A vaccine for Lyme disease could be coming. But will patients accept it?
For more than two decades, Marci Flory, a 40-year-old emergency room nurse from Lawrence, Kan., has battled the recurring symptoms of chronic Lyme disease, an illness which she believes began after being bitten by a tick during her teenage years.
Over the years, Flory has been plagued by an array of mysterious ailments, ranging from fatigue to crippling pain in her eyes, joints and neck, and even postural tachycardia syndrome or PoTS, an abnormal increase in heart rate after sitting up or standing. Ten years ago, she began to experience the onset of neurological symptoms which ranged from brain fog to sudden headaches, and strange episodes of leg weakness which would leave her unable to walk.
“Initially doctors thought I had ALS, or less likely, multiple sclerosis,” she says. “But after repeated MRI scans for a year, they concluded I had a rare neurological condition called acute transverse myelitis.”
But Flory was not convinced. After ordering a variety of private blood tests, she discovered she was infected with a range of bacteria in the genus Borrelia that live in the guts of ticks, the infectious agents responsible for Lyme disease.
“It made sense,” she says. “Looking back, I was bitten in high school and misdiagnosed with mononucleosis. This was probably the start, and my immune system kept it under wraps for a while. The Lyme bacteria can burrow into every tissue in the body, go into cyst form and become dormant before reactivating.”
The reason why cases of Lyme disease are increasing is down to changing weather patterns, triggered by climate change, meaning that ticks are now found across a much wider geographic range than ever before.
When these species of bacteria are transmitted to humans, they can attack the nervous system, joints and even internal organs which can lead to serious health complications such as arthritis, meningitis and even heart failure. While Lyme disease can sometimes be successfully treated with antibiotics if spotted early on, not everyone responds to these drugs, and for patients who have developed chronic symptoms, there is no known cure. Flory says she knows of fellow Lyme disease patients who have spent hundreds of thousands of dollars seeking treatments.
Concerningly, statistics show that Lyme and other tick-borne diseases are on the rise. Recently released estimates based on health insurance records suggest that at least 476,000 Americans are diagnosed with Lyme disease every year, and many experts believe the true figure is far higher.
The reason why the numbers are growing is down to changing weather patterns, triggered by climate change, meaning that ticks are now found across a much wider geographic range than ever before. Health insurance data shows that cases of Lyme disease have increased fourfold in rural parts of the U.S. over the last 15 years, and 65 percent in urban regions.
As a result, many scientists who have studied Lyme disease feel that it is paramount to bring some form of protective vaccine to market which can be offered to people living in the most at-risk areas.
“Even the increased awareness for Lyme disease has not stopped the cases,” says Eva Sapi, professor of cellular and molecular biology at the University of New Haven. “Some of these patients are looking for answers for years, running from one doctor to another, so that is obviously a very big cost for our society at so many levels.”
Emerging vaccines – and backlash
But with the rising case numbers, interest has grown among the pharmaceutical industry and research communities. Vienna-based biotech Valneva have partnered with Pfizer to take their vaccine – a seasonal jab which offers protection against the six most common strains of Lyme disease in the northern hemisphere – into a Phase III clinical trial which began in August. Involving 6,000 participants in a number of U.S. states and northern Europe where Lyme disease is endemic, it could lead to a licensed vaccine by 2025, if it proves successful.
“For many years Lyme was considered a small market vaccine,” explains Monica E. Embers, assistant professor of parasitology at Tulane University in New Orleans. “Now we know that this is a much bigger problem, Pfizer has stepped up to invest in preventing this disease and other pharmaceutical companies may as well.”
Despite innovations, patient communities and their representatives remain ambivalent about the idea of a vaccine. Some of this skepticism dates back to the failed LYMErix vaccine which was developed in the late 1990s before being withdrawn from the market.
