Recommended Topic Related To:

Lymerix

"Thanks to effective vaccine, the United States has been polio-free since 1979. But poliovirus is still a threat in some countries. Be part of the success story and get your child vaccinated on schedule.

Polio, or poliomyelitis, is an in"...

Lymerix

Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)

CLINICAL PHARMACOLOGY

Microbiology

Lyme disease is a multisystem disease caused by infection with the bacterial spirochete, B. burgdorferi, which is transmitted by Ixodes ticks. The enzootic life cycle of B. burgdorferi is dependent upon its transmission between an insect vector, the Ixodes tick, and a reservoir host, most commonly the white-footed mouse. Tick larvae usually feed in the late summer and acquire B. burgdorferi from an infected animal host. Nymphal ticks feed in the late spring and summer, and serve as the most common source of human infection. Adult ticks feed in the fall, winter and early spring, with the white-tailed deer being the preferred host. Adult ticks can also transmit B. burgdorferi to humans.1 Both deer and rodent hosts are necessary to maintain the enzootic cycle of B. burgdorferi.

Epidemiology

Lyme disease is the most commonly diagnosed vector-borne disease in the United States, with over 99,000 cases reported to the Centers for Disease Control and Prevention (CDC) from 1982 to 1996. During that time, the incidence of reported cases increased by at least 32-fold. Although most cases have been reported in the Northeast, upper Midwest and Pacific coastal areas of the United States, infections have been reported in almost all states.2 The incidence rates vary considerably from state to state and even within states at the county level.2

The trend of an increasing incidence in some established endemic areas continues, along with the geographic spread of the causative organism to new areas.1,2,4,5

Lyme disease has a bimodal age distribution, with the highest number of cases occurring in children 2 to 15 years of age and adults 30 to 55 years of age.4

The primary risk factor for Lyme disease is exposure to wooded or grassy areas inhabited by B. burgdorferi-infected ticks. Such areas may include woodlands, meadows, or residential yards in endemic areas.5 Cases have been reported in people whose only exposure to B. burgdorferi has been while on vacation in an endemic area.1

Lyme disease has been reported to occur throughout the year.7, 8 Peak incidence of Lyme disease varies by region and may vary annually based on fluctuations in local climatic conditions.1,5,7,8 For example, the peak occurs in the late spring and summer in the Northeast United States, coincident with the feeding of nymphal ticks, the most common source of human infection. Transmission can occur also in the fall, winter, and early spring when adult ticks are feeding.1

Clinical Manifestations: Lyme disease has a variable incubation period.5 Lyme disease is a multisystem disease, which has been described as having early and late stages. The early stage is usually characterized by a rash (erythema migrans) and may be accompanied by fever, fatigue, myalgias and/or arthralgias. Erythema migrans represents a localized cutaneous infection and is the presenting symptom in 60% to 80% of cases. Early disseminated manifestations include secondary skin lesions, neurologic involvement (meningitis, facial palsy, other cranial neuritides, radiculoneuritis), cardiac involvement (atrioventricular block, myocarditis), and musculoskeletal symptoms usually consisting of migratory pain in joints and the surrounding soft tissue structures.9

Late stage disease (persistent infection) occurs months to years after initial infection and may be manifested as chronic arthritis, chronic neurologic abnormalities or acrodermatitis chronica atrophicans. Not all patients with Lyme disease have this characteristic progression of symptoms. Late stage disease usually requires more intensive therapy and may result in permanent sequelae. In particular, late neurologic involvement is associated with chronic, slowly progressive disease.10

The rate of asymptomatic infection has not been well studied in adults. In the LYMErix (lipoprotein outer surface a vaccine) [Lyme Disease Vaccine (Recombinant OspA)] study, the rate of asymptomatic infection (for definition, see Clinical Efficacy, Asymptomatic B. burgdorferi infection below) was approximately 0.25% per year with one case of asymptomatic infection occurring for every four cases of erythema migrans.

Late stage disease may result from early disease that is either unrecognized or fails to respond to treatment, or from asymptomatic infection. The relative importance of these conditions in predisposing to the development of late stage disease is unknown.

Diagnosis: Diagnosis is based on clinical manifestations, epidemiologic information and laboratory evaluation. Confirming the diagnosis may be difficult in some cases.

