next speaker.

Pneumococcal vaccines are
indicated for young children,

and also adults over 65,

and others with certain
high-risk medical conditions.

You mostly have focused your
work on PCV in children.

Is there more that you want people to know

about PCV in children,

and its relationship to
antimicrobial resistance?

- Well, before the introduction of PCVs,

young children had the
highest risk of infection

due to antibiotic-resistant strains,

and choosing an effective
therapy for children

with a drug-resistant
pneumococcal infection

was challenging.

So, vaccination with PCV
has been an excellent tool

to reduce the risk of a child acquiring

a resistant infection caused
by one of the serotypes

that are included in the vaccine.

And, as I mentioned earlier
about indirect effects,

PCVs also help protect
unvaccinated individuals

by reducing circulation
of those resistant strains

in the community.

But another important thing
here is that children are

major contributors of antibiotic use,

and use of antibiotics is one
of the most important drivers

of antibiotic resistance.

Just between 2000 and 2010 alone,

during the period that PCV7 was introduced

for routine infant use,
overall antibiotic prescribing

declined 18% among
children and adolescents.

But more recent estimates suggest

that implementation of
these higher valency

15 and 20-valent pneumococcal
conjugate vaccines

might reduce up to 700,000
antibiotic prescriptions annually

for acute respiratory infections

like otitis media,
pneumonia, or sinusitis.

So, to continue to see the benefits of PCVs

in reducing antimicrobial resistance,

we really need young children to continue

to receive this vaccine, and
I know you asked about kids,

but CDC is also doing work on PCV impact

on AMR among adults.

It's just been a really big year

for pneumococcal conjugate vaccines.

PCV15 and 20 are now recommended
for use in older adults,

as well as adults with
certain risk conditions,

and if you're a clinician
attending this webinar

and interested in these up-to-date

pneumococcal vaccine recommendations,

the recommendations are
updated on our website,

and in addition, there is
an interactive app called

"PneumoRecs VaxAdvisor"
that you can reference

to see whether your patient is eligible

to receive a pneumococcal
conjugate vaccine.

- Thanks, Kristin.

I'm old enough to have remembered

when this vaccine was first introduced

when I was in clinical training,

and it's just been an absolute miracle,

PCV is the best studied
vaccine, in terms of AMR impact,

and so, that was a great overview.

In fact, when the WHO recently reviewed

over 300 papers on the
impact of vaccines on AMR,

pretty much 95% of them were
around the introduction of PCV.

We should be seeing additional ones

as new vaccines are introduced,

and we realize that we
need to be measuring this.

- Absolutely.

- So okay, well, thanks so much,

and we'll go ahead and turn
to our second panelist,

Dr. Yonatan Grad, and
thanks for joining, Yonatan,

and I'm reminded that I should ask you

to introduce yourself
again before we get started

with the questions, thanks.

- Sure.

I'm Yonatan Grad.

I'm an Associate Professor

of Immunology and Infectious Diseases

at the Harvard Chan
School of Public Health,

and also trained clinically
in internal medicine

and infectious diseases.

- Well, thanks so much.

So, first question, your
lab focuses on preparing

and responding effectively
to infectious disease threats

and investigates how pathogens evolve

and spread using a combination
of mathematical modeling,

genomics, microbiology,
and epidemiological tools.

Could you share more about this
work and why it's important?

- Sure.

So, as we've been hearing about,

the problem of antimicrobial resistance

really happens across scales,

from the molecular and genetic

to the global, environmental,
population level.

And in our lab, we try to
think about this problem

across those scales.

So, at the molecular level,

we think about antibiotics
as an evolutionary pressure

that drives the emergence of resistance,

selecting for bacteria that can grow

even in the presence of these antibiotics.

What are the mechanisms

by which the bacteria
develop this resistance?

So, to try to get at this, we
have to use basic biology,

and work with these bugs in the lab

with Bunsen burners, and
Petri dishes, and so on,

and then we also have to
understand that these microbes

actually live out in the real world,

not just in this Petri dish,
and not just in our lab.

So, they're exposed to other pressures,

and compete with other
microbes for the resources

that they need in order to
grow, and divide, and transmit.

So, we have to think about them

within these real world environments,

and then we have to think
about these processes

at the human scale.

We're the ones who are
really driving the emergence

of antibiotic resistance
with our use of antibiotics

to treat these infections.

So how do we use the antibiotics?

This is what you referred
to earlier as AMU,

the antimicrobial use.

How does that use shape the
ecology of the microbes?

And then we have to think about
how we, as humans, interact,

because we are the major
vehicle for dissemination

of these microbes.

One example that I often
give when talking to students

and provide this in lectures I give is

think about a hermit
who's off in the woods,

who subsists on a diet of antibiotics.

Penicillin for breakfast,
ciprofloxacin for lunch,

azithromycin for dinner.

You might imagine that this
person is going to be replete

with antibiotic-resistant bacteria,

but if it's a hermit off in the woods

never interacting with the village,

how much does this actually matter

for the spread of antimicrobial resistance

in the village, or globally?

Well, probably not that much

if there's not too much interaction,

but if there is interaction,

then we have the opportunity for spread.

So, we also have to think about
the interaction of people,

and recognize that antimicrobial
resistance is really

a global phenomenon, where what happens

in one part of the world impacts

what happens everywhere else.

So, again, this is something
that ranges across scales

from the basic biological and genetic

all the way up to population level.

- Thanks, I love the hermit analogy.

I might have to use that at some point.

Some of the major themes
of your work have been AMR

and Neisseria gonorrhoeae,
which is the cause

of the sexually transmitted
illness gonorrhea.

Can you tell us a little bit
more about AMR and gonorrhea?

- Absolutely, so gonorrhea
is one of the most common

bacterial infections out there.

This often comes as a surprise to people,

but in fact, it is a huge burden.

So, the CDC estimated that in 2021,

the last year for which we have data,

there were over 700,000
reported cases of gonorrhea

in the U.S. alone,

and a true incidence that
may be double this number,

since many infections with
Neisseria gonorrhoeae,

as you mentioned, the cause of gonorrhea,

can be asymptomatic.

This number has been steadily
increasing since about 2009.

In fact, it's more than
doubled since then,

and we've been seeing a
similar trend globally,

with the estimate of around
90 million cases, or so

of gonorrhea each year around the world.

One of the big problems here
is antimicrobial resistance.

So, we are down to our last line antibiotic

to treat gonorrhea.

This is ceftriaxone.

It's an antibiotic that is delivered

by intramuscular injection.

We've already seen resistance

to ceftriaxone spreading globally.