At the same time, scientists at Yale University are developing a messenger RNA vaccine which aims to train the immune system to respond to tick bites by exposing it to 19 proteins found in tick saliva. Whereas the Valneva vaccine targets the bacteria within ticks, the Yale vaccine attempts to provoke an instant and aggressive immune response at the site of the bite. This causes the tick to fall off and limits the potential for transmitting dangerous infections.
But despite these innovations, patient communities and their representatives remain ambivalent about the idea of a vaccine. Some of this skepticism dates back to the failed LYMErix vaccine which was developed in the late 1990s before being withdrawn from the market in 2002 after concerns were raised that it might induce autoimmune reactions in humans.
While this theory was ultimately disproved, the lingering stigma attached to LYMErix meant that most vaccine manufacturers chose to stay away from the disease for many years, something which Gregory Poland, head of the Mayo Clinic’s Vaccine Research Group in Minnesota, describes as a tragedy.
“Since 2002, we have not had a human Lyme vaccine in the U.S. despite the increasing number of cases,” says Poland. “Pretty much everyone in the field thinks they’re ten times higher than the official numbers, so you’re probably talking at least 400,000 each year. It’s an incredible burden but because of concerns about anti-vax protestors, until very recently, no manufacturer has wanted to touch this.”
Such was the backlash surrounding the failed LYMErix program that scientists have even explored the most creative of workarounds for protecting people in tick-populated regions, without needing to actually vaccinate them. One research program at the University of Tennessee came up with the idea of leaving food pellets containing a vaccine in woodland areas with the idea that rodents would eat the pellets, and the vaccine would then kill Borrelia bacteria within any ticks which subsequently fed on the animals.
Even the Pfizer-Valneva vaccine has been cautiously designed to try and allay any lingering concerns, two decades after LYMErix. “The concept is the same as the original LYMErix vaccine, but it has been made safer by removing regions that had the potential to induce autoimmunity,” says Embers. “There will always be individuals who oppose vaccines, Lyme or otherwise, but it will be a tremendous boost to public health to have the option.”
Vaccine alternatives
Researchers are also considering alternative immunization approaches in case sufficiently large numbers of people choose to reject any Lyme vaccine which gets approved. Researchers at UMass Chan Medical School have developed an artificially generated antibody, administered via an annual injection, which is capable of killing Borrelia bacteria in the guts of ticks before they can get into the human host.
So far animal studies have shown it to be 100 percent effective, while the scientists have completed a Phase I trial in which they tested it for safety on 48 volunteers in Nebraska. Because this approach provides the antibody directly, rather than triggering the human immune system to produce the antibody like a vaccine would, Embers predicts that it could be a viable alternative for the vaccine hesitant as well as providing an option for immunocompromised individuals who cannot produce enough of their own antibodies.
At the same time, many patient groups still raise concerns over the fact that numerous diagnostic tests for Lyme disease have been reported to have a poor accuracy. Without this, they argue that it is difficult to prove whether vaccines or any other form of immunization actually work. “If the disease is not understood enough to create a more accurate test and a universally accepted treatment protocol, particularly for those who weren’t treated promptly, how can we be sure about the efficacy of a vaccine?” says Natasha Metcalf, co-founder of the organization Lyme Disease UK.
Flory points out that there are so many different types of Borrelia bacteria which cause Lyme disease, that the immunizations being developed may only stop a proportion of cases. In addition, she says that chronic Lyme patients often report a whole myriad of co-infections which remain poorly understood and are likely to also be involved in the disease process.
Marci Flory undergoes an infusion in an attempt to treat her Lyme disease symptoms.
Marci Flory
“I would love to see an effective Lyme vaccine but I have my reservations,” she says. “I am infected with four types of Borrelia bacteria, plus many co-infections – Babesia, Bartonella, Erlichiosis, Rickettsia, and Mycoplasma – all from a single Douglas County Kansas tick bite. Lyme never travels alone and the vaccine won’t protect against all the many strains of Borrelia and co-infections.”
