History of LymeRix

Lyme disease, a bacterial infection spread by certain types of ticks, is a growing problem in the United States. First described in 1977 as “Lyme arthritis” after a cluster of cases was reported in Old Lyme, Connecticut, the disease is most common in the Northeast and upper Midwest, but has been reported from every U.S. state.[i][ii] Each year about 20,000 new cases are reported, while experts note that the true incidence may be three times higher or more.[iii] As of 2009, the disease ranked 7^th on a list of the leading nationally notifiable diseases reported to the Centers for Disease Control and Prevention (CDC), despite more than 90% of cases being found in only 10 states. (Other diseases on the list include Chlamydia, chickenpox, pertussis, and AIDS.)

The first and only licensed vaccine against Lyme disease was developed by SmithKline Beecham (now GlaxoSmithKline). Given in a three-dose series, the vaccine had an unusual method of action: it stimulated antibodies that attacked the Lyme bacteria in the tick’s gut as it fed on the human host, before the bacteria were able to enter the body. This was about 78% effective in protecting against Lyme infection after all three doses of the vaccine had been given.

The vaccine, called LYMERix, was licensed in 1998. By 2002 SmithKline Beecham had withdrawn it from the market, and Pasteur Mérieux Connaught decided not to apply for a license for its own Lyme vaccine candidate, despite having already demonstrated its efficacy in a Phase III clinical trial. Today there are no vaccines available to prevent Lyme disease, and it is unlikely that any will be licensed in the near future. The debut and subsequent withdrawal of the Lyme disease vaccine has lasting implications for future vaccine development and use.

Disease Transmission and Symptoms

Lyme disease is caused by the Borrelia burgdorferi bacteria, passed to humans through the bite of infected black-legged ticks (in the Northeast, these are sometimes called deer ticks), which initially get the disease from mice. The transmission of the bacteria from an infected tick to a human can take hours – often more than a day – but the ticks’ small size makes them easy to overlook on the body, allowing time for this transmission to occur unimpeded.[iv] They are typically about the size of the head of a pin, and can bite without being noticed.

The most commonly known symptom of Lyme disease is the “bull’s-eye” or “target” rash, which appears in most cases. The rash begins at the site of the tick bite between three and 30 days after exposure and usually grows in size for several days. When Lyme disease is diagnosed, antibiotics are prescribed for treatment. If the disease is left untreated, other symptoms can develop in the weeks following exposure: additional rashes; joint pain and swelling; shooting pains; dizziness and heart palpitations; severe headaches; and loss of muscle tone in the face (known as Bell’s palsy).

If the disease remains untreated beyond this point, arthritis can develop. This occurs in about 60% of patients whose infections are not treated, and can cause swelling and severe pain in the joints. In addition, as many as 5% of patients whose Lyme infections are not treated develop chronic neurological problems. These can occur months or even years after transmission.

Even after treatment, some patients continue to have symptoms of Lyme disease. More common in patients whose diagnoses were made further along in the course of the infection, these symptoms are referred to as Post-treatment Lyme disease syndrome.

Vaccine Licensure, Recommendation, and Initial Use

In response to growing reports of Lyme disease cases in the United States – from 1982 to 1996, the number of reported cases increased by 32 times – SmithKline Beecham developed LYMERix, which was licensed in 1998. The licensed product was a recombinant vaccine containing an outer surface protein (OspA) from theBorrelia burgdorferi bacteria. Before licensure, 6,478 people received a total of 18,047 doses of the vaccine during clinical testing. The most common adverse events noted within 30 days of receiving at least one dose of the vaccine included pain or reaction at the injection site, joint pain, muscle pain, and headache. Of these, only pain and reactions at the injection site occurred much more frequently in the vaccine recipients than in those who received a placebo.[v][vi]

The efficacy trial for the vaccine showed that it was 78% effective in preventing Lyme disease after all three doses were given. It was also shown to be 100% effective at preventing asymptomatic cases, where an individual would get the disease and develop antibodies against it but never develop any symptoms.

