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.”
With this new technology, hospitals and pharmacies could make vaccines and medicines onsite
Most modern biopharmaceutical medicines are produced by workhorse cells—typically bacterial but sometimes mammalian. The cells receive the synthesizing instructions on a snippet of a genetic code, which they incorporate into their DNA. The cellular machinery—ribosomes, RNAs, polymerases, and other compounds—read and use these instructions to build the medicinal molecules, which are harvested and administered to patients.
Although a staple of modern pharma, this process is complex and expensive. One must first insert the DNA instructions into the cells, which they may or may not uptake. One then must grow the cells, keeping them alive and well, so that they produce the required therapeutics, which then must be isolated and purified. To make this at scale requires massive bioreactors and big factories from where the drugs are distributed—and may take a while to arrive where they’re needed. “The pandemic showed us that this method is slow and cumbersome,” says Govind Rao, professor of biochemical engineering who directs the Center for Advanced Sensor Technology at the University of Maryland, Baltimore County (UMBC). “We need better methods that can work faster and can work locally where an outbreak is happening.”
Rao and his team of collaborators, which spans multiple research institutions, believe they have a better approach that may change medicine-making worldwide. They suggest forgoing the concept of using living cells as medicine-producers. Instead, they propose breaking the cells and using the remaining cellular gears for assembling the therapeutic compounds. Instead of inserting the DNA into living cells, the team burst them open, and removed their DNA altogether. Yet, the residual molecular machinery of ribosomes, polymerases and other cogwheels still functioned the way it would in a cell. “Now if you drop your DNA drug-making instructions into that soup, this machinery starts making what you need,” Rao explains. “And because you're no longer worrying about living cells, it becomes much simpler and more efficient.” The collaborators detail their cell-free protein synthesis or CFPS method in their recent paper published in preprint BioAxiv.
While CFPS does not use living cells, it still needs the basic building blocks to assemble proteins from—such as amino acids, nucleotides and certain types of enzymes. These are regularly added into this “soup” to keep the molecular factory chugging. “We just mix everything in as a batch and we let it integrate,” says James Robert Swartz, professor of chemical engineering and bioengineering at Stanford University and co-author of the paper. “And we make sure that we provide enough oxygen.” Rao likens the process to making milk from milk powder.
For a variety of reasons—from the field’s general inertia to regulatory approval hurdles—the method hasn’t become mainstream. The pandemic rekindled interest in medicines that can be made quickly and easily, so it drew more attention to the technology.
The idea of a cell-free protein synthesis is older than one might think. Swartz first experimented with it around 1997, when he was a chemical engineer at Genentech. While working on engineering bacteria to make pharmaceuticals, he discovered that there was a limit to what E. coli cells, the workhorse darling of pharma, could do. For example, it couldn’t grow and properly fold some complex proteins. “We tried many genetic engineering approaches, many fermentation, development, and environmental control approaches,” Swartz recalls—to no avail.
“The organism had its own agenda,” he quips. “And because everything was happening within the organism, we just couldn't really change those conditions very easily. Some of them we couldn’t change at all—we didn’t have control.”
It was out of frustration with the defiant bacteria that a new idea took hold. Could the cells be opened instead, so that the protein-forming reactions could be influenced more easily? “Obviously, we’d lose the ability for them to reproduce,” Swartz says. But that also meant that they no longer needed to keep the cells alive and could focus on making the specific reactions happen. “We could take the catalysts, the enzymes, and the more complex catalysts and activate them, make them work together, much as they would in a living cell, but the way we wanted.”
In 1998, Swartz joined Stanford, and began perfecting the biochemistry of the cell-free method, identifying the reactions he wanted to foster and stopping those he didn’t want. He managed to make the idea work, but for a variety of reasons—from the field’s general inertia to regulatory approval hurdles—the method hasn’t become mainstream. The pandemic rekindled interest in medicines that can be made quickly and easily, so it drew more attention to the technology. For their BioArxiv paper, the team tested the method by growing a specific antiviral protein called griffithsin.
First identified by Barry O’Keefe at National Cancer Institute over a decade ago, griffithsin is an antiviral known to interfere with many viruses’ ability to enter cells—including HIV, SARS, SARS-CoV-2, MERS and others. Originally isolated from the red algae Griffithsia, it works differently from antibodies and antibody cocktails.
Most antiviral medicines tend to target the specific receptors that viruses use to gain entry to the cells they infect. For example, SARS-CoV-2 uses the infamous spike protein to latch onto the ACE2 receptor of mammalian cells. The antibodies or other antiviral molecules stick to the spike protein, shutting off its ability to cling onto the ACE2 receptors. Unfortunately, the spike proteins mutate very often, so the medicines lose their potency. On the contrary, griffithsin has the ability to cling to the different parts of viral shells called capsids—namely to the molecules of mannose, a type of sugar. That extra stuff, glued all around the capsid like dead weight, makes it impossible for the virus to squeeze into the cell.
