HHS Working Group on Lyme and Other Tickborne Diseases: Emerging Issues in Tickborne Disease 6/13/19

HHS Working Group on Lyme and Other Tickborne Diseases: Emerging Issues in Tickborne Disease 6/13/19


Coordinator: Thank you all for standing by. I would like to inform all participants
that your lines are on a listen only mode until the Question and Answer
session of today’s call. Today’s call is also being recorded. If there are any objections,
you may disconnect at this time. I will now turn the call over to Mr. Paul Mead. Sir, you may begin. Dr. Paul Mead: Great. Thank you very much. Good morning or good afternoon and
welcome everybody to the Health and Human Services Working Group on Lyme
and other Tickborne Diseases Webinar on Emerging Issues in Tickborne Diseases. My name is Paul Mead. I’m the Chief of the Bacterial Diseases Branch
in the Division of Vector-borne Disease at CDC and I appreciate you all joining today. Just a quick reminder before we begin that
the views of the participants are their own and do not necessarily reflect those
of their agencies or institutions. Let me say a few words before we get
started just to remind everybody why ticks and tickborne diseases are a
significant public health problem. Of all vector-borne diseases
reported in the U.S., 95% are caused by pathogens spread by ticks. In recent decades, the number of tickborne
cases reported per year has increased steadily and cases have been reported over
an expanding geographic area. We are also seeing an increasing number of new tickborne agents recognized
to cause human disease. And finally, although not yet a trend we are
monitoring-or many groups are monitoring-the spread of the Asian longhorned tick which
has recently been recognized ion the U.S and has the potential to serve as a vector for
endemic and potentially exotic human pathogens. Shown here are the number of reported cases
of some of the key tickborne illnesses for the last two years of
completed reporting, 2016 and 2017. And the bottom line here is that these pathogens
have caused almost 60,000 reported cases of tickborne illness. The worst year ever. But the objective of today’s webinar is
really to highlight some emerging trends in tickborne diseases and
what can be done about them. And our speakers and topics today are
first Denise Bonilla from USDA agency who will provide an update on the Asian
longhorned tick – Haemaphysalis longicornis. Then Dr. William Nicholson from my sister branch at CDC will discuss the alpha-gal Allergy
Following Tick Bite: What we Really Know. Third Dr. Kevin Esvelt from the Massachusetts
Institute of Technology will discuss Mice Against Ticks in a Community-Guided Effort
to Prevent Lyme Disease via gene editing. And finally, Dr. Ben Beard from our
division will provide an overview of the national strategy
of vector-borne diseases. We will hold questions until the end of the
session and ideally, we would like people to submit their questions online
through the web interface. This will allow us to try and get
to the most questions possible. When you do submit questions please
provide your identity and indicate to which speaker your questions are addressed. And as I said, we will save the questions
until the end of this presentation. So without further ado let me just mention that
there is a web site to get further information. Why don’t we move onto our
first speaker, Denise Bonilla? Denise Bonilla: Right. I’m going to – trying to
pull up my presentation. All right. Can everyone see my presentation? Dr. Paul Mead: Yes. We can. Thank you. Denise Bonilla: All right. Thank you. Well, first thank you for the
invitation to participate today. Again, my name is Denise Bonilla. I’m an entomologist at the USDA in
our Veterinary Services Strategy and Policy Ruminant Health Center. Today I’m going to give you an update, just
a snapshot of what’s going on in the world of longhorned ticks here in the United States. Here our story starts, back in 2017 in
Hunterdon County New Jersey a lady came into the local mosquito control complaining
of ticks on her sheep and herself. In late October, the entomologist
there went out to investigate and found the sheep was badly infested with
multiple stages of a tick that didn’t quite look like the ticks that had been found in the area. Long story short, later the tick made its
way Rutgers in Monmouth County Tick Lab where it received a molecular
identification to Haemaphysalis longicornis – the longhorned tick – the Asian longhorned tick. On November 9, 2017, NVSL taxonomically
confirmed this identification. This was significant because this was the
very first time this tick had been seen out of USDA quarantine. What first looked like a local infestation in
one county in New Jersey soon became evident that it was much more widespread
than we had originally thought. Today we have 11 confirmed states. Virginia leads the county
count with 24 counties. West Virginia with 15 counties
has the oldest recorded specimen from a white tailed deer in 2010. This ID only happened because our
National Veterinary Services Lab went back and re-examined rabbit ticks
Haemaphysalis leporispalustris. These two ticks look similar and I suggest
anyone who has rabbit tick archives go back and take another look and make sure
that they are not longhorned ticks. Joining this list of states are also New
Jersey, New York, Pennsylvania, North Carolina, Maryland, Arkansas, Connecticut,
Kentucky and most recently Tennessee. It seems like whenever we – whenever we
make a map another county comes up positive and so Tennessee actually has three
confirmed counties at this point. Haemaphysalis longicornis is what they call the
scrub or bush tick in other parts of the world. Here in the United States, the proper
name is the Asian longhorned tick. It is a three-host tick. And you can find all three
active stages on one host. It originated in North East Asia but
then invaded Australia and New Zealand. Has the ability to survive
harsh winters and other parts of the world enjoys meadows,
paddocks and moisture. Here you can see the longhorned tick – female
on the lower right and the nymph to the left and on the top are the Ixodes scapularis to
the top right is the female, male to the left, and then a nymph with poppy seeds
in the middle to show the size. There is two major forms of this
tick – there is a bisexual form and a parthenogenetic invasive form. This parthenogenesis means that a female can
lay fertile eggs without the presence of a male. Without the guys to hold them back these
girls can create large populations quickly. And these thousands of ticks possibly feeding on
just one animal can feed until the animal dies. In Australia, this life style is obligate and
males only really occur once every 400 females. Personally, one of my biggest concerns is how
this tick happily feeds alongside other tick species on the same host. This co-feeding may possibly
impact the transmission cycles of our endemic tickborne diseases and will
definitely further complicate our knowledge of tickborne disease ecology
here in the United States. These ticks are further a concern
because of the large number of viral, bacterial and protozoal pathogens
that are associated with them in other parts of the world. No pathogens have been found in the ticks
that have been tested in the U.S. to date. You can see here they are potentials
for vectoring species of Theileria, Babesia, and scary hemorrhagic viruses. This list you are looking at right now– these pathogens were confirmed
by transmission experiments. This list now is more pathogens found in these
ticks that were found infected in the field. Here you’ll see some related strains of our
endemic tick diseases such as anaplasmosis, ehrlichiosis, borreliosis
and some viruses– Powassan. So now that we know how important the
tick can be, I want to take you back to examining our situation here in the U.S.