Based on the clinical trial data, the vaccine was given a permissive recommendation by the Advisory Committee on Immunization Practices. A “permissive recommendation” means that a vaccine is not added to the childhood or adult immunization schedules, like vaccines against common childhood diseases (measles, rubella, influenza, etc.). Instead, the vaccine is considered for use only in individuals or groups who have specific risk factors for a disease.

The Lyme disease vaccine was considered for use in individuals between 15 and 70 years old living or working in areas with high rates of Lyme disease. People with very little exposure to areas with heavy tick infestations were not recommended to receive the vaccine.

Between the time of its licensure in 1998 and July 31, 2000, about 1.5 million doses of the vaccine were distributed.[vii]

Post-Licensure Monitoring, Safety Studies, and Lawsuits

As with all vaccines, post-licensure monitoring was conducted on the Lyme disease vaccine, including analysis of reports to the Vaccine Adverse Events Reporting System (VAERS). [For more information about safety monitoring of vaccines after licensure, see the “Next Steps: Approval and Licensure” section of our article on Vaccine Development, Testing, and Regulation.]

VAERS is an open system that accepts reports about adverse events following vaccinations from anyone, including health care providers, vaccine recipients and their relatives, vaccine manufacturers, and lawyers. VAERS data should not be used without careful analysis: someone may report, for example, that they developed headaches three days after a vaccination. However, this is not hard data: the headaches may be a side effect of vaccination, or they may simply be a coincidence. Individual reports on their own should not be used as data points without further analysis.

VAERS reports can, however, be helpful in identifying extremely rare vaccine side effects. For example, after the first rotavirus vaccine was licensed in 1999, reports made to VAERS suggested that an unexpected number of cases of intussusception were occurring after rotavirus vaccination. In response to the higher-than-expected number of reports made to VAERS, further analysis was done and showed that in about 1 of every 10,000 children vaccinated against rotavirus, the vaccine caused intussusception. The vaccine was then withdrawn.

Between December 28, 1998 and July 31, 2000, 905 reports were made to VAERS about adverse events after the administration of the Lyme disease vaccine. Of these, 66 were classified as serious – that is, they resulted in a life-threatening illness, hospitalization or lengthened hospitalization, or disability. After examining the reports, researchers “did not detect unexpected or unusual patterns of reported adverse events.”[viii] (In other words, the data did not indicate that the events occurred at a higher rate than would be expected in the population regardless of Lyme vaccination.)

Reports of arthritis following Lyme disease vaccination were also given close attention given that Lyme disease itself can cause arthritis. Specifically, scientists had already noted that individuals with a particular genetic constitution were more likely to experience immune responses to Lyme disease that could lead to Lyme arthritis; as a result, they examined the hypothesis that the vaccine could cause Lyme arthritis in patients with that genetic predisposition.

As research was done to test the hypothesis, the media began to cover the topic heavily. Although stories usually pointed out that no study or research to date had shown that the vaccine could cause arthritis, headlines on the same articles tended to present the issue pessimistically: “Concerns Grow Over Reactions to Lyme Shots,” “Lyme Vaccine May Cause Problems,” and “Lyme Disease Vaccine’s Safety Is Questioned” all appeared in 2000 and 2001.

Soon, anti-Lyme vaccine groups were formed with the goal of ending the vaccine’s production. A class-action lawsuit was filed, asking SmithKline Beecham to update the vaccine’s label to include the possibility that it could cause arthritis.[ix] Other individual lawsuits claimed that the vaccine had caused arthritis and various other adverse effects.

