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Analysis
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Health
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Science + Tech

My Dog Can Get a Shot for Lyme Disease. Why Can’t I?

The LymeRix debacle didn’t just torpedo one vaccine. It poisoned the well for future ones. Excerpt from a new book.

Brian Owens 27 Jul 2021 | TheTyee.ca

Brian Owens is a freelance science writer and editor based in St. Stephen, New Brunswick. His work has appeared in Hakai Magazine, Nature, New Scientist, the Canadian Medical Association Journal and the Lancet.

[Editor’s note: This excerpt is from science writer Brian Owens’s new book, 'Lyme Disease in Canada'. For more than a year, Owens has been covering science journal roundups on COVID findings for The Tyee. We are pleased to share this excerpt from his new book, which delves into why Canada has a widely adopted vaccination protocol for Lyme disease in dogs — but not one for humans. Yesterday, we spoke with Owens about Lyme disease, ticks and the most shocking thing he learned while researching for his book.]

Why, more than 40 years after it was first identified, is there still no vaccine available to prevent Lyme disease in humans? Since you can choose among multiple vaccines offered by several different companies when it comes to vaccinating your dog against Lyme disease, why can’t people get one?

As it turns out, there was one available for a few years around the turn of the millennium, before it was pulled from the market. The story of what happened to that vaccine demonstrates how difficult it will be to get control of the disease, and offers a cautionary tale for future attempts to develop another one.

The first Lyme disease vaccine, LymeRix, was developed by the pharmaceutical company SmithKline Beecham (now known as GlaxoSmithKline) in the 1990s. It was available in the U.S. and Canada from late 1998 to early 2002, when the company abruptly stopped manufacturing and selling it in the face of low demand and bad press.

LymeRix was what is known as a “recombinant vaccine,” based on a purified B. burgdorferi protein that was made in the lab and grown in other bacteria before being injected into humans. The human immune system would recognize the protein as an invader and create antibodies to it, which would then be on the lookout for that protein, ready to recognize it and attack if it ever showed up again.

At first, LymeRix showed a lot of promise. Almost 6,500 people received it during clinical testing, and only minor side effects were seen: pain and reactions at the injection site, temporary joint and muscle pain and mild headaches — the kind of side effects seen with many vaccines, including ones for seasonal flu and COVID-19. In fact, the side effects were seen in both the vaccine group and the control group that was given a placebo. The vaccine required three doses, and the clinical trials showed that it was about 78 per cent effective after all three had been given — not spectacular, but still better than the average seasonal flu vaccine.

And it was initially popular. Around 1.5 million people got the vaccine in the first couple of years, but the tide soon turned against it. By 2001 sales had slumped to just 93,000 doses, and just 10,000 doses were sold in the first few months of 2002, before it was discontinued. So what happened?

The vaccine did have some drawbacks. It was only effective against the North American strain of B. burgdorferi, so would not work against Lyme disease picked up elsewhere in the world (and that meant the company could not sell it overseas). The three-dose schedule, with a second shot after one month and the third after a year, was complicated and meant that people would not be fully protected until they had received all three doses, a year after they started the process.

Because it had not been tested in children during the initial clinical trials, it was only approved for people between the ages of 15 and 70 who lived or worked in areas with high rates of Lyme disease. This left out one of the most important groups for Lyme disease prevention — children under the age of 15 are among those at the highest risk of contracting the disease, but they were not allowed to take advantage of the protection that the vaccine offered.

The shot was also not added to the routine vaccination schedule for children or adults, but was given a “permissive recommendation,” which meant that the decision about whether to vaccinate someone was left up to a discussion between a person and their doctor to determine if they fit the criteria. It was difficult to determine exactly what someone’s risk was to see if they should get the vaccination. Did you need to have ticks right in your backyard? What about someone who worked in an office all day, but went hiking on weekends?

Often, physicians were not well educated about the disease or the vaccine. “I was astounded when LymeRix came out how many of my colleagues didn’t know a damn thing about the disease or why a vaccine was needed,” says Dr. Stanley Plotkin, a physician who played a pivotal role in discovering the vaccine for the rubella virus in the 1960s, and who now works as a consultant to vaccine manufacturers and governments. “That’s part of why it failed.”

