Lyme Disease Vaccine

Abstracts & Commentary

Synopsis: The Lyme disease vaccine is effective when given on a 0, 1, and 6 month schedule. The vaccine is currently recommended for persons between the ages of 15 and 70 who may have significant exposure to ticks carrying Borrelia burgdorferi.

Sources: Van Hoecke C, et al. Alternative vaccination schedules (0, 1, and 6 months versus 0, 1, and 12 months) for a recombinant Osp A Lyme disease vaccine. Clin Infect Dis 1999;28:1260-1264; CDC. Recommendations for the use of Lyme disease vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1999;48(RR-7):1-25.

Lymerix and imulyme are two lyme disease vaccines that have been developed recently using recombinant Borrelia burgdorferi lipidated outer surface protein A (rOspA) as immunogen.1,2 LYMErix is the only one currently licensed by the Food and Drug Administration for use in the United States. The report from MMWR reviews Lyme disease and summarizes the recommendations for the use of LYMErix as provided by the Advisory Committee on Immunization Practices. Van Hoecke and colleagues studied the efficacy of the vaccine using a shorter immunization schedule.

Lyme disease is the most frequently reported tick-borne disease in the United States,4 primarily occurring in the Northeast, mid-Atlantic, and North Central regions, as well as some areas in northern California. It is transmitted by Ixodes scapularis in the eastern United States, and by Ixodes pacificus in the western United States. The majority of the disease results from bites by infected nymphs. Transmission occurs usually only after the tick has been attached for 36 hours.5 The incubation period ranges from 3 to 30 days, but is usually 7 to 14 days.

Lyme disease involves multiple systems and may manifest at different stages. In its early stages, Lyme disease is frequently diagnosed by characteristic lesions, erythema migrans, and may be associated with nonspecific symptoms such as fever, malaise, myalgia, arthralgia, fatigue, and headaches. Later manifestations include secondary erythema migrans rash, neurologic symptoms (lymphocytic meningitis, cranial neuropathy, and radiculoneuritis), musculoskeletal symptoms (arthralgia and myalgia), and cardiac symptoms (myocarditis and atrioventricular block). Diagnosis is based primarily on clinical findings in the setting of known exposure to ticks. Serologic testing with ELISA and confirmatory Western immunoblot test (WB) may be helpful. Early diagnosis and treatment are effective in preventing late-stage complications such as Lyme arthritis or encephalopathy.

LYMErix is made from recombinant lipidated outer surface protein A (rOspA) of B. burgdorferi. The protein is expressed in E. coli, then purified, and adsorbed onto aluminum hydroxide adjuvant. B. burgdorferi residing in tick gut at the start of feeding expresses mainly OspA. As feeding continues, the expression of OspC increases and the expression of OspA decreases. The rOspA induces antibodies that kill the spirochetes within the tick gut, thereby providing protection against B. burgdorferi.6 Administered by the intramuscular route, the vaccine should be given before the start of B. burgdorferi transmission season, which usually begins in April. The vaccine-induced antibodies to rOspA cause false-positive ELISA tests for Lyme antibodies. However, WB results can differentiate between immuunization and actual infection, because anti-rOspA antibodies do not develop after natural infections.

Using a 0, 1, and 12 months schedule, the vaccine provided 49% protection after two doses and 76% protection after three doses against definite Lyme disease. For asymptomatic infection (WB seroconversion without symptoms of Lyme disease), the efficacy rates were 83% after two doses and 100% after three doses.1

The recommendations for the vaccine are based on assessed risks, which include the geographic distribution of Lyme disease and the activities of the person considering the vaccine. The vaccine should be considered for persons aged 15-70 years residing, working, recreating in, or traveling to areas of high or moderate risk whose exposure to tick-infected habitat is frequent or prolonged. The vaccine should also be considered in persons aged 15-70 years with previous uncomplicated Lyme disease who are at continued high risk. The vaccine is not recommended for children younger than the age of 15 years, pregnant women, persons with treatment-resistant Lyme arthritis, or persons whose exposure to tick-infested habitat is minimal or none.