In 2002, in response to low vaccine uptake, public concern about adverse effects, and class action lawsuits, SmithKline Beecham withdrew the vaccine from the market despite the fact that both pre- and post-licensure safety data showed no difference in the incidence of chronic arthritis between those who received the vaccine and those who had not. Today there are no vaccines available to prevent Lyme disease, and it is unlikely that another will be developed and licensed in the near future – not because of a lack of interest or problems with development, but because of the precedent set by the first vaccine’s ultimate failure in the court of public opinion.

“A Cautionary Tale”

There is no evidence to suggest that the Lyme disease vaccine ever caused Lyme arthritis, but it was taken off the market largely in response to lawsuits alleging exactly that. Why?

First, the Lyme disease vaccine faced a unique challenge after receiving a “permissive recommendation” upon licensure. Vaccines that are added to a recommended routine vaccination schedule are given to everyone in a particular age group, so long as an individual does not have a contraindication to vaccination. The measles, mumps, and rubella combination vaccine, for example, is given to all children at a particular age; at a routine doctor’s visit, a doctor knows to administer the vaccine if the child has reached a certain age and has not yet been vaccinated. This is the case for vaccines against common childhood illnesses, like measles, mumps, and rubella.

With a permissive recommendation, however, vaccine administration is trickier. In the case of the Lyme disease vaccine, the vaccine’s use was to be considered for “individuals between 15 and 70 years old living or working in areas with high rates of Lyme disease.” This was potentially confusing. For example, should an office worker receive the vaccine if she lived in a geographical area with a high rate of Lyme disease? What meets the definition of a “high rate” of Lyme disease? What if she was rarely outdoors? What if she owned a dog that might be more likely to carry ticks into her home?

The permissive recommendation left a large responsibility on doctors not only to know whether their patients lived or worked in an area with high rates of Lyme disease, but also to take the time to discuss the vaccine during a visit that might be for an entirely different reason. While routine visits to the doctor are common during childhood and include time spent discussing vaccination status, doctor’s visits during adulthood are usually in response to a specific condition, and don’t include much time for discussion about vaccines that a patient may or may not be a candidate to receive. Because of the somewhat confusing permissive recommendation, the Lyme disease vaccine did not reach as many individuals as it otherwise might have.

Second, vaccines on the recommended routine schedules are typically covered by the National Vaccine Injury Compensation Program (NVICP). This program, created in 1988, offers compensation to individuals who are injured by vaccines, providing protection for both consumers and manufacturers. The program is funded by a $0.75 tax on any vaccine recommended for routine use in children, and claims are paid for any covered illness or injury that is presumed to be caused by a vaccine, such as anaphylaxis from a vaccine containing tetanus toxoid. (A full list of covered claims is available here. See our article on vaccine injury compensation programs, including NVICP, here). The program was created partially in response to lawsuits against vaccine manufacturers: if too many lawsuits are filed against a particular vaccine – even in the absence of proof that the vaccine causes harm – the cost of fighting the lawsuits can lead a company to raise the price of a vaccine, or even halt its production completely. The NVICP requires that individuals first file a claim with the U.S. Court of Federal Claims, offering some protection against frivolous lawsuits and those without scientific merit. (If a plaintiff rejects the federal court’s decision, he or she can then choose to file a lawsuit outside the NVICP.)

The Lyme disease vaccine, because it was not on the recommended vaccination schedule, was not covered by the NVICP. As a result, claimants could file lawsuits directly against SmithKline Beecham, and did.

Finally, the vaccine suffered from poor coverage in the press. Claims about side effects, particularly about the vaccine causing arthritis, were widely reported in the absence of evidence, leading to confusion about the safety of the vaccine and likely discouraging people who might otherwise have received it. All of these factors combined to the declining use of the vaccine before it was finally discontinued in 2002.

