Over the last decade, public health officials have adopted a multifaceted strategy in attempting to contain the global Lyme disease threat. Prominent among the stratagems employed has been a strong vaccine development effort. Just as the polio vaccine was the first step in virtually eliminating that disease from the American public health landscape decades ago, immunoprophylaxis against Lyme disease could, in theory, reduce the incidence of new Lyme cases dramatically, thus sparing countless individuals from the chronic form of the disease.
At a hearing convened on May 26, 1998, a vaccine review committee assembled by the U.S. Food and Drug Administration (FDA) recommended approval for a vaccine formulation developed by SmithKline Beecham Pharmaceuticals. Final FDA approval was issued on December 21, 1998. It will be marketed under the product name LYMErix. A second pharmaceutical company, Pasteur Mérieux Connaught, has also conducted Phase III trials and will likely be seeking FDA approval for their own vaccine (known as ImuLyme) shortly. Although the approval of a Lyme disease vaccine would obviously be welcome news, the recommendation for approval did not come easily and was accompanied by several important caveats. According to Dr. Patricia Ferrieri of the University of Minnesota, who chaired the FDA committee, "It's rare that a vaccine be voted on with such ambivalence and a stack of provisos."
The Lyme Disease Network has received numerous requests from individuals seeking information and guidance on the issues posed by the new vaccines. We don't feel it is appropriate for us to make a specific recommendation as to whether or not individuals should opt for receiving the vaccine -- that is a decision to be made by the potential vaccine recipient in consultation with his or her physician. In response to the volume of requests, however, we offer the following discussion of the Lyme disease vaccine effort and a short review of selected issues that were raised by the FDA review committee.
Lyme disease is a multisystemic illness caused by the spirochetal bacterium Borrelia burgdorferi sensu lato. The organism is usually transmitted to humans by the bite of an infected ixodid tick. The commonest early manifestation of Lyme disease is the skin rash erythema migrans, sometimes accompanied by non-specific flu-like symptoms, such as sore throat, fever, headache and adenopathy. About 20 percent of patients develop frank neurological signs within the first few weeks of infection, including cranial neuritis, radiculitis and meningitis. Cardiac abnormalities can also occur early in the illness, the most common of which is atrioventricular block, sometimes requiring the insertion of a pacemaker.
Later disease manifestations include arthritis, usually of the large joints, and a variety of neuropsychiatric syndromes, often involving disturbances of cognition, mood and sleep. Chronic neurological manifestations include disorders of sensation related to spinal nerve involvement, and, less commonly, demyelinating multiple sclerosis-type syndromes, often accompanied by white matter changes on brain MRI scans.
Patients with Lyme disease who are treated with antibiotics early in the course of their illness tend to do well, but treatment of the later manifestations is often less effective. Some retrospective studies have indicated that as many as one-third of Lyme disease patients continue to have persistent signs and/or symptoms after treatment for the disorder  . The potential of Lyme disease to cause chronic morbidity has been one of the major motivating factors in the vaccine development effort.
THE ROAD TO A VACCINE:
Both SmithKline and Connaught use Outer Surface Protein A (OspA) of B. burgdorferi as the stimulating antigen for their preparations. (The SmithKline formulation uses an adjuvant, while the Connaught formulation does not.) While OspA is prominently expressed by B. burgdorferi in ticks, its production appears to be down-regulated by the microbe when its tick vector feeds on mammalian hosts. The early antibody response to OspA in humans is weak and fleeting, if it occurs at all.
Several years ago, when scientists first began testing OspA vaccine preparations in mice, they made a startling discovery. The vaccine worked, but its mechanism of efficacy was highly unusual. Instead of priming the rodents' immune systems to recognize OspA and react quickly after challenge by B. burgdorferi , the researchers discovered that anti-OspA antibodies in the mouse sera were traveling into the tick's midgut and killing the Lyme spirochetes there, before they were even transmitted to the mice . The prominent expression of OspA by B. burgdorferi in ticks was a vital component of this process.