Valneva CEO Thomas Lingelbach admits that the Pfizer-Valneva vaccine is not perfect, but predicts that it will still have significant impact if approved.
“We expect the vaccine to have 75 percent plus efficacy,” he says. “There is this legacy around the old Lyme vaccines, but the world is very, very different today. The number of clinical manifestations known to be caused by infection with Lyme Borreliosis has significantly increased, and the understanding around severity has certainly increased.”
Embers agrees that while it will still be important for doctors to monitor for other tick-borne infections which are not necessarily covered by the vaccine, having any clinically approved jab would still represent a major step forward in the fight against the disease.
“I think that any vaccine must be properly vetted, and these companies are performing extensive clinical trials to do just that,” she says. “Lyme is the most common tick-borne disease in the U.S. so the public health impact could be significant. However, clinicians and the general public must remain aware of all of the other tick-borne diseases such as Babesia and Anaplasma, and continue to screen for those when a tick bite is suspected.”
Scientists Are Working to Decipher the Puzzle of ‘Broken Heart Syndrome’
Elaine Kamil had just returned home after a few days of business meetings in 2013 when she started having chest pains. At first Kamil, then 66, wasn't worried—she had had some chest pain before and recently went to a cardiologist to do a stress test, which was normal.
"I can't be having a heart attack because I just got checked," she thought, attributing the discomfort to stress and high demands of her job. A pediatric nephrologist at Cedars-Sinai Hospital in Los Angeles, she takes care of critically ill children who are on dialysis or are kidney transplant patients. Supporting families through difficult times and answering calls at odd hours is part of her daily routine, and often leaves her exhausted.
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5 percent of patients die from the attack, and 20 percent within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1 percent of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20 percent of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."
This article was originally published by Leaps.org on July 28, 2021.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Did Anton the AI find a new treatment for a deadly cancer?
Bile duct cancer is a rare and aggressive form of cancer that is often difficult to diagnose. Patients with advanced forms of the disease have an average life expectancy of less than two years.
Many patients who get cancer in their bile ducts – the tubes that carry digestive fluid from the liver to the small intestine – have mutations in the protein FGFR2, which leads cells to grow uncontrollably. One treatment option is chemotherapy, but it’s toxic to both cancer cells and healthy cells, failing to distinguish between the two. Increasingly, cancer researchers are focusing on biomarker directed therapy, or making drugs that target a particular molecule that causes the disease – FGFR2, in the case of bile duct cancer.
A problem is that in targeting FGFR2, these drugs inadvertently inhibit the FGFR1 protein, which looks almost identical. This causes elevated phosphate levels, which is a sign of kidney damage, so doses are often limited to prevent complications.
In recent years, though, a company called Relay has taken a unique approach to picking out FGFR2, using a powerful supercomputer to simulate how proteins move and change shape. The team, leveraging this AI capability, discovered that FGFR2 and FGFR1 move differently, which enabled them to create a more precise drug.
Preliminary studies have shown robust activity of this drug, called RLY-4008, in FGFR2 altered tumors, especially in bile duct cancer. The drug did not inhibit FGFR1 or cause significant side effects. “RLY-4008 is a prime example of a precision oncology therapeutic with its highly selective and potent targeting of FGFR2 genetic alterations and resistance mutations,” says Lipika Goyal, assistant professor of medicine at Harvard Medical School. She is a principal investigator of Relay’s phase 1-2 clinical trial.
Boosts from AI and a billionaire
Traditional drug design has been very much a case of trial and error, as scientists investigate many molecules to see which ones bind to the intended target and bind less to other targets.
“It’s being done almost blindly, without really being guided by structure, so it fails very often,” says Olivier Elemento, associate director of the Institute for Computational Biomedicine at Cornell. “The issue is that they are not sampling enough molecules to cover some of the chemical space that would be specific to the target of interest and not specific to others.”
