Lyme Disease Vaccine (Recombinant OspA) – LYMErix; recombinant Borrelia burgdorferi outer surface protein A (OspA)
Status - formerly marketed; withdrawn in 2002
Organizations involved:
GlaxoSmithKline Biologicals S.A. – Manuf.; R&D; Tech.; Former
GlaxoSmithKline Inc. – USA mark.; Former
GlaxoSmithKline plc – Parent; Former
SmithKline Biologicals S.A. – R&D; Tech.; Former
Symbicom AB – R&D; Tech.; Former
National Cancer Institute (NCI), NIH – Tech.
National Institutes of Health (NIH) – Parent org.
Description: Lyme Disease Vaccine (Recombinant OspA) or LYMErix vaccine is an aqueous formulation of recombinant Borrelia burgdorferi sensu stricto ZS7 bacterial outer surface lipoprotein A (L-OspA) as expressed by transformed Escherichia coli (E. coli) cells complexed with aluminum hydroxide (alum) adjuvant. Full-length L-OspA is expressed by E. coli strain AR58 transformed with plasmid pOA15 (apparently related to plasmid pAS1) containing the ospA gene of B. burgdorferi strain ZS7, with the lipid moiety of the molecule appended after translation, resulting in L-OspA. This immungen is adsorbed onto aluminum hydroxide adjuvant in phosphate-buffered saline, resulting in L-OspA with adjuvant (LYMErix). B. burgdorferi L-OspA is a single chain 257-amino acid polypeptide with lipid molecules covalently bonded to the N-terminus.
LYMErix was packaged as a sterile suspension with no need for reconstitution (just shaking) in single-dose vials and prefilled syringes for intramuscular injection. Each 0.5 ml dose contained 30 µg of L-OspA adsorbed onto 0.5 mg aluminum (as aluminum hydroxide) adjuvant, in 10 nM phosphate buffered saline (PBS) with 2.5 mg of 2-phenoxyethanol, a bacteriostatic preservative.
Nomenclature: Lyme Vaccine, rDNA/GSK [BIO]; LYMErix [TR]; Lyme Disease Vaccine (Recombinant OspA) [FDA]; Lyme Vaccine, recombinant [SY]; Borrelia burgdorferi outer surface protein A (OspA), recombinant [SY]; L-OspA with aluminum hydroxide adjuvant [SY]
Note, it is common for the ‘L’ to be dropped from ‘L-OspA’ when referring to LYMErix and/or B. burgdorferi outer surface (lipo)protein A antigen, even in technical materials. Thus, it is often difficult to determine whether the protein with or without terminal lipid is being referred to. However, ‘OspA’ generally refers to B. burgdorferi lipoprotein A (L-OspA).
Borrelia burgdorferi subtypes including ZS7, B31, and N40, are often referred to as group I, while alternative nomenclature refers to group I strains as group A.
Biological.: Borrelia burgdorferi sensu stricto, a spirochete bacterium, is the causative agent of the chronic infection Lyme disease or Lyme borreliosis in North America. The spirochete is transmitted to humans and animals through the bite of a tick (particularly, Ixodes ricinus, the common deer tick). Infection can cause serious dermatological, arthritic, neurological and other pathological disorders. Borrelia, like Treponema pallidum, which causes syphilis, and leptospirae, which cause an infectious jaundice, belong to the eubacterial phylum of spirochetes. Borrelia burgdorferi has a protoplasmic cylinder surrounded by a cell membrane, then by flagella, and then by an outer membrane. Embedded in the outer membrane are two major proteins, the 31 kDa outer-surface protein A (L-OspA) and the 34 kDa outer surface protein B (L-OspB). These two proteins have been shown to vary from different isolates and from different passages of the same isolate, as determined by molecular weight and reactivity with monoclonal antibodies. OspB may not be produced at all in cultures of B. burgdorferi.
The potency of LYMErix is determined by measuring serum antibody response to OspA in mice by ELISA.
LYMErix is unique among all vaccines having received FDA approval in that it does not have in vivo functionality in humans. Rather, the L-OspA antibodies induced in humans by the vaccine are effective in Ixodes ticks, e.g., deer ticks, the carriers or vectors to humans of B. burgdorferi. When B. burgdorferi-infected ticks bite humans who have been vaccinated with LYMErix, the vaccine-induced antibodies are taken up by the tick and neutralize the B. burgdorferi bacteria in the midgut of the tick, preventing transmission of the organism to the human host. Human L-OspA polyclonal antibodies, e.g., induced by vaccination (LYMErix) or prior natural infection, neutralize B. burgdorferi in the gut of the tick as the tick sucks blood from its human host. B. burgdorferi expresses L-OspA while residing in the midgut of the infected tick. OspA expression is downregulated after tick attachment and is usually undetectable or absent when B. burgdorferi is transferred by the tick into the human host. This mechanism has been suggested by a pre-clinical study in which B. burgdorferi was 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.
Persons with Lyme disease (symptomatic B. burgdorferi infection) develop neutralizing antibodies to B. burgdorferi outer surface proteins, with lipoprotein OspA (L-OspA) being immunodominant. Administration of L-OspA to mice results in the formation of specific IgG antibodies, including those directed against a specific epitope, LA-2 (designated LA-2 equivalent antibodies). LA-2 antibodies have bactericidal activity. LA-2-equivalent antibody titers have been shown to correlate with protection against infection in laboratory animals. Studies have shown that mice immunized with recomL-OspA are protected against disease after challenge with B. burgdorferi-infected ticks.