In fact, just here in
Massachusetts in January,

it was reported the first case of isolates

that carry a particular
gene that confers resistance

to ceftriaxone in a background that,

where the bugs also had resistance,

or reduced susceptibility to
all other antibiotics used

to treat Neisseria gonorrhoeae infection.

So those were the first cases in the U.S.,

but those same strains have been observed

all around the world and
are rising in prevalence.

So, without new drugs and other tools

to address this problem, we're really,

we are facing the problem

that's of huge proportions,

a highly prevalent, untreatable infection.

And just to go over what would happen,

untreated infection in women,

we see pelvic inflammatory disease

that can result in infertility
and ectopic pregnancy.

In men, we can get scarring of the urethra

and inflammation of the
epididymis and the testicles,

and we can also see the
Neisseria gonorrhoeae bacteria

spread throughout the body,
cause disseminated disease.

It can cause inflammation in the joints,

and also can cause heart infections,

and facilitate the infection with HIV.

In the era before antibiotics,

gonorrhea was actually
one of the primary causes

of arthritis in young people.

So, if we don't address this problem,

this is really where we're headed back to.

- Thanks.

Let's go on to discuss
the potential benefit

that a gonorrhea vaccine
might have on AMR.

Could you tell us a
little more about that?

- Sure, so this picks up on
the themes that you brought up

and that we also heard from Kristin

about the effect of PCV on pneumococcus.

As opposed to PCV,

where we have this wonderfully
successful vaccine,

we do not yet have a
vaccine for gonorrhea.

Although they are in the works,

it has really been a hard problem.

That said, it turns out
that a vaccine developed

for a cousin of Neisseria gonorrhoeae,

Neisseria meningitidis, serogroup B,

one of the causes of
meningococcal meningitis,

looks like it could
actually confer protection

against gonorrhea to some extent,

and that is now in clinical trials

really to test this hypothesis,

and we hope to see results
in the next couple of years.

So, in a way that's very
similar to what we heard about

for PCV, we anticipate that
the impact of a vaccine

for gonorrhea will be at least twofold.

One, it will reduce the
burden of gonorrhea,

so great in and of its own,

but then in addition, two,

it will reduce the antibiotics
used to treat gonorrhea.

And so, we think this will help to reduce

the selective pressures that
drive antibiotic resistance.

Now, we think this will
be particularly important

for young people, where you
have the highest concentration

of gonorrhea cases.

So, a gonorrhea vaccine there
could substantially reduce

the use of antibiotics,

and gonorrhea right now is- about-

is the reason for about 2.5%
of all antibiotic prescriptions

in the 20 to 24-year-old age group.

So, there's really an opportunity
for a substantial reduction

in antibiotic prescribing in that group.

- Okay, thanks, and you've
touched on this fourth question

a little bit, but let's
expand it a bit more.

Why is it particularly important
to consider the development

of vaccines together with
the various novel diagnostics

and new antibiotics to
address these clinical

and public health challenges posed,

including, and especially for this,

for the purposes of our discussion

those related to drug resistance?

- Yeah, so this gets back to
one of the slides you showed

in the introduction, where
you had both the WHO strategy

and the Gavi strategy.

We need all the tools we
can to address this problem.

So, as I mentioned, we're
on our last line antibiotic

for treatment of Neisseria gonorrhoeae.

That's ceftriaxone.

So, we urgently need new antibiotics.

We have an increasing burden of disease,

so we need more tools to prevent it,

like vaccines, as we've
been talking about.

We also need new and better diagnostics.

So right now, most diagnosis
in the United States

is by nucleic acid amplification test,

which is basically PCR.

Most people are familiar with this now

through diagnostics for COVID-19,

and it's a very similar kind of test,

but that test does not tell us anything

about the antimicrobial
susceptibility of the infections.

It doesn't tell us which
drugs we can, or can't use

for treatment of Neisseria gonorrhoeae.

And so, end up just using ceftriaxone,

which is the drug that we
think the vast majority

are going to be susceptible to.

But it turns out through
surveillance work by the CDC

and others that many of the
gonorrhea infections in the U.S.

are still susceptible
to other antibiotics.

So, if we had diagnostics
that could tell us about

the susceptibility of each
individual's infection,

we could use potentially ciprofloxacin,

or penicillin, or another drug,

and really distribute
those selective pressures,

and not just use ceftriaxone,

helping to expand the clinical lifespan

of each of these antibiotics,

and really help to address this problem

of antimicrobial resistance.

So, all three of these elements are key

to a comprehensive response strategy.

We need the new antibiotics,

we need the new
diagnostics, as I mentioned,

and we need a vaccine, as we
were talking about before,

to, again, address this problem,

overall burden and antimicrobial use

for treatment of gonorrhea.

- Okay, thanks, thanks very much.

I think that's our questions for now,

and we'll in a minute turn
to our third panelist,

Dr. Shelley Magill.

But first just to mention, to follow up

on your discussion of
gonorrhea, it really is,

it was amazing to me to see the results

from the Neisseria meningitidis trials

showing the impact on gonorrhea.

Certainly was unexpected,

and we really do need to
develop something more

to prevent this really clever organism.

I think it's one of the best
at developing resistance.

And so, I really appreciate you giving us

a quick overview of that.

Okay, well, so now, we'll
turn to Shelley Magill.

Shelley, if you would
reintroduce yourself,

and then we'll get started
with the questions.

Thank you, Yonatan.
- Sure, thanks, Tony.

So I'm an infectious disease physician

and medical officer in the
U.S. Public Health Service,

and I serve as the
Deputy Chief for Science

in the Epidemiology, Research,
and Innovations Branch

in CDC's Division of
Healthcare Quality Promotion,

where Tony used to work.

- Okay, we'll get started
on the first question.

Shelley, your branch is
involved in conducting

population-based surveillance

and analyzing electronic
health records data

to characterize the burden of AMR

among some of the key
healthcare-associated pathogens

in particular. Your division
has recently done work

on how the COVID-19 pandemic
affected AMR in the U.S..

Could you tell us a little
bit about those results?

Thanks.
- Sure,

and first, let me provide a little bit

of background information for context.

This'll refer back to some
of the slides that you had.

So, our division at CDC monitors

antimicrobial resistance in the U.S.,

and particularly resistance

in healthcare-associated pathogens,

using a couple of different approaches.

One is through the National
Healthcare Safety Network,

which is the nation's largest system

for tracking healthcare-associated
infections in hospitals,

nursing homes, and other
healthcare settings,

and then another approach is using data

from large sets of electronic
health records, or EHRs,

and staff in our branch
analyze EHR data to help create

the national report on
Antimicrobial Resistance Threats

issued in 2019 that you
mentioned in your introduction.

