Francesca Tomasi received her B.A. from the University of Chicago and currently researches tuberculosis metabolism and drug targets.
Before the turn of the century, it lived virtually in oblivion. Now, it costs over $1 billion per year to treat in the US alone, it is a global public health problem, and every summer during tick season people are warned about its chronic symptoms. What is Lyme disease, why does it cause so much morbidity, and what can we do to protect ourselves?
Borrelia burgdorferi is a species of bacteria known as a spirochete, for its corkscrew-like shape. The organism itself is named after Willy Burgdorfer, a medical entomologist who first isolated B. burgdorferi in 1982. This tiny little pathogen is the causative agent of Lyme disease, along with a few other Borrelia species, and its life cycle moves between ticks and vertebrates. The bacteria reside within ticks, which then feed on vertebrates, thereby transmitting the bacteria to a new host in which they can carry out the rest of their life cycle. When another tick feeds on this host, it ingests more Borrelia, and the cycle continues. While humans tend to be dead-end hosts, since we take antibiotics for Lyme infections and engage in anti-tick behavior (long sleeves, tick checks, and repellent), human to human transmission has been well-documented via blood transfusions.
Borrelia infection is associated with symptoms resembling those of rheumatoid arthritis: namely, joint and muscle pain. Severe fatigue and neurological disorders like numbness, weakness, and cognitive impairment may also occur, increasing in severity and complications if an infection is left untreated. Progressed neurological symptoms like facial palsy, irregular heart rhythms, and meningitis have been reported in extreme cases. Currently, the CDC estimates approximately 30,000 cases of Lyme disease in the US, emphasizing that only a fraction of infections are actually reported. In fact, recent studies place case estimates closer to between 296,000 and 376,000 cases per year in the United States, and at least 85,000 more in Europe.
Lyme disease, as mentioned above, is curable with antibiotics. When treated early and for two to four weeks with doxycycline, amoxicillin, or cefuroxime axetil (all oral antibiotics), individuals typically recover fully and quickly. Patients with more progressed neurological or cardiac symptoms may receive intravenous antibiotics like penicillin, but they, too, usually recover.
Something known as post-treatment Lyme disease syndrome (PTLDS) may also occur, though. In this case, patients treated for Lyme disease have lingering symptoms for weeks to months after treatment. While the exact causes of PTLDS are unknown, many experts believe that damage incurred on tissues and the immune system during infection contribute to these persisting symptoms. The CDC does stress that long-term antibiotic regimens for Lyme disease are not correlated with improved recovery rates; rather, long-term use of these antibiotics is often associated with negative side effects and additional complications.
The Solution, Part I
In the 1990s, GlaxoSmithKline (GSK; then known as SmithKline Beecham), came up with an effective immunization against Borrelia infections. The vaccine mimicked a bacterial surface protein and primed the immune system to produce antibodies against it. And rather than waiting for Borrelia to enter a human host before antibodies could attack, the moment an infected tick bit an immunized individual, it would swell with antibody-laden blood that subsequently attacked any Borrelia residing within the tick.
The vaccine, called LYMErix, successfully passed phase 3 clinical trials (which involved nearly 11,000 volunteers) and gained FDA approval in 1998. It was a three-dose vaccine with up to 80 percent effectiveness, and it entered the market with a few caveats. To start, 80% efficacy means that one fifth of fully immunized individuals could still get Lyme disease if exposed. Furthermore, a multi-dose vaccine is inherently more difficult to implement on a large scale than a single-dose one, since each visit has to fall within a certain time period. For LYMErix, the second dose had to be administered one month after the initial dose, and the third dose at the one-year mark. Medical reviewers have also pointed out that GSK’s phase III trials failed to include young children, who are particularly high-risk for getting caught between ticks and developing Lyme disease.
What’s more, LYMErix was only effective against B. burgdorferi – this is the predominant Lyme-causing Borrelia species in North America, but for international subspecies the vaccine would not be helpful. Lastly, just as someone on malaria prophylaxis is more likely to be a little less careful about getting a mosquito bite, individuals immunized against Lyme disease were less likely to engage in the more immediate tick prevention efforts named above. This change in behavior not only increases risk of Lyme disease (especially without a 100% effective vaccine), but it also shoots up the risk of other serious tick-borne illnesses such as babesiosis and Rocky Mountain spotted fever.