Back in winter in 2017, this tick disappeared in New Jersey and we all held our breaths
hoping that it won’t emerge again in the spring. But sure enough on 4:00 pm on March, Friday
the 13th, I received a call from New Jersey that the ticks were again active. They were finding nymphs at that point and that
appears to this normal pathway here in bold. However, in New York in 2019 the first stage
found after diapause was actually adults. And by May, people in different states
were recording all stages as active. And all of these ticks were being found by
flagging, dragging, and carbon dioxide traps. These are detections graphed by host in months. If you ignore that December blip
right there that was just a data blip. You can see that there are blank areas in
the winter and we can obviously see here that we have a tick that diapauses
and re-emerges in the spring. This tick is a generalist feeder
worldwide and we are starting to close in on our worldwide list that we now have
positives from humans, birds, domestic animals, livestock, and large-to-medium wild mammals. Although small mammals have been sampled,
these ticks so far haven’t been found on them. One note of potential good news is
that even though they will bite humans, humans don’t seem to be a preferred
host and they — and here in the U.S. — it seems that they are not
aggressively trying to bite humans. So what’s next? We want you to be educated so that you
can detect these ticks in your area and treat before they become established. Here to the left you can see what we
know so far in line with detections. Here to the right is a map
from a grouping of models where the three best-fit models overlaid create
the red areas where these ticks are likely to become established if introduced. Now that I have adequately scared you, I would
like to offer you a few tools to deal with this. First, you can tell, first of
all you can tell the difference between this tick and the native Haemaphysalis. One of the tricks is the palpal extensions
on both the central and dorsal sides. Longicornis have them on both
sides of the palp, other ticks and other Haemaphysalis here
don’t have it on both sides. Now we also have this key down here
that can help, but a word of caution. So when this tick is found in a new state
or county or on a new host it tends to rile up the media and cause concern to our
animal and public health stakeholders. For this reason that we ask – for this
reason we ask that first detections in an area get either a molecular
confirmation or our entomologist at our National Veterinary Services Lab
are happy to do a secondary taxonomic ID. Here are some more tools. They can be found by Googling
USDA Vector-borne disease. Down here on the bottom,
right– this guidance is– was crafted to help our animal health partners. There is a lot of information on longhorned
ticks but also there is good information on how to deal with any kind of exotic
tick that might come into an area. It also has the NVSL submission information
and instructions on how to ship the ticks. And we also have a fact sheet. This is our situation report in the top right. This is the joint-factsheet
we have with the CDC. And these links that are on here have
some really good information on ticks and tickborne diseases and some
nice photos of the longhorned ticks. So last of all, I just want you to
remember that these are just ticks. They are not anything like super powered demons. While they’re important, they can
be killed and they can be managed. We have had environmental
treatments in New Jersey of Lambda-cyhalotrin and
carbamate that have worked. New Jersey used a (permethrin) wash
on the index sheet that worked. And so far, no ticks tested by USDA/ARS showed
– none of them have shown pyrethrin resistance. Mowing and cleaning around the
premises may help with tick incursions. And as always, please remember to wear
your repellant and check yourself, your family, and your animals for ticks. If you have livestock that are impacted, please
check with your agricultural extension agents or your veterinarians or us in
VS we’re always happy to help. So with that there are just so many people
to acknowledge, so this is outdated daily so appreciate all of the help of all people. It’s been an amazing response
and it will continue to be a dynamic relationship
with many, many stakeholders. So here is my information if you have
questions after today or if you have concerns or need someone to talk to,
please feel free to reach out. We have a monthly stakeholder call for
Asian longhorned tick and if you would like to be included in that call different
agencies and states give updates and I’m happy to include you if you would like to drop
me a line and I will add you to the list. And with that, I thank you for your attention. Dr. Paul Mead: Thank you Ms. Bonilla for that
overview and your efforts on this whole issue. Our next speaker is Dr. William
Nicholson from CDC who will be discussing the alpha-gal allergy
following tick bite and please bear with us as we try and work out getting
the slides pulled up. Dr. William Nicholson: I’m
not having any luck here. I see it but I can’t move it. There we go. Can you hear me? Dr. Paul Mead: Yes. We can, Thanks. Dr. William Nicholson: Okay. I appreciate the opportunity to
talk today about a new condition that is generating concern alpha-gal allergy. Today I’d like to talk about what is
alpha-gal, discuss some of the clinical and epidemiological features
associated with this condition. How it’s managed? And how the connection between
alpha-gal and ticks was made and what do we really know about that? Alpha-gal is the short name for
Galactose-alpha-1, 3-galactose. Here is the molecule here. It’s an oligosaccharide. It’s synthesized by glycosylation using
enzyme alpha-1, 3-galactosyltranferase. This enzyme is not active in humans,
greater apes, and Old World monkeys. So it’s found in the tissues of most
mammals including sheep, cattle, and swine but it’s not found in the apes, it’s
not found in fish, birds or reptile tissues. Antibodies of the IgG and IgM classes
are made by humans to alpha-gal as they meet these various needs. And so they are usually present in
those particular classes of antibodies. Of concern to some regulatory agencies might
be the fact that alpha-gal is also found in a number of food additives,
pharmaceuticals, vaccines and some tissues that are used for xenotransplantation. The story begins with a monoclonal antibody
that was produced for chemotherapy for cancer. Cetuximab is a mice human
chimeric monoclonal antibody against the epidermal growth factor receptor. And alpha-gal epitope is actually found
in the Fab arm portion of the molecule. So the initial trials with this chemical
for metastatic colon cancer started in 2000 and it was finally approved in 2004
and later expanded for other cancers. In 2007, O’Neil and Associates found that there
was a high incidence of infusion reactions in Tennessee and North Carolina patients. And this occurred 5 to 20
minutes after infusion. Normally this is delivered
intravenously so it was very, very quick. And because many people reacted
on the first dose of the drug, this suggested that they had
