Lyme

by Mary Beth Pfeiffer

  Mosquitoes have far shorter lifespans than disease-toting ticks: about two weeks versus two years. Adelman’s technology could quickly dispatch mosquitoes, even if it involved several generations to take effect. Ticks, however, live mainly in a state of Rip van Winkle-like repose, waking only for three blood meals, one in each life stage, over the course of perhaps eight seasons. Applied to ticks, Adelman’s idea would take literally years to become established. But making male-only ticks could theoretically be done, Adelman told me. Except for one thing. Money. Unlike Zika, Lyme disease doesn’t have it, doesn’t get it, isn’t showered with it.

  Yet Lyme disease produces pain and sometimes profound disability, as with Zika, and likely on a bigger scale. As of April of 2017, Zika’s American count since the outbreak began in 2015 stood at 224 infections that were contracted in the United States and about 5,000 from travel to other countries. Ninety-one infants were born in the United States with Zika-related birth defects through July of 2017, and eight more died in utero. By contrast, sixty-three American deaths were formally attributed to Lyme disease in 2014. About 300,000 to 400,000 people are infected in the United States annually, with 10 to 20 percent of casualties developing long-lasting, recurrent complications. Both illnesses can be serious but can also be fleeting and inconsequential, especially so for early, adequately treated Lyme disease.

  This isn’t about which disease tops the other as a public health calamity. It is about whether responses to each are proportional. Zika prompted panic and got attention. Lyme disease, by contrast, has long been so much background noise, acknowledged but minimized by public health officials and the researchers they relied upon. In 1991, the Annals of Internal Medicine published an article mocking Lyme disease patients entitled, “From the Centers for Fatigue Control, Weekly Report—Lime Disease, United States.” “Lime disease” occurred more frequently among middle- and upper-class people and women, the article snidely reported, with studies showing a strong link to reading stories about Lyme disease.

  In 1998, and in the same vein, a proposed Lyme vaccine was famously referred to as “as yuppie a vaccine as I’ve ever heard of” by a Duke University pediatrician. The comment was made at a meeting of a committee that advised the CDC on vaccines. The committee voted against recommending the vaccine in high-risk areas, opting instead to give the highly unusual advice that it “should be considered.” Sixteen years later, a committee member reflected on that regrettable moment. “By calling it a ‘yuppie vaccine,’ by damning it with the faint praise of a ‘should be considered’ recommendation, we killed it,” Paul Offit, chief of infectious diseases at the Children’s Hospital of Philadelphia in Pennsylvania, told the journal Nature Medicine. “Some on the committee seemed to view the vaccine as a luxury for the anxious affluent rather than a public health necessity,” the article recounted. Indeed, this is part of a pattern that has persisted for many years. A researcher I quoted earlier said he was denied funding with the comment by a reviewer that this was a “middle-class disease.”

  The $2.7 million that the CDC gave out in Lyme grants in 2016 was less than 1 percent of the agency’s research awards that year, a figure even I was shocked to learn. When I questioned this in the spring of 2017, the CDC referred me to its “Ongoing Research” website page. Of the six projects listed, three had already been wrapped up, including two several years earlier. It was hardly a robust list of active research, which, on the day I raised the question, was quickly relabeled, “Ongoing and Published Research.” Zach Adelman, the mosquito researcher on the brink of tackling a global public health scourge has a theory on the paltry funding for Lyme disease. “The symptoms are not as heart-wrenching,” he explained. “They don’t photo as well. You don’t have hemorrhagic fever. You’re not dripping blood out of your eyes. You don’t have deformed babies. But,” he said of Lyme disease, “it’s the same thing.” In other words, the pain of Lyme disease can be as intense, the damage as significant.

  Ironically, in the early years of Lyme disease research, there were reports in the scientific literature similar to those of Zika, of babies and fetuses infected with, and potentially damaged by, Lyme spirochetes passed by their mothers. Among sixty-six “adverse outcomes” involving gestational Lyme disease, assembled for a 2001 textbook on infectious diseases in children, twenty-six involved death in utero or shortly after birth. In these studies, spirochetes were found in the hearts, brains, and kidneys of such babies, establishing, as a 2001 literature review in the journal Teratology put it, “B. burgdorferi can cross the placenta.” The Lyme organism was found in a stillborn baby with a heart defect and in six second-trimester fetuses, three with cardiac defects. But because researchers had been unable to document inflammation—namely illness—in fetuses and babies, and the defects were highly varied, gestational infection has largely been dismissed. Researchers, unwisely, moved on. Many ill mothers have told me they believe they gave Lyme disease to their children.

  In August of 2016, NPR reported, “Fourteen people likely caught Zika in a neighborhood north of downtown Miami….That means mosquitoes in that area have picked up the virus and are spreading it.” The Zika threat nonetheless quickly waned, likely from “herd immunity,” in which Zika-infected people develop antibodies against future infection and the virus dies off. No such phenomenon exists for Lyme disease, which also lacks images of insects that fly and infants destined for lives of dependency. The same week NPR told of those 14 Zika cases, 331 Lyme disease infections were reported in the United States, perhaps a fifth of which would lead to lingering cognitive, neurological, or joint problems.

