The vaccine that bites back!

It was nature that brought Marconi to the threshold of that breakthrough a decade ago, even if it took something unnatural to get him across it.

It’s a thread he follows back to his childhood years angling with stick-tied fishing line in a lake in Brooklyn’s Prospect Park; to preteen and teenage years at a lakefront home in Denville, New Jersey, unearthing creatures from muddy depths and the woods beyond (“paradise,” he says); to being lured by mountains to Missoula, Montana, for graduate school after college in his home state. 

a“I still turn over rocks in my yard to see what kind of insects are underneath them and feed the birds and try to catch snakes when I can.”

That interest in biology increasingly drew toward the microscopic as Marconi wended through doctoral and postdoc programs, from studying the ways bacteria produce proteins — workhorses that transport substances, provide structure, spur chemical reactions and shield against infection, among other things — to the synthesis of the amino acids that comprise them. It was an intense focus on understanding how bacteria work and, in turn, the ways those processes might be exploited.

Marconi, 65, was in a postdoc fellowship in New Jersey in the late 1980s when he read a magazine article about this bacteria-caused “mysterious illness spreading across the U.S.,” he says. It was the first time he’d heard of Lyme disease, and his interest grabbed hold. He decided to return to Montana for a second postdoc stint, this time in Hamilton, an hour south of Missoula, at the National Institutes of Health’s Rocky Mountain Laboratories. 

“The choice was really pretty simple,” he says. There he’d have an opportunity to get elbow deep in the pathogenic particulars of Lyme and other tick-borne diseases, surrounded by some of the people who had helped illuminate them; people like medical entomologist Willy Burgdorfer, Ph.D., the person for whom the Lyme-causing bacteria would be named.

That momentum had blown into Montana several years after two mothers raised alarms in 1975 about an arthritic illness affecting dozens of children in and around the southern Connecticut town called Lyme, from which the disease takes its name. Allen C. Steere, M.D., and other researchers at Yale University, 40 miles away, characterized the burgeoning illness and eventually suggested it might be tick-related. In 1981, Burgdorfer and others found and identified a spiral-shaped pathogen in the gut of a prominent East Coast tick species, leading Yale researchers to determine it was the cause of the illness.

At the NIH lab from 1990-1994, Marconi studied the variability of that bacteria, Borreliella burgdorferi, before joining the VCU faculty. 

“I thought I was a pretty hotshot young investigator, working on Lyme disease,” he says. “But when I arrived here in Richmond, Virginia, at that time the overwhelming majority of infectious disease doctors here did not believe it was a real disease. … That’s the way Lyme disease has been: It was understood and recognized in certain pockets of the Northeast — clinicians were seeing it, they were understanding it — but people outside of that area said, ‘Well, that’s over there; that’s not affecting me.’”

Scientists now know that B. burgdorferi is the primary cause of Lyme in North America (while related bacteria cause the disease in Europe and Asia). They know that it’s carried by two species of black-legged ticks: Ixodes scapularis, also called deer ticks, which cause the disease across much of the nation’s affected areas; and lxodes pacificus, or the Western black-legged tick. And scientists know that a black-legged tick generally needs to be attached to a human for at least 24 hours for the bacteria to migrate.

The hallmarks of Lyme are also now well-established. But catching the disease early, when it’s easiest to treat with common antibiotics (like doxycycline or amoxicillin), can still be difficult. 

Classically, Lyme shows up as a rash at the bite site. As the bacteria continues to spread, it commonly brings flu-like symptoms but also potentially more serious issues like meningitis, inflammation around the brain and spinal cord; Bell’s palsy, a drooping of facial muscles; and heart- tissue inflammation or problems with the heart’s electrical signaling. If left untreated for several months, arthritis and joint swelling can form, particularly in the knees. For some people, these issues can become chronic, even after the infection is cleared.

