Ep. 41: Is There a Human Lyme Vaccine on the Horizon?

Show Notes

With global warming affecting the tick population, the time is right to try again with a human Lyme disease vaccine. I talk with Dr. Richard Marconi, professor at Virginia Commonwealth University's Department of Microbiology and Immunology, about his research into ticks, Lyme, and the promise of a human vaccine.

What is Sounds of Science?

Sounds of Science is a monthly podcast about beginnings: how a molecule becomes a drug, how a rodent elucidates a disease pathway, how a horseshoe crab morphs into an infection fighter. The podcast is produced by Eureka, the scientific blog of Charles River, a contract research organization for drug discovery and development. Tune in and begin the journey.

- [Mary] I'm Mary Parker,
and welcome to this episode

of Eureka's Sounds Of Science.

(uplifting music)

Anyone who has spent any
time outside in tick country

knows about the dangers of Lyme disease,

caused by a bacteria
transmitted through tick bites.

Lyme disease can have
severe lasting consequences

in some people.

Luckily for our pets,

there are vaccines to guard against Lyme,

but only for animals.

Here to talk about why that is

and how scientists are
addressing this imbalance

is Dr. Richard Marconi,

Professor of Microbiology and Immunology

at Virginia Commonwealth
University Medical Center.

Part of Dr. Marconi's research

involves developing potential
human Lyme vaccines.

Welcome, Rich.

So can you start by
telling us a little bit

about your background
and research experience?

- [Richard] Sure, no, thank
you first for having me, Mary.

I appreciate the opportunity
to talk with you today.

- [Mary] Yeah, thanks for coming.

- [Richard] My pleasure.

I earned my bachelor's degree in biology

at William Paterson College in New Jersey.

And after graduating
from William Paterson,

I went to the University of Montana

where I studied microbiology
and biophysical chemistry.

After graduating with my PhD,

I did my first
post-doctoral training stint

at the Roche Institute
for Molecular Biology,

which brought me back to the
East Coast, back to New Jersey.

And there I studied bacterial metabolism.

And that was in the late 1980s.

And at that time,

Lyme disease was really
becoming quite a hot topic.

I very vividly remember seeing

the cover page of Newsweek magazine,

which highlighted that there was this new

and mysterious disease

that was creeping across the country.

I became very interested in that.

So I decided at that point

that I wanted to get involved
in Lyme disease research

and do a second
post-doctoral training stint.

So I accepted an intramural
research training award

at the Rocky Mountain Laboratories

in beautiful Hamilton, Montana.

- [Mary] My folks are
actually from Montana,

so yeah, it's just gorgeous out there.

They lived in Missoula, so.

- [Richard] Yeah, in fact,

Rocky Mountain Laboratories is about

50 or 60 miles south of Missoula.

But you know, it was
wonderful to work there

because Rocky Mountain Laboratories

is part of the National
Institutes of Health.

So it's a really well-funded,

well-developed research facility,

and it's become known

as one of the leading centers in the world

for studying tick-borne diseases.

When I was there,

I also had the pleasure of
working with a gentleman

named Willy Burgdorfer.

And as some folks may know,

the causative agent of Lyme disease

is in fact called Borrelia burgdorferi.

So it was named after
Dr. Willy Burgdorfer.

- [Mary] Wow, I didn't
know that. (chuckles)

- [Richard] Yeah, so I
had a great opportunity

when I was there to study with people

who were really right there

at the very beginning of Lyme disease.

And it was a wonderful
training experience.

And then after leaving
Rocky Mountain Laboratories,

I accepted an assistant professor position

at Virginia Commonwealth University,

and that was in 1994.

And I've worked my way
through the ranks here,

and now I'm a full Professor of Medicine.

And I had basically been
studying tick-borne diseases

with an emphasis on Lyme disease

for 30 plus years at this point.

- [Mary] Wow, well,
you're definitely the guy

to talk to about this topic then.

So can you tell me about Lyme disease

and other tick-borne
diseases that are of note?

- [Richard] Sure, well, you
know, in the United States,

or I should say North America,

we have a couple of very
significant tick-borne diseases

that we need to think about
and be concerned about.