And that report provided
national estimates of infections

and deaths due to key resistant pathogens,

and showed that between 2012 and 2017,

deaths from antimicrobial
resistance decreased

by about 18% overall, and
nearly 30% in hospitals,

and we also saw significant
reductions in infections

due to some important
healthcare-associated pathogens,

like methicillin-resistant Staphaureus Staphylococcus aureus),

which we call MRSA, vancomycin
resistant Enterococcus,

or VRE, and certain resistant
gram-negative bacteria,

probably because of investments
in infection prevention

and control and improving
antimicrobial use.

But even though the 2019 report showed

that there had been a
lot of great progress,

I think it's important to
point out, just as you did,

that the overall burden of
antimicrobial resistance

in the U.S. was still high,

so 2.9 million infections
and about 36,000 deaths,

not including infections and deaths

due to Clostridioides
difficile, or C. diff.

In addition, the data showed
that there were some bacteria

that are definitely important
in healthcare settings,

but that may be increasing
in the community.

There are increases in infections
caused by these bacteria,

which are the extended
spectrum beta-lactamase,

or ESBL-producing Enterobacterales.

Because of the COVID-19 pandemic,

CDC issued a special report in July 2022

using the same EHR-based
method to evaluate

the effect of the pandemic on the status

of antimicrobial resistance
threat pathogens,

and that report showed
very concerning findings

that you alluded to, that
much of the progress we'd seen

in previous years had been
reversed by the pandemic,

and, in fact, resistant
hospital onset infections

and deaths both increased at least 15%

during the first year of the pandemic.

We saw increases in
hospital-onset infections

due to most of the main
healthcare-associated

resistance threat pathogens,

and that includes
carbapenem-resistant enterobacterales,

or known as CRE, Acinetobacter,

resistant Candida auris, and others,

and these increases are
probably in part a result

of challenges implementing
recommended infection prevention

and control practices
in healthcare facilities

during the pandemic, because of shortages

in personal protective
equipment and staffing,

and increased severity of
illness and length of stay

in hospital patients may
also have played a role.

Analyses of more recent
data suggest that increases

in hospital onset resistant
infections did persist in 2021,

and that underscores the
importance of infection prevention

and control, as well as
the need for developing

innovative prevention measures,

like vaccines that can help
reduce antimicrobial resistance.

- Thanks, that was really helpful to hear,

although unfortunate that
we've had these reversals.

So, it's clear we need many
different tools for reducing AMR.

This is our second question.

Can you tell us a little bit

about what vaccines are in the pipeline

that could be important
for reducing infections

due to these
healthcare-associated infections

Pathogens?
- Yes, and I'd like to mention

that the World Health
Organization has put together

a very helpful overview and
analysis of bacterial vaccines

in clinical and preclinical development

that was released in July
2022 and is available online,

and in that document, they
categorize the pipeline vaccines

that can impact AR into
four main categories

ranging from the first
category of vaccines

that are already licensed
to the fourth category

for those pathogens where there's limited,

or no candidates in the pipeline

and low development feasibility.

And not surprisingly, many
of the bacterial pathogens

we think of as being primarily
healthcare-associated

are in this fourth category,

and that includes
Acinetobacter, Staphaureus,

and Pseudomonas aeruginosa.

On the positive side,

there are two
healthcare-associated pathogens

for which there have been some
more promising developments.

One is C. diff for which
a vaccine was recently

in late stage clinical trials,

and this investigational
vaccine was studied

in a Phase III trial for prevention

of symptomatic primary C. diff infection

in adults 50 and older.

Although it was well-tolerated,

the trial failed to meet the
pre-specified primary endpoint

of primary C. diff infection prevention.

But, it's important to note
that in preliminary analyses

of two secondary endpoints,
vaccinated subjects were noted

to have a reduced duration
of C. diff infection,

as well as less severe disease.

Now, what this means for the future

of this particular vaccine candidate

is unclear at this time.

And the other pathogen
that I wanted to mention

for which there is an
investigational vaccine

in a Phase III trial is
extraintestinal pathogenic E. coli,

which is known as ExPEC.

E. coli is a very
important human pathogen.

It's a common cause of infections
in healthcare settings,

including resistant infections,

like ESBL and CRE infections,

and it's also a common community pathogen

and major cause of urinary
tract infections and sepsis.

The candidate vaccine
is a nine-valent vaccine

directed against the
major serotypes of E. coli

that cause invasive disease.

and it's being studied for the prevention

of invasive ExPEC disease
in adults 16 and older,

who have a history of
urinary tract infection

in the past two years.

The primary outcome is the
first invasive ExPEC event

with microbiological
confirmation from a sterile site,

or urine caused by a vaccine serotype,

and the study began in 2021,

and has an estimated primary
completion date in 2025.

So, we'll look forward
to learning more about

how this vaccine candidate performed

in the not-too-distant future.

- Great, thanks.

Those are exciting developments,

of course, also delayed
a bit by the pandemic,

and all the interruptions
associated with that.

Tell us more about how your branch

and others at CDC can
contribute to understanding

the impact of vaccines on AMR.

- Well, in addition to the
analyses I've mentioned

that we conduct on EHR data

to track antimicrobial
resistance over time,

we also support the CDC's
Emerging Infections Program,

which is a network of
state health department

and academic partner
institutions that's been in place

since the 1990s, and our
division has worked with the EIP

for the past 15 to 20 years to conduct

population-based
surveillance for infections

due to some of the most common
and clinically important

healthcare-associated and
Antimicrobial-resistant pathogens,

including MRSA, C. diff, and CRE,

and one of the key features

of population-based
surveillance systems is that

they try to capture all
infections occurring in people

who live in the geographic area

where the surveillance is taking place,

regardless of whether
that infection started

in a healthcare facility,
or in the community.

We've been working with
the EIP sites this year

to pilot a surveillance project

for invasive E. coli infections,

capturing infections due to both resistant

and susceptible E. coli,
and as I mentioned earlier,

E. coli is a major cause of AR

and healthcare-associated infections,

and also a leading cause
of urinary tract infections

and sepsis.

That there is an
investigational ExPEC vaccine

in a late stage trial makes
it particularly important

to have population-based
surveillance in place,

and our surveillance data on
invasive E. coli infections

can provide critical information

about baseline rates of
infection during a time

when there's no vaccine available,

as well as key information
about the pathogen itself.

We collect isolates as part
of the EIP surveillance

as well as detailed
demographic and clinical data

on the people with infections,

and we have the opportunity

to characterize the
isolates in the laboratory,

and determine the
distribution of serotypes,

and the antibiotic resistance
profiles of organisms

causing invasive infection.