OspA appears to be a good vaccine candidate for other reasons as well. Compared to OspB, OspC and OspD, it exhibits the least variability between strains of B. burgdorferi  . Studies advanced by researchers and the vaccine manufacturers on recombinant OspA vaccines in animal models suggest antibody production against this protein is broadly protective against B. burgdorferi strains commonly found in the northeastern United States   . Another study has indicated that the vaccine was effective against B. burgdorferi. strains from a more diverse range of geographic locales . The SmithKline Beecham recombinant vaccine employs the OspA sequence of B. burgdorferi sensu strictu strain ZS7, which has been shown to be effective in the mouse model .
SmithKline Beecham started with small Phase I studies to evaluate safety and efficacy of their vaccine in 350 healthy adults. They then proceeded to Phase II efficacy and dosing trials in 353 adults with no previous exposure to B. burgdorferi . Finally, a large scale, multicenter, double-blind, randomized, placebo-controlled Phase III study was initiated to evaluate the vaccine in a larger population. Almost 11,000 subjects received vaccine or placebo at enrollment and 1 and 12 months later, for a total of three doses. Subjects were followed for two years and outcomes were characterized as "definite Lyme disease," "possible Lyme disease" and "asymptomatic infection" (seroconversion without symptoms). Short-term and long-term adverse events were also recorded. The study results were published in the New England Journal of Medicine on July 23, 1998 .
RESULTS AND DISCUSSION:
1) Issues of Efficacy
According to the authors of the study report, 22 subjects in the vaccine group and 43 subjects in the placebo group contracted definite Lyme disease during the first year, for a 49 percent vaccine efficacy rate. During the second year (after the final vaccine dose), 16 vaccine recipients and 66 placebo recipients contracted definite Lyme disease, for a vaccine efficacy rate of 76 percent.
It should be pointed out that the diagnostic criteria used in the study were extremely strict. Seroconversion was required for all post-erythema migrans "definite Lyme disease" cases (only a handful of these were diagnosed in the study), and cases of erythema migrans were not counted as definite unless accompanied by culture positivity, seroconversion or PCR positivity. Even with these restrictions, the overwhelming majority (97%) of "definite Lyme disease" diagnoses in both the vaccine and placebo populations were cases of erythema migrans.
It could be argued that the over-reliance on serology may have led to the underdiagnosis of true Lyme disease cases in both the EM population and among subjects with possible later manifestations of Lyme disease. As one committee member remarked during the meeting, "I think the sponsors' data would support that even in culture-proven cases, not everybody seroconverts. So that the serological data cannot be used as a gold standard. And the fact that someone has EM and doesn't seroconvert doesn't mean that it is not a Borrelia burgdorferi infection" . Still, especially in non-EM cases, it is difficult to conceive of a reliable alternative diagnostic algorithm that the authors could have employed. But it should be noted that in the absence of serological confirmation, it is likely that some true LD cases were bumped into the "possible Lyme" category, and were thus excluded from the final analysis.
The higher efficacy rate during the second year of the study was apparently a function of much higher anti-OspA IgG antibody titers in vaccinated individuals after the final vaccine dose, at 12 months, as compared with their titers a year earlier, after only two doses. It appears that LYMErix is unusual in the vaccine world in that it takes a full year, at least under the proposed dosing schedule, to build optimal immunity. Furthermore, antibody titers dropped quite rapidly in study subjects even after the third injection; by the end of the second year the mean antibody titer level among vaccinated individuals had declined to the levels of a year earlier. These findings suggest that additional boosters will be necessary to maintain antibody levels sufficient to neutralize the spirochete during tick feeding. Unfortunately, the threshold antibody level that confers protection against B. burgdorferi infection has yet to be determined.
Even assuming that this protective level can be identified, how safe are repeated doses of the OspA formulation? There are virtually no data on the long term outcomes of additional boosters after two years. (SmithKline Beecham is presently studying a small cohort of patients who have received one or two additional boosters; at the time of the FDA committee meeting, SKB representatives were "not aware of any unusual events in these people who have received four or five doses" .) At present, the indication filed with the FDA calls for three doses, on the 0-1-12 schedule. If the manufacturer pursues an indication for approval of additional boosters, additional requests will have to be filed. But at this point, researchers don't know the protective antibody level, they don't know how many boosters will be required, they don't know whether they are safe, and there is no FDA blessing for any subsequent vaccine dose. These unknowns are a potential cause for concern.