Of course, the last point is not a direct side effect of LYMErix but a basic consequence of human behavior. As with the vaccine’s other limitations, advisory boards decided that the benefits outweighed the risks in Lyme-endemic regions such as the northeastern United States. The Advisory Committee on Immunization Practices, however, did not recommend LYMErix for people in low-risk regions, young children, and elderly adults, similarly to more recent decisions made concerning a novel dengue vaccine.
Disaster struck in the form of a class-action lawsuit in Philadelphia, Pennsylvania. Over 100 individuals filed for this suit, claiming adverse effects from LYMErix. The FDA was forced to re-examine adverse reactions reported from the vaccine trial as well as in more recent immunizations. It found that while approximately 26.8 percent of LYMErix recipients experienced soreness, redness, or swelling at the site of injection, only 8.3 percent of controls (individuals who received a placebo injection). These side effects are harmless, though, as they pass within three days without any treatment.
Ever notice how your arm often gets pretty sore after a flu shot? Vaccines like LYMErix and flu shots are typically injected intramuscularly, meaning deep within the muscle, which allows them to enter the bloodstream very quickly to begin priming an immune response. It is therefore natural to experience some soreness or irritation around an injection site. And since your body is forced to fight something when you get a shot, it is also normal to experience the occasional fever or malaise for a day or two.
The main cause for concern surrounding LYMErix, however, was not a little bump, bruise, or two-day fever. Rather, individuals were reporting more systemic reactions such as joint pain. The FDA’s investigation found no significant difference between vaccinated and placebo groups when it came to these symptoms (1.3 percent versus 1.2 percent). The stipulation with these data, however, is that the clinical trial followed patients for only one year, which gave lawyers an edge: what might happen with LYMErix vaccination in the longer term?
By 2001, three years after LYMErix entered the market, over 1.4 million doses had been distributed throughout the US, the majority concentrated around New Jersey. Out of these 1.4 million, there were 905 reports of the self-limited reactions described above, and 59 of post-vaccination arthritis. The FDA’s analysis, however, found that arthritis incidence related to vaccination was similar to background arthritis rates in non-vaccinated individuals, and the supposed LYMErix-induced arthritis cases were not found to be temporally associated with second or third doses, and effect one would expect to see in an immune-mediated (dose or exposure-related) event. Hence, the FDA declared that GSK’s Lyme vaccine did not cause harm to patients.
Nonetheless, the damage was done the moment lawsuits were involved. By its fourth year on the market, demand for the vaccine had dropped irreconcilably and, faced with social pressure and media-propagated fears, GSK voluntarily discontinued LYMErix in 2002. The story of LYMErix has become for many a cautionary tale of the power of anti-vaxxers and false information. Since neither the FDA for GSK could definitely link the vaccine to significant adverse events, this may in fact have been what happened.
In 2002, after LYMErix was discontinued, cases of the illness rose by 40% in the United States. There are two lessons to be learned here. One is to weigh scientific validation: there are so many scientific and legislative controls in place when it comes to designing, approving, and implementing vaccines and vaccination programs. The second lesson is that, with or without a vaccine, preventive measures ought always to be a priority. This is true for cholera (filtering water, even through a sash), dengue fever and malaria (bed nets, mosquito sprays), Lyme disease (long sleeves, tick repellents) or any other infectious disease that can be prevented with minor behavioral changes and at minimal cost. Vaccines are rarely 100% effective. But who would argue that no protection at all is better than some?
It is during the past 15 years that Lyme disease has grown into an epidemic.
Let’s Try This Again
Last week, the French biotech Valneva announced FDA and European approval to move its new candidate Lyme vaccine into phase I clinical trials – testing safety and efficacy in people. Valneva’s vaccine works like LYMErix – targeting the OspA protein – but also takes into account OspA proteins in other Borrelia species for wider immune coverage. Valneva’s vaccine has a ways to go before entering the market – statistically, over 90% of vaccines that pass from animal trials into human trials fail in phase I – but the scientific community has openly asserted it is time for a new Lyme vaccine.
It cannot be done without public support, though. The pharmaceutical industry, like any business, is extremely reliant on demand for production. Infectious disease treatments aren’t exactly money-makers the way other drugs like Lipitor or Plavix are. It is difficult to incentivize companies to pour billions of dollars and hundreds of thousands of hours into fighting pathogens unless there is a visible, imminent threat (for example, an airborne Ebola-like virus ripping across the globe). Lyme disease is a serious problem, though, stealthy as it might be, and with changing climates and environments, its public threat is only expected to grow.