During clinical trials involving 6,478 individuals receiving a total of 18,047 doses, LYMErix has been generally well tolerated.

Subjects with the following conditions: chronic joint or neurologic illness related to Lyme disease; diseases associated with joint swelling (including rheumatoid arthritis) or diffuse musculoskeletal pain; second- or third-degree atrioventricular block or a pacemaker were excluded from the efficacy trial because such conditions could interfere with the assessment of Lyme disease in the trial. Therefore, data are limited regarding the safety of the vaccine in subjects with these conditions (see below).

Unsolicited Adverse Events

The most frequently reported (³1%) unsolicited adverse events within 30 days of vaccination for all subjects receiving at least one dose (n= 10,936) in the double-blind, placebocontrolled efficacy trial are shown in Table 2.

* Includes events obtained through spontaneous reports following each dose and events reported 1 month after doses 1 and 2 (when all subjects were queried regarding the occurrence of any adverse event since the previous vaccination).

a. p-value <0.05.

b. p-value <0.01.

c. p-value <0.001.

The most frequently reported (³1%) unsolicited adverse events occurring more than 30 days following vaccination for all subjects (n= 10,936) in the double-blind, placebocontrolled efficacy trial are shown in Table 3.

*Data for adverse events occurring more than 30 days after dose 1 are not provided because most subjects received dose 2 approximately 30 days after dose 1.

Note: No significant differences in adverse events were noted between treatment groups after any dose and overall.

Separate post hoc analyses were conducted to assess two subsets of musculoskeletal events which occurred either early (≤30 days) or late (>30 days) post-vaccination. There were no significant differences, either early or late, between the vaccine and placebo recipients with regard to experiencing arthritis, aggravated arthritis, arthropathy or arthrosis. However, vaccine recipients were significantly more likely than placebo recipients to experience early events of arthralgia or myalgia after each dose [for dose 1: odds ratio (OR), (95% CI) = 1.35 (1.13, 1.61); dose 2: OR = 1.28 (1.05, 1.56); dose 3: OR = 1.59 (1.18, 2.16)]. With regard to late events of arthralgia or myalgia, there were no significant differences between vaccine and placebo recipients.

There was no significant difference in the rates of cardiac adverse events between vaccine and placebo recipients. Neurologic adverse events which occurred at a rate <1% in the vaccine group and were noted to occur with a similar frequency in placebo recipients included: carpal tunnel syndrome, migraine, paralysis, tremor, coma, dysphonia, ataxia, multiple sclerosis, myasthenia gravis, meningitis, trigeminal neuralgia, nystagmus, neuritis, neuralgia, nerve root lesion, neuropathy, hyperesthesia, hyperkinesia, and intracranial hypertension.

Overall, approximately 18% of subjects enrolled in the study had a prior history of some musculoskeletal condition (19% vaccinees, 18% placebo recipients). In a post hoc subgroup analysis, there was no significant difference between vaccine and placebo recipients with regard to development of musculoskeletal events (defined as arthritis, arthropathy, arthrosis, synovitis, tendinitis, polymyalgia rheumatica, bursitis or rheumatoid arthritis and lasting more than 30 days) in those with a prior history of musculoskeletal conditions. However, both vaccine and placebo recipients with a prior history of musculoskeletal conditions were more likely to experience musculoskeletal events than subjects without such prior history.

Solicited Adverse Events

The frequency of solicited local and systemic adverse events was evaluated in a subset of subjects (n= 938) who comprised the total enrollment at one study center in the efficacy trial. Of these 938 subjects, 800 completed a 4-day diary card following each of three doses, and were evaluable according to protocol. Table 4 shows the percentage of subjects reporting a solicited symptom following any one of the three doses and overall. The majority of the solicited events were mild to moderate in severity and limited in duration.

* Severe = measuring 3.0 cm and persisting longer than 24 hours.
† Severe = preventing everyday normal activity.
a. p-value <0.05.
b. p-value <0.01.
c. p-value <0.001.

Subjects with Previous Lyme Disease

Subjects with previous Lyme disease were assessed using two definitions: subjects whose baseline sera were evaluated for Western blot (WB) positivity and subjects who at study entry selfreported a previous history of Lyme disease.

Study participants did not routinely have baseline sera tested by WB for Lyme disease. WB at baseline was performed for subjects who were noted to have a positive or equivocal WB during a visit for suspected Lyme disease or when tested at months 12 or 20. Baseline serology was thus found to be positive in 250 subjects out of 628 tested. The nature and incidence of adverse events (either early or late) did not differ between vaccinees determined to have been WB-positive at baseline (n= 124) compared to vaccinees determined to have been WB-negative at baseline (n= 151).

There were 1,206 subjects enrolled in the study who self-reported a previous history of Lyme disease (610 vaccinees, 596 placebo recipients). For adverse events occurring within the first 30 days, there was an increased incidence of musculoskeletal symptoms in vaccinees with a history of Lyme disease compared to vaccinees with no history of Lyme disease (20% vs. 13%, p <0.001). No such difference was observed in the placebo group (13% vs. 11%, p= 0.24). Subjects with a previous history of Lyme disease had an increased incidence of late (30 days post-vaccination) musculoskeletal symptoms compared to subjects without a history of Lyme disease in both the vaccine and placebo groups. There was no significant difference in late musculoskeletal adverse events between vaccine and placebo recipients with a history of Lyme disease (33% vs. 35%, p= 0.51).

Subjects with a self-reported prior history of Lyme disease had a greater incidence of psychiatric disorders (early and late); central, peripheral and autonomic nervous system disorders (late); and gastrointestinal disorders (late) than subjects with no prior history of Lyme disease. However, there was no significant difference in the incidence of any of these disorders between vaccine and placebo recipients with a prior history of Lyme disease.

Among the 10,936 subjects enrolled in the efficacy trial and followed for 20 months, a total of 15 deaths occurred (10 vaccine, 5 placebo). None of these deaths were judged to be treatmentrelated by investigators. In the vaccine group, causes of death included: cancer (5), myocardial infarction (3), sudden death (1), cardiac arrest (1). In the placebo group, causes of death included: cancer (1), sudden cardiac death (1), cardiac arrest (1), septic shock (1), homicide (1).

As with all pharmaceuticals, it is possible that expanded commercial use of the vaccine could reveal rare adverse events not observed in clinical studies.

No data are available on the immune response to LYMErix when administered concurrently with other vaccines. As with other intramuscular injections, LYMErix should not be given to individuals on anticoagulant therapy, unless the potential benefit clearly outweighs the risk of administration.

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