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 <strong>YSM</strong>, 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
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