Another consequence of the vaccine not being added to the routine vaccination schedule was that it was not covered by the U.S. National Vaccine Injury Compensation Program. The program was created both to help people harmed by rare side effects, but also to help shield vaccine manufacturers from lawsuits. If too many lawsuits are filed against a particular vaccine — even without any solid proof that the vaccine causes harm — the cost of fighting the lawsuits can lead a company to raise the price of a vaccine, or even halt its production completely.

Without this protection, people who thought they had been hurt by the vaccine could sue SmithKline Beecham directly, and they did. And even though this was mainly a U.S. phenomenon, the effects of these lawsuits spilled over into Canada as well.

As with all vaccines, the company and the regulators continued to monitor reactions to the vaccine, to keep an eye out for any serious but rare side effects that might have been missed during clinical trials. In the U.S., this involves monitoring submissions to the Vaccine Adverse Events Reporting System.

This system can be useful for identifying extremely rare side effects, the kind that can only be expected to show up once a large enough group of people has received a particular vaccine. This has happened before.

Between the end of December 1998 and the end of July 2000, there were 905 reports of adverse events associated with LymeRix in VAERS, 66 of which were classified as serious — meaning they resulted in life-threatening illness, hospitalization or disability. Reports of arthritis were given particular attention. Since arthritis is one of the symptoms of Lyme disease itself, it was plausible that the synthetic version of the Borrelia protein used in the vaccine might be somehow able to trigger arthritis in some vaccine recipients.

There was some potential evidence that this might be the case, and at least some of it came from a highly credible source: Allen Steere himself, the doctor who had co-discovered Lyme disease, and who had spent 10 years working on the development of the vaccine and headed up the clinical trials. Previous research and clinical observations had found that arthritis caused by Lyme disease seemed to be related to the host’s own immune function; that is, it was an autoimmune condition that somehow prompted the patient’s immune system to attack healthy tissues.

Steere’s team suggested that this might be caused by “molecular mimicry,” in which the foreign protein just happens to be similar enough to one of the body’s own proteins that the antibodies generated by the vaccine will recognize and attack both the invader and the native protein. They found that part of the genetic sequence of OspA (a protein used in the development of the vaccine) resembled an immune system protein called “human lymphocyte function associated antigen-1” that helps move immune cells from blood vessels to inflamed tissue.

In test-tube experiments, the hLFA-1 protein did appear to be involved — it prompted immune cells from treatment-resistant Lyme arthritis patients to trigger inflammation processes. It seemed at least possible that in people with the HLA-DR4 gene variant, which is around 30 per cent of the population, the coincidental resemblance between OspA and the immune system protein hLFA-1 could cause the vaccine to trigger arthritis.

Between the VAERS reports and the molecular mimicry hypothesis, there was enough concern among both scientists and the public that the U.S. Food and Drug Administration ordered a further review of the alleged safety issues. A panel of experts looked closely at the evidence and determined there was no compelling evidence that the vaccine caused arthritis, and that the benefits of vaccination outweighed the theoretical risks. A review of the reports in VAERS found that the incidence of arthritis among vaccine recipients was no higher than the background rate among unvaccinated people. In fact, there were significantly fewer reports of arthritis among people who got the vaccine than would be expected, given the background rate among the general population.

The molecular mimicry idea was discarded, including by Steere and his colleagues, because although it is a solid hypothesis, it has never actually been proven in real life outside of the lab — not just in the case of Lyme arthritis, but in any autoimmune disease where it has been suspected. As more experiments were conducted, Lyme disease researchers showed that many other proteins could also activate OspA-specific immune cells in the test tube, and some of them did not even share similar genetic sequences. Steere never found any real evidence that vaccine doses of OspA could trigger persistent arthritis.

The FDA did order an expanded post-licencing safety study, which was planned to run for four years, but it ended after two when the vaccine was withdrawn. In those two years, however, more than 2,500 people got the vaccine as part of the study and there were no differences in side effects between them and the control group.