been sensitized in some way to an epitope that would cause the reaction. Chung later discovered that
this was an IgE response and that IgE was directed
against the alpha-gal antigen. [unintelligible] So the proposed mechanism was
that when the Cetuximab cross linked to IgE that was bound to mast cells which would cause
activation in degranularization with things. The release of a number of chemicals
that would cause the itching and anaphylactic syndrome that might be seen. So how was this associated with ticks? This association occurred on two different
continents at about the same time. Dr. van Nunen in Australia had
identified this being associated with ticks primarily with Ixodes holocyclus. And Thomas Platts-Mills and
Scott Commins working in Virginia at the time also saw a connection
with ticks and tick bites. Dr. Platts-Mills had been working with
the response to the Cetuximab and noticed that the geographic distribution was
fairly restricted and began to say, “What else would have that
geographic distribution?” And someone in the lab said, “Well,
that just looks like the CDC map for Rocky Mountain spotted fever distribution.” That was kind of a big leap, but as we know
this is not just Rocky Mountain spotted fever, but spotted fever group rickettsia
in the United States. And the allergies tended to associate
with that distribution and with the map of Amblyomma americanum and
so that was how the connection with Amblyomma americanum was first made. But the evidence was in association
with not a lot of strong evidence that it was truly associated with this tick. They also did a seroprevalence study and they
found that the highest seroprevalence of IgE to alpha-gal was found in the
southeastern and south central United States and it correlated fairly well
with the hatched area there which is the estimated distribution
of Amblyomma americanum. It was seen that IgE to alpha-gal increased
with time following one or more tick bites and in this figure, you will see that
with the increasing tick bites the level of IgE to alpha-gal increased. Bites that had a longer duration of a
hypersensitivity reaction-so you were itching and had edema for a longer period would
result in higher levels of IgE to alpha-gal. So the question was that “Is
really associated with the ticks?” So they took whole tick extracts,
ground those up, and showed that they could use the
tick to inhibit the bonding of IgE. And so that suggested that crushed
whole ticks did contain the alpha-gal but was that alpha-gal being
produced by the tick or could it possibly be in
the blood meal of the tick? Other ticks have been associated
[with alpha-gal]. I will talk more about that later. In Ixodes ricinus, researchers
found that it could be localized to the GI tract of Ixodes ricinus nymphs. You may or may not be able to see this very
well but it is a reddish color in the gut of the gut is shown in A and B. Amblyomma
sculptum has also been associated with this condition. So experiments to induce salivation
by pilocarpine produced saliva. These were inoculated into knock-out
mice and they produced anti-alpha-gal. So it suggested that this was a
salivary delivered oligosaccharide. A very recent study that just
came and I’d recommend looking at because they have very nice images
using immunoblotting, mass spec, and immunolocalization– they were able to show that Amblyomma americanum does
contain alpha-gal antigens within the partially fed salivary
gland and in the saliva itself. But interestingly Ixodes scapularis,
which has been associated at this point with this condition, does also
contain the alpha-gal antigen. Amblyomma maculatam and Dermacentor
variabilis did not seem to contain the antigen. When this condition occurs, as we mentioned
before with the intravenous introductions to Cetuximab, you get a response very
quickly, within 20 minutes after infusion. But what we are generally talking
about now is the red meat allergy, which is a delayed-type reaction. This occurs 2 to 6 hours after the meal
before you begin to see the allergic symptoms. And so some of the doctors have referred to
this as “midnight hives after a meat dinner.” There is redness, hives, itching, angioedema,
respiratory difficulty, hypertension, GI conditions can occur and you can
get anaphylaxis with this condition. But it’s not an every-time allergy. There are other co-factors which
include the volume of the meat ingested, the fattiness of the meat, whether it’s
organ tissue or not, alcohol ingestion. All of this may influence the
absorption of the antigen in the gut and then later you see the
expression of an allergic response. University of Virginia Researchers have recently
linked IgE to alpha-gal to plaque buildup in the arteries of the heart and this
generally occurred in older people. It could also be somewhat of a co-factor if
they’re eating a significant amount of meat. But a lot of these associations are based on a
lot of single case reports or small case series and not necessarily larger studies. But what we do know is this
occurs within a few to six months after a tick bite, it’s usually
a singular allergy. It’s not associated to allergy
to other antigens. The B Group blood type seems
to convey some level of protection against the alpha-gal allergy. It’s generally seen in older
adults but may be seen in children. So somehow, the bite is sensitizing
the body to produce IgE and then later you get the
response to the meat ingestion. Most of the cases are occurring in late
summer and fall and at least anecdotally, those are often associated with larval ticks. But a part of this may be the number of larval
ticks that you may be bitten by at any one time. There are diagnostic tests available. Probably the most common is the ImmunoCAP IgE to
alpha-gal that’s available at commercial labs. The distribution in the United States, as
shown on the right, is now about 39 states so you can see that it’s well outside the
range of the single tick, Amblyomma americanum. The distribution worldwide is
six continents in 19 countries. I have them listed here. So this is a growing concern worldwide. Associated in those are different
countries with a variety of tick species, you can see that Amblyomma is well represented,
a number of Ixodes species, and as I said, not yet associated with Ixodes scapularis. And as Denise just mentioned Haemaphysalis
longicornis this is now another concern – oops. I lost everything. Okay. What is the public health burden
of this emerging condition? Platts-Mills and Commins have estimated in the
United States there have been about 5,000 cases since it’s discovery through 2013. And of those, about 1,000 have been
identified there as they worked in Virginia. Dr. Commins moved to North
Carolina, he’s now at UNC and he’s seeing approximately
8 to 10 patients per week. Arkansas has reported 270 cases
with one death between January 2013 and September 2015, and reported
this in a poster. It’s fewer in Australia but van Nunen says
she has about 1 to 2 patients per week and had seen over 600 cases by December 2014. Again, no official statistics are kept so
these are based on reports in the literature. But the incidence in Virginia is about 13
per 100,000 and in Australia 113 per 100,000. How is it managed? Tick bite prevention measures are,
