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.”
This spring, just like any other year, thousands of young North American engineers will graduate from their respective colleges ready to start erecting buildings, assembling machinery, and programming software, among other things. But before they take on these complex and important tasks, many of them will recite a special vow stating their ethical obligations to society, not unlike the physicians who take their Hippocratic Oath, affirming their ethos toward the patients they would treat. At the end of the ceremony, the engineers receive an iron ring, as a reminder of their promise to the millions of people their work will serve.
The ceremony isn’t just another graduation formality. As a profession, engineering has ethical weight. Moreover, engineering mistakes can be even more deadly than medical ones. A doctor’s error may cost a patient their life. But an engineering blunder may bring down a plane or crumble a building, resulting in many more fatalities. When larger projects—such as fracking, deep-sea mining or building nuclear reactors—malfunction and backfire, they can cause global disasters, afflicting millions. A vow that reminds an engineer that their work directly affects humankind and their planet is no less important than a medical oath that summons one to do no harm.
The tradition of taking an engineering oath began over a century ago in Canada. In 1922, Herbert E.T. Haultain, professor of mining engineering at the University of Toronto, presented the idea at the annual meeting of the Engineering Institute of Canada. The seven past presidents of that body were in attendance, heard Haultain’s speech and accepted his suggestion to form a committee to create an honor oath. Later, they formed the nonprofit Corporation of the Seven Wardens, which would oversee the ritual. Next year, in 1923, with the encouragement of the Seven Wardens, Haultain wrote to poet and writer Rudyard Kipling, asking him to develop a professional oath for engineers. “We are a tribe—a very important tribe within the community,” Haultain said in the letter, “but we are lacking in tribal spirit, or perhaps I should say, in manifestation of tribal spirit. Also, we are inarticulate. Can you help us?”
While Kipling is most famous now for “The Jungle Book” and perhaps his poem “Gunga Din,” he had also written a short story about engineers, “The Bridge Builders.” His poem “The Sons of Martha” can be read as a celebration of engineers:
It is their care in all the ages to take the buffet and cushion the shock.
It is their care that the gear engages; it is their care that the switches lock.
It is their care that the wheels run truly; it is their care to embark and entrain,
Tally, transport, and deliver duly the Sons of Mary by land and main.
Kipling accepted the ask and wrote the Ritual of the Calling of an Engineer, which he sent to Haultain a month later. In his response to Haultain, he stated that he preferred the word “Obligation” to “Oath.” He wrote the Obligation using Old English lettering and the old-fashioned capitalization. Kipling’s Obligation binds engineers upon their “Honor and Cold Iron” to not “suffer or pass, or be privy to the passing of, Bad Workmanship or Faulty Material,” and pardon is asked “in the presence of my betters and my equals in my Calling” for the engineer’s “assured failures and derelictions.” The hope is that when one is tempted to shoddy work by weakness or weariness, the memory of the Obligation “and the company before whom it was entered into, may return to me to aid, comfort, and restrain.”
Using the Obligation, The Seven Wardens created an induction ceremony, which seeks to unify the profession and recognize engineering’s ethics, including responsibility to the public and the need to make the best decisions possible. The induction ceremony included recitation of Kipling’s “Obligation” and incorporated an anvil, a hammer, an iron chain, and an iron ring. The inductee engineers sat inside an area marked off by the iron chain, with their more senior colleagues outside that area. At the start of the ritual, the leader beat out S-S-T in Morse code with the hammer and anvil—the letters standing for Steel, Stone, and Time. A more experienced and previously obligated engineer placed the ring on the small finger of the inductee engineer’s working hand. As per Kipling, the ring’s rough, faceted texture symbolized “the young engineer’s mind” and the difficulties engineers face in mastering their discipline.
A persistent myth purports that the original iron rings were made from the beams or bolts of the Quebec Bridge that failed twice during construction.
The first induction ceremony took place on April 25, 1925, in Montreal to obligate two of the Seven Wardens, along with four graduates from the University of Toronto class of 1893. On May 1 of that year, 14 more engineers were obligated at the University of Toronto. From that time to today most Canadian professional engineers have gone through that same ritual in their various camps, called Kipling camps—local chapters associated with various Canadian universities.
Henry Petroski, Duke University’s professor of civil engineering and history, notes in his book, “Forgive Design: Understanding Failure,” that Kipling’s poem “Sons of Martha” is often read as part of the ritual. However, sometimes inductees read Kipling’s “Hymn of Breaking Strain,” instead, which graphically depicts disastrous outcomes of engineering mistakes. The first stanza of that poem says:
The careful text-books measure
(Let all who build beware!)