But certainly at the top of
the list is Lyme disease.

And the reason I say that

is because it is the most
common tick-borne disease

in the Northern hemisphere.

So it is clearly the most important

of the tick-borne diseases
in terms of its numbers.

But others that we need
to be concerned about

include diseases called
ehrlichiosis anaplasmosis.

And of course, Rocky
Mountain spotted fever.

- [Mary] Yeah, so can you tell me

about how Lyme disease
circulates in nature?

- [Richard] One of the key
things to know about Lyme disease

is that a tick,

when an adult female Ixodes tick

lays the eggs in order to renew the cycle,

what emerges from the eggs

is the stage of the
tick called the larvae.

And the larvae are infection-free.

They are not carrying Lyme disease.

And the reason for that

is that Lyme disease cannot be transmitted

from the adult female
tick through the egg,

to the larvae.

So there's no what we call,
transovarial transmission.

So what that means

is that the only way that
a tick can become infected

is if it feeds on an infected animal.

Now, there's also another
very important point to note

is that there is no animal
to animal transmission

of Lyme disease.

So I can't get it from you,

you can't get it from your dog,

your dog can't pass it onto
another mammal, et cetera.

So for Lyme disease to propagate nature,

what has to occur, and again,

I sort of put this in the context of,

this is like, what came
first, the chicken or the egg?

But you have an uninfected
larval stage tick,

which will seek out a blood meal.

Now larval stage ticks,

because of their biological properties,

tend to be a ground-dwelling ticks.

And they tend to feed on
ground-dwelling mammals,

things like moles, voles, shrews, mice,

things in that category.

If they happen to feed
on an infected animal,

then those larval stage ticks
will acquire the infection.

Now the larval stage ticks feed only once.

So if they fed on an infected animal,

they become infected,

and they carry that infection with them

throughout the rest of
their developmental cycle.

And what happens after a
larval stage tick feeds,

is that it undergoes a molting process,

or the process of molting.

And after molting,

the larval stage tick will develop

into what's called the nymphal stage tick.

Now this is then the
first stage of the tick

that has the potential

to now transmit the Lyme spirochetes

onto another animal.

And of course, if the nymphal stage tick

is not already infected prior
to it taking a blood meal,

when it feeds, it now has the potential

to a second chance of
acquiring that infection.

The nymphal stage ticks,

in contrast to the larval stage ticks,

are anatomically different.

And it's a very important difference

because larval stage
ticks only have six legs,

and that's why they tend
to stay on the ground.

They're not particularly good climbers.

But the nymph stage ticks
will have eight legs.

And that allows them to get
higher up into the vegetation

and to seek access to larger mammals.

- [Mary] Okay, that makes sense.

- [Richard] Yeah, so that's
really important in the process.

If the nymphal stage tick's in the process

of transitioning from
the larvae to the nymph,

if they did not develop that
extra set of hind limbs,

they probably would not be
able to get access to us

and cause Lyme disease
in us or in our dogs.

So that's an important transition.

Now, the nymphal stage tick

also just takes one blood meal.

And it's really remarkable
when ticks feed,

because they can increase their body mass

by as much as 500-fold.

So that's a pretty good meal.

- [Mary] Yeah, I've seen that, actually.

I found one on my carpet.

I don't know if it came from
me or my dog many years ago.

And it was about the size of a peanut M&M.

- [Richard] Yeah, that's
quite interesting.

I've actually had the same experience.

- [Mary] So it might be
important to note now,

maybe just for my own peace of mind,

because I hate ticks so much.

Do they serve an important
ecological purpose?

Do they, for example,

provide food for a
cuter animal? (chuckles)

- [Richard] That's a great question.

And it's certainly not the
first time I've been asked.

And I've pondered that
for quite some time,

and actually tried to find
an answer to that question.

And we don't know.
- Oh wow, okay.

- [Richard] What the role of ticks is

in the larger scheme of things.

But what we do know is that
they are ancient creatures

and they have been around for a long time.

They're hardy, they're durable,

and all indications are
that they will be around

for quite a bit longer, and
potentially even outlast us.

- [Mary] At this rate, yeah, probably.

- [Richard] Yeah.