None of this changed the mind of those already convinced the vaccine had harmed them, or that it had the potential to harm others. Anti-Lyme vaccine groups formed, and their concerns were amplified by some high-profile media coverage. The bad press was particularly bad timing for LymeRix, as it came just as the modern anti-vaccine movement was starting to take off — driven by Andrew Wakefield’s fraudulent claims that the childhood measles, mumps and rubella vaccine could cause autism.

A class-action lawsuit was filed against SmithKline Beecham to force the company to include a warning that the vaccine might cause arthritis. An array of other individual lawsuits alleging that the vaccine caused arthritis or other side effects sought damages from the company. Faced with the expense of defending these lawsuits, along with bad press, an increasingly skeptical public and disappointing sales, the company voluntarily withdrew the vaccine from production in early 2002. The lawsuits were settled soon afterwards.

LymeRix remains the only fully approved vaccine to be withdrawn because of low demand despite a continually high, and rising, rate of disease.

“It was taken off the market because of anti-vaccine forces,” says Steere. “It doesn’t change the fact that we do have a safe and effective vaccine.”

But the LymeRix debacle did not only torpedo one vaccine. It also poisoned the well for future ones.

At around the same time LymeRix was hitting the market, another vaccine, made by French pharmaceutical company Pasteur Mérieux Connaught (now Sanofi Pasteur), completed clinical trials. It was based on a different strain of B. burgdorferi but used the same three-dose, recombinant OspA-based strategy. It appeared to work even better than LymeRix — the trials showed that it was 92 per cent effective after three doses. But the company never even submitted it to regulators for approval. After seeing the problems that SmithKline Beecham ran into, Pasteur Mérieux decided that the size of the market was just too small, and the potential for distracting and expensive lawsuits too high, to make the vaccine profitable.

A few years later, Baxter International, an Austrian pharmaceutical company, took a stab at creating a Lyme vaccine. Baxter completed safety trials for the vaccine in 2013, but never took it any further.

Any of these vaccines could still be brought back if there was sufficient interest. In fact, the patent on LymeRix has expired and its original approval is still valid, so any company could start making and selling a generic version of it if they wished. But the lingering memory of its failure means it is unlikely anyone would be willing to take the risk.

There is one glimmer of hope, however. The French company Valneva, which specializes in vaccines for unmet medical needs, has been working on a new Lyme disease vaccine — as of 2021 the only one in clinical development. Its vaccine candidate, known for now as “VLA15,” shares some similarities with the previous efforts but has been modified to minimize the perception of safety concerns.

VLA15 also works against six strains of B. burgdorferi that are common in North America and Europe, and even some parts of Asia — greatly expanding the size of the potential market. Like LymeRix, it requires three doses. As of 2021, the company was still working on determining the optimal schedule, but it looks like the course of shots would be completed in a maximum of six months, instead of the full year needed for LymeRix.

Initial results from the vaccine’s first round of phase two safety trials in adults were released in 2020. No serious side effects were reported, and it appeared to generate a strong immune response in the people who received the shot. The company did safety trials in children as well, to cover one of the major gaps left in previous attempts at a vaccine.

Valneva has partnered with the pharmaceutical giant Pfizer to complete clinical testing and bring the vaccine to market, a process that will take several more years. The phase three trials will likely last for two years, covering two tick seasons, to ensure that the researchers can gather enough data to draw statistically sound conclusions. The company is hoping to have the vaccine approved for use in many countries, including Canada, in 2024 or 2025.

It remains to be seen whether the Valneva vaccine will prove effective, and whether the public will be willing to take it.

Allen Steere is optimistic. “I’m still hopeful that there will be enough demand for a vaccine to outweigh the counter-vaccine forces,” he says.

It is, after all, our best hope for beating Lyme disease.


Excerpted from 'Lyme Disease in Canada' by Brian Owens. Copyright 2021 Brian Owens. Published by Formac Publishing Co. Ltd. Reproduced by arrangement with the publisher. All rights reserved.  [Tyee]

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