“Every time we have a vaccine or an antibody against a specific SARS-CoV-2 strain, that strain then mutates and so you lose efficacy,” Rao explains. “But griffithsin molecules glom onto the viral capsid, so the capsid essentially becomes a sticky mess and can’t enter the cell.” Mannose molecules also don’t mutate as easily as viruses’ receptors, so griffithsin-based antivirals do not have to be constantly updated. And because mannose molecules are found on many viruses’ capsids, it makes griffithsin “a universal neutralizer,” Rao explains.
“When griffithsin was discovered, we recognized that it held a lot of promise as a potential antiviral agent,” O’Keefe says. In 2010, he published a paper about griffithsin efficacy in neutralizing viruses of the corona family—after the first SARS outbreak in the early 2000s, the scientific community was interested in such antivirals. Yet, griffithsin is still not available as an off-the-shelf product. So during the Covid pandemic, the team experimented with synthesizing griffithsin using the cell-free production method. They were able to generate potent griffithsin in less than 24 hours without having to grow living cells.
The antiviral protein isn't the only type of medicine that can be made cell-free. The proteins needed for vaccine production could also be made the same way. “Such portable, on-demand drug manufacturing platforms can produce antiviral proteins within hours, making them ideal for combating future pandemics,” Rao says. “We would be able to stop the pandemic before it spreads.”
Top: Describes the process used in the study. Bottom: Describes how the new medicines and vaccines could be made at the site of a future viral outbreak.
Image courtesy of Rao and team, sourced from An approach to rapid distributed manufacturing of broad spectrumanti-viral griffithsin using cell-free systems to mitigate pandemics.
Rao’s idea is to perfect the technology to the point that any hospital or pharmacy can load up the media containing molecular factories, mix up the required amino acids, nucleotides and enzymes, and harvest the meds within hours. That will allow making medicines onsite and on demand. “That would be a self-contained production unit, so that you could just ship the production wherever the pandemic is breaking out,” says Swartz.
These units and the meds they produce, will, of course, have to undergo rigorous testing. “The biggest hurdles will be validating these against conventional technology,” Rao says. The biotech industry is risk-averse and prefers the familiar methods. But if this approach works, it may go beyond emergency situations and revolutionize the medicine-making paradigm even outside hospitals and pharmacies. Rao hopes that someday the method might become so mainstream that people may be able to buy and operate such reactors at home. “You can imagine a diabetic patient making insulin that way, or some other drugs,” Rao says. It would work not unlike making baby formula from the mere white powder. Just add water—and some oxygen, too.
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.
These doctors have a heart for recycling
This is part 3 of a three part series on a new generation of doctors leading the charge to make the health care industry more sustainable - for the benefit of their patients and the planet. Read part 1 here and part 2 here.
One could say that over 400 people owe their life to the fact that Carsten Israel fell in love. Twenty years ago, as a young doctor in Frankfurt, Germany, he began to court an au pair from Kenya, Elisabeth, his now-wife of 13 years with whom he has three children. When the couple started visiting her parents in Kenya, Israel wanted to check out the local hospitals, “just out of professional curiosity,“ says the cardiologist, who is currently the head doctor at the Clinic for Interior Medicine in Bielefeld. “I was completely shocked.“
Often he observed there were no doctors in the E.R.s, and hte nurses could render only basic first aid. “When somebody fell into a coma, they fell into a coma,“ Israel remembers. “There weren’t even any defibrillators to restart a patient’s heart,” while defibrillators are standard equipment in most clinics in the U.S. and Europe as lifesaving devices. When Israel finally visited the largest and most modern hospital in Nairobi, he found it better equipped but he learned that its services were only available to patients who could afford them. The cardiologist there had a drawer full of petitions from patients with heart ailments who couldn’t afford lifesaving surgery. Even two decades ago, a pacemaker cost $5,000 in Kenya, which made it unaffordable for most Kenyans who earn an average of $600 per month.
Since 2003, Israel and a team of two doctors and two nurses visit Kenya and Zambia once or twice a year to implant German pacemakers for free. Notably, the pacemakers and defibrillators Israel exports to Africa would end up in the landfill in Germany. Clinics have to pay for specialized services to dispose of this medical equipment. “In Germany, I could go to jail if I used a defibrillator that is one day past its expiration date,“ Israel says, “but in Kenya, people don’t have the money for the cheapest model. What nonsense to throw this precious medical equipment away while people in poorer countries die because they desperately need it.“
Israel works at the breakpoint between the laws in a wealthy country like Germany and the reality in the global South. The U.S. and most European countries have strict laws that ban the reuse of medical implants and enforce strict expiration dates for medical equipment. “But if a pacemaker is a few days past its expiration date, it still works perfectly fine,“ Israel says. “And it also happens that we implant a pacemaker and five months later it turns out that the patient needs a different kind. Then we replace it and we’d have to trash the first one in Germany, though it could easily run another 12 years.“
“If we get this right, we have lots of devices we can implant, hips and knees, etcetera. Where this will lead is limitless," says Eva Kline Rogers, the program coordinator for My Heart, Your Heart.
Israel has been collecting donations of pacemakers and defibrillators from manufacturers but also from other doctors and from funeral homes for his nonprofit Pacemakers for East Africa since 2003. Most funeral homes in the U.S. and Europe are legally obliged to remove pacemakers from the dead before cremation. “Most pacemakers survive their owners,“ says Israel. He sterilizes the pacemakers and finds them a new life in East Africa. Studies show that reused pacemakers carry no greater risk for the patients than new ones.