- [Mary] Speaking of going back to humans,

what are some of the long-term
effects of Lyme disease

for people that get it?

- [Richard] Sure, well, Lyme
disease can be a very serious

and debilitating infection.

But first I'll start by saying

that the good news is that,

when Lyme disease is diagnosed early,

it's readily treatable.

You know, there is some controversy

in the area of diagnostics

and other issues such as a condition

called post-treatment
Lyme disease syndrome.

But overall, for those people
who are diagnosed early,

a three-week to four-week
course of doxycycline

usually proves to be quite effective

in eliminating the illness.

Now, having said that,

the initial symptoms of Lyme disease

are somewhat difficult to identify

as a Lyme disease infection.

So whether it's ourself,

or in our companion animals, in our dogs,

the initial symptoms are malaise,

just not really feeling so well,

potentially a very low grade fever,

achiness, et cetera.

It may sound funny to say this,

but in about 60 to 70% of human patients,

an erythema migrans lesion,

or a bullseye rash will develop

at the site of the tick bite.

And frankly, if that rash develops,

you're kind of one of
the lucky individuals,

because it's a very characteristic

early clinical manifestation
of Lyme disease.

And most clinicians are well-versed

and can easily identify that bullseye rash

as a symptom of Lyme,

and therefore initiate
treatment very early.

But if Lyme is not caught early,

then, as I said a few minutes ago,

some very significant long-term

clinical manifestations can develop.

And to understand what those symptoms are

and why they occur,

it's important to know

that an infection with the
Lyme disease spirochetes

is in fact a true chronic infection.

So I wanna be clear on
what I mean by that.

When a mammal gets infected by
the Lyme disease spirochetes,

the infection will essentially
persist indefinitely.

Lyme is a multisystemic infection

that can affect the cardiovascular system,

musculoskeletal system,

the nervous system, et cetera.

So some of these specific types

of clinical things that may develop

in a longterm Lyme disease patient

include neurological deficits,

carditis, or inflammation of the heart,

prolonged periods of arthritis,

which interestingly
enough typically develop

in one or more of the large joints,

and other serious skin manifestations,

something called acrodermatitis
chronica atrophicans,

is common in Europe, less
common in North America,

but it's a very significant
condition of the skin

that leads to necrosis
and tissue destruction,

and can be quite potentially disfiguring.

So again, the key for Lyme disease

is to prevent and treat early.

- [Mary] Yeah, my husband actually got

Lyme disease recently.

Luckily he had very obvious rash,

the bullseye rash,

and his doctor was able to diagnose it

over a webcam. (chuckles)

So he just went and
picked up his prescription

and took care of it.

So he got off easy, comparatively.

Is there any effect of
Lyme disease on the tick

or are they just carriers?

- [Richard] They are just carriers.

We know of no impact that the spirochetes

have on the tick itself.

- [Mary] Yeah, well,

we pretty much covered treatment options.

So I understand there was a
human Lyme vaccine at one time.

Can you share that story?

- [Richard] Sure, so in the early days

of seeking to develop
vaccines for Lyme disease,

one of the most obvious
targets that was identified

to utilize as a vaccine antigen

was a protein called outer
surface protein A, or OspA.

So that was the first
protein that was pursued

in the development of
a Lyme disease vaccine.

And it was successfully developed.

And in 1998, a vaccine entered the market,

which was called LYMErix.

And LYMErix consisted solely

of this purified form of
outer surface protein A.

And studies had shown that
LYMErix was pretty effective,

but it required multiple doses

in order to achieve a high
level of protective immunity.

So it required three doses

to achieve a protective
efficacy of about 72%.

Now, really when that
vaccine came onto the market,

we really thought that
was gonna be the answer

to the Lyme disease problem.

But not long after it entered the market,

concerns began to be raised

about adverse events that
could be attributable to,

or associated with delivery
of the vaccine to humans.

Most specifically,

people were concerned
about the possibility

of arthritic events and other
autoimmune-type of responses.

So at the time that these concerns

became known to the public,

they really got amplified by the media,

social media, and by patient
advocacy groups as well.

And the consequence of that

was that the demand for the vaccine

dropped rather dramatically,

out of fear of adverse events.