And with ongoing surveillance,

we can monitor the impact of
public health interventions,

like the effect of a new vaccine,

and of course, very important to note,

the other systems CDC has
in place to monitor safety.

Data collected through ongoing
surveillance can provide

information on strain-specific
effects of a new vaccine,

and inform potential future
vaccine modifications,

similar to what we heard
about earlier from Kristin

with Streptococcus pneumoniae

and the pneumococcal
conjugate vaccine work done

by our partners in the EIP

Active Bacterial Core
surveillance program.

- Thanks, Shelley.

That really is an important
surveillance system

both for monitoring vaccine
impact and its impact on AMR,

and thanks for giving
us that quick overview.

Last question then for you,

last direct question, is
how could vaccine licensure

and deployment help address

some of this inappropriate
antibiotic prescribing behaviors

by clinicians, and therefore reduce AMR,

and how can public health

and healthcare professionals
support these efforts?

- Sure, so there's a number of ways

in which vaccines can help improve

antimicrobial prescribing,

and you've talked a little
bit about this already,

and that reduction in prescribing in turn

can help reduce antimicrobial resistance.

So first, antibiotics are
very commonly prescribed

for respiratory infections,

even though viruses are the major causes

of many of those infections,

and therefore treatment with antibiotics

is not always indicated.

There are data showing that
vaccines against viruses,

such as the influenza vaccine,

can reduce antibiotic
prescribing in adults,

and probably also in children,

and reductions in antibiotic prescribing

when antibiotics are not
needed can help prevent

the emergence of resistance in bacteria.

There are also some data now
for the COVID-19 vaccine.

McFadden and colleagues showed

that vaccination was associated

with reduced antibiotic
prescribing in adults over 65

in the outpatient setting.

Also, vaccines like the
pneumococcal conjugate vaccine

that we've heard about make the likelihood

of bacterial infection lower,

and many bacterial and
viral vaccines can reduce

the severity of infections that do occur,

which may reduce the need for antibiotics,

as well as the prescribing
of inappropriate antibiotics.

In terms of your second question,

there's many ways that public health

and healthcare professionals
can support efforts

to increase the uptake
of existing vaccines

that have the potential
to improve prescribing

and reduce antimicrobial resistance.

Healthcare professionals are

the patients' most trusted
source of medical information,

so, the information that a
patient, or caregiver receives

during a medical visit has
really important impact.

Healthcare professionals can ensure

there's an open channel of
communication with their patients

and their patients' caregivers
about the availability

and the value of vaccines
for reducing illness

due to certain viruses and bacteria,

and healthcare professionals
can provide counseling

and education to patients
about common viral infections

that should not be
treated with antibiotics.

It's important that
people feel comfortable

asking their healthcare
providers any questions

they might have, so that they
can make the best decisions

for themselves and the
people they care for.

Reminders from health departments

and healthcare professionals
about when it's time

to get an annual influenza
vaccine, for example,

and information about new vaccines

that are becoming available,

including information about benefits

and potential risks and side
effects are all very important.

And public health professionals
can work to ensure

that vaccines and clear
information about vaccines

are widely available and easily accessible

in the communities they serve.

They can partner with
local groups, employers,

or other organizations to make
sure they're able to reach

as many people as possible.

- Thanks, thanks, Shelley.

It's really exciting to hear
about some of these potential,

of at least a few

new healthcare-associated
infection vaccines,

and also about how our
surveillance systems can be adapted

and hopefully expanded
to better capture impact

both of the vaccine on the disease itself,

and the AMR component of those infections,

and it sounds like the
EIP program in particular

is well-established to be
able to do that sort of thing

as it did for PCV.

So, let's go ahead, and
thank you, Shelley, first.

Let's go ahead and turn to Ramanan,

and again, reminding Ramanan to go ahead

and reintroduce yourself,

and then we'll get to
your questions, thanks.

- Thanks, Tony, thanks for having me.

My name is Ramanan Laxminarayan.

I'm Founder and Director
at the One Health Trust,

and also a Senior Research
Scholar at Princeton University.

And I'm an economist and
epidemiologist by training.

- Okay, and so, Ramanan
is going to talk to us

a little bit more from a
global perspective about AMR.

You have extensive experience
working to understand AMR

and the multifaceted and complex actions

that are necessary to combat it globally.

Talk to us about some of
the actionable strategies

that countries that are
very diverse in their needs

and their governments and their resources

can implement to help prevent AMR.

- Thanks, Tony, so I think
it's pretty clear to this point

that, you know, resistance anywhere is

a potential threat everywhere,

and many of the folks on this
webinar are probably familiar

with the case of Pseudomonas

that were transmitted because
of contaminated eyedrops

that were manufactured in India,

and then, you know,
resulted in five deaths

and multiple cases of
blindness across the states.

So, you can have MDR (multidrug resistance) in one place,

but it can very quickly
get to other places.

So, what happens in any other
country is of consequence

in every other country,

and there is very clearly a
need for global coordination.

Now, it was with that understanding

that at the 2015 World Health Assembly

the member states adopted a resolution

that basically committed
every country to develop

a national action plan for AMR,

and the thinking behind it was

that these national action
plans would help, you know,

improve understanding
and awareness of AMR.

They would strengthen the evidence base

through surveillance and research.

You would have a reduction of infections

through water and sanitation, hygiene,

infection prevention and control,

and potentially vaccines as well,

optimize how antibiotics are being used,

and basically increase
investments in diagnostics,

you know, new tools, vaccination,
and other interventions.

So, I think the actionable strategies

that countries with diverse
needs have are right there,

the basic need to reduce infections.

So, if you don't have the infections,

you don't have to deal with
AMR in the first place,

and that's water and sanitation, vaccines,

infection prevention and control.

These are the most obvious ways to do it,

and these need to be implemented
in a One Health fashion,

not just in the human domain,
but also, in the animal domain.

And the other aspect of these
national action plans was

that although not many
countries necessarily follow

that guidance, they were most effective

when they were multi-sectoral.

In other words, governments
themselves are not

the primary player, or
influencer of actions

that result in AMR.

So, many things are done
by the private sector,

because of their incentives.

Many things are done by
professional associations, you know,

how their guidelines are set up.

So, the best national action
plans and the best strategies

that countries were going to use were ones

which involved an all-of-society
kind of an approach.

But unfortunately, that was
not necessarily the case

in most countries.

People just followed what
they were asked to do,

and you now have, I
think, about 140 countries

with national action plans,

but not all of them are going to
get us to where we need to be.

- Thanks.

You touched a good bit
on the second question

that I was going to ask you,

but expand a little bit more
about antimicrobial resistance

national action plans, and
why they're a viable tool

to combat the global threat of AMR,

and tell us more about the role

and impact that these
action plans have had

and how they do support,
continue to support

global efforts to combat AMR.