In the study by Van Hoecke et al, the efficacy of LYMErix administered on a schedule of 0, 1, and 6 months was compared to that of 0, 1, and 12 months. The study was performed at two centers, one in Belgium and one in the Czech Republic. Eight hundred volunteers, aged 15-50 years, were randomized to receive the vaccine with either schedule. Adverse reactions were assessed. IgG antibodies to rOspA were measured by ELISA, and geometric mean titers (GMTs) were derived. One month after the third dose, 91% of recipients in the 6-month group developed protective levels of antibody for one tick season compared to 93% in the 12-month group. Seventy-five percent of vaccine recipients reported at least one local symptom, most commonly pain at the injection site. Nineteen percent reported systemic symptoms such as headache and malaise.

Comment by Lin h. Chen, MD

The ACIP recommendations are clear and concise, and Van Hoecke et al showed comparable efficacy when LYMErix is given at 0, 1, and 6 months vs. 12 months. Nevertheless, some concerns and questions remain regarding LYMErix. The risk for possible immunopathogenicity of rOspA vaccine is foremost among these, as summarized in the report in MMWR. In chronic Lyme arthritis patients, the levels of antibody to OspA have been noted to correspond to the severity and duration of the arthritis.7 Also, persons who express certain MHC II molecules are more likely to develop refractory Lyme arthritis along with high levels of antibody to OspA in serum and synovial fluid after B. burgdorferi infection.8 Given the unclear relationship between immune reactivity to OspA and refractory Lyme arthritis, the vaccine is not recommended in persons with a history of chronic Lyme arthritis.

Next, the main European and Asian genospecies that cause Lyme disease are B. garinii and B. afzelii, which are antigenically different from B. burgdorferi sensu stricto, and vary in their expression of OspA.9 It is speculated that combinations of immunogenic proteins may be needed to develop a vaccine that is effective against multiple genospecies.10 While the Van Hoecke study was conducted in Europe, it did not specify whether OspA was protective against all genospecies that cause Lyme disease in the region.

Finally, it appears that boosters may be needed, but there are no recommended schedules yet. As with all new vaccines, more information regarding the long-term vaccine efficacy and safety is needed.

In summary, travelers to high- or moderate-risk areas and who may have potentially frequent or prolonged exposure to ticks should consider the Lyme disease vaccine. The schedule of 0, 1, and 6 months provides reasonable protection during the first year, compared to the 0, 1, 12 months schedule. The vaccine is currently approved for use in persons aged 15-70 years only, and the efficacy in genospecies outside the United States is unknown. The primary defense against Lyme disease and other tick-borne infections remains avoidance of tick-infested habitat, use of personal protection measures, and checking for and removing ticks.

References

1. Steere AC, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998; 339(4):209-215.

2. Sigal LH, et al. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. N Engl J Med 1998;339(4):216-222.

3. Steigbigel RT, Benach JL. Immunization against Lyme disease—an important first step. N Engl J Med 1998; 339(4):263-264.

4. CDC. Lyme disease—United States 1996. MMWR Morb Mortal Wkly Rep 1997;46:531.

5. Piesman J, et al. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol 1987;25:557-558.

6. De Silva AM, et al. Influence of outer surface protein A antibody on Borrelia burgdorferi with feeding ticks. Infect Immun 1999;67:30-35.

7. Akin E, et al. Immunoglobulin (IgG) antibody response to Osp A and Osp B correlates with severe and prolonged Lyme arthritis and the IgG response to P35 correlates with mild and brief arthritis. Infect Immun 1999;67:173-181.

8. Kalish RA, et al. Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and Osp B of Borrelia burgdorferi. Infect Immun 1993;61:2774-2779.

9. Baronton G, et al. Delineation of Borrelia burgdorferi sensu stricto, B. garinii sp.nov., and group VS461 associated with Lyme borreliosis. Inf J Syst Bacteriol 1992;42:378-383.

10. Lovrich SD, et al. Seroprotective groups of Lyme borreliosis spirochetes from North America and Europe. J Infect Dis 1994;170:115-121.

Which of the following statements regarding Lyme disease vaccine is false?

a. The Lyme disease vaccine currently licensed by the FDA is a recombinant outer surface protein A.

b. The Lyme disease vaccine should be considered for travelers to high-risk areas who may have prolonged or frequent exposure to tick-infested habitat.

c. The Lyme disease vaccine is not recommended for pregnant women or children younger than the age of 15 years.

d. Avoidance of tick habitat, use of insect repellent, and regular checking and removal of ticks are important measures in preventing Lyme disease.

e. The Lyme disease vaccine should be given to all residents of endemic areas.