The FDA, the CDC, and all of
the other relevant agencies

looked very, very carefully at the data

to determine if it was in fact possible

that the LYMErix vaccine
was inducing adverse events.

And the strong conclusion

was that the vaccine was quite safe

and that there were no issues

that warranted its
removal from the market.

And the review was
really rather exhaustive.

So I'm very much in the
camp where I believe

that there truly were no
significant adverse events

associated with the vaccine.

Nonetheless, you know, at the
time, when this was going on,

as I mentioned, it really
destroyed the market

for the vaccine.

So the vaccine was
actually voluntarily pulled

by the manufacturer in 2001,

and they cited largely market concerns,

that it wasn't getting
sufficient uptake in the market.

Having said that,

while the vaccine I think was truly safe,

there were in fact, some problems with it

that made it less
attractive to the public.

One of those was the fact

that it required multiple
booster vaccinations

in order to achieve a reasonable efficacy.

- [Mary] I understand
that vaccination for Lyme

is relatively routine
in veterinary medicine.

I mean, I understand
that because, (chuckles)

I have owned dogs and cats, my whole life.

Particularly for dogs,

what types of vaccines are
currently available for dogs?

And can they be adapted for human use?

- [Richard] Well, I'll
start by talking about

the primary difference
between the two categories,

or two major types of vaccines

that are now being used in dogs.

Basically there are two major types.

One type of Lyme disease vaccine

is generically referred
to as a bacterin vaccine.

And the second type is a
vaccine that's referred to

as a subunit vaccine.

So the difference between the two

is that bacterins

are fairly simple types
of vaccines to produce.

So for example,

if we wanted to make a bacterin
vaccine for Lyme disease,

what we would do is we would
grow up a rather large batch

of the Lyme disease spirochetes.

You can do this in a laboratory.

You grow them up in a liquid media.

And after they have grown up

and you have achieved
a sufficiently dense,

what we call culture of the bacteria,

you recover those bacteria,

you inactivate them or kill them,

because of course you
don't want your vaccine

to cause an infection.

So the bacteria are killed.

Then they're emulsified, and homogenized,

and filtered to remove,

obviously, things like
clumps in a vaccine.

We don't want clumps in a vaccine.

So they're filtered,

and then that becomes the
actual vaccine preparation.

So a bacterin actually consists

of everything that the Lyme
disease spirochetes grow

when we grow them in the laboratory.

And we know very well,
with a lot of detail,

what is produced by these
bacteria in the laboratory

while they're growing in culture.

And they make about
1500 different proteins.

So a bacterin vaccine contains
that whole complete mix

of all of those proteins.

And that's, you know,

those have been moderately
effective vaccines

and very useful in veterinary
medicine for some time.

But what we're trying to do

in the world of vaccinology as a whole

is move to cleaner vaccines,

ones that are more defined
in their composition.

And that's where the subunit
vaccines come into the picture

in terms of Lyme disease,

LYMErix, the vaccine
that I mentioned earlier

is in fact a subunit vaccine.

It consists of a single protein,

and we refer to that protein
as recombinant protein,

which simply means that it
was produced in the laboratory

and then carefully purified

under very controlled circumstances.

So with LYMErix, when that
vaccine was delivered,

instead of 1500 proteins,

you're getting one single protein.

And that's a positive step forward.

There's a second vaccine available,

which is a vaccine that we developed,

called Vanguard crLyme,

which consists of two proteins.

It contains OspA and a very
unique modified version

of a second protein called OspC.

So to summarize that,

two types of vaccines,
bacterins and subunits.

Bacterins are basically,

what we call a whole cell lysate.

And the subunit vaccines are
purified recombinant proteins.

- [Mary] What are some
of the other difficulties

associated with the development
of a human Lyme vaccine?

So like what are some of the hurdles

that need to be overcome?

- [Richard] Yeah, I think
one of the biggest hurdles

that those of us who have worked

on vaccines for Lyme
disease have encountered

is that the bacteria
that causes Lyme disease

are remarkably variable.

So there's a lot of
diversity in these bacteria.

And when you're making a vaccine,

you of course wanna make a vaccine

that can protect against all
of the different variants.