- So the national action plans
are a tool to combat AMR,

because they basically are recognizing

that unlike other diseases, say, HIV,

where, you know, you can
prevent with condoms,

you can improve blood supply,
there's, you know, treatment,

it's a little simpler with other diseases,

which don't have to deal
with the array of sectors

and influencers of AMR.

So, the national action plans
were really thought of as a way

of bringing all those sectors into play.

And many countries, like I mentioned,

already have these plans,
but there are real major gaps

and variability in the maturity

of these national action
plans across countries,

and these are how good the
policy and strategic planning is,

you know, whether they
have medicines management

and prescribing systems, you know,

across countries with this technology

for optimized antimicrobial prescribing,

context, culture, behaviors.

These things are very important,

and you know, culture is very important.

There are reasons why
the average Swede gets

half the amount of antibiotics per person

that the average person
of the United States does,

and there's some reason
why the average person

in West Virginia gets twice
the amount of antibiotics

on a per capita basis than
someone in Alaska, or California.

That has nothing to do
with the levels of disease.

Those have to do with context,
culture, and behaviors,

and that all these are outside
of the domain of medicine,

and I think, and, you know,
and, last but not least,

you know, operational
delivery, monitoring,

engaging patients, you know,

explaining to them why they
may not need the antibiotic.

There's a lot about AMR

which is not about medicine at all.

It's about behavior,

and I think we saw that
with COVID as well,

and I think we're missing some
big pieces in social sciences

in terms of incentives,
understanding, you know,

how to change behaviors,
which at the end of the day,

you know, changing
behaviors and changing norms

are really going to be the way

in which we're able to achieve
a long-term equilibrium

with respect to antibiotic
use that is different

from where we are today.

But we're still quite far from that.

In addition, I think
these plans are a vehicle

for thinking about these things,

but they also need to be funded,

and many, I would say most
national action plans,

are not funded at this point.

So, they're aspirational documents.

They're sitting in someone's computer,

or, you know, they probably have a meeting

organized around it, you know,
twice a year, or whatever,

but they are not necessarily the vehicles

that are driving change,
because unlike other diseases,

which, you know, as you
mentioned at the outset,

1.27 million people who die
directly attributable to AMR,

that's almost the same
as the number of people

who die because of HIV
and malaria put together.

But AMR doesn't really get
anywhere close to that level

of global support, or
funding, and without that,

we're not really going to make progress

just by having the plans alone.

- Thanks.

Yeah, the cultural aspects
are really interesting

and under-studied, as you note.

Third question, now, could you share more

about how countries can incorporate

immunization programs and vaccine use

into their national
antimicrobial action plans?

- So I think vaccines are going to be

probably the most important
tool for dealing with AMR

in the short term, and that's
for a number of reasons.

You know, if you really
look at the 20 pathogens

that account for the
greatest share of AMR burden,

four of these, Streptococcus
pneumoniae, group B strep,

Salmonella Typhi, and
Haemophilus influenzae Type B (Hib)

are all targets of vaccines
that we already have,

or they're likely to be
available in the near term.

So collectively, these pathogens

in that 1.27 million account

for about 860,000 AMR-associated deaths,

so associated deaths actually
is the 5 million denominator

across all LMIC settings,

and of these, a little less than half,

about 367,000, are in children
under the age of five.

So, the Hib vaccines and the
pneumococcal conjugate vaccines

have been rolled out for a while.

We have to remember that, you know,

the proportion of kids who
actually get these vaccines

and get all the doses
is really quite small.

It's only still about 70% for the Hib,

and it's about 43% for the
pneumococcal pneumonia,

so, everything that Kristin
mentioned at the beginning.

We're still not translating that evidence

into actually getting shots in arms,

and it's still unimaginable that we have

such an effective vaccine
just for, you know,

child survival alone, and
then add on the benefit

of the AMR, this seems like a no-brainer,

but we still don't get these to happen.

We've had the typhoid conjugate vaccine.

It was first introduced in the
program in 2019 in Pakistan,

and then it's been in
Nepal, Liberia, Zimbabwe,

all of which have introduced
the vaccine as a way

of dealing with multidrug-resistant typhoid.

So, this idea that

vaccines are going to be a major tool

for tackling AMR is already out there,

but there are two worlds that
need to talk to each other.

One is the vaccine world

that is only now beginning to realize

that AMR is going to
be an important reason

why vaccines will have to
be rolled out, or expanded,

or new vaccines will
have to be introduced,

and the AMR world is just
now beginning to realize

that vaccines are probably
going to be the most important,

and I say most important
with a great degree of care.

I think water and sanitation
is also equally important,

but in an immediate sense,

which doesn't require as much resources,

vaccines are going to be, you know,

the best shot that we have

at moving our agenda on AMR along,

and getting these two
worlds to really engage

and recognize that they have
a lot of overlap in interest

is really, you know, what many others

and us are trying to do.

I remember a few years
ago when Gavi puts out

its, you know, vaccine
investment strategy,

and I remember being part of the process,

they really wanted to have
AMR be part of that process,

but there simply was not the evidence

which was able to link
vaccination coverage,

or introduction of vaccines

with avoidable antibiotic consumption,

or reduction in AMR burden.

But I think we've come a long
way in the last few years,

and I think we have far
better evidence today

than we did just a few years ago.

- Thanks.

You segued nicely into the last question

we were going to ask you, which
is a little more specificity

in what has happened in the past few years

to provide quantifiable
evidence to support

that vaccines can reduce AMR

in addition to their
preventing the disease

they're intended to prevent.

Can you tell us a little more
about that and what's changed?

- Right, so I think there's
been a very focused effort.

At the One Health Trust,

we've been working with at
the Gates Foundation and WHO.

In fact, we had a tripartite,

and we put together a consortium of people

in multiple universities
to pick up pieces of this,

and essentially, you
know, write the papers

on pneumococcal pneumonia.

Kristin was part of, you know,
one of the papers on that.

We had work on typhoid,

on new vaccines that have
not yet been introduced,

including tuberculosis.

We've also looked at
non-bacterial pathogens,

you know, malaria, HIV.

So, we've covered a
whole range of vaccines,

existing, or new potential vaccines,

to be able to quantify the
effect on both AMR burden,

as well as on antibiotic consumption.

Some of these have been made
possible by the fact that

vaccine trials these days,
at least in some instances,

are increasingly collecting data

on antibiotic prescriptions.