as we constantly try to suggest for infection prevention, will help and you
will see a decline in IgE levels over time if no additional tick bites occur. It can be treated, you know, in the
immediate stage with Benadryl or Epinephrine. But generally, it’s the avoidance
of mammalian meat in the diet. As people are treated, some dairy
products may added over time, some lean meat maybe reintroduced
to see if there is a response. And generally, people will maybe come
back into being able to take red meat. Desensitization for allergy is very limited
in use and not really widely available. What we are doing now is our division has
tasked us with looking at this condition because we are the rickettsial group and
work with Amblyomma americanum a great bit. The epi group is looking at a
descriptive study based on a database of previously diagnosed patients
with Dr. Commins. And they have a case control study
that will begin enrolling patients. There is always a concern about tick
bite history because it’s likely subject to recall bias as far as number
and the timing of such bites. We are hoping to use some of the serologic
assays to look for antibodies in the patients to tick salivary proteins such
as Calreticulin or AV422 and hope that they will give us a marker of tick bite. These markers have been tested some in humans– Calreticulin in humans, and
AV422 in both humans and animals. These do cross-react against genera of
ticks so we have currently expressed in our branch Calreticulin, and AV422 derived
from Amblyomma americanum and we will be working on some assays that we hope will help us answer
this question if there really was a tick bite. I know that’s a lot in a short period of time
but I appreciate the opportunity to present it and we’ll be happy to answer any questions. Here is my information here. Thank you Paul and back to you. Dr. Paul Mead: Great. Thank you William for that. Our next speaker is Dr. Kevin Esvelt from
MIT who will be talking about mice and ticks. And please hold on for a moment while
we try and bring up his presentation. There we go. Dr. Esvelt, are you on? Dr. Kevin Esvelt: All right. Hello everyone. Thank you for the opportunity to speak. I’m going to just spend a bit of time
letting you know about a potential new way to address tickborne disease– in this case
through genome editing of the reservoir. So we are interested in combating diseases
spread by Ixodes scapularis and specifically, by altering the primary host,
the white-footed mouse. There we go. So as all of you certainly know, tickborne
disease is especially concentrated in the northeast of the country
here in Massachusetts two of the worst afflicted areas are the
islands of Nantucket and Martha’s Vineyard. And it’s these communities we have been working
with in developing a possible new approach to combating and specifically
preventing tickborne disease. Now as you know, Borrelia burgdorferi is
passed between host organisms and Ixodes. And this is an ecological cycle of transmission,
which, as a side effect, results in transmission to humans when infected Ixodes bite people. The Mice Against Ticks Project aims to
heritably immunize the white-footed mice so that they can no longer
efficiently infect the ticks — because Peromyscus leucopus is responsible for infecting more ticks than
any other individual host. Our goal is to drive the
infection cycle in reverse. Fewer infected ticks will mean
fewer secondary reservoirs, which will mean fewer infected ticks, and so on. So how can this be done? Well, of course, there was a protective
vaccine and there is still one available for animals against Osp A on Borrelia. Our goal is to engineer mice to produce
protective antibodies against Borrelia, and possibly against Ixodes themselves, by first identifying white-footed
mice antibodies against these markers. Isolating B cells that make these antibodies
and specifically the DNA within those B cells, producing them in a laboratory and testing
them to confirm binding, neutralization, and eventually protection against infection. Now we’ve identified an initial set
of antibodies from Peromyscus leucopus that bind Osp A, and we’re currently
isolating more with the help of a CDMRP award. And you might say, “Well, why bother
isolating white-footed mice antibodies when there are already perfectly functional
antibodies from most mammals and humans?” And the answer is that this project is
community-guided and it has been from the start. That is we went to the residents
of these islands and we said, “We believe it may be possible to prevent
disease by heritably immunizing these mice. There are different ways
that we could go about it – among them we could isolate white-footed
mice antibodies which are of course going to be present at some low level in a few mice
and encode those in a white-footed mice genome so that they will be passed on to descendants. Or we could just use pre-existing antibodies
from other organisms such as lab mice or people and encode those in the mice.” And the community’s response was overwhelmingly,
“We are interested in this idea but please try to keep genome editing as natural as possible.” That is, “We are open to the idea of engineered
mice,” was by far the majority response. “We would prefer if you tried not to use any
DNA or functions that are normally present in white-footed mice if at all possible.” So that’s what we are doing. The project is guided by these steering
committees on each islands’ appointed by the boards of health and we regularly visit
the islands and talk to local residents in order to find out what they think and whether
community opinion has been changed in any way. And we have had a number of media
coverage and constantly hear from people outside of the islands as well. So our core technical team right
now is at MIT, Tufts, and Harvard and we are currently bringing
on new collaborators. Our timeline for this project is uncertain because no one has ever done
anything like this before. No has ever, in fact, made
Peromyscus leucopus transgenic before, although in this case our goal is to make them
technically cisgenic because again we don’t want to move in any DNA from any other species
and in so far as it can be helped. So Phase 1 involves identifying the protective
antibodies, which we are now well in the process of doing, and building a new mice
including engineering Peromyscus leucopus, which again we are making progress in. And also preparing for field trials. That is identifying appropriate islands
and collecting baseline ecological data because we will need to know what happens to
the environment if you introduce large numbers of heritably immunized Peromyscus leucopus. Then Phase 2 would involve introducing
these mice onto small islands. Ideally, one area would receive the altered
heritably immunized mice – the engineered mice. Another area would receive lab reared
wild-type mice that is a similar form of introducing mouse genes into the population. But they would just be normal wild type genes. And the third region would receive no change. And then these trials will be monitored
by primarily independent ecologists who will then deliver their