Lyme’s telltale rash, however, can take up to a month to appear, and for as many as 30% of patients, it never materializes or goes unnoticed. And though the rash is often associated with a bull’s-eye appearance, it actually can take many shapes: an expanding red circle with a clearing in the middle, or with no clearing, or with a scab in the center, or with faint borders or an ovular shape or even appearing as a cluster of rashes. It might be harder to spot on darker skin tones, too. 

Other symptoms of early-stage Lyme are so garden-variety — fever, headache, fatigue — that one scientific journal article noted they likely overlap with hundreds of conditions. Even a blood test early on might not help. Those are designed to detect antibodies, a sign that the body is fighting the infection, which can take time to amass.

On top of all that, many people don’t even realize they’ve been bitten. It’s a sleight of mouth performed by what’s essentially a tiny, eight-legged, bloodsucking shadow.

“Let’s face it, they are beautiful creatures. I love them, but I might be the only one on this planet,” says Lorenza Beati, M.D., Ph.D., curator of the Smithsonian’s U.S. National Tick Collection, housed at Georgia Southern University. 

Black-legged ticks (two of the more than 900 species fanned out across all continents) have a two- to three-year lifespan. They begin as the size of a grain of sand and end only as big as a sesame seed. Much of their lives is spent in forest leaf litter or atop a tall blade of grass or shrubbery waiting with open arms for a blood donor. It’s a process scientists have romantically dubbed “questing.” 

That happens just three times in a black-legged tick’s life, once at each developmental stage, but each of those meals is a marathon gorging that can last several days. At the larval and nymph stages, they prefer small animals, including mice and other rodents from which the ticks pick up the Lyme-causing bacteria. Adult female ticks (the males die after mating) then look for larger mammals, like deer. Humans and our pets work just as well. 

For a tick to get noticed and plucked mid-meal would be to risk probable death, Beati says. So they often seek the hairy, enfolded or otherwise hidden retreats on our bodies. 

Earlier in her career, Beati spent four years collecting ticks in Connecticut and took all the precautions: shirt tucked into pants, pants tucked into knee-high boots, repellent sprayed along the openings of her clothes. She was bitten just twice in those years, both times in the one spot she hadn’t fortified — under her watch.

Once a tick finds a spot like that, it has all it needs for success: The bite supplies a blood thinner to prevent clotting, an antihistamine to prevent an itch response, anaesthetic to numb the area and an immunosuppressant to keep the operation hassle-free. 

“Imagine these tiny little creatures — [their] body is a bag, their brain is a little ganglion in the middle — producing all these pharmacological compounds, super-complicated ones, and injecting everything into their bite,” Beati says. “It’s probably one of the best pathogen-injecting machines you can imagine.”

There was, briefly, a human vaccine for Lyme on the market. And at that time, Marconi says, “we thought this was going to solve the problem.”

That was nearly 30 years ago. 

The U.S. Food and Drug Administration approved the vaccine, called Lymerix, at the end of 1998. In an inoculatory twist, the shot didn’t kill B. burgdorferi in humans, it killed the bacteria while still inside a biting tick, as the tick consumed blood that now swarmed with antibodies. In clinical trials, a three-dose regimen over two years reduced symptomatic Lyme infection by 76%.

More than 1.4 million doses of Lymerix were distributed in its first year and a half. Regulators collected about 900 reports of adverse events, which are not necessarily caused by the vaccine but can help illuminate unexpected safety concerns. Anyone can file a report, and they ranged from joint stiffness and muscle pain — the most frequently reported — to arthritis, and several dozen deemed serious, including hospitalizations and deaths. Those largely were not considered unusual or unexpected compared to Lymerix’s clinical trials. But the complaints as well as lawsuits that were filed brought media attention and renewed scrutiny from federal regulators.

In 2001, an FDA advisory panel concluded the vaccine’s benefits still outweighed the risks, and it required that the drugmaker, GlaxoSmithKline, continue to collect safety data. Then, in 2002, projecting fewer than 10,000 people would seek the vaccine that year, GlaxoSmithKline voluntarily pulled it from the market. 