And the word variant has
become a common term these days

as we hear what's going on with COVID.

But the level of diversity and variation

in the Lyme spirochetes,

meaning if you compare one Lyme
disease strain with another,

is really pretty remarkable.

So that posed a real
significant challenge.

How can you make a vaccine

that will protect against
all those different strains?

And, you know, we were able
to find an answer to that,

which is, I think really exciting

and has a lot of potential for
other vaccines down the road.

And I'll just be very
brief in describing this,

but I mentioned that the
vaccine that we developed

contains a protein called OspC.

Well, it doesn't actually contain OspC.

It contains a modified form of OspC

that we created in the laboratory.

And in brief, as we were
pondering, in the early days,

how could we make an OspC protein

that could protect against
all of the different variants

of that protein that exist in nature?

We came to the conclusion
that we could not allow nature

or that nature would never provide us

with the answer to this.

So we had to create our own answer.

So what we did is we found

the immunologically
important parts of OspC,

and we took those from
many different variants

of the OspC protein,

and we assembled those pieces together.

Basically we created a new gene,

and then from that, created a new protein

that had OspC pieces from many different

Lyme spirochetes strains joined together.

And we call that chimeritope technology.

So that was exciting to
be able to figure out

how to make a broadly protective vaccine.

And that's one of the challenges
that we have to encounter

in moving the vaccine into humans.

We have to make sure that
the vaccine is tailored

to address the diversity of
strains that can infect humans.

But scientifically, you know,

I think we're kind of getting
there for human vaccine.

There's another human vaccine
that is in clinical trials.

It is an OspA-based vaccine.

So hopefully, there will be a
couple of different options.

But there's one other
challenge that arises

in developing a human vaccine.

And that is that with
the failure of LYMErix

or the demise of LYMErix,
you know, back in 2002,

it really dampened interest

by the pharmaceutical companies

and the vaccine manufacturers

to pursue another human vaccine.

So Lyme disease vaccine research

sat idle for quite some time.

And, you know, you can create a vaccine,

but then you have to get people to use it.

You have to get them to accept it.

So what we need to do,
what we all need to do,

those of us working in this area,

is we need to develop a vaccine

that requires minimal number of boosters.

And of course that has no adverse
events associated with it,

which of course is obvious.

But the key thing is
we wanna have a vaccine

that doesn't require three
doses a year, et cetera,

because that's just generally doesn't work

with the human population.

- [Mary] Can you think of anything else

that researchers or drug
developers would need

to bring a human vaccine to market?

- [Richard] Well, I think, you know,

most of the vaccine efforts
that are ongoing now,

except for one,

which is actually in the
hands of large pharma,

who's working on clinical trials,

what's really needed is we need
to increase public awareness

about Lyme disease.

Lyme disease, it's interesting,

because most everybody
knows about Lyme disease.

And it's sort of an
interesting disease to people

because they're fascinated by the fact

that it's transmitted by a tick.

So, and everybody knows somebody

who's had Lyme disease,

or they've had a dog that
has had Lyme disease.

So we need to further
increase the awareness

of the fact that this is an infection

that can in fact be prevented.

And it can be prevented with very safe

and very clean vaccines.

The second thing that we need,

is we need, you know,

the public to express their
interest in such a vaccine

because that will
motivate and drive pharma,

or investors, and
midsize biotech companies

to pick up the effort
to advance a vaccine.

So it's both an awareness
issue that we need to address

as well as for lack of a better term,

a business issue, to
advance the Lyme vaccine.

- [Mary] That makes sense.

Maybe you could get a
celebrity spokesperson.

I understand one of the Real Housewives

of one of the cities has Lyme disease

and has spoken about it a lot.

So celebrity endorsements never hurt.

- [Richard] They never hurt.

And you know, Lyme doesn't pick.

Lyme has no boundaries
on who it will infect.

So it's interestingly,

that's associated with healthy activities.

So we tend to think of disease

as something that might
often be associated with,

you know, bad practices, or.

- [Mary] Right, no hiking,
camping, mountain climbing.

- Exactly.
- Things like that, yeah.

- [Richard] Yeah, so anybody can get it.

And it doesn't matter if
you're a celebrity or not,

you're on the table as a candidate.