report to the communities as well as to the regulatory agencies on the outcomes. And then Phase 3 will potentially involve
releasing mice on large inhabited islands such as potentially Nantucket and
Martha’s Vineyard and possibly small, uninhabited islands such as Cuttyhunk Island. If that is successful, then ideally we will have
developed technologies initially in Mus musculus and then translate to Peromyscus that
could apply this approach to the mainland. Now before I get to that– a little
bit about ecological studies. So this is the primary concern that most
citizens and ecologists have with respect to the project that is, “What might
go wrong in the environment given that we don’t understand all
relevant ecological interactions?” And the answer is, we have suspicions
but we really can’t say for sure. The safe way to find out is to introduce
the mice at a small scale ideally, mostly in uninhabited setting
like the field trial islands, and then see what happens over time. But ideally, we want islands that are
highly representative of Nantucket and Martha’s Vineyard as
the primary communities. So we have a set of different islands some of
which are public and some of which are private and we are currently – Sam Telford at Tufts has
been doing fieldwork along with some members at my laboratory, developing
baseline data collection and adding to existing repositories
of data on these islands. And looking at optimization for whether it can
be done on a single island or adjacent islands or whether we can use nest
boxes to improve introduction. And we are doing a great deal
of computational modeling. And all this work has been supported
by the Rainwater Foundation. Now how could you possibly
introduce enough mice? That is, if you want to disrupt transmission
of Borrelia or any other pathogen from mice to ticks, you need most of the mice
in the environment to be immune. One way of doing that on an island is
simple to introduce enough immune mice because there is not sufficient gene flow with
wild type populations, introducing enough copies of the protective antibody and
coding genes, which will be produced in this case, from the liver cells. Interim populations would result in most
descendants inheriting an engineered gene and consequently being resistant to infection. But on the mainland there are billions of
Peromyscus leucopus and we cannot raise enough and introduce enough copies efficiently
to immunize an entire mainland population. So many people look to gene drugs. So CRISPR genome editing has allowed us
duplicate naturally occurring phenomenon such as gene drives, which is what
occurs when a generic element spreads through a population even if it does
not provide a fitness advantage. And in this case, we don’t expect immunity
to Borrelia to provide a fitness advantage to Peromyscus leucopus because it does
not cause symptoms in that species. So with a gene drive it’s a way of
ensuring inheritance of an engineered trait and essentially, it involves making
CRISPR genome editing recursive and encoding the CRISPR system into
the genome, of in this case the mouse, such that it edits the wild type copy
and heterozygotes and converts it into the engineered version,
encoding the antibodies. This might sound either good or
terrifying depending on your perspective, but we assume that there is no
realistic possibility of either social or diplomatic approval to using
the basic kind of gene driver – the self-propagating kind
for Mice Against Ticks. And that’s just because our
models show this kind of CRISPR-based gene drive system will
spread to affect the entire species. That is it will spread to all states in the
country, end up into Canada and down into Mexico and we just don’t see that as feasible. That in fact goes against the
very idea of a field trial. You cannot test that sort
of system in a field trial. And it would force this intervention
on everyone, as well as creating international
diplomatic complications. So instead, with NIH support from a DP2
New Innovator Award in Mus musculus, we are working to develop a – what we
call a Daisy Drive System which splits up the components of a CRISPR
system onto different chromosomes and Component C cuts and
causes Component B to drive. So it cuts the wild type version of B
and the B engineered DNA is copied over. The B element causes the A element to be
copied and the A element would, in this case, encode the antibodies of interest. And the net effect of this daisy chain
drive system – and apologies it looks like the animations are not quite
working the way they should. If you have a CBA mouse, for example, that has
all three links in this daisy gene and it mates with a wild type, if it’s
homozygous across all those, then all of the mice will inherit same DNA. But one of the mice two generations
down will no longer have inherited C because C is a normal gene and it does
not have any kind of inherited advantage. So this mouse has lost the C element,
which means that there is nothing causing B to be copied in the germline of this mouse. And that means that when it
mates with a wild type some of its offspring will not encode
the B element, leaving only A — meaning in the next generation there be mice that do not inherit any engineered
elements at all. In other words, the daisy
chain drive is self-exhausting. Every genetic link in this chain is lost in
turnover generations much like genetic fuel and that means that the end alteration,
the antibodies, don’t spread indefinitely. But it does mean that we
can release, in principle, a handful of mice and alter
the local population. We may even be able to keep it confined
within political boundaries of a given town by driving what’s known as
an under-dominant system. So this is a system in which there is selection
for whichever allele is in the majority. So the altered engineered
allele that is protective against disease would be selected
for in towns that wanted it. And so in those towns we could
release these daisy threshold mice that would spread the alteration
within the town efficiently. The daisy elements would run out of
steam and there would be selection for the engineered antibodies where
they were in the majority in the town. But natural selection would act
against them on the outskirts where wild types are in the majority. This is obviously a more than decade
long plan, but our eventual goal is to develop the technology in these uninhabited
offshore islands, determine if it’s effective. If so, introduce it– assuming the communities
continue to support it onto inhabited islands and then in the meantime develop this technology
in Peromyscus leucopus for our potential use on the mainland — with the goal of
allowing every community to decide whether or not they would want to
engineer their local population in order to prevent tickborne disease. And of course, if it does work for
tickborne disease it could also work for potentially other kinds of
diseases that are vector-borne or have any kind of reservoir in a wild species. If you have any questions, please
feel free to contact me by email and you can also find more
information on Mice Against Ticks, specifically on our responsivescience.org. Thank you. Dr. Paul Mead: Thank you Dr. Esvelt. Our next speaker and final speaker is Dr.