“As a result of that happening, Lyme disease vaccine research really slowed down for several years,” Marconi says. “Big Pharma had just basically said: This is too much trouble; this isn’t worth it to us.” 

At the time, Lyme wasn’t yet the household name it is today. But while science stalled, the ticks didn’t. The year Lymerix received FDA approval, a study reported that the Eastern black-legged tick had appeared in 952 U.S. counties, and the Western black-legged tick was found in 16. A follow-up census published nearly two decades later, in 2016, found the eastern species in hundreds of additional counties — 1,420 across 43 states, or nearly half of the counties in the contiguous U.S. The western species had stretched out almost sixfold, to 95 counties in six states. Over the same timespan, cases of Lyme reported to the CDC doubled.

“Any company that had decided to really continue and march forward on [a human vaccine] would’ve been in a perfect spot when the concerns faded away and the disease was exploding,” Marconi says. “So now everyone’s playing catch-up on it.”

Around 2008, a half-dozen years or so after Lymerix was pulled, Marconi’s scientific work was ready to be translated into a new type of a vaccine, but he found pharmaceutical companies still skittish of the investment — for humans. 

In veterinary medicine, he found a more willing audience. The first Lyme vaccine for dogs had become available nearly 20 years earlier, in 1990.

“Because dogs are more likely to be exposed to these organisms, and therefore more likely to become sick because of these organisms, veterinary medicine has been way ahead of human medicine in regard to the understanding of some of these tick-borne diseases,” says Edward Breitschwerdt, D.V.M., a professor of medicine and infectious diseases at North Carolina State University College of Veterinary Medicine, who has collaborated with Marconi. 

Plus, dogs happen to be a good analogue for human illnesses, he says. “When dogs develop disease it looks so much like the disease in humans, and that’s whether we talk about systemic lupus erythematosus” — the most common form of lupus in humans — “rheumatoid arthritis, Lyme disease. You name it.”

Marconi liked Lymerix’s unconventional approach — killing the bacteria before it even reaches humans — but it came with limitations. The vaccine worked by targeting a protein on the surface of B. burgdorferi, but it turns out the bacteria makes that protein only while inside a tick; it stops as the bacteria moves into a mammal. (Marconi compares this adaptation to the way we’d choose a sweater or a T-shirt based on the weather.) Any bacteria that managed to leave the tick would find the human undefended as the vaccine directed the immune system to look for a protein the bacteria is no longer making. 

For a vaccine like Lymerix to work, the body also would need to keep those defenses constantly at the ready, so it could be gulped by a tick at any given moment, rather than a more natural, reactionary ebb and flow of defenses. Likely, that would’ve meant more frequent shots, Marconi says.

That’s a transmission-blocking vaccine. Typically, vaccines operate more like instruction manuals for what to do once an invading pathogen is found. A shot introduces a weakened or dead virus or bacteria, or even just a piece of one, so the body can figure out what immunological proteins, called antibodies, it needs to manufacture to clear out that specific infection. Then, ideally, production of those antibodies tapers off and the immune system saves the blueprint for next time. 

Marconi’s canine vaccine directs the immune system to attack a protein found on the surface of B. burgdorferi that, unlike Lymerix’s target, is present when the bacteria is inside mammals. 

Once his lab started down that road, however, researchers realized that variants of the Lyme-causing bacteria can carry any of around 35 iterations of this surface protein. Guarding against one would hardly do the trick.

It called for an unnatural solution: a bespoke, lab-made Franken-protein that could protect against all variations. 

To do that, the team sequenced the DNA of all three dozen or so protein variations and isolated only the bits of genetic code that would spur the body to react and produce antibodies. Those slivers were combined — only about half were needed, it turns out, to reach critical mass, Marconi says — to create an entirely new piece of DNA. In turn, that creates a single protein containing the instructions the body needs to make antibodies for all the possible variations.