  In the late 1970s, Stephen Wikel, a newly minted PhD in veterinary microbiology from the University of Saskatchewan, made a series of observations about ticks that, had the stars aligned, might have stopped the modern-day epidemic of tick-borne disease in its tracks. He was the Zach Adelman of his generation, with an elegant and promising idea but without, as it turned out, the money.

  Four decades ago, Wikel found that the more times a guinea pig or rabbit was bitten by a tick, the more sensitive the animal became to the bite. Moreover, ticks fared far worse when they fed on animals that had been bitten before. They didn’t grow as fat, weren’t as fertile, laid more impaired eggs, didn’t molt as efficiently, and died sooner. What was at the root of this acquired resistance, he thought? Somehow, these animals had begun to develop ways to fight off some of the magical properties of tick saliva, the ones that subverted normal host immunity, numbed skin, and prevented blood clotting and healing at the bite site, and allowed ticks to feed to their hearts’ content. If that process could be identified, Wikel thought, if it could be artificially simulated in would-be tick hosts—in people—science would have found a means to prevent infection. This would not merely be a way to prevent one tick infection like Lyme disease. This would ward off ticks altogether.

  “Block the key molecules that allow for the creation of this privileged site for the pathogen to be dumped in.” That was how Wikel described the idea for me for what is called an antitick vaccine. Having blocked those molecules, and disarmed the tick’s all-powerful saliva, the human immune system could do its job against an invader on newly hostile territory. Ticks would not be able to plant a toehold. They would fall off, and perhaps even die. Wikel chiseled away at the science behind this idea for several decades, writing many papers on the “cutaneous interface” between tick and host. He contributed greatly to the literature but retired without a vaccine. Government interest, once enthusiastic, waned. Funding dried up. Ever committed, however, Wikel still has hope.

  Short of restoring balance to a wounded planet, there are two options to curb Lyme and tick-borne disease. First, get rid of or, more practically, sharply reduce ticks. Second, stop them from infecting people. We are a long way from reaching either of those goals. It is a problem of will, not ability. Science has tackled bigger problems and in less time.

  The Lesson of AIDS

  Mayla Hsu became a scientist in the 1990s,
in an era when the line charting infections with HIV and deaths from AIDS had been on a steep upward climb for more than a decade. A student at McGill University in Montreal, she was compelled by the challenge of helping unravel the cause and cure of a devastating health scourge. Those were heady days. There was money for fellowships, conferences, and research. The National Institutes of Health provided reagents to speed experiments and assure consistent results. Research institutes supported a trove of mentors and peers with whom to work and grow. Grant by grant, lab by lab, PhD by PhD, an infrastructure was built to find an answer. Science did.

  When I spoke to her in the spring of 2017, Hsu had left a productive career in HIV research where she had published successfully on, among other things, the ways the organism was able to evade drug therapy. Now in her midforties, she had turned her attention to Lyme disease as research director of a nonprofit organization, Global Lyme Alliance, one of several donation-driven organizations that were funding Lyme disease science. In contrast to HIV, Hsu saw in Lyme disease a research milieu starved for government grants, lacking encouragement for new researchers, and painfully short of the resources that had minted a generation of scientists like hers. “There is no career path for these people that want to study Lyme disease,” she told me. Significantly, Lyme disease was also of little interest to the pharmaceutical industry, she found, which had seen money to be made in HIV drugs. Hsu called Lyme disease not a parallel to HIV but “an anti-parallel.”

  Zach Adelman, the mosquito researcher at Texas A&M, was witness to Lyme disease’s second-class status when he sat on a government panel to review applications for funding. There, scientists from many disciplines were brought together to decide the future of government research. But however big the Lyme problem was, he found the community of tick researchers represented there to be small and subordinate, mostly because their science had not been funded in the past. Hence, grant proposals for tick-disease research were drowned out by better-funded interests, in something of a cycle that perpetuates itself, interrupted only by a breakthrough disease, like Zika, that changes priorities. It doesn’t help that leaders in treatment policy have portrayed Lyme disease as an easy disease to diagnose and treat, while minimizing its devastating impacts on many.

  In 1982, Congress allocated the first $12 million for AIDS research and treatment. That was a year after the Lyme disease organism, Borrelia burgdorferi, was identified in a US government lab and the year before the AIDS virus was identified. But that is where the two epidemics diverge. By 1997, AIDS research money to the National Institutes of Health amounted to $1.5 billion. That year, the AIDS death toll, which had reached its apex in the United States of 41,699 in 1996, began a precipitous decline. A standard of care had been discovered that turned HIV from a fatal to chronic infection. The reason was money, lots of money, poured into an epidemic that was crying out for it. The lack of such funding for Lyme disease is why Stephen Wikel’s idea for a vaccine against tick saliva remains a great idea waiting fulfillment. The disease lacks the infrastructure that turned Mayla Hsu—and many more like her—into a microbiologist and immunologist in the era of AIDS.