Ben Beard Deputy Director for the Division of Vector-Borne Disease who will
be reviewing the National Strategy for vector-borne disease control. Dr. Ben Beard: Thanks Paul. And let me try to get the
correct slides up here. Okay. I’m sorry for the delay here. Okay. So what I would like to do just really
quickly here since we are running out of time is just tell you a little bit about the national strategy efforts
here for vector-borne diseases. And basically, to give sort of
a framework for this is some of you would know vector-borne
diseases are very rapidly and is hugely increasing in the United States. And so, you know, over the last 15 years
or so since 2004 through 2017 there were over 700,000 cases of vector-borne diseases
that were reported here in the United States. The number of reported cases of diseases these
are carried by mosquitoes, ticks and fleas, and this has more than tripled
over this period of time. And that in fact 75% of all
vector-borne diseases over this period of time are tickborne diseases and
chiefly among those being Lyme disease. And then another important point to make is the
mosquito-borne disease epidemics have happened more frequently. Most recently we’ve had Zika, prior to that we had a dengue outbreak
and chikungunya that occurred. And then finally, just the idea that reported
diseases really only reflect a very small number of the actual numbers of
vector-borne diseases — because the underreporting ranges here in the
U.S anywhere from 8- to 12-fold for Lyme disease to close to 70-fold for West Nile virus. We’ve also seen a number of new disease
threats-I mentioned chikungunya and Zika. We’ve also seen seven new tickborne disease
agents that have been identified here in the U.S over the last, you know, since 2004 at least
and we’ve already heard about H. longicornis. Additionally more people are
at risk because of local – global commerce that moves these
mosquitos, ticks and fleas around the world. Also infected travelers go from disease endemic
areas and come here to the United States and other parts of the world as
well, bringing with them pathogens that they have been potentially exposed to. And then of course mosquitoes and ticks move
these around the U.S. causing local outbreaks. And then we’ve also had issues
like change in climate and land use patterns that has an impact. So the backdrop of this really was the
impetus for a paper that we recently published in the American Journal of
Tropical Medicine and Hygiene. Really, it was a call of
action – call to action – for a national strategy or
a national action plan. And this paper, you know, really calls
for concerted sustained national effort to address the existing problems and reverse
the upwards trends of vector-borne diseases. And it also mentions that the
response will require coordination across a national network of collaborators. So to say a little bit about this
plan – this national strategy we at CDC have been leading the coordination of
this effort and the strategic priority seeks to improve the national vector-borne
human case surveillance, to improve vector-borne disease
prevention, diagnosis and treatment efforts. And then finally to build
capacity in state and local levels to implement vector-borne disease
prevention and control programs. The – in terms of a national
strategy development status, the formal drafting process
began in December of 2018 and has involved 6 different
federal departments and 12 agencies. You see these in the list below here so
agencies from our Department of Health and Human Services, Department of Defense,
U.S Department of Agriculture, EPA, Department of Interior and from FEMA
and the Department of Homeland Security. The effort was actually completed in April
of 2019 in terms of the first draft of this and the national strategy document has now
been cleared through CDC and it’s in clearance in Health and Human and Services
right now and HHS will network it with the other federal departments
who are involved in the effort. And so we anticipate that the release date
for this will be sometime around the summer of 2019, hopefully next month in July. And the national strategy will provide
a basis for developing action plans for vector-borne diseases prevention
and control in the United States. And by action plans what we mean by that are
really efforts that are aimed at getting more down into the details of exactly
what needs to be accomplished. How do we measure success? What are the timelines for implementation? And who specifically will
have responsibility for this? So finally this is a really busy slide
and I’m not going to go through it other than to say this just really shows that from
the first meeting that occurred in February – I’m sorry, in December of 2018 – some
of the key activities that were done in that process, to strategy development. A series of webinars that we had with
these different departments where we sorted through all of the details, the
vision statement, a mission statement and some overarching goals and
then some specifics sub-strategies. And then to where we are right now– as I said
that the document is going through clearance. So I think with that I will stop
and turn it back to Dr. Mead. And I think we may have a few minutes for
questions and answers and I think then time for the webinar has been extended a little
bit so that there is time for more discussion. Thanks. Dr. Paul Mead: Okay. I believe we are ready to take
questions at this point and I don’t know if our presenters can see their questions. William are you able to see the –
there were a number of questions on alpha-gal one of which was whether or not… Dr. William Nicholson: I don’t see them. Dr. Paul Mead: Okay. I’m sorry. Well, then – and I don’t
either now unfortunately. My apologies to everyone. But the first – one of the questions that
seemed to be a theme whether or not alpha-gal or the syndrome was likely
to be traced or reportable like other tickborne diseases
through surveillance. Dr. William Nicholson: Yes. Not really my call on that. I think we are just trying to get a handle
on what’s really going on at this point. We are hoping that this large, case control
study will provide some evidence of some of the risk factors rather than these
associations that have been made in these individual case reports. But that’s a much bigger
question than I would answer. I mean, it’s certainly generating a lot of
attention and that’s really why our division and branch is beginning to look at this. I mean, normally we are not
looking at noninfectious conditions. But I think, you know, there has been enough
attention that we do need to look at it and see if we can work with
these experts basically and – that are actually seeing patients
rather than us just enumerating reports. Dr. Paul Mead: Okay. Thank you. And another question that has come up
is will there be a copy of the slides or the presentation available after the meeting? Yes. The meeting will – is recorded and will be
available online although I can’t give you the exact timeframe for that
but we will be posting this when transcription and everything are available. On the issue of reportable diseases a question
has come up again for Dr. Beard about what – how the CDC determines reportable diseases
and would they consider adding Ehrlichiosis to that list given its life-threatening nature? And maybe that’s also a question
for Dr. Nicholson. Dr. Ben Beard: Yes. Paul, I can answer that as well as yourself. You know, the way diseases become reportable
in the United States is really by an action of the Council of State and
Territorial Epidemiologists (CSTE). So this is the states actually
have to determine whether or not a disease is nationally notifiable, then along with that comes
case definitions and things. For example, the question
about red meat allergy. It has to be a decision of the CSTE that this
should be reportable and then there would have to be case definitions drafted and
all the ways to make it reportable. And then of course with ehrlichiosis