At a consensus meeting of the CDC and ASTPHLD (Association of State, Territorial and Public Health Laboratory Directors), a two-step approach was recommended if serologic evaluation of Lyme disease is required.11 A sensitive screening test such as an enzymelinked immunosorbent assay (ELISA) or immunofluorescent assay (IFA) is recommended as the initial laboratory test and if positive or equivocal, immunoblot (Western blot) testing should be performed to confirm the results (see PRECAUTIONS, Laboratory Test Interactions).

LYMErix (lipoprotein outer surface a vaccine) Mechanism of Action: LYMErix (lipoprotein outer surface a vaccine) stimulates specific antibodies directed against B. burgdorferi. The organism contains several outer surface proteins, with lipoprotein OspA being immunodominant.12 Administration of lipoprotein OspA to mice resulted in the formation of specific IgG anti-OspA antibodies, including those directed against a specific epitope, LA-2 (designated LA-2 equivalent antibodies). These antibodies have demonstrated bactericidal activity. Studies have shown that mice immunized with recombinant lipoprotein OspA are protected against disease after tick challenge with B. burgdorferi.13 LA-2 equivalent antibody titers have been shown to correlate with protection against infection in laboratory animals.14

B. burgdorferi express OspA while residing in the midgut of the infected tick, but OspA is downregulated after tick attachment and is usually undetectable or absent when B. burgdorferi is inoculated into the human host.15 Thus, a novel hypothesis has been proposed to explain the effectiveness of lipoprotein OspA vaccination: when infected ticks bite humans who have been vaccinated with LYMErix (lipoprotein outer surface a vaccine) , the vaccine-induced antibodies are taken up by the tick and interact with the B. burgdorferi in the midgut of the tick, thereby preventing transmission of the organism to the host. This mechanism has been suggested by a pre-clinical study in which B. burgdorferi were detected by immunofluorescence assay in none of the ticks that fed on OspA-immunized mice, compared with 72% of ticks that fed on control-immunized mice.13

Clinical Efficacy

A randomized, double-blind, multicentered, placebocontrolled trial has shown that LYMErix (lipoprotein outer surface a vaccine) confers protection against Lyme disease.16 This trial was conducted in highly endemic areas of the United States, primarily in the Northeast, and enrolled 10,936 subjects (5,469 vaccinees; 5,467 placebo recipients) ages 15 to 70 years. Subjects with a history of previous Lyme disease were not excluded from this trial.

Subjects vaccinated with three doses of LYMErix (lipoprotein outer surface a vaccine) or placebo at months 0, 1 and 12 were observed for 20 months after the first injection (January 1995 through November 1996). The primary endpoint of the trial was the incidence of definite Lyme disease after two doses of vaccine. Each subject was actively followed for symptomatic disease during the entire observation period and was assessed for possible asymptomatic infection (as evidenced by IgG Western blot seroconversion) at months 12 and 20.

Definite Lyme disease

In the pivotal efficacy trial, definite Lyme disease was defined as clinical manifestations (erythema migrans, neurologic, musculoskeletal or cardiovascular involvement) with laboratory confirmation (positive culture for B. burgdorferi from skin biopsy; positive polymerase chain reaction [PCR] result for B. burgdorferi from skin biopsy, synovial fluid, or CSF; or IgM or IgG Western blot seroconversion) as defined by CDC/ASTPHLD criteria.11

Post-second dose efficacy was measured beginning at 4 weeks following the second dose through to month 12. Post-third dose efficacy was measured from the third dose through to month 20.

Prevention of Definite Lyme Disease: Vaccine efficacy against definite Lyme disease was 78% (95% CI: 59% to 88%) after three doses of vaccine administered according to protocol (13 cases among 4,765 subjects in the vaccine group; 58 cases among 4,784 subjects in the placebo group). Vaccine efficacy against definite Lyme disease was 50% (95% CI: 14% to 71%) after two doses of vaccine administered according to protocol (20 cases among 5,148 subjects in the vaccine group; 40 cases among 5,166 subjects in the placebo group).

Asymptomatic B. burgdorferi infection

In the pivotal efficacy trial, subjects were defined as having asymptomatic infection when, in the absence of recognizable clinical symptoms, IgG Western blot seroconversion occurred either between months 2 and 12 of the first year, or between months 12 and 20 of the second year.

