YSM Issue 96.4

FOCUS
Infectious Disease
Beyond Lyme Disease:
A Vaccine Against Ticks
While pharmaceutical
companies try to revive
OspA vaccine efforts,
Fikrig and Flavell have moved
on. They are searching for success with a
different approach—one that might be able
to prevent all tick-borne illnesses. Besides
Lyme disease, Ixodes ticks are also carriers
of illnesses such as babesiosis, Powassan
virus, and anaplasmosis, which can cause
debilitating health effects in humans. Fikrig
and colleagues utilized an anti-tick approach
to a vaccine in their recent paper published
in Science Translational Medicine in 2021.
The idea of using an mRNA vaccine for tick
immunity was formulated in 2019 in
collaboration with Drew Weissman,
who is now a co-winner of the
2023 Nobel Prize in Physiology or
Medicine for his work on mRNA
vaccine technology (which was
foundational for the development
of the Pfizer-BioNTech COVID-19
vaccine). The mechanism of these vaccines
relies on the delivery of mRNA, which
directs the production of a small, harmless
piece of a target antigen in host cells so that
the immune system will learn to mount a
response against them if encountered again.
Rather than targeting specific antigens
associated with Lyme disease, the researchers
focused on the source—proteins found in the
tick’s saliva, which is secreted into humans at
the site of the bite.
After identifying nineteen salivary proteins
with high immunogenicity (ability to trigger
an immune response), the researchers created
a cocktail of mRNA encoding those proteins.
They placed this cocktail, called
19ISP, in lipid nanoparticles—
which protect the mRNA from
premature degradation—for
delivery. Two weeks after
injecting it into guinea pigs,
antibodies against ten of the
nineteen proteins were detected
in the serum of the immunized
guinea pigs, while none were observed in
the control group, suggesting that exposure to
19ISP triggered a humoral response.
Following this, the guinea pigs then
underwent tests to examine whether 19ISP
vaccination was effective in generating tick
immunity and resistance against Lyme
disease. “We showed that if you give [19ISP]
to a guinea pig and then put ticks on it,
the ticks feed very poorly, you get redness
where the ticks feed, and the [ticks] detach
and die quickly. And then we showed that if
you put ticks that have the disease-causing
agent in them, the guinea pigs will not get
Lyme disease,” Fikrig said.
In comparison, control guinea pigs
had low rates of tick detachment, did not
show redness, and were susceptible to B.
burgdorferi. These results suggest that
19ISP may be a viable solution in both
the early detection of tick attachment
and the facilitation of tick detachment. “I
think we have a vaccine that can increase
tick recognition and prevent Borrelia
transmission,” Fikrig said. “And hopefully,
at some point, that may be available
to the public. We don’t know yet,
but it may be useful in preventing
more than just Lyme disease.”
Future Directions
The “anti-tick” approach is
crucial because Ixodes represent just one
genus of ticks that carry illness. Other
ticks pose their own threats. Saliva from
Amblyomma ticks, for example, is thought
to cause red meat allergy in humans,
according to Fikrig. The tick’s saliva
proteins may contain the sugar
molecule alpha-gal, which is
found in most mammals but
not in humans. When the tick’s
ABOUT THE AUTHOR
saliva is transferred to humans, alpha-gal
is flagged as a foreign antigen, triggering a
severe immune response when alpha-gal is
encountered again, such as in red meat and
milk. “I think that our anti-tick vaccine can
be the first ever vaccine against an allergic
condition,” Fikrig said. In the past, it was
demonstrated that immunity to Ixodes
ticks can protect against other diseasespreading
tick species (e.g. Amblyomma
and Dermacentor); however,
their specific 19ISP cocktail
has yet to be tested for this
cross-protection.
In addition to solving
these mysteries, Fikrig
and Flavell are working
with a worldwide network of
collaborators to explore whether the antiinsect
approach can be applied to other
infectious diseases. Flavell highlighted
that this approach may be applicable
to other creatures that spread disease.
“We’ve brought together a consortium
of people to develop this concept, and if
we’re very lucky, we could hopefully make
a dent in diseases like malaria, which is
a huge problem," Flavell said. Despite
previous roadblocks in the history of
Lyme disease vaccines, the researchers
have continued to forge ahead to meet
greater success than before—and
pioneered an approach that
could revolutionize vaccines for
allergies and broader infectious
disease prevention. ■
CINDY MEI
CINDY MEI is a junior in Grace Hopper studying neuroscience. In addition to writing for YSM, she
serves as vice president on the Junior Class Council and co-director of Yale Math Competitions. She also
conducts epilepsy and Tourette’s syndrome research at the Yale School of Medicine.
THE AUTHOR WOULD LIKE TO THANK Erol Fikrig and Richard Flavell for their time and enthusiasm
about their research.
CITATIONS:
Fikrig, E., Barthold, S.W., Kantor, F.S., & Flavell, R.A. (1990). Protection of mice against the Lyme disease
agent with recombinant OspA. Science, 250 (4980), 553-556. doi: 10.1126/science.2237407.
Ho, E. (1993) Lyme Disease: Unmasking the Great Imitator. Yale Scientific Magazine, p. 62-64.
Sajid, A., Matias, J., Arora, G., Kurokawa, C., Deponte, K., Tang, X., Lynn, G., Wu, M., Pal, U., Strank, N.O.,
Pardi, N., Narasimhan, S., Weissman, D., & Fikrig, E. (2021). mRNA vaccination induces tick resistance
and prevents transmission of the Lyme disease agent. Science Translational Medicine, 13 (620), doi:
10.1126/scitranslmed.abj9827
18 Yale Scientific Magazine December 2023 www.yalescientific.org