So, I think one of the
slides that you presented

at the beginning, Tony,
you know, came from a paper

that we published in PNAS (Proceedings of the National Academy of Sciences of the United States of America) that based,

that was based on an
RSV trial by a company,

which was able to also look
at antibiotic prescriptions

in the intervention and the control arm,

and I know this adds to
the burden for these trials

in terms of what people
are tracking and so forth,

but without the systematic evidence,

the companies that are doing
the trial are, you know,

failing to take advantage of, A)

an important reason why those
vaccines will get introduced,

and B) a very important
public health benefit,

which is to actually show
the value of the vaccines

in dealing with AMR, you know,
when such benefit does exist.

I'm not claiming that it
exists in every single case,

but the trial is the
best time to do those,

to get that kind of evidence,

and I think it would be
great if all vaccine trials,

whether for viral vaccines,
or for bacterial vaccines,

start systematically incorporating

the effect on antibiotic resistance

and antibiotic use as
one of their endpoints,

and I suspect that as we're done

with the big blockbuster vaccines,

like, you know, the
pneumococcal vaccine, rotavirus,

which also has a big effect
on antibiotic consumption,

by the way, you know,
potentially, of course,

you know, the TB and malaria vaccines,

but a lot of the other vaccines
are much smaller, right?

So, it's going to be cholera, or typhoid,

or, you know, much more small,
much smaller populations.

And here, AMR is going to
be that thumb on the scale,

which is going to
encourage the vaccination,

because it is that additional reason

beyond the direct
reduction of disease burden

that makes it possible.

So, I think the evidence
is getting a lot better.

Like I said, you know, as
we now have a set of about,

I don't know, 13, or 14 papers now,

which cover the waterfront
with respect to,

you know, quantifying the evidence,

there was now a very nice paper from WHO,

which summarizes evidence as
well across multiple pathogens.

So, I think our evidence base
has grown significantly,

but we need more, especially
when the opportunity exists

to get them in the context
of clinical trials.

- Thanks, Ramanan.

It's great to hear about how
we're developing more evidence

and how this will help
persuade both the public

and the policymakers to adopt vaccines

as part of the solution to AMR.

I'm also glad you mentioned
the typhoid conjugate vaccine,

a really exciting new vaccine,

and as I recall, the trials,

to my point that I made
a little bit earlier

about how the vaccines are agnostic

in terms of whether an organism
is resistant, or sensitive,

as I recall, the trials did show

that effectiveness was equivalent

for the highly resistant typhoid bacteria

as it was for the less resistant ones.

Okay, so that's great.

Thanks, thanks, Ramanan.

We do have a last section.

We have time to talk about,
to all four panelists,

about some overarching questions.

We have two prepared to give to you,

and I guess we can maybe start off going

in order of the speakers.

The first question is from
each of your perspectives,

where do you see opportunities to design

and implement innovative
vaccine strategies

across domestic and global spaces

to help slow the emergence
and spread of AMR?

Go ahead, Kristin, if you
could tackle that first.

Maybe we'll go in reverse
order for the second one.

- Sounds good.

So, as I've mentioned a few times,

our pneumococcal conjugate
vaccines currently protect

against a subset of serotypes
that are most likely to cause

resistant, or severe disease.

But there's exciting
research that would create

a serotype independent vaccine

that uses the whole pneumococcal cell,

and this would be a really
exciting advancement

in vaccine development, as the
serotype independent vaccine

could offer additional protection

as well as reduce the burden

of resistant pneumococcal disease.

But in addition to this
as a novel strategy,

there are already newer
formulations of PCVs

that have emerged that
either cover new serotypes,

or a different combination of serotypes

that will prevent disease
and resistant disease.

There are also more manufacturers

in the pneumococcal market now,

which increases the
availability of these vaccines

across the global market,

which increases coverage,
as Ramanan put nicely,

getting more shots into arms.

So, there's a lot of encouraging
and exciting advancements

about how these new PCVs
can be used as a tool

to reduce resistance.

- Great, thanks.

Okay, so turning to Yonatan,

and the moderator does remind
me that we have lots of time,

so, you can be expansive
in your answers here.

This is your chance.

It's not the speed round,

So, feel free to be plenty expansive.

So again, the question was, Yonatan,

the same one that Kristin got,

is from each of your perspectives,

where do you see opportunities to design

and implement innovative strategies

across domestic and global spaces

to help slow the emergence
and spread of AMR?

- Okay, so trying to be expansive,

I think there are a bunch of
things that we've touched on

that merit a little bit more discussion.

So, one of them is a concept

that I think we've alluded to
a number of different times,

but just to put a name to it,

and that's bystander selection.

That's the idea that when
we take an antibiotic,

not only are we applying
pressure to the pathogen

we're attempting to treat,

say, taking ceftriaxone for gonorrhea,

but, in addition, we're
applying that pressure

to all of the different bacteria
that are on us and in us,

and remember, we're colonized
with Staph aureus on our skin,

or at least a good fraction
of the population is,

E. coli in our gut,

sometimes strep pneumo (Streptococcus pneumoniae) in our nasopharynx.

So, when we take these antibiotics,

we're not just exposing
the particular pathogen

to antibiotic pressure.

We're exposing all of
these commensal bacteria's

that could potentially become
pathogens to infection.

So, limiting the use of antibiotics

through things like vaccines,

whether it's for, vaccine for influenza

and inappropriate use of antibiotics

to treat respiratory infections,

vaccines for pneumococcus,
where it would be,

you know, limiting pneumococcal disease

and preventing antibiotic use that way,

has a broad effect not just
for those particular pathogens,

but for all of the other bacteria

that are subject to this
bystander selection.

So, I just wanted to kind
of put that out there

as an important element to consider

when we think about the
benefits of vaccination,

and that I think is both
domestic and global.

The global element is
a really critical one,

as Ramanan mentioned, and has
been brought up before in this,

and it's really this concept, you know,

we think about this for climate
change and other things,

so it's act local, think global, right?

Like that a lot of the
antimicrobial resistance problem

is not just a very local one.

We really have to think about
this as a global challenge.

What happens in one part
of the world affects

the rest of the world.

This is the case for all
of the different pathogens.

We heard the example of
Pseudomonas in eyedrops.

For Neisseria gonorrhoeae,
we see the resistance

to ceftriaxone really
emerging in East Asia.

And then through genomics, we
actually can track the spread

of these isolates, and it's those strains

that are making their way
into the rest of the world.

So, understanding what's happening

in these places is really critical.

How do we understand what's happening?

Well, I think that our
monitoring of antibiotic use

and antibiotic resistance globally

really needs to improve, right?

We have to have a much
better understanding

of who is using antibiotics,

how do people access them,

what are they using them for.

It is, as we've been discussing,
both a cultural issue,

but also, one that requires

not just the technological innovation,

but innovation around how we
do surveillance and monitoring.