“It would take a team of a couple of individuals two or three months to make a single test vaccine protein,” Marconi says of the genetic tools available at the time, around 2008, a process now reduced to weeks. “Then we’d test it, and we’d say, ‘This one works OK but not good enough.’ So then we’d make another version of it.”

They did that at least 60 times for the canine vaccine. The trick wasn’t simply in which slivers of DNA to include, it was also the order in which those were assembled. “It took us years to move through that process.”

“It’s a really slick, very clever way to get around this dilemma” of a good target protein that has many variations, says Jon Skare, Ph.D., a professor and associate head of the microbial pathogenesis and immunology department at Texas A&M University’s College of Medicine and a longtime collaborator with Marconi. “He deserves a lot of credit for sticking it out. … It was an investment and a labor of love for him to do this.”

Marconi’s dog vaccine, Vanguard crLyme, includes both the lab-made protein and the natural protein originally targeted by Lymerix, offering two ways to stop the bacteria. 

Translating that work for human use was always on the horizon for him, and the effort to chip away at Lyme, regardless of affected species, continued to be of interest to government grant funders: Over the past two decades Marconi’s vaccine development work has garnered nearly $4.8 million in grants from the National Institutes of Health, plus $12.5 million across his career for the fundamental science that underpins the work.

With the concept well-established, Marconi’s lab created a version of the vaccine optimized for the pathogen strains that humans are most likely to encounter. It leans on two lab-designed proteins that take broader aim at stopping the disease both in the tick and, if needed, in the human. In October 2024, Marconi’s team published a paper finding that a three-dose regimen protected 80% of mice in the study, which increased to 90% for mice whose third dose had a higher amount of one of the lab-made proteins.

As of this spring, he awaits publication of the primate study with rhesus macaques, in which the vaccine gave them full protection from Lyme-causing ticks five months after inoculation, Marconi says. 

His hope is that the results will entice a pharmaceutical company that “wants to pick this up and run with it,” shepherding the vaccine through human trials and toward FDA approval and manufacture. It’s a side of the work that he’s less well-suited for. “Our goal is to develop [vaccine candidates] and then partner with others who can do it with much greater speed and have the legal and regulatory knowledge to get it through the process.”

Still, the path ahead feels uncertain. 

On one hand, there’s competition: Pfizer and Valneva jointly have a vaccine that’s already been tested in humans. The pharmaceutical companies announced this March that, in yet-unpublished findings, their vaccine reduced Lyme infections by just over 73%, as measured almost a month after the last of four doses, given over the course of two years. The vaccine hits the same protein target as Lymerix but is engineered to hunt variations of that target that are also found in Europe.

On the other hand, the mere topic of vaccines has become ever more politically and culturally volatile, if not toxic, in the U.S. in recent years. Marconi recently had two companies bow out of discussions about his human Lyme vaccine. They’re waiting, he supposes, for the winds to shift. 

He did that after the fall of Lymerix, but Marconi now has no intention of going back to the sidelines. “We’re not giving up, and we’re not going to slow down,” he says. “We’re going to keep moving forward on all aspects of this. Ultimately I think the tide will change.”

A couple times each week, Marconi’s phone or inbox will light up and on the other end is someone who aches with a hopefulness that teeters on desperation. Someone willing to lob Hail Marys at researchers when it seems physicians aren’t hearing them.

They reach out about the possibility of an undiagnosed tick-borne illness, and “the majority of the people I talk to truly are sick,” Marconi says. “If you’re ill and you need intervention to make you better, when no one can tell you what’s going on that just becomes consuming. I would say that a lot of the folks who call me are consumed by their situation, and I understand that. They’ve put a lot of time, most of them, into trying to research what’s actually happening.”

That can be a slippery slope. But more often, he says, these exchanges reveal gaps in clinical awareness about Lyme disease and other tick-borne illnesses. 