It is also theoretically possible that the vaccine may change the clinical picture of infection, making vaccine failures difficult to detect. One well documented case study in the literature describes this phenomenon . According to the authors, "Physicians may eventually be faced with possible vaccine failures, and the presentation of Lyme disease may be modified in patients who are infected after vaccination. Partial protection gained from the OspA vaccine may be associated with the absence of erythema migrans, which would mask the infection at its earliest, most treatable stage."
Still, there is little doubt that this is generally an effective vaccine, at least over the time period studied. Yes, we wish that its performance in the first year was better. But if researchers can find a way to safely maintain high OspA antibody titers among vaccinees over the long term, it will be a major first step toward a dramatic reduction in the number of future Lyme disease cases.
2) Issues of Safety
Most vaccines have mild side effects. According to the FDA, "No prescription drug or biological product, such as a vaccine, is completely free from side effects. Vaccines protect many people from dangerous illnesses, but vaccines, like drugs, can cause side effects, a small percentage of which may be serious. The FDA continually monitors reports to determine whether any vaccine or vaccine lot has a higher than expected rate of events. About 85% of vaccine adverse event reports concern relatively minor events, such as ordinary fevers or redness and swelling at the injection site" 
According to the SmithKline Beecham investigators, significantly more vaccine than placebo recipients in the LYMErix study had reactions typically associated with vaccination - local soreness and swelling at the injection site, or systemic symptoms such as fever, chills and myalgias. Most of these were mild to moderate in severity. After thirty days, no significant differences in type (or frequency) of symptoms were recorded between the two groups.
More importantly, the investigators reported no statistically detectable difference in late adverse events between vaccine and placebo recipients among patients who were seropositive at base line for Lyme disease, nor were any differences in late adverse events noted between the vaccine and placebo groups among patients with a self-reported history of Lyme disease.
Nevertheless, members of the vaccine review committee expressed considerable concern about the safety of the OspA vaccine in individuals with a previous history of Lyme disease. One specific subset of patients, those with the HLA-DR4 genetic marker, may be at increased risk for adverse events from the vaccine. Past research has shown that patients with this marker are more likely to develop chronic arthritis as a result of B. burgdorferi infection than are patients without it. A likely mechanism for this chronicity is that HLA-DR4-positive patients apparently develop an untoward T-cell response to human proteins that resemble those of B. burgdorferi .
Recently, scientists have identified a specific candidate human protein, known as LFA-1, that may be the target of this autoimmune response . Unfortunately, the B. burgdorferi antigen that seems to be triggering this response is found on OspA -- the stimulating antigen of the vaccine preparation. Thus, in theory, the vaccine itself could cause symptoms in a genetically vulnerable population. The number of patients in the vaccine study population with the HLA-DR4 allele and a history of Lyme disease was too small to draw conclusions from, but it was noteworthy to the vaccine review committee that two of them developed arthritis and paresthesias after vaccination.
The committee also expressed reservations about the long term safety of the vaccine in the population at large. "My substantive concerns here are the longer-term issues," said Thomas Fleming, a biostatistician at the University of Washington and a consultant to the FDA. "It remains a concern whether the vaccine could be eliciting or inducing chronic sequelae over an interval of time that would not have been detected within the period of follow-up."  Ultimately, the committee recommended active surveillance to assess the vaccine's long term safety, along with the establishment of a vaccine registry to keep track of any potential complications that could develop in the future.
It is clear that further study is needed to determine the optimal dosing schedule for the vaccine, and to confirm its safety over the long term. For now, potential vaccine recipients will have to balance the vaccine's proven benefits against its more nebulous safety picture. It is not an easy calculation to make, even for the experts. As one vaccine review committee member stated after the meeting, "We have a vaccine that I'm comfortable with, but it's not something I would push tomorrow."
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