Itching for an mRNA Lyme Vaccine Against Lyme Disease

Lyme vaccine directly targets the ticks. 

A tick sneakily crawls onto a small patch of human skin, burrowing into its newfound home. As time passes, due to the lack of Lyme vaccine for patients the tick can't be eliminated and it starts biting down, passing a small bacterium into the bloodstream. The bacterium, Borrelia burgdorferi, sets off alarm bells in the body – leading to infection, symptoms, and in some cases, chronic illness. All of this commotion, known as Lyme disease, began from a single tiny tick.

Under Dr. Erol Fikrig, M.D., from Yale University and Dr. Drew Weissman, M.D. Ph.D., from the University of Pennsylvania, a team of researchers has developed an mRNA-based Lyme vaccine that aims to prevent Lyme disease by deterring the tick itself. Recently published in Science Translational Medicine, the researchers used a cocktail of 19 different mRNAs to encode for several key proteins that can both alert the human immune response to the presence of a feeding tick and also impede the tick’s feeding capabilities.

“This is an intriguing approach of trying to disrupt the transmission from the tick, since [Lyme disease] is tick-borne,” Dr. John Aucott, M.D., who directs the Lyme disease clinical research center at Johns Hopkins University told BioSpace. (Aucott was not involved in this study). “This opens up the possibility that you can target the tick vector and interrupt the transmission because the transmission life cycle is also fixed.”

Because transmission of the disease-causing bacterium from the tick can take 24 to 48 hours, the researchers aimed to use this time window as “a unique opportunity to disrupt transmission,” explained Dr. Jaqueline Matias dos Santos, Ph.D., one of the Lyme vaccine study’s first authors, in an e-mail statement. 

How Researchers made Lyme Vaccine Target the Ticks?

“We were interested in taking a new approach to vaccination,” Fikrig added. “In this case, we’re not targeting the pathogen. We thought we’d take a different tactic and try to target the vector, the tick, to see if we can prevent infectious disease.”

To make the Lyme vaccine target the tick, the researchers selected an array of 19 proteins that were expressed in tick saliva. Tick saliva contains a complex blend of multi-functional proteins – some of which act as immunosuppressants or assist in pathogen infectivity. The proteins encoded by the 19 mRNAs were chosen because of their potential role in mediating tick feeding. Some proteins were selected via their binding activity to tick-resistant animal sera, which could indicate a potential role in generating immunity. Other proteins were selected for their known roles in tick acquisition or infestation.

The mRNAs that encoded these 19 proteins were packaged into lipid nanoparticles and injected into the host. According to Matias dos Santos, the nanoparticle delivery method can protect the mRNA from degradation. Once inside the organism, the mRNA is translated by the organism’s own cellular machinery into proteins that then elicit a protective immune response through antibody generation.

In order to test the effectiveness of this protein Lyme vaccine cocktail as a preventative measure against Lyme disease, the researchers used guinea pigs as their model organism. Following immunization of the guinea pigs with the mRNA vaccine, they found successful antibody generation against many of the selected proteins in the vaccine – indicating that a humoral immune response was indeed elicited following vaccination.

After challenging the guinea pigs with ticks, the researchers discovered that early erythema, or local reddening of the skin at the bite site, occurred in the vaccinated guinea pigs as opposed to unvaccinated guinea pigs. According to the researchers, a reaction in the form of erythema could increase the possibility of the human host actually identifying the tick and removing it – thus potentially preventing transmission of the bacterial pathogen in the first place.

“Only 30% of people [with Lyme disease] recognize a tick bite,” Aucott explained. “This means that 70% of people never knew they had been bitten by the tick. If you can make those 70% of tick bites (or all of them) more irritating so that people are taught to pull the ticks off early, then you could prevent a lot of Lyme disease.”

Besides early erythema, the guinea pigs injected with Lyme vaccine also showed signs of tick immunity – like tick rejection, poor tick feeding and detachment. “When a tick starts to feed on an mRNA-vaccinated individual, redness occurs and antibodies that are directed to the salivary proteins migrate to that site,” Fikrig explained. He hypothesized that the immunization caused complexes of antigens and antibodies to form, causing cell congregation at the bite site. This, combined with immune cell infiltration, could irritate the tick and complicate its ability to take a “blood meal.”

Fikrig likened this to the tick “drinking out of a clogged straw”, where the ticks that attached onto vaccinated guinea pigs were smaller and less engorged than those on the unvaccinated guinea pigs.

The researchers also conducted RNA sequencing of blood isolated from guinea pigs who were given Lyme vaccine doses. In these results, they discovered that many immune cell signaling pathways and several inflammatory cytokines were upregulated. “The upregulation of pro-inflammatory cytokines is the host’s immune response to the antigens,” Matias dos Santos said. “We think that this will be a positive thing and plays an important role in mediating tick rejection.”

While the researchers aim to test the mRNA vaccine on other animal models like rabbits, Fikrig noted that the group is also looking to find a potential “magic bullet” – sifting through each of the 19 mRNAs to see if inoculation with just one, or a few, would be sufficient to induce tick resistance. Additionally, they are interested in seeing if protection can extend to other tick-borne pathogens as well.

For Fikrig, the change in the approach of making the Lyme vaccine i.e. from targeting the disease pathogen to targeting the disease vector itself represented a shift in scientific thinking. “In my opinion, the most important thing about the study is that it is the first time where a vaccine against an infectious disease does not target the infection. It targets the arthropod [the tick],” Fikrig said. “We’re hopeful that some of the principles we’re learning from the tick will be applicable to other arthropod-borne diseases."