Many people today are unaware that there ever was a human vaccine against Lyme disease – though many are aware of a vaccine to protect dogs – and the incidence of the disease in the United States continues to rise. The combination of poor communication about the recommended use of the vaccine and the poor reporting about possible side effects should not be forgotten in light of the current distrust of vaccines among some members of the public. A 2006 editorial inNature remarked that in the case of Lyme disease, “unfounded public fears place pressures on vaccine developers that go beyond reasonable safety considerations.”[x] Still, the authors acknowledged that public opinion is a strong factor in companies’ decisions to pursue the development of a vaccine, stating, “It may go against the scientific grain for marketing considerations to play such a part in steering vaccine development. But in the real world, this may be unavoidable.”

Despite these challenges, the authors concluded, “Lyme disease is a serious illness and those who live in areas where it is spreading deserve a vaccine.”

Early clinical trials are underway for at least one new candidate vaccine. A combined phase 1/2 study is estimated to be completed in October 2013.

Sources

[i] Centers for Disease Control and Prevention. Cases by State – Lyme Disease. CDC Website. 2011. Available at:http://www.cdc.gov/lyme/stats/chartstables/casesbyyear.html. Accessed January 5, 2012.

[ii] Steere AC, Malawista SE, Snydman DR, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities.Arthritis Rheum. 1977; Jan-Feb;20(1):7-17.http://www.ncbi.nlm.nih.gov/pubmed/836338

[iii] Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons an We Learn? Clin Infect Dis. (2011) 52 (suppl 3): s253-s258.http://cid.oxfordjournals.org/content/52/suppl_3/s253.abstract

[iv] Montgomery County Department of Parks. Ticks & Lyme Disease. Montgomery County MD Website. 2011. Available at:http://www.montgomeryparks.org/PPSD/Natural_Resources_Stewardship/Living_with_wildlife/lyme_disease/lyme_disease.shtm. Accessed January 5, 2012.

[v] GlaxoSmithKline. Package Insert – LYMErix Lyme Disease Vaccine (Recombinant OspA). 2001. Available athttp://us.gsk.com/products/assets/us_lymerix.pdf

[vi] Steere AC , Sikand VK, Meurice F et al. Vaccination against Lyme Disease with Recombinant Borrelia burgdorferi Outer-Surface Lipoprotein A with Adjuvant.N Engl J Med. 1998; 339:209-215.http://www.nejm.org/doi/full/10.1056/NEJM199807233390401#t=articleTop

[vii] National Institute of Allergy and Infectious Diseases. Lymem Disease Vaccine Production. U.S. Department of Health and Human Services / National Institutes of Health website. 2011. Available at:http://www.niaid.nih.gov/topics/lymedisease/research/pages/vaccine.aspxAccessed January 24, 2012.

[viii] Lathrop SL, Ball R, Haber P et al. Adverse event reports following vaccination for Lyme disease: December 1998–July 2000. Vaccine. 2002;20:1603-1608.http://www.sciencedirect.com/science/article/pii/S0264410X0100500X

[ix] Noble HB. 3 Suits Say Lyme Vaccine Caused Severe Arthritis. New York Times. June 13, 2000. http://www.nytimes.com/2000/06/13/science/3-suits-say-lyme-vaccine-caused-severe-arthritis.html

[x] Anon. When a vaccine is safe. Nature. 2006; 439:509.http://www.nature.com/nature/journal/v439/n7076/full/439509a.html

Additional Sources and Further Reading

King LP. The Ongoing 30-Year Lyme Disease War: Case Study of a Failure to Communicate. The Yale Forum on Climate Change & The Media. 2008. Available at: http://www.yaleclimatemediaforum.org/2008/11/30-year-lyme-disease-war. Accessed January 24, 2012.

Nardelli DT, Munson EL, Callister SM, Schell RF. Human Lyme Disease Vaccines: Past and Future Concerns. Future Microbiology. 2009;4(4):457-469.

Offit PA. The Cutter Incident: How America's First Polio Vaccine Led to the Growing Vaccine Crisis. Yale University Press; 2005.

Steere AC, Dwyer E, Winchester R: Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N. Engl. J. Med. 1990;323, 219-223.

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