“The interesting thing is that most of the patients that will reach out to me will tell me, ‘Well, they actually never tested me for Lyme disease,’ which is sometimes shocking, because this person will specifically remember the tick bite, they specifically remember developing a rash, things like that,” he says. “Or you’ll have individuals who had exposure to a tick, they’ll get tested for Lyme disease, but they don’t get tested for the other tick-borne diseases.”

Marconi says his lab recently screened blood samples, obtained from a biobank, of hundreds of people who had gone to hospitals for treatment or testing for Lyme. Many were negative for Lyme — but more than 10% were positive for other tick-borne illnesses, diseases for which the person had never been tested. 

“I think those of us who work in the area of tick-borne diseases, we’re all well-aware that the world doesn’t just revolve around Lyme disease. There are other diseases,” Marconi says. “But it takes a while to make it from the scientific lab into the clinical setting.”

He’s hoping to nudge along that transition. Marconi is working on a more powerful diagnostic test for Lyme and for other, burgeoning tick-borne illnesses, with the idea that within two years they all could be combined into one, making it easier for physicians.

“Typically a diagnostic will test for antibodies to one protein,” he says, the usual signal that the immune system is ramping up to tackle a threat. “But the disease-causing agent makes lots of [proteins], so you’re missing the opportunity of increasing sensitivity by focusing just on one.” 
Using the same approach as with Marconi’s Lyme vaccine, patients’ blood could be screened for the presence of antibodies that react to a brand-new protein — or a slew of them — that’s made from the cobbled together genetic material of more than a dozen pathogen proteins.

For the moment, besides Lyme, he’s focusing on anaplasmosis and ehrlichiosis, both caused by bacteria, and babesiosis, which is caused by a parasite. Like Lyme, all three can cause flu-like symptoms early on (though babesiosis is often asymptomatic) and can become severe or even life-threatening if untreated. 

And he’s following his Lyme template to produce vaccines for these illnesses, too, with an eye eventually on a combined inoculation.

Cases of anaplasmosis, ehrlichiosis and babesiosis reported to the CDC are a fraction of the Lyme figures. But for Marconi there’s an urgency to them that reaches back to veterinary medicine, to the significance of understanding the health of the animals all around us. 

He points to data collected by the Companion Animal Parasite Council, which shows that Lyme, anaplasmosis and ehrlichiosis infections among dogs have ballooned in recent years. Anaplasmosis infections rose 815% between 2012 and 2025, climbing to more than 784,000; ehrlichiosis rose more than 500% in that time, to nearly 332,500; and Lyme rose more than 200% to more than 534,000. The organization estimates these figures probably represent just 30% of what’s happening in the country. 

The CDC’s counts for humans are minute by comparison but growing. Notably, the number of anaplasmosis cases grew to 7,280 in 2023, three times higher than it was a decade prior.

In wildlife, too, he says, the same issues are “rampant.” Tick-borne diseases are “far more prevalent in the animals that are walking through our yards and walking in the woods than anyone appreciates.” 

Last year, for instance, his lab analyzed blood samples from 61 eastern gray squirrels in Pennsylvania and found 62% had antibodies for B. burgdorferi and 17% for the pathogen that causes anaplasmosis, indicating a past or current infection. In a 2020 study of blood samples from 128 eastern coyotes collected in the same state, the lab found nearly 65% had antibodies for the Lyme bacteria and 73% for anaplasmosis. Just over 50% had both. 

Increasingly, he says of all sorts of wildlife species, “we’re moving into their domain, they’re moving into our domain — we’re intersecting.” 

It leads Marconi to view this work more broadly than developing a vaccine for dogs, or for humans, or against the wriggling machinations of one pathogen in the belly of a tick. It’s increasingly about the health of living things as a constant, not as our health and theirs, he says. “What goes on in nature is going to get us eventually, too.”