The load, the shock, the pressure
Material can bear.
So, when the buckled girder
Lets down the grinding span,
'The blame of loss, or murder,
Is laid upon the man.
Not on the Stuff—the Man!
As if to strengthen the importance of these concepts, a persistent myth purports that the original iron rings were made from the beams or bolts of the Quebec Bridge that failed twice during construction. The bridge spans the St. Lawrence River upriver from Quebec City, and at the time of its construction was the world’s longest at 1,800 feet. Due to engineering errors and poor oversight, the bridge’s own weight exceeded its carrying capacity. Moreover, engineers downplayed danger when bridge beams began to warp under stress, saying that they were probably warped before they were installed. On August 29, 1907, the bridge collapsed, killing 75 of 86 workers. A second collapse occurred in 1916 when lifting equipment failed, and thirteen more workers died.
The ring myth, however, couldn’t be true. The original iron rings couldn’t have come from the failed bridge since it was made of steel, not wrought iron. Today the rings are made from stainless steel because iron deteriorates and stains engineers’ finger black.
On August 14, 2018, Morandi Bridge over Polcevera River in Genoa, Italy, collapsed from structural failure, killing 43 people.
Adobe Stock
The Seven Wardens decided to restrict the ritual to engineers trained in Canada. They copyrighted the obligation oath in Canada and the United States in 1935. Although the ritual is not a requirement for professional licensing, just like the Hippocratic Oath is not part of medical licensing, it remains a long-standing tradition.
The American Obligation of the Engineer has its own creation story, albeit a very different one. The American Order of the Engineer (OOE) was initiated in 1970, during the era of the anti-war protests, Apollo missions and the first Earth Day. On May 4, 1970, the National Guard shot into a crowd of protesters at Kent State University, killing four people. The two authors of the American obligation—Cleveland State University’s (CSU) engineering professor John Janssen and his wife Susan—reflected these historical events in the oath they wrote. Their version of the oath binds engineers to “practice integrity and fair dealing.” It also notes that their “skill carries with it the obligation to serve humanity by making the best use of the Earth’s precious wealth.” As Petroski explains in his book, “campus antiwar protestors around the country tended to view engineers as complicit in weapons proliferation [which] prompted some [CSU] engineering student leaders to look for a means of asserting some more positive values.”
Kip A. Wedel, associate professor of history and politics at Bethel College, wrote in his book, “The Obligation: A History of the Order of the Engineer,” that the ceremony was not a direct response to the Kent State shootings—it was already scheduled when the shootings happened. Yet, engineering students found the ceremony a positive action they could take in contrast to the overall turmoil. The first American ritual took place on June 4, 1970, at CSU. In total, 170 students, faculty members, and practicing engineers took the obligation. This established CSU as the first Link of the Order, as the OOE designates its local chapters. For their first ceremony, the CSU students fabricated smooth, unfaceted rings from stainless steel pipe. Later they were replaced by factory-made rings. According to Paula Ostaff, OOE’s Executive Director, about 20,000 eligible students and alumni obligate themselves yearly.
Societies hope that every engineer is imbued with a strong ethical sense and that their pledges are never far from mind. For some, the rings they wear serve a daily reminder that every paper they sign off on is touched by a physical reminder of their commitment.
These ethical and responsible engineering practices are especially salient today, when one in three American bridges needs repair or replacement, some have already collapsed, and engineers are working on projects related to the bipartisan infrastructure bill President Biden signed into law in 2021. Canada has committed $33 billion to its Investing in Canada Infrastructure Program. At the heart of these grand projects are many thousands of professional engineers, collectively working millions of hours. The professional vows they took aim to assure that the homes, bridges and airplanes they build will work as expected.
In the 1966 movie "Fantastic Voyage," actress Raquel Welch and her submarine were shrunk to the size of a cell in order to eliminate a blood clot in a scientist's brain. Now, 55 years later, the scenario is becoming closer to reality.
California-based startup Bionaut Labs has developed a nanobot about the size of a grain of rice that's designed to transport medication to the exact location in the body where it's needed. If you think about it, the conventional way to deliver medicine makes little sense: A painkiller affects the entire body instead of just the arm that's hurting, and chemotherapy is flushed through all the veins instead of precisely targeting the tumor.
"Chemotherapy is delivered systemically," Bionaut-founder and CEO Michael Shpigelmacher says. "Often only a small percentage arrives at the location where it is actually needed."