So, I would say that, you know,
from a global perspective,

these innovative strategies
extend beyond thinking about

how we get vaccines to people,
but also, who needs them,

where, and how are we
using the different tools

that we have available to us,

and what the impact is ecologically

on antimicrobial use and resistance.

So, I think there's a fair amount there

that needs to be developed.

I think it's a similar kind
of issue around, you know,

the vaccine trials, as we've heard about,

as we put these vaccine trials into place,

and look about- look at the
impact on the burden of disease,

we also need to monitor not
only the use of antibiotics,

but the impact on antibiotic resistance,

and that's potentially a much
longer term effect, right?

We can't just look at what happens within,

say, six months, or a year, or
a couple years of the trial,

because we may not see the full effect

of reduction in antimicrobial
use over that time span.

So we need to think about both the timing,

the temporal impact of
some of these changes,

as well as the geographic distribution,

keeping in mind, of course,
as we've been talking about,

these bugs move all over the place.

So, I think there are many opportunities,

but I think a lot of work that
we need to do that's critical

around monitoring and surveillance.

- Thanks, Yonatan.

Shelley, you're up next.

The same question, opportunities to design

and implement innovative
vaccine strategies

across domestic and global spaces.

Just so-
- Thanks, Tony.

So, I'll, I guess, focus
on the domestic space.

I think there's a lot of opportunity

to increase uptake of vaccines
that are already available,

particularly in adult populations.

It can be more challenging for adults

to get all of the recommended vaccines

than is for children in the U.S.,

and many of the healthcare settings

in which adults receive care in the U.S.,

like specialty care settings
for specific medical,

or surgical issues, may not be focused on,

or familiar with providing
information on vaccines,

or delivering vaccinations.

And even if the provider's comfortable

providing comprehensive,
accurate vaccine information

to patients, the clinic might
not have vaccine available,

and might not know where to
refer patients for vaccinations,

such as to another provider,

a retail pharmacy in the community.

So, I think there's a real
opportunity to develop approaches

in different clinical settings
that improve availability

and accessibility of vaccines

and information about
those vaccines for adults.

- Thanks, yeah, very important.

And it will be a challenge,
as you mentioned,

especially for adult vaccines.

I am interested to see how
we'll deliver RSV vaccines

to pregnant women, for example.

Okay, and so, Ramanan, you're
up in the clean-up spot here

for the from your perspectives,
opportunities to design

and implement innovative
vaccine strategies.

The floor is yours-
- Well, I think, you know,

all the good points
have already been made.

I'll just go back to,
again, the evidence part.

I think on the strategy standpoint,

we've got two kinds of vaccines,

the ones which are going
to be able to prevent

a huge amount of antibiotic consumption,

and the ones which are going to be,

like the typhoid vaccine,
really our, you know,

our only tool to be able
to deal with an emergency

when it actually does occur.

And I think the opportunities
for the first one are

probably going to rely a
lot on an influenza vaccine.

Influenza, the influenza season is

the single most important reason
for antibiotic consumption

and especially inappropriate
antibiotic consumption

around the world.

The evidence is very clear
both of the United States

as well as globally,

and I don't know what the state of play is

for a universal flu shot,

but whoever's working
on that better hurry up,

because that is probably
going to be our best bet

for dealing with antibiotic consumption

at a very grand scale.

Now, when it comes to be able to deal

with the burden of AMR,

I think we are probably going to see

a lot more with respect to
vaccines against, you know,

specific bacterial
pathogens that people get

when they're hospitalized.

Hospitals are where people, you know,

the greatest burden is, and
it could be a staph vaccine.

I know we've tried many
times for a staph vaccine,

and haven't been particularly successful,

but we have to keep trying,

and I think that the mRNA
platforms offer new hope

that perhaps there will be
ways to develop these vaccines

in ways that are different from
what we've done in the past.

So, I'm optimistic, but I think
we've got these two, sort of,

you know, two things that
we have to keep in mind.

One is we've got to use
the vaccines to tamp down

on the consumption, and the other one,

we've got to look for ways to save lives

that are being lost to AMR right now.

And last, but not least,
let me also remind everyone

that we're talking largely
about human vaccines.

The opportunities for animal
vaccines are tremendous.

In fact, animal vaccination is

a significantly underused tool,

because unlike for human vaccines,

where we have a Gavi, in animal vaccines,

there is no such public funding mechanism,

and everything that we can
do to be able to use vaccines

that are able to improve
productivity in animals

and also reduce the need for antibiotics,

you know, whether for metaphylaxis,

or, you know, obviously,
for disease prevention,

I mean, for growth promotion
or for disease prevention,

would be really helpful.

But this is, again, a domain
where a lot more needs to,

a lot more work needs to happen.

- Thanks, Ramanan, and
I did say I might go

in reverse order,

and this is convenient,
because you did mention

reasons for hope for the
future of vaccines as a tool

for combating AMR. Can you-

Here's your chance to expand
on that a little bit more,

and what other reasons for
hope there are for this?

- I think an important reason
for hope is simply that

people's attitude towards
vaccines has changed broadly.

I don't mean, obviously, there are pockets

where people are vaccine hesitant,

or don't want to take
vaccines, and so forth,

but I think the idea that
vaccines pulled us out of COVID

is generally recognized around the world,

the idea that adults need vaccines,

which is not a thing at all.

I know in the United States
we have seasonal flu vaccines.

That's not true in many
parts of the world.

The idea that adults could
get a vaccine is also become

more acceptable thanks to COVID.

I mean, in most LMICs, COVID
was the first reason, you know,

it was the only reason
so far that any adult

would get a vaccine shot.

So, I think we're now
starting to enter a world

in which adult vaccines are okay,

vaccines are seen as being useful,

and potentially we have vaccines,
which could in the next,

I would say, you know,
next 10 to 20 years,

be able to help us tackle
many of the challenges of AMR

by reducing the burden,

particularly for the sets of infections

where we have the highest
numbers of resistant infections,

and particularly the
healthcare-associated infections.

So, I think the combination
of what we might have

with new vaccine development
using new platforms

and a general receptiveness
will get us much further than,

you know, than what we
could have thought about

just four, or five years ago.

- Thanks.

Shelley, I'm turning to
you for reasons for hope

for the future of vaccines as a tool.

- Yeah, agree with all those points,

and you know, new
technologies, new opportunities

for developing vaccines
against new pathogens,

vaccines we haven't had before,

those are all obviously opportunities for,

or chances for optimism.

But, as I mentioned, there's
a lot of room for improvement

with the vaccines that we already have,

and I think, you know, we
should continue working

to maximize their use

in alignment with current recommendations.