the question about that is ehrlichiosis is
actually already reportable. And so if there are any questions about what
diseases are reportable you find that through – actually if you go to (MMWR) Morbidity
and Mortality Weekly Report, you know, all those disease are line listed in there. Especially if you go to the
annual summary documents. And Paul I don’t know if you want
to elaborate on that more generally, but that would be pretty much
what I would say about it. Dr. Paul Mead: All right. William anything to add about
surveillance data on ehrlichiosis and… Dr. William Nicholson: No. I think over time we are trying to make
it better because we do have, you know, a number of things locked under
singular categories when we know that they are actually caused by a
variety of actual individual pathogens. And so it’s always very difficult to do that. We – you know, there has been a recent
revision of the CSTE definition going through the last meeting on
spotted fever group because we know that represents a large number of species. And, you know, the name was
changed several years back but we know that that creates a burden. And as far as adding something
as a notifiable disease, I think most of the state health
departments realize that it’s a burden on them to follow up on these cases. So I don’t know that they would
necessarily be looking to add even more. But I do think getting a more specificity on
our case definitions will help because we would like to know for example, ehrlichiosis, how
much is actually due to [Ehrlichia] ewingii, versus Ehrlichia chaffeensis versus possibly
others and, you know, those are somewhat locked. Dr. Paul Mead: Got it. On that topic, it has also been asked whether or not would it be worth monitoring ehrlichiosis
patients for meat allergy since the infection as a result of exposure to that tick? Is that part of your plan? Dr. William Nicholson: Not currently. I mean, we will be doing testing on
those patients that are enrolled to see if they show any correlation with ehrlichiosis
seroconversion even if there is no illness, we think that would be important to do. And in the Arkansas study
that was reported in a poster, they did look at just the
geographic distribution — and the distribution of red meat allergy was
similar to within the state in terms of number of cases, as well as geographic
distribution as ehrlichiosis. But again, it’s an association at this point. I think it will be important
to do that over time. But again, some of those ehrlichiosis cases
could also be due to Ehrlichia ewingii, which again, is transmitted
by Amblyomma americanum. We don’t necessarily have those samples in hand. A lot of those are sent to commercial labs and
we will never see a sample from that patient. Dr. Paul Mead: Great. Thank you. Sorry, one final question for you right now. I’m sorry I beat up on you but there has been a
question about is there any issue with vaccines? There has been some healthcare
personnel stating that there are at least 29 vaccines contraindicated
presumably in patients with alpha-gal allergy. Is that something you are aware of? Dr. William Nicholson: It’s certainly a caution. We’ve had a conference call with
the vaccine safety people at CDC and others to at least be aware of that. But how much of a problem that
is we really have no idea. But, you know, most vaccines have
been used-some animal products like gelatin, is a very common one. It’s at a very, very low concentration but it’s
used as a stabilizer in a lot of these products. And so glycerol is sometimes included – I
mean, the potential is there but the reality– I don’t know that it’s really
been looked at that closely. Dr. Paul Mead: Okay. Thank you. A couple of questions for Dr. Beard. The first one is regarding the national
strategy will there be a report due out this summer and will it be posted? Dr. Ben Beard: Yes. Thank you Paul. Yes. What our plans are, at a minimum,
is to post it on our Web site and so it will be available publicly there. I’m sure there will be other venues
in which, you know, it’s presented. But at a minimum, we will have it posted
on a Web site for the public to access. Thanks. Dr. Paul Mead: A question presumably for Dr.
Esvelt, although maybe others have comments. Is there any research to block the microbiome
in ticks to make them inhospitable to pathogens? Dr. Kevin Esvelt: So we had originally
considered altering the ticks, but the problem with any kind of generational
drive-based approach is it requires many generations to spread. So affecting an entire tick population would
either require waiting many, many decades or releasing– raising and
releasing hundreds of millions or billions of ticks into the environment. And our experience in talking to communities
is that people were not so keen on the notion of being bitten by engineered ticks,
even if it would prevent diseases. They would rather that we alter the
reservoirs, if at all possible, which is, and also the mice reproduce much more quickly
so it’s just a more feasible strategy. That said, we are working on ways of
immunizing the mice against the ticks directly, using subolesin as a tick protein
marker which causes, in some cases, the ticks to fall off before they
get a complete blood meal and die. So if we can turn a major reservoir host
such as Peromyscus leucopus inhospitable to the ticks then we should be able to
substantially reduce the population, at least of Ixodes, and possibly of
other ticks if we can target them. But that’s very much speculative. The rest of it is more engineering but
it should be feasible given enough time. I can’t say how long it will take. But that one may not just be possible. We are not sure yet. Dr. Paul Mead: Okay. Thank you. Another question for Dr. Beard. Can you comment on CDC’s position regarding
of the value of testing human-biting ticks? And I believe the question refers to
ticks removed from a person as opposed to necessarily recovered from the environment. Dr. Ben Beard: Yes. Thanks. So our current view is that we don’t
see a great value in testing ticks that have been collected off people
for pathogens for clinical purposes. And what I mean by that is for
the purpose of guiding whether or not a patient should be treated
or not treated prophylactically based on whether the tick they
removed was positive or negative. And the reason for that is if the tick
is negative then that doesn’t mean that the person might not have had another
tick that was on them that they didn’t see that could have exposed them as well. Typically, especially in nymph stages of ticks
come in large numbers and so the one that was on you might have been negative
but there might have been another that was on you that was positive. And so if you decided not to treat just
simply because the tick was positive or negative then it could be misleading. And then in additionally if the
tick was positive, you know, it may or may not have transmitted the illness. So what we basically say is if a
person lives in a disease endemic area that they had a tick that’s been on
them for, you know, up to 36 hours or more that they should be
treated prophylactically, you know, to prevent pathogens that
may have been in that tick. So we don’t see a large additional
value in testing those ticks however. So I do want to mention though that
that doesn’t mean that we are not in favor of testing ticks for pathogens. And in fact, we have recently been able to
provide funding to state health department to collect ticks to specifically
Ixodes scapularis and Ixodes pacificus that we’ve written guidance for — and
we are in the process of writing guidance for the other important tick vectors. And so what we are working with the states to do
is to get better information on the distribution and the density of ticks that we collect
and what pathogens are in those ticks. And what we are hoping is that this will help
us better define areas of human risk in areas where Lyme disease is not so common. And at least we can know better about