But what if it was possible to send a tiny robot through the body to attack a tumor or deliver a drug at exactly the right location?
Several startups and academic institutes worldwide are working to develop such a solution but Bionaut Labs seems the furthest along in advancing its invention. "You can think of the Bionaut as a tiny screw that moves through the veins as if steered by an invisible screwdriver until it arrives at the tumor," Shpigelmacher explains. Via Zoom, he shares the screen of an X-ray machine in his Culver City lab to demonstrate how the half-transparent, yellowish device winds its way along the spine in the body. The nanobot contains a tiny but powerful magnet. The "invisible screwdriver" is an external magnetic field that rotates that magnet inside the device and gets it to move and change directions.
The current model has a diameter of less than a millimeter. Shpigelmacher's engineers could build the miniature vehicle even smaller but the current size has the advantage of being big enough to see with bare eyes. It can also deliver more medicine than a tinier version. In the Zoom demonstration, the micorobot is injected into the spine, not unlike an epidural, and pulled along the spine through an outside magnet until the Bionaut reaches the brainstem. Depending which organ it needs to reach, it could be inserted elsewhere, for instance through a catheter.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu.
Imagine moving a screw through a steak with a magnet — that's essentially how the device works. But of course, the Bionaut is considerably different from an ordinary screw: "At the right location, we give a magnetic signal, and it unloads its medicine package," Shpigelmacher says.
To start, Bionaut Labs wants to use its device to treat Parkinson's disease and brain stem gliomas, a type of cancer that largely affects children and teenagers. About 300 to 400 young people a year are diagnosed with this type of tumor. Radiation and brain surgery risk damaging sensitive brain tissue, and chemotherapy often doesn't work. Most children with these tumors live less than 18 months. A nanobot delivering targeted chemotherapy could be a gamechanger. "These patients really don't have any other hope," Shpigelmacher says.
Of course, the main challenge of the developing such a device is guaranteeing that it's safe. Because tissue is so sensitive, any mistake could risk disastrous results. In recent years, Bionaut has tested its technology in dozens of healthy sheep and pigs with no major adverse effects. Sheep make a good stand-in for humans because their brains and spines are similar to ours.
The Bionaut device is about the size of a grain of rice.
Bionaut Labs
"As the Bionaut moves through brain tissue, it creates a transient track that heals within a few weeks," Shpigelmacher says. The company is hoping to be the first to test a nanobot in humans. In December 2022, it announced that a recent round of funding drew $43.2 million, for a total of 63.2 million, enabling more research and, if all goes smoothly, human clinical trials by early next year.
Once the technique has been perfected, further applications could include addressing other kinds of brain disorders that are considered incurable now, such as Alzheimer's or Huntington's disease. "Microrobots could serve as a bridgehead, opening the gateway to the brain and facilitating precise access of deep brain structure – either to deliver medication, take cell samples or stimulate specific brain regions," Shpigelmacher says.
Robot-assisted hybrid surgery with artificial intelligence is already used in state-of-the-art surgery centers, and many medical experts believe that nanorobotics will be the instrument of the future. In 2016, three scientists were awarded the Nobel Prize in Chemistry for their development of "the world's smallest machines," nano "elevators" and minuscule motors. Since then, the scientific experiments have progressed to the point where applicable devices are moving closer to actually being implemented.
Bionaut's technology was initially developed by a research team lead by Peer Fischer, head of the independent Micro Nano and Molecular Systems Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany. Fischer is considered a pioneer in the research of nano systems, which he began at Harvard University more than a decade ago. He and his team are advising Bionaut Labs and have licensed their technology to the company.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu, who leads the cooperation with Bionaut Labs. He agrees with Shpigelmacher that the Bionaut's size is perfect for transporting medication loads and is researching potential applications for even smaller nanorobots, especially in the eye, where the tissue is extremely sensitive. "Nanorobots can sneak through very fine tissue without causing damage."
In "Fantastic Voyage," Raquel Welch's adventures inside the body of a dissident scientist let her swim through his veins into his brain, but her shrunken miniature submarine is attacked by antibodies; she has to flee through the nerves into the scientist's eye where she escapes into freedom on a tear drop. In reality, the exit in the lab is much more mundane. The Bionaut simply leaves the body through the same port where it entered. But apart from the dramatization, the "Fantastic Voyage" was almost prophetic, or, as Shpigelmacher says, "Science fiction becomes science reality."
This article was first published by Leaps.org on April 12, 2021.