  In December of 1998, the first vaccine against Lyme disease, called LYMErix, was licensed by the US Food and Drug Administration and marketed by the pharmaceutical company SmithKline Beecham. The vaccine’s success was limited, and its commercial life short. For one, even if people got all three doses—a cumbersome hurdle to immunity—just 78 percent would be protected. That figure dropped to 50 percent if two doses were received. For another, and most crucially, the vaccine was said to have elicited Lyme-like arthritic symptoms, which was the apparent death knell for LYMErix. A study of adverse events, published in the journal Vaccine, found no “unexpected or unusual patterns” after the first 1.4 million doses had been administered. Nonetheless, it dutifully reported, there had been 101 reports of various kinds of arthritis and sixty-six adverse events that involved “life-threatening illness, hospitalization, prolongation of hospitalization, persistent or significant disability/incapacity, or death.”

  SmithKline pulled the vaccine from the market the same month the study came out in early 2002, citing poor sales. I can’t say whether the vaccine was unsafe. But a Lyme-only vaccine is inherently flawed because it does not address a key problem. Ticks carry more than Lyme disease. The week I wrote this, a study was published in the journal mSphere showing 30 percent of adult ticks from Long Island, New York, infected with Babesia microti, which causes babesiosis, on top of 67 percent that carried the Lyme pathogen. Some also harbored Borrelia miyamotoi, for which there is no diagnostic test, and deadly Powassan virus, with a 5 to 10 percent fatality rate. And while their pathogen loads are growing, ticks are also spreading widely and in huge numbers. No one should think they are protected with a vaccine that targets Borrelia burgdorferi only. It is something, to be sure. It is better than nothing—I would welcome it in fact—because Lyme disease makes other infections, like babesiosis, worse. But we need a better vaccine than one that only tackles Lyme. We need more protection.

  In Europe, a concerted effort is being made to do that, to build a vaccine that works against ticks—Stephen Wikel’s dream come true—and not only against Lyme borreliosis, as it’s called there. Seven institutes in six countries have been funded by the European Union in a project called ANTIDotE, which loosely stands for Anti-tick Vaccines to Prevent Tick-borne Diseases in Europe. In the United States, scientists at Tufts, Yale, and other institutions are also doing basic research that could lead to a vaccine; some of their science is integral to the effort. But there’s nothing akin in the United States to the coordinated, European Union-funded approach.

  Europe has been in this place before, after all, and it has prevailed. Consider tick-borne encephalitis, or TBE, a virus common in ticks from the fringes of France in the west of Europe to Asia in the east, from Albania in the south to Russia in the north. The disease causes brain swelling and sensory problems in 20 to 30 percent of infected people and can lead to long-term psychiatric problems or even permanent neurologic damage. About a week after onset of neurologic symptoms, the virus kills one or two of a hundred infected people. That kind of injury and death toll may explain why the first vaccine for the disease was unveiled in 1941, just four years after the organism was identified. It suggests why there is concern now in Europe for the growing potential of ticks to inflict harm.

  Lyme disease and TBE are similar in many ways, with a key exception. TBE’s fatalities occur quickly and can be documented. Lyme disease’s true mortality rate is unknown. But there are perhaps a hundredfold the number of Lyme borreliosis cases in Europe today as TBE. In the Netherlands, the country leading the ANTIDotE project, 1.5 million people are bitten by ticks annually, nearly a tenth of the population, resulting in 25,000 Lyme cases in one tiny country. Research there is showing an increase of infected ticks, a longer tick season, and growing areas of tick habitat. Just as in many other parts of the world.

  The Wonders of Spit

  To a one, tick scientists I spoke with for this book were in awe of, were humbled in fact, by the survival tactics of ticks and, in particular, by what’s contained in tick saliva. “The success of their life strategy can be attributed, in part, to saliva,” wrote a group of American and Czech researchers in 2016, in an article with the words “Spit-acular Saliva” in the title. Tick spit holds an “armamentarium” of molecules, a Czech scientist named Michalis Kotsyfakis told me, each to carry out specific tasks. The challenge is figuring out which molecules of perhaps thousands serve what purpose—some are anticoagulants, some thwart signals between human immune cells, some stop production of them, others facilitate feeding. Then, the trick is identifying other molecules that may be waiting in the wings, like reinforcements in combat. Knock one out of commission with a vaccine intended to set off an attack of antibodies, and a handful more step up to do the job.

  “We need to find the cornerstone,” the Greek-born Kotsyfakis told me in a Skype call fro
m Prague. In fact, he added, “We try to find two or three cornerstones to make everything collapse.” Kotsyfakis, a bearded, slightly balding man who worries for people who don’t understand the threat of ticks, began studying tick saliva as a postdoctoral fellow at the US National Institutes of Health in the early 2000s. He worked for five years under the mentorship of Jose Ribeiro, a government scientist legendary for his dedication to unraveling the tick mystique. Kotsyfakis now heads the Laboratory of Genomics and Proteomics of Disease Vectors at the Academy of Sciences of the Czech Republic, where he dissects ticks at the level of genes and molecules. He and his colleagues, part of the EU’s ANTIDotE project, have identified a handful of “pluripotent” proteins that might be used as the basis of an antitick vaccine. “Understanding the molecular mechanisms that govern the life cycle of ticks,” they wrote, “is within grasp.”