Hedy Tung

Deer ticks are the primary vector of tick-borne diseases in North America, yet no anti-tick vaccine exists to prevent tick bites and transmission of disease. 

Amid this unmet need, researchers at the School of Medicine developed a method to identify the proteins ticks release while feeding on their hosts. Over time, humans and animals can develop resistance to tick bites by producing antibodies that recognize these proteins, blocking disease transmission. 

To pinpoint which proteins trigger this immune response, the team created an antigen library called IscREAM, which contains over 3,000 deer tick antigens and allows for rapid screening of those most likely to aid in developing future diagnostic tests and vaccines.  

“IscREAM stands for the Ixodes scapularis rapid extracellular antigen monitoring, and is a pretty apt name because who wouldn’t scream when they find a tick on them!” wrote Thomas Hart, former postdoctoral associate at the School of Medicine who spearheaded the creation of IscREAM. “We took almost every possible antigen — over 3,000 different proteins — from I. scapularis and engineered yeast cells to display the protein on their surface.”

Creating IscREAM

Hart explained that IscREAM provided a way to effectively categorize the thousands of proteins ticks secrete to find those that lead to resistance. To identify which tick proteins the immune system responded to, the team combined engineered yeast cells expressing tick proteins with an antibody isolated from blood from tick-exposed Lyme disease patients, guinea pigs and mice. 

The team then monitored the yeast cells to see which ones the tick-resistant antibodies bound to. This data, Hart explained, helped researchers filter through the proteins to identify which triggered an immune system response. 

This information allowed the team to identify new ways to induce tick resistance, or reduced likelihood of tick attachment, feeding and disease transmission, in individuals who have not yet been bitten by a tick. 

The Research Journey

According to Yingjun Cui, a researcher at the School of Medicine who authored the study, the team’s work first began with the development of an mRNA anti-tick vaccine. This process, Cui explained, involved collaborating with Drew Weissman’s lab at the University of Pennsylvania, who was awarded a Nobel Prize in Physiology or Medicine for their role in developing COVID-19 mRNA vaccines.

The vaccine works by injecting mRNA — the instructions for a protein that causes an immune-response — into the cells, building tick resistance. Cui emphasized that the initial vaccine was limited in tick-borne disease prevention, so the team continued work after publishing their first study on the topic in 2021 to improve the vaccine. 

The most recent study incorporating IscREAM took the past two years to complete. As Hart explained, the team first looked through all of the proteins in deer ticks to find the candidate proteins secreted or exposed outside the tick cells. Then, the team began their screens of each tick antigen in their expansive library. 

“Creating IscREAM was honestly a lot of fun. It was a lot of work, of course, but it was interesting work, and it’s always exciting to build a technology like this, and to see it come to fruition,” wrote Hart. 

The team worked with the Weissman lab to craft three mRNA cocktails encoding 25 antigens in tick cement — the “glue” they use to bind their mouthpieces to hosts — that would cause an immune system response in the host. From 2023 to 2024, the team immunized guinea pigs with each cocktail and found that one in particular resulted in lower tick weight and early detachment. 

“We are narrowing down the antigen number now, and our initial experiment has a promising result that the guinea pigs immunized with a small cocktail containing 5 mRNAs developed comparative tick rejection to the big cocktail,” Cui wrote. 

Future applications 

Erol Fikrig, professor of medicine at the School of Medicine, said that the team was inspired to take a new global approach to examining all the interactions a tick has with the antibody response in the human body. 

For Fikrig, the team’s research aims to answer two key questions. 

“The first question is, when you’re bitten by a tick, what is it you’re recognizing in terms of making an antibody to that tick bite?” said Fikrig. “The second thing is, are there targets in there that could be linked to tick rejection?”

In Fikrig’s view, the answer for the first question could help pave the way for new diagnostic tests for early tick bites. In the future, patients concerned about having Lyme disease could perform a test to check for Lyme disease and a test if they have had a recent tick bite to confirm their suspicions. 

In terms of the second, Fikrig believes that the team’s work identifying proteins associated with tick rejection shows promise for preventing tick-borne disease transmission.

“In this paper, we show that when you immunize with a cocktail of 25 proteins, we can develop an immune response,” noted Fikrig. “It’s detectable against all of those proteins, which means that it’s a potential target for an anti tick vaccine.”

Fikrig categorized the study as a first step toward creating a diagnostic test and vaccine, and hopes that further research could help bring both to the public within the next 10 years. 

There are over 40,000 tick-borne disease cases in the United States each year.