Lyme disease is on the rise. Why is there still no vaccine? – AAMC

Imagine trying to medicate a bug.

That was the task taken on by a group of researchers at MassBiologics of UMass Chan Medical School (UMass Chan) in Massachusetts: They developed a way to get an antibody into ticks to neutralize the bacterium that causes Lyme disease, the most common vector-born disease in the United States.

But no, the researchers did not give shots to ticks. They injected the antibody into humans so that people can transmit the antibody to ticks that bite them.

We are trying to deliver a medicine to a tick so that it doesnt pass on the infection to the patient, says Mark S. Klempner, MD, a professor of medicine at UMass Chan. The patient provides the vehicle to deliver the antibody to the infected tick.

Targeting ticks to prevent Lyme rather than fighting off an infection after it begins is the fundamental strategy behind three projects that aim to create the only medication to prevent the disease in people. The disease sets off a series of escalating symptoms, starting with a red rash, fatigue, fever, headache, and a mild stiff neck, and sometimes escalating if left untreated to serious complications to joints (arthritis), the heart, and the nervous system.

The current projects come two decades after the first human Lyme vaccine, LYMErix, was pulled from the market because of factors that researchers believe their new products will overcome. Heres where the projects stand:

If any of these products are eventually approved by the Food and Drug Administration (FDA), it would put humans nearly on par with dogs; they can get four Lyme vaccines made just for them. The lack of a human version has little to do with the science of making one. Klempner knows that well, as he worked on one of two Lyme vaccines that showed strong clinical trial results in the 1990s.

It was not very difficult to develop, Klempner recalls of the vaccine, Imulym, made by Pasteur Merieux Connaught but never brought to market. In terms of difficulty from a biological and medical standpoint, it was relatively straightforward.

The new efforts build on the basic strategy of those vaccines.

Creatures that spread diseases through bites such as mosquitos that transmit malaria and raccoons that transmit rabies usually deliver the virus, bacteria, or parasite instantly. But when a black-legged tick latches onto someone, it takes at least 36 hours to pass along the Lyme-causing bacterium, Borrelia burgdorferi, says Gary Wormser, MD, chief of the Division of Infectious Diseases at New York Medical College. That lag, he notes, provides time for antibodies to get into the ticks gut and prevent transmission of the bacterium before it sets off an infection in the human.

Whats more, the bacterium has virtually no machinery to survive mutation, Klempner says, so that researchers can identify and stick with antibodies that eradicate the bacterium rather than having to keep up with mutated versions. (Rapid viral mutation is a main reason that scientists have yet to develop a vaccine against HIV.)

LYMErix, manufactured by what was then SmithKline Beecham, induced patients to produce antibodies that a tick would absorb from its victims blood and that neutralized Borrelia burgdorferi. Studies showed the vaccine to be about 75% effective in blocking the disease. The FDA approved it in 1998.

It wasnt a perfect vaccine, but it was good, says Eugene Shapiro, MD, professor of epidemiology and investigative medicine at Yale School of Medicine in Connecticut.

As a marketable product, however, LYMErix faced compounding drawbacks. Sam Telford, ScD, professor of vector-borne infections and public health at Tufts University in Massachusetts, who helped run the vaccines clinical trials, notes that Lyme was far less prevalent then and was more restricted to a few geographic regions, thus limiting the market for a vaccine. (The Ixodes ticks that can carry Lyme disease, commonly known as deer ticks, have been most common in the northeast, Mid-Atlantic and north-central states, but their reach has been expanding.)

That, along with Lyme being seen as easily treatable if you catch it at the early stages, led the Centers for Disease Control and Prevention (CDC) to issue a lukewarm recommendation for the vaccine as rarely necessary and prompted many doctors to shrug it off, Telford recalls. Potential consumers felt lukewarm as well, for reasons that included the inconvenience of the three-dose regimen of injections over 12 months, uncertainty over how long the protection would last, and the absence of approval for use on anyone under 15 because LYMErix was not tested in children.

The final blow, Telford says, was claims by some recipients that the vaccine induced a form of arthritis. Although an FDA analysis of side effects among vaccinated people found no evidence to support the allegation, LYMErix sales fell under the weight of the negative publicity and a class action suit. The manufacturer (renamed GlaxoSmithKline) withdrew the vaccine in 2002.