In addition, as has
already been mentioned,

I think increasingly
there is a recognition

of the critical threat that
antimicrobial resistance poses

to the world, not only among public health

and healthcare professionals,

but also policymakers and the public.

And increasingly, too,
we're seeing data supporting

the value of vaccines for
reducing antimicrobial resistance.

One example is a recently
published modeling study

by investigators at a
number of organizations,

including the International
Vaccine Institute,

Novo Nordisk Foundation, WHO,

and the London School of
Hygiene and Tropical Medicine,

where the authors found that
a substantial burden of death

and disability globally could be averted

through use of vaccines

against 15 common bacterial pathogens.

So, I think with this increased awareness

and increasingly robust evidence base,

more innovative approaches,

like the development of new
vaccines, will gain traction.

- Thanks, Shelley.

Yonatan, do you wanna
take a stab at this one?

Reasons for hope and optimism?

- Sure.

I think, echo all of the
points that we've heard,

and add a couple.

One is around funding.

So, there is more of an
investment by funding agencies

in the research to develop these tools,

and I think recognizing that

they have increasing acceptability,

although, you know, it
has to be mentioned that

the anti-vaccine sentiment
that's out there is another issue

that really, we have to work on.

Communication, sharing
clearer information,

combating disinformation, all of that is,

I think, a critical
element in the strategy

to promote vaccine uptake broadly.

But the success of the COVID vaccines,

the introduction of RSV vaccines,

I think all of this has also
encouraged the private sector

to invest heavily in
development of new vaccines.

So, I think that is with, again,

ideas of preventing disease,
preventing disease limits

the use of antibiotics,
limiting the use of antibiotics

I think will help reduce the pressures

on antimicrobial resistance,

in addition to preventing infections

by antimicrobial-resistant organisms.

So, I think all of that
is very encouraging.

I'd also say that another element here is

the delivery of these vaccines
to places that need them,

and the development of new solutions

and approaches to this
kind of infrastructure.

So, I was recently in Rwanda,

and near a hospital in rural Rwanda,

where it takes a long
time to get there by road.

From Kigali, the capital
city, to this hospital,

it's around a three-hour drive

on both paved and unpaved roads.

How do you get urgent
supplies to places like that?

Well, in this case, one of the solutions

was actually using drones,

that what was a three-hour drive was

a 20-minute drone flight,

and with the right
infrastructure for delivery,

we can start to access populations
that otherwise would have

a very hard time getting these vaccines

that we recognize as being so valuable.

So, the development of
infrastructure around

delivery of vaccines, medicines, and so on

I think is another hugely
important area of advancement

with great potential for
really improving the lives

and health of people all around the world.

- Thanks.

Yeah, those are some important points.

I'm glad you were able to make them.

Kristin, I'm turning to you.

I've been a bit unfair to you,

because you're getting the last bit,

and I know a lot of it's been said,

but I bet there are specific
examples you can give us

about optimism, particularly around PCV.

Go ahead.

- Yeah, sure, I mean, all the
panelists have really made

the excellent points here, you know,

the importance of increasing
vaccine confidence

and acceptability, the
global recognition of AMR

as a critical public health problem,

and vaccines as a tool to address it,

in addition to the complement
of all the other approaches

that we're using as well,

improving the pipeline of new vaccines,

using new technologies,
particularly for those pathogens

that are most associated with resistance,

or improving our existing vaccines,

and from my perspective, I
think what gives me hope is that

there are a lot of new
pneumococcal vaccines

in the pipeline.

You know, in the last two years alone,

both PCV15 and PCV20 were
recommended for routine infant use

and use among older adults and
adults with risk conditions,

which will offer additional
protection against acquiring

a resistant infection,
and beyond PCV15 and 20,

there are even more vaccines
in the pipeline as well,

but it still remains important
to get these shots into arms

and improve vaccine
confidence and acceptability.

Aside from pneumococcal
conjugate vaccines though,

implementation of other
vaccines like the RSV vaccine

can offer additional
protection to reduce the burden

of resistant pneumococcal disease,

because as it has been mentioned,

these vaccines for viral
infections prevent resistance,

because viral infections can often trigger

secondary bacterial infections,

and our viral infections
are large contributors

to unnecessary antibiotic use.

So, all of these vaccines
can lead to a reduction

in resistance by both reducing the burden

of resistant infections,

reducing unnecessary
antibiotic prescribing,

and everything I've heard
today has just given me

a lot of hope in how these vaccines

and future vaccines can be used as a tool

to combat resistance in the future.

- Great.

Thanks, Kristin.

Yeah, it's great to
hear that the developers

of pneumococcal vaccines are not resting

on their well-deserved laurels,

and going after even better targets,

such as this universal one you mentioned.

Well, we've come to the
end of the questions,

and so, thanks so much,
everyone, for joining,

and thanks to our panelists
for such a great discussion.

I have a chance,

just a couple of minutes
to do a quick wrap-up,

and this might be particularly important

for those who signed in late,

and didn't hear some of the
early parts of the presentation.

Today, we heard four perspectives

on how vaccines are an important tool

for combating antimicrobial resistance.

Dr. Kristin Andrejko talked about

the pneumococcal conjugate vaccines

and really showed how they're
one of the best examples

of how one can use vaccines to reduce AMR.

Gonorrhea vaccines were
discussed by Dr. Yonatan Grad,

who noted the many ways that
this is an important disease.

It's high on the wishlist of
both WHO and the U.S. authorities

for getting a vaccine,

and then what an important
driver that gonorrhea is

for antibiotic resistance.

And so, thanks for your overview of that.

Dr. Shelley Magill, our third speaker,

gave us an overview mostly focused

on the healthcare-associated
infection vaccines,

but also, a good bit about how
the surveillance platforms

that are set up for both HAIs

and through some of the other parts of CDC

and state health departments in the U.S.

also, to be able to monitor
the impact of vaccines

once they're introduced
both on disease and on AMR.

And then finally, Dr. Ramanan
Laxminarayan provided us

a really good global overview,

and touched on some of
the points that are needed

to be included in national action plans,

and both their promise
and the fact that we have

a lot of work to do still
to get these action plans

into something that's
actually having an impact,

and also touched on some
of the other aspects

of how vaccines reduce AMR.

So thanks all for joining,

and be sure to tell your
friends and colleagues,

those of you who are listening,

that this is available
for viewing, I believe,

on a YouTube link,

and probably you can get that CDC website,

and really appreciate your time today,

and this is such an exciting topic,

and I'm really glad we
were able to talk about it.

So, with that, I think we can wrap it up.

We're pretty much on time,

Okay, well, anyway, thanks for joining us,

and have a good rest of your day.

Thank you.