VLA15: A New Vaccine for Lyme Disease

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In late July 2017, the FDA granted fast-track designation to a new Lyme disease vaccine candidate called VLA15. Fast-track designation means that the review of the vaccine will be expedited, with an eye toward earlier availability to the general public. This vaccine was fast-tracked to fight the rapidly growing problem of Lyme disease, which results in considerable disability and long-term suffering.

Lyme disease is the fastest-growing vector-borne infectious disease and the top tick-borne illness in the United States. According to the CDC, in 1995, there were a little more than 10,000 cases of Lyme disease in the United States. By 2015 there were more than 35,000 cases—representing a threefold increase.

Importantly, VLA15 isn’t the first Lyme vaccine. In 2002, LYMErix was pulled from the market for various reasons, including antivaccination sentiments, media hype, and lawsuits stemming from perceived adverse effects—including arthritis.

VLA15: The Current Vaccine

The new Lyme vaccine, VLA15, is a multivalent vaccine, which means that it confers protection against more than one strain of Borrelia, the bacteria that causes Lyme disease. More specifically, VLA15 targets Outer Surface Protein A (OspA), which is the most dominant protein in Borrelia transferred by ticks. Because it targets six different types of OspA—representing six different strains of Borrelia—this vaccine has the potential to protect against Lyme disease spread in the United States, Europe, and worldwide.

In light of the vaccine’s fast-track designation, Valneva, the company that manufactures VLA15, has stepped up Phase II clinical trials to early 2018. According to a July 2017 press release, Phase I clinical trials involve 180 participants from three sites, two in the United States and one in Belgium.

In this partially randomized study, the researchers are evaluating the safety and tolerability of various doses and formulations of the VLA15 vaccine. The researchers will determine immunogenicity, or the ability of the vaccine to provoke an immune response, by measuring immunoglobulin G (IgG) antibody levels against the six most common strains of Lyme borreliosis in the United States and Europe.

Of note, IgG antibodies are the smallest common antibody and represent about 80 percent of the antibodies in the body. These antibodies are needed to fend off bacterial and viral infections.

LYMErix Vaccine: A Look Back

Before VLA15, there was LYMErix. Despite being straddled with controversy, the LYMErix vaccine was moderately effective and free of serious adverse effects. People vaccinated with LYMErix showed around an 80 percent reduction in Lyme disease during the year following vaccination.

The LYMErix vaccine was monovalent, meaning that it targeted OspA belonging to only one strain of Borrelia. In other words, unlike VLA15, which targets OspA belonging to six strains of Lyme Borrelia, LYMErix didn't confer protection against all ticks that spread Lyme disease. Instead, LYMErix protected only against Lyme disease spread in the United States.

Shortly after physicians started administering LYMErix, the vaccine was suspected of causing arthritis in those who received it. The OspA protein closely resembles a protein that’s naturally found in the body:  human lymphocyte function-associated antigen-1 (hLFA-1) adhesion molecules. By training the body to attack not only Borrelia but also itself it was hypothesized that LYMErix contributed to the development of antibody-mediated arthritis. This adverse effect was particularly concerning in people with a special type of biomarker called HLA-DR4; these people were more likely to develop treatment-resistant arthritis.

In addition to concerns about arthritis, other questions lingered. For example, LYMErix was never tested in small children, who are at high-risk for being exposed to Lyme disease. Furthermore, It was unclear how long people who received the vaccine would be protected. Experts were unsure whether people who received the vaccine would need booster shots. In fact, it was suggested that booster shots could be needed every year—making the vaccine more costly and inconvenient.

After approval by the FDA in 1998, LYMErix initially enjoyed positive prime time exposure and rising popularity. After about a year, however, media coverage shifted to cover people who claimed to experience debilitating adverse effects of the vaccine. People complained of various issues, but musculoskeletal complaints dominated coverage.

Consider the following excerpt from a note written to the FDA by person who received the LYMErix vaccine:

My name is [redacted] and I am HLA-DR4 positive. Eighteen months ago I ran five miles a week and worked out at least an hour a day. I was very healthy … Within six months of getting the lymerix vaccine, I couldn’t get out of bed by myself and was in constant excruciating joint and muscle pain. My joints have started making snapping noises.

Around the turn of the millennium, there was a rise in antivaccination sentiment that also ended up hurting LYMErix. This erosion in public trust was due to two big events. First, in 1998, Andrew Wakefield and colleagues fraudulently reported in the Lancet about an association between the MMR vaccine and autism. This claim—although a bold-faced lie—scared countless unwitting denizens, and parents started not to give their children vaccines. Second, in 1999, the rotavirus vaccine, RotaShield, was pulled over concerns about increased risk of intussusception, or telescoping bowel, in children. Intussusception is a medical emergency.

In 1999, the Philadelphia law firm of Sheller, Ludwig & Badey brought a class action lawsuit against SmithKlineBeechum, which manufactured LYMErix. (This suit was settled in 2003.) With all the media attention and pending litigation, the FDA was moved to re-examine LYMErix.