That experience chilled research into prophylactic treatments against Lyme, Klempner says, even though biologically, its an easy target.

Over the past 20 years, cases of Lyme disease have multiplied and spread , with experts citing climate change (which can make cold areas more hospitable to the ticks lifecycle) and the increasing encroachment of human development adjacent to forested animal habitats.

Lyme disease is all over the place in much of the U.S., Telford says.

Nailing down its prevalence is tricky. The CDC says it gets about 30,000 reported cases from doctors each year, but notes that this number does not reflect all diagnosed cases. An analysis based on private insurance claims , conducted by CDC researchers, estimated that each year 476,000 people in the U.S. are diagnosed and treated for the disease. (Some people are treated based on symptoms without confirmation of having Lyme.) A recent report from the nonprofit FAIR Health, which studies health care costs and coverage, found that from 2007 to 2021 Lyme diagnoses rose 357% in rural regions and 65% in urban areas.

The growth of cases and public awareness have encouraged researchers that a market exists for prophylactics against Lyme. The medical need for vaccination against Lyme disease is steadily increasing as the geographic footprint of the disease widens, Pfizer and Valneva said in a news release last month about their vaccine project.

Here is a summary of the three most advanced development projects:

Pfizer and Valneva: Their vaccine, VLA15, induces the patient to create antibodies that block a protein, OspA, on the surface of the Borrelia burgdorferi bacterium. Blocking OspA inhibits the bacteriums ability to leave the tick and infect humans, the companies state.

The vaccine requires three doses. With a phase 2 trial showing promising results in producing immune responses, the companies have started a phase 3 trial to enroll approximately 6,000 participants, ages 5 years and up, at 50 sites where Lyme is prominent. Because the vaccine produces antibodies to combat strains of the virus in Europe as well as the United States, there are test sites in the U.S., Finland, Germany, the Netherlands, Poland, and Sweden.

Shapiro notes that this vaccine does not include an epitope the part of a molecule to which an antibody attaches itself that was implicated in the arthritis claims against LYMErix.

The companies say they hope to have the vaccine licensed in 2025.

MassBiologics: Rather than prompt a patient to produce antibodies, the Lyme Pre Exposure Prophylaxis (Lyme PrEP) delivers a monoclonal antibody a lab-made protein that binds to the surface of the bacteria against the common U.S. strain of Lyme. Like VLA15, this medication targets the OspA protein.

Lyme PrEP conveys immunity almost immediately, Klempner says, as opposed to the weeks it might take a person to develop antibodies on their own after several shots. The person is immune within hours or days, he says.

In addition, Klempner notes, one antibody is less likely to trigger adverse effects in a patient than a medication that involves numerous antibodies, and the shot would be given once a year, at the start of tick season.

With a phase 1 trial showing no significant adverse effects, Klempner,former executive vice chancellor at MassBiologics, hopes a phase 2-3 clinical trial to test effectiveness can start in spring 2023.

Yale SOM: Yale University researchers designed a vaccine that recognizes a ticks saliva and sparks a skin reaction that makes it hard for ticks to hang on and feed. Created with mRNA technology which helps to accelerate the production of vaccines, such as those against COVID-19 this medicine quickly produces redness at the site of a tick bite, alerting victims to the bite and increasing the chances that they can remove the tick before it delivers the Lyme-causing bacterium.

If you can remove the tick that was on for less than 36 hours, youre not going to get Lyme, Wormser says.

Trials on guinea pigs showed that when ticks were removed after redness appeared, none of the immunized animals developed Lyme disease. In addition, the ticks fed poorly and detached sooner than normal, Yale reports.

These advances provide hope for a Lyme disease vaccine within several years. Yet researchers offer caution. They warn that people vaccinated against Lyme will have to take precautions against other diseases that ticks transmit, like by wearing long-sleeved clothing in wooded areas and inspecting themselves for ticks after forest forays.

Its not like you can go out and say, Im vaccinated, I dont have to worry about tick bites, Telford says. There is no such thing as a good tick bite.

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Lyme disease is on the rise. Why is there still no vaccine? - AAMC