Prevention of Asymptomatic Infection: Vaccine efficacy against asymptomatic B. burgdorferi infection was 100% (95% CI: 30% to 100%) after three doses of vaccine administered according to protocol (0 cases among 4,765 subjects in the vaccine group; 13 cases among 4,784 subjects in the placebo group). Vaccine efficacy against asymptomatic B. burgdorferi infection was 83% (95% CI: 25% to 96%) after two doses of vaccine administered according to protocol (2 cases among 5,148 subjects in the vaccine group; 12 cases among 5,166 subjects in the placebo group).

Possible Lyme disease

In the pivotal efficacy trial, possible Lyme disease was defined as a flu-like illness (fever, chills, fatigue, headache, joint or muscle aches) with IgM or IgG Western blot seroconversion, or physician-diagnosed erythema migrans with negative laboratory results.

Prevention of Possible Lyme Disease: Following the threedose course of vaccine administered according to protocol, efficacy was 48% (95% CI: 1% to 73% ) against possible Lyme disease. Fourteen of the subjects in the vaccine group developed a possible case of Lyme disease, compared to 27 placebo recipients. Following two doses of vaccine administered according to protocol, the vaccine efficacy against possible Lyme disease was 21% (95% CI: -45% to 56%). Nineteen subjects who received two doses of vaccine developed possible Lyme disease, compared to 24 placebo recipients.

The data regarding flu-like illnesses due to possible Lyme disease may be confounded by possible cross-reactivity and/or co-infection with Ehrlichia, which may cause a flu-like illness and false-positive IgM Western blot for B. burgdorferi.17

Lyme Disease Manifestations and Laboratory Diagnosis in the Efficacy Trial: The clinical presentation of the 131 cases of definite Lyme disease was as follows: erythema migrans, 128 (32 vaccine, 96 placebo); arthritis, 1 (vaccine); trigeminal neuralgia, 1 (placebo); and facial palsy, 1 (placebo). Of the 128 cases with erythema migrans, additional presenting clinical manifestations included: facial palsy, 3 (1 vaccine, 2 placebo) and trigeminal neuralgia, 1 (placebo). The duration of erythema migrans was similar for both vaccinees and placebo recipients.

Subjects were treated at either acute presentation of Lyme disease symptoms, following laboratory confirmation of symptoms, or following laboratory confirmation of asymptomatic infection. Active surveillance and prompt treatment of identified cases may have accounted for the low incidence of late Lyme disease manifestations. A similar proportion of definite Lyme disease cases in both vaccine and placebo groups were confirmed by positive culture, PCR analysis, or Western blot seroconversion.

Immunogenicity in Persons 15 to 70 Years of Age: In the pivotal efficacy trial, immunogenicity of LYMErix [Lyme Disease Vaccine (Recombinant OspA)] was assessed by measuring IgG anti-OspA antibodies and LA-2 equivalent antibodies in a subset of subjects 15 to 70 years of age enrolled at one study center. Table 1 shows the seropositivity rates and geometric mean titers (GMTs) following the second and third doses of LYMErix (lipoprotein outer surface a vaccine) .

Table 1.

Immunogenicity in Vaccinees.

Antibody

Sampling Time

Seropositivity*

GMT-EL.U./mL

   

% (n/ N)

(95% CI)

Total IgG Anti-OspA 1 mo. after dose 2

99% (260/ 264)

1227 (1029, 1463)

  Pre-dose 3

83% (201/ 241)

116 (96, 139)

  1 mo. after dose 3

100% (267/ 267)

6006 (5180, 6963)

  7 mos. after dose 3

98% (262/ 267)

1991 (1686, 2351)

     

GMT- ng/ mL (95% CI)

LA-2 Equivalent 1 mo. after dose 2

96% (236/ 245)

909 (773,1067)

  Pre-dose 3

58% (150/ 258)

132 (118, 149)

  1 mo. after dose 3

99% (220/ 222)

4402 (3686, 5257)

  7 mos. after dose 3

97% (217/ 223)

1935 (1628, 2300)


* Seropositivity defined as an IgG OspA antibody titer >/=20 EL. U./mL or a LA-2 equivalent antibody titer

³100 ng/mL.

At month 12.

n/N = number of seropositive subjects/total subjects tested.

% = percentage of seropositive subjects.

Subjects in the placebo group did not develop detectable anti-OspA seropositivity at the sampling time points indicated in the above table.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.


NIH talks about Ebola on WebMD