Relay’s unique hardware and software allow simulations that could never be achieved through traditional experiments, Elemento says.
Some scientists have tried to use X-rays of crystallized proteins to look at the structure of proteins and design better drugs. But they have failed to account for an important factor: proteins are moving and constantly folding into different shapes.
David Shaw, a hedge fund billionaire, wanted to help improve drug discovery and understood that a key obstacle was that computer models of molecular dynamics were limited; they simulated motion for less than 10 millionths of a second.
In 2001, Shaw set up his own research facility, D.E. Shaw Research, to create a supercomputer that would be specifically designed to simulate protein motion. Seven years later, he succeeded in firing up a supercomputer that can now conduct high speed simulations roughly 100 times faster than others. Called Anton, it has special computer chips to enable this speed, and its software is powered by AI to conduct many simulations.
After creating the supercomputer, Shaw teamed up with leading scientists who were interested in molecular motion, and they founded Relay Therapeutics.
Elemento believes that Relay’s approach is highly beneficial in designing a better drug for bile duct cancer. “Relay Therapeutics has a cutting-edge approach for molecular dynamics that I don’t believe any other companies have, at least not as advanced.” Relay’s unique hardware and software allow simulations that could never be achieved through traditional experiments, Elemento says.
How it works
Relay used both experimental and computational approaches to design RLY-4008. The team started out by taking X-rays of crystallized versions of both their intended target, FGFR2, and the almost identical FGFR1. This enabled them to get a 3D snapshot of each of their structures. They then fed the X-rays into the Anton supercomputer to simulate how the proteins were likely to move.
Anton’s simulations showed that the FGFR1 protein had a flap that moved more frequently than FGFR2. Based on this distinct motion, the team tried to design a compound that would recognize this flap shifting around and bind to FGFR2 while steering away from its more active lookalike.
For that, they went back Anton, using the supercomputer to simulate the behavior of thousands of potential molecules for over a year, looking at what made a particular molecule selective to the target versus another molecule that wasn’t. These insights led them to determine the best compounds to make and test in the lab and, ultimately, they found that RLY-4008 was the most effective.
Promising results so far
Relay began phase 1-2 trials in 2020 and will continue until 2024. Preliminary results showed that, in the 17 patients taking a 70 mg dose of RLY-4008, the drug worked to shrink tumors in 88 percent of patients. This was a significant increase compared to other FGFR inhibitors. For instance, Futibatinib, which recently got FDA approval, had a response rate of only 42 percent.
Across all dose levels, RLY-4008 shrank tumors by 63 percent in 38 patients. In more good news, the drug didn’t elevate their phosphate levels, which suggests that it could be taken without increasing patients’ risk for kidney disease.
“Objectively, this is pretty remarkable,” says Elemento. “In a small patient study, you have a molecule that is able to shrink tumors in such a high fraction of patients. It is unusual to see such good results in a phase 1-2 trial.”
A simulated future
The research team is continuing to use molecular dynamic simulations to develop other new drug, such as one that is being studied in patients with solid tumors and breast cancer.
As for their bile duct cancer drug, RLY-4008, Relay plans by 2024 to have tested it in around 440 patients. “The mature results of the phase 1-2 trial are highly anticipated,” says Goyal, the principal investigator of the trial.
Sameek Roychowdhury, an oncologist and associate professor of internal medicine at Ohio State University, highlights the need for caution. “This has early signs of benefit, but we will look forward to seeing longer term results for benefit and side effect profiles. We need to think a few more steps ahead - these treatments are like the ’Whack-a-Mole game’ where cancer finds a way to become resistant to each subsequent drug.”
“I think the issue is going to be how durable are the responses to the drug and what are the mechanisms of resistance,” says Raymond Wadlow, an oncologist at the Inova Medical Group who specializes in gastrointestinal and haematological cancer. “But the results look promising. It is a much more selective inhibitor of the FGFR protein and less toxic. It’s been an exciting development.”