In the U.S., University of Michigan professor Thomas Crawford heads up a similar initiative, My Heart, Your Heart. “Each year 1 to 2 million individuals worldwide die due to a lack of access to pacemakers and defibrillators,” the organization notes on its website. The nonprofit was founded in 2009, but it took four years for the doctors to get permission from the FDA to export pacemakers. Since receiving permission, the organization has sent dozens of devices to the Philippines, Haiti, Venezuela, Kenya, Sierra Leone and Ukraine. “We were the first doctors ever to implant a pacemaker in Sierra Leone in 2018,” says Crawford, who has traveled extensively to most of the recipient countries.
Even individuals can donate their pacemakers; the organization offers a prepaid envelope. “My mother recently passed and she donated her device,” says Tina Alexandris-Souphis, one of the doctors at University of Michigan who collaborates on My Heart, Your Heart. The organization works with World Medical Relief and the U.K. based charity Pace4Life to maintain a registry of the most urgent patients and send devices to where they are needed the most.
My Heart, Your Heart is also conducting a randomized controlled trial to provide further evidence that reused pacemakers pose no additional risk. “Our vision is that we establish this is safe and create a blueprint for organizations around the world to safely reuse these devices instead of them being thrown in the trash,” says Eva Kline Rogers, the program’s coordinator. “If we get this right, we have lots of devices we can implant, hips and knees, etc. Where this will lead is limitless.” She points out that in addition to receiving the donated devices, the doctors in the global South also benefit from the expertise of renowned cardiologists, such as Crawford, who sometimes advise them in complex cases.
And Adrian Baranchuk, a Canadian doctor at the Kingston General Hospital at the Queen’s University, regularly travels through South America with his “cardiology van” to help villagers in remote areas with heart problems.
Israel says that he’s been accused of racism, in thinking that these pacemakers are suitable for those in the global South - many of whom are people of color - even though officials in wealthier countries consider them to be trash. The cardiologist counters such criticism with stories about desperate need of his patients. At his first medical visit to Nairobi that he organized with a local cardiologist, six patients were waiting for him. “In Germany, they would all be considered emergencies,” Israel says. One eighty-year old grandmother had a heartrate of 18. “I’ve never before seen anything like this,” Israel exclaims. “At first I thought I couldn’t find her pulse before I realized that her heart was only beating once every three seconds.” After the surgery, she got up, dressed herself and hurriedly packed her bag, explaining she had a ton of work to accomplish. Her family was in disbelief, Israel says. “They told me she had been bedridden for five years because as soon as she tried to get up she would faint.”
Israel has been accused of racism, in thinking that these pacemakers are suitable for those in the global South even though they're considered to be trash by officials in wealthier countries. The cardiologist counters such criticism with stories about desperate need of his patients.
Carsten Israel
The hospital in Nairobi where Israel conducts the surgeries, charges patients $200 for the use of its facilities. If patients can’t afford that sum, Israel will pay it from the funds of his nonprofit. For some people, $200 far exceeds their resources. Once, a family from the extremely poor Northern region of Kenya told him they couldn’t afford the $3 for the bus ride to Nairobi. Israel suspected this was a pretense because they were afraid of the surgery and agreed to reimburse the $3, “but when they came, they were wearing rags and were so rail-thin, I understood that they really needed every cent they had for food.”
Israel is a renowned cardiologists in Germany. And yet, he considers his work in East Africa to be particularly meaningful. “Generally, most patients in Germany will get the treatment they need,” he says, “and I never before experienced that people have an illness that is easily curable but simply won’t be treated.” He also feels a heavy responsibility. Many patients have his personal cell phone and call him when they have problems or good news about how they’re doing.
Some of those progress reports come much faster than in Israel’s home country. Before he implanted a pacemaker in a tall Massai in Kenya, the man had been picked on by his family because he wouldn’t help much with the hard work on the family peanut farm. “When I examined him, he had a pulse of 40,” Israel says. “It’s a miracle he was even standing upright, let alone hauling heavy bags.” After the surgery, Israel advised his patient to stay the night for observation, but the patient couldn’t wait to leave. Two hours later, he returned, covered in sweat. He’d been running sprints with his brothers to test the new device. Israel shakes his head. In Germany, it would be unthinkable for a patient to engage in athletics immediately after surgery. But the patient was exuberant: “I was the fastest!”
The success stories are notable partly because the challenges remain so steep. In Zambia, for instance, there is a single cardiologist; she determined to become one after losing her younger sister to an easily curable heart disease. Often, the hospitals not only lack pacemakers but also sterile surgery equipment, antibiotics and other essential material. Therefore, Israel and his team import everything they need for the surgeries, including medication. If necessary, they improvise. “I’ve done surgery with a desk lamp hanging from the ceiling by threads,” Israel says. He already knows that he will need to return to Kenya in six months to replace the pacemaker of one of his patients and replace the batteries in others. If he doesn’t travel, lives are at risk.