- [Mary] And, you know, speaking of which,

is global warming or climate change

influencing the spread of Lyme disease,

and therefore the need
for a human Lyme vaccine?

I think the answer to this is
yes, but go ahead. (chuckles)

- [Richard] Yeah, well,

I would certainly answer yes as well.

But I would just qualify it

by saying that environmental science

is not my area of expertise.

So I will simply relay to you

what I'm learning from the entomologists

and others who are studying

the impacts of environmental
change and global warming

on what's most relevant to
what we're talking about,

and that's the tick population.

The tick population is
expanding dramatically.

It's a great time to be a tick, frankly.

And if you look at how
the tick population,

and I'm very specifically talking about

the ticks that cause Lyme disease.

If you look at how the population
of those ticks have spread

and increased over the
past several decades,

it's truly remarkable.

Back in 1996, the ticks that
transmitted Lyme disease

were largely found in fairly
tight geographic regions

in the Northeast, the upper Midwest,

and even a little bit in the South.

But studies by the CDC have shown that

when they compare the tick
distribution from 1996

with a study that was done in 2015,

we now see that the entire Northeast,

well down into the mid-Atlantic states

is essentially a high density tick zone.

The same sort of spread has
occurred in the upper Midwest,

and there's an increase
in the tick population

on the West Coast as well.

And real importantly,

we're seeing this spread
go northward as well.

So Lyme is quite a significant
problem in Canada as well,

particularly on both the east
and west coasts of Canada.

- [Mary] I understand that
it's not necessarily just Lyme

that is creating a
problem for other species

with the tick population explosion.

Most, for examplqe,

I understand are at
very high risk of anemia

because they're so covered in ticks

that they don't have enough
blood left for themselves.

- [Richard] Yeah, that's very true.

And you know, that has
been a real concern,

certainly in the upper Midwest

and even more in the very upper Northeast,

in Maine, for example.

Obviously wildlife, you know,

has no protection from ticks,

and they are exposed to tremendous,

tremendous numbers of ticks.

We have recently been studying

the effects of these tick-borne
diseases on wildlife,

and it's been really quite fascinating.

But the situation that
you're referring to,

utilizing moose as an example,

that's not necessarily

just the Lyme disease transmitting ticks

that are a problem there.

There are many different types of ticks

and some of them can really consume

rather large blood meals.

And so when any animal gets infested

with thousands of ticks,

it's going to have a consequence

because these ticks are
very voracious feeders.

And as I said, they'll
increase their body mass

over 500, 600 fold from
just a single blood meal.

So you're right, it is a real problem.

And it's affecting certain
species of wildlife

in a very negative way.

- [Mary] Yeah, that giant tick

I was telling you about earlier,

when I picked it up off the floor,

I thought it was like an
ugly bead or something

that had fallen off of an ugly necklace.

And then I saw it as
little tiny legs wriggling,

and it was probably the
most horrifying thing

I've ever seen. (laughs)

- [Richard] See, and now I
would in fact be different.

And I'd say, this is great that I've found

a great tick specimen, but.

- [Mary] Yep, so what is the likely future

of a human Lyme disease vaccine?

Do you think we'll have
one in the next 10 years?

- [Richard] I do, I'm optimistic.

- [Mary] Good. (chuckles)

- [Richard] As I said,
there is currently one

that is in clinical trials.

I don't know whether
that particular vaccine

will be the end all be all
to deal with Lyme disease.

And as with any type of disease

in which we're developing,

which vaccines are being developed,

you wanna see multiple approaches

being taken to the table
to solve the problem,

and that's what's going on.

So I do think because of
the increasing numbers

of cases of Lyme disease,

the spread of the tick population,

the increasing awareness in the public,

that we will in fact move
towards a human vaccine.

And I do think it will occur
within the 10 year window.

- [Mary] Excellent,
well, that's good news.

- [Richard] Yes, it is.

- [Mary] Thank you so much

for sharing your expertise with us.

This has been a really
fascinating conversation

and a little gross, but that's okay.

- [Richard] Well, it's been my pleasure

and thank you for your time.

- [Mary] Thank you.

(uplifting music)