The FDA re-examined results of Phase III clinical trials and found that significantly more vaccine recipients than those who received placebo (26.8 percent versus 8.3 percent, respectively) experienced local reactions, which were self-limited and lasted only a few days, including the following:

  • soreness
  • redness
  • swelling at the injection site
  • muscle pain
  • fever
  • chills

However, no difference in joint symptoms was observed between the experimental (i.e. vaccinated) and control (i.e. placebo) groups: 1.3 percent of those vaccinated experienced joint symptoms versus 1.2 percent of controls. Importantly, the researchers followed adverse effects for only a year, and longer-term effects are uncertain. In other words, there’s always the possibility that joint symptoms could manifest long-term.

The FDA also looked at data from post-marketing surveillance. Of 1.4 million vaccinations administered by 2001, there were 905 reports of mild, self-limited reactions, which didn’t require treatment, and 59 cases of arthritis. This rate of arthritis in those receiving the vaccine equaled that of the general population.

Based on re-evaluation of Phase III results and an assessment of post-marketing surveillance data, the FDA concluded that the evidence did not indicate that LYMErix caused arthritis. Despite this validation, GlaxoSmithKline, which now owned LYMErix thanks to a merger, had had enough and decided to close the book on the Lyme disease vaccination. In the end, the hype and drama surrounding LYMErix—an effective vaccine that increased risk of only mild adverse effects—took it down.

Lyme Disease: A Closer Look

Lyme disease was first discovered in Lyme, Connecticut, after a cluster of children developed rheumatoid arthritis. Investigators figured out that these cases were not autoimmune and caused by a tick instead. By 1983, researchers identified Borrelia burgdorferi, a previously unknown spirochete bacteria, as the specific cause. Of note, in Europe and Asia, Lyme disease is caused by Borrelia afzelii and Borrelia garinii, resulting in some regional differences in presentation.

Although many people think that Lyme disease is restricted to the northeast United States, it’s actually found in many other regions including mid-Atlantic states, north-central United States, the Midwest, and the West Coast.

Lyme disease is debilitating because it affects the entire body. Typically, the illness begins with erythema migrans, an expanding rash, as well as fatigue, muscle pains, and fever. If left untreated, Lyme disease can lead to more serious musculoskeletal, neurological, and cardiac issues. During the chronic phase of the illness, the predominant complaint is arthritis affecting large joints.

When Lyme disease is caught early, it’s treated with the oral antibiotic doxycycline. In patients who experience neurological symptoms and a more advanced or complicated course, several weeks of intravenous antibiotic treatment are needed. Most people who receive antibiotic treatment eventually recover from Lyme disease. However, even after treatment, some people continue to experience lingering musculoskeletal pain, neurocognitive issues, and fatigue, which is referred to as post-Lyme disease syndrome.

Although a vaccine is in development, for now the best way to prevent tick bites that lead to Lyme disease is to take precautions. After possible exposure, it’s important to check your body for ticks. Of note, the Ixodes tick, which carries Borrelia, is smaller than more-common wood or dog ticks. It can take more than 36 hours for an Ixodes tick to bite a human, and timely removal of the tick can avoid infection.

In residential areas that are rich in ticks, it’s a good idea to clear underbrush, use pesticide, and wear protective clothing.

Prophylaxis with doxycline within 72 hours results in a nearly 90 percent reduction in the risk of developing Lyme disease. However, nearly 75 percent of people who develop erythema migranes, the first sign of Lyme disease, can’t recall getting bit with the tick in the first place. Thus, although definitely best for the patients, it’s tricky to catch Lyme disease early on.

Summing Up

A vaccine for Lyme disease is currently in the works, and efforts to approve it are being expedited. But we still have no way to prevent Lyme disease other than good sense and precaution.

Lyme disease is a burgeoning problem with high personal, emotional, and economic costs. If you live in an area where Lyme disease is endemic and you enter wooded and brush habitats where the Ixodes tick lives, be careful. Wear protective clothing and avoid high-risk areas whenever possible. Always check for ticks after any potential exposure and contact your physician with any concerning symptoms. Finally, if you have brush areas in your yard, it’s a good idea to get them cleared.

If you have a dog, it’s a good idea to check the dog’s coat for ticks and avoid letting your dog frequent leaf litter, brush, and forest ground, where ticks are found. Of note, commercial pesticide sprays, collars, and topical treatments are available. Ticks on dogs can cause disease in the dogs themselves and spread to people. If you think that your dog has been infected with Lyme disease, contact a veterinarian.

Sources:

Badawi, A, et al. A systematic review and meta-analysis for the adverse effects, immunogenicity and efficacy of Lyme disease vaccines: Guiding novel vaccine development. Can J Public Health. 2017;108(1):e62–e70.

Delage, G. Rotavirus vaccine withdrawal in the United States; The role of postmarketing surveillance. Can J Infect Dis. 2000;11(1): 10–12.

FDA. LYMErix  Vaccine Victim’s Stories and Related Articles.

Nigrovic, LE, Thompson, KM. The Lyme vaccine: a cautionary tale. Epidemiol Infect. 2007;135:1–8.

Valneva press release. Valneva Receives FDA Fast Track Designation for its Lyme Disease Vaccine Candidate VLA15. July 24, 2017.

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