the risks that they are based on, the ticks that are there, and
the pathogens that they harbor. So the short answer is, we don’t see
great value in testing ticks for diagnosis and clinical purposes but we do see a great
value in testing ticks for surveillance purposes and we’re involved in those activities. Dr. Paul Mead: Thank you. And if I may add just one other point that
I think is sometimes overlooked which is that typically, when testing specimens from
a patient there are fairly rigorous standards of laboratory practices that have
to be enforced in order to ensure that medical decisions are being
made on good and solid data. One of the other challenges
with tick testing regimens is that because they aren’t testing a human
specimen, labs do not necessarily have to meet the same standards of
diagnostic care as clinical laboratories. And yet we see that sometimes patients are
going to their provider with this information and getting– it is influencing medical care. So there is some concern about having
sort of medical care provided based on laboratory testing which does not necessarily
really meet the standards that would be required of any clinical testing laboratory. There is one other question
– or several other questions. But one is whether or not there are
any BSL4 level tickborne agents? And I believe there are some in the viral area like (CCHF) Congo-Crimean Hemorrhagic
Fever as well as some others. But do any of the other speakers perhaps
Ben or William want to add to that list? Dr. Ben Beard: This is Ben and
I could comment really quickly. The pathogens that are here in the United
States we are not aware of any that are BSL4. I think Powassan is BSL3 as
far as I know so is Heartland and Bourbon viruses in other
parts of the country. And in other parts of the
world they are the, you know, the Russian spring-summer encephalitis
(TBE), Crimean-Congo Hemorrhagic Fever. I know the Crimean-Congo
as Paul mentioned is BSL4. I’m not so sure about the others. But there is a quick guide to this the
BMBL which are the guidance for work with proper bio-safety and
bio-containment of pathogens in laboratories and it’s got an updated list
of all of these pathogens and what the current bio-safety
level is for each of these. Dr. Paul Mead: Okay. Thank you. We have another question, which is, can any
of the presenters comment on the upward trend of co-infection as in the case of Ixodes
scapularis, Lyme disease, Babesiosis, Ehrlichia, Powassan disease dependent upon the length
of attachment and inoculants transferred? It also shows the Asian longhorned
tick has been shown to carry various pathogens
in respective regions. And Ms. Bonilla you had comments
first on some of the pathogens that have been associated with H. longicornis? We may have lost her or maybe it’s not a
fair question but do other want to comment, Dr. Beard on co-infections
and increasing trends? Dr. Ben Beard: I can comment
on that really quickly. Sorry, I hope you can’t see my screen right now. I was trying to call a recent presentation
where I had a list of all the pathogens that have been in Asian longhorned tick. So in terms of the pathogens
that have been found in Asian longhorned ticks there has
been a wide range of Anaplasma species that have been found Bartonella species,
a number of Borrelia species as well, Coxiella, Ehrlichia, Rickettsial species. There have been a number of viruses –
Tickborne encephalitis, Langat, Thogoto virus, Severe fever with thrombocytopenia
virus for sure which is one of the ones we are particularly concerned about. And then in terms of protozoa and pathogens – a
number of Babesia species and Theileria species. And so, you know, there is the potential
for that because of all of the pathogens that tick has carried in
other parts of the world. Here in the United States in
terms of co-infections, you know, the one that I’m most familiar with I think
it would have to be Ixodes scapularis. And as many of you will know this tick feeds in
its immature stages – larva and in some cases as nymphs on wild rodents
chiefly Peromyscus species and – which are very important reservoirs for
a number of important human pathogens. So this include Borrelia– Lyme Borreliosis
and in some cases Borrelia mayonii as well and then Anaplasma and Powassan
virus and Babesia. So, you know, ticks that have fed on rodents
that have co-infections for these pathogens, you know, are likely to be co-infected as well. And there have been a number of publishers
– studies that have been published that have looked at co-infection
rates and wild collected ticks. And, you know, I can’t comment off the top of
my head on what the co-infection rates are, maybe Dr. Mead or Dr. Nicholson can. But it seems to me that its range somewhere
around, you know, between 1 and 5% in most of the studies that I remember
seeing and this is with one or two or possibly three different pathogens. In terms of infections in
people, there have been a number of studies that have looked at this. I can’t comment on whether these
rates are going up or are not. I do know that the rates of all the
reportable tickborne diseases have in fact been increasing very significantly. So you might assume there would be
some increase in co-infection rates. But I think all of that is driven by the
fact that these diseases that are carried by blacklegged ticks are very much emerging. I think the reason for that is that changing
land use patterns, increasing deer populations and the way that the built environment
and suburban areas have expanded into areas where ticks are very common. And all of this has led to increasing exposure
of people to potentially infected ticks. And I think the more common this is the more
likely you are to have co-infections as well. So I will stop with that and others
might want to comment further. Dr. Paul Mead: Okay. Anything to add Dr. Nicholson? Dr. William Nicholson: Often we only look
for what we are looking for and, you know, if there was a co-infections in those ticks
we may or may not be even looking at that. Dr. Paul Mead: Thank you. Dr. Beard this is a similar
question about the national strategy. Is there – do you know how that
information will be disseminated? Or is there a way that people can sign
up to be notified when it is released? Dr. Ben Beard: Yes. I think what I will suggest is if you
want to just check back at our Web site, you know, at around mid to late July. If you don’t want to do that on a regular
basis because we really don’t know – what we don’t know is how long this is going
to take for this to come through clearance and it’s not in our control so we
will post it as soon as it’s cleared. But I do know that you can go to
our Web site www.cdc.gov/lymedisease which is the Lyme disease web site and
you can register for updates so that when there is a change or update on
the page you’ll get a notification and so you can go in and see what was changed. And that might be a way to do that. And I don’t know Dr. Mead if you
are familiar more with that process but that’s what I will suggest doing. Dr. Paul Mead: Yes. That makes sense. As you point out it’s hard to
know exactly when things will come out when they are going through a chain. I’m looking for additional questions. I think we have covered most
of the topics raised. And with that then I think what I would
like to do is thank the various presenters for their excellent presentations, for taking
time to share them with you and with all of you for tuning in to hear this. A reminder, you can get more information
on tickborne diseases at both the web site that Dr. Beard mentioned
or just www.cdc.gov/ticks. And with that, I think we will close out this
session and remind you all to wear repellants and do tick checks and bathe after
you’ve been in an exposed area. So I will turn it back over to the
operator for any final comments. Coordinator: Thank you everyone for your
participation in today’s conference. You may disconnect at this time. END

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