The outer surface lipoprotein A (L-OspA) of the B. burgdorferi bacterium has been implicated as causing persistent arthritis in patients with Lyme disease. Higher levels of L-OspA antibodies in patients have been associated with increased severity of arthritis joint swelling. L-OspA is similar to the human HLA DR4 protein on the surface of certain blood cells. Persons positive for (expressing) HLA DR4 have been shown more likely than others to develop persistent arthritis from Lyme disease, and may be more prone to arthritic complications from LYMErix. However, there is insufficient evidence to definitively link the vaccine as causing arthritis (although critics allege that the FDA’s vaccine adverse effects reporting system is inherently inadequate to perform such analyses).
Companies.: LYMErix was originally developed by SmithKline Biologicals S.A., now GlaxoSmithKline Biologicals S.A., a subsidiary of GlaxoSmithKline plc, and was manufactured by GlaxoSmithKline Biologicals S.A., CBER/FDA est. no. 1617. LYMErix was marketed in the U.S. by GlaxoSmithKline Inc., and was marketed by GSK affiliates internationally. In early 2002, GSK announced it was halting further manufacture (see the Status section below).
Manufacture: Isolated, purified, soluble Borrelia lipoproteins can be obtained from purification of Borrelia cell cultures, but this approach is not practical for vaccine manufacture. The growth and subsequent purification of (lipo)proteins from crude cell extracts of Borrelia is very time-consuming and expensive, and the growth and manipulation of live Borrelia cultures adds significant risk for workers. The association of the Borrelia lipoproteins with the cell membrane of the B. burgdorferi spirochete also creates problems in the separation and purification of these proteins from crude cell extracts. Recombinant manufacturing is more cost-effective and practical.
Full-length OspA protein is expressed by E. coli strain AR58 transformed with plasmid pOA15 containing the OspA gene from B. burgdorferi strain ZS7 grown in Barbour-Stoenner-Kelly’s medium (as described in Schailble, et al., J. Exp.Med., 170. 1989). As indicated by patent licensing (see Tech. transfer section below), the pAS1 cloning vector is used to achieve high levels of OspA expression. Fermentation media consist primarily of inorganic salts and vitamins with small quantities of antifoam (polysiloxane or silicone compounds), kanamycin sulfate (an aminoglycoside antibiotic), and yeast extract. Silicone compounds and kanamycin sulfate are removed to levels below the limits of detection (<7 ppm and <10 ppb, respectively) in the final product. The generation time is about 20-24 hours. The lipid moiety of the molecule is attached to the protein within the yeast cell after translation, resulting in L-OspA. Purified L-OspA is adsorbed onto aluminum hydroxide in phosphate-buffered saline, resulting in L-OspA with aluminum hydroxide adjuvant (LYMErix). The product insert/labeling stated, “No substance of animal origin is used in the commercial manufacturing process.”
Methods for large-scale manufacture and purification of a related veterinary vaccine were reported by Pfizer investigators in Bioseparation, vol 6., p. 115-23, 1996.
FDA class: Biologic BLA
CBER class: Bacterial Antigens and Vaccines
Approvals: Date = 19981221; first approval, BLA
Indications: [full text of the “INDICATION AND USAGE” section from product insert/labeling]:
LYMErix is indicated for active immunization against Lyme disease in individuals 15 to 70 years of age.
Individuals most at risk may be those who live or work in B. burgdorferi-infected tick-infested grassy or wooded areas (e.g., landscaping, brush cleaning, forestry, and wildlife and parks management), as well as those who plan travel to or pursue recreational activities (e.g., hiking, camping, fishing and hunting) in such areas. Most cases of Lyme disease in the United States are thought to be acquired in the peri-residential environment, through routine activities of property maintenance, recreation, and or exercise of pets.
Previous infection with B. burgdorferi may not confer protective immunity. Therefore, people with a prior history of Lyme disease may benefit from vaccination with LYMErix.
Safety and efficacy of this vaccine are based on administration of the second and third doses several weeks prior to the onset of Borrelia transmission season in the geographic area (see DOSAGE AND ADMINISTRATION).
LYMErix is not a treatment for Lyme disease.
As with any vaccine, LYMErix may not protect 100% of individuals. The vaccine should not be administered to persons outside of the indicated age range.
Status: The BLA was filed on Sept.15, 1997. Approval was granted on December 21, 1998; review time = ~15.2 months (~1.27 year). This was the first approval for LYMErix, and the product was first marketed in the U.S.
In Feb. 2002, GSK announced it was discontinuing manufacture and marketing of LYMErix. This was not a recall, although purchasers could return vaccine stocks for a refund. Dozens of lawsuits had been filed claiming permanent disability due to a rare form of autoimmune arthritis after vaccination. Several days before GSK’s announcement, the Lyme Disease Association and the International Lyme and Associated Disease Society met with FDA to express concerns about the vaccine’s safety, with some suggesting this prompted action by GSK.
FDA had reported that there was no clear evidence of a causal association between the vaccine and arthritis. The Centers for Disease Control and Prevention (CDC) reviewed 905 adverse reactions reported to the FDA’s Vaccine Adverse Event Reporting System (VAERS) between Dec. 1998 and July 2000 and found no safety problems other than hypersensitivity reactions (see Vaccine, Feb. 22, 2002, p. 1603), although there were 50 reports of suspected arthritis, 34 of arthrosis, 9 of rheumatoid arthritis, and 12 of facial paralysis; with 7.4% of reports classed as serious. Concurrently, the CDC reported Lyme disease was at a record level in the U.S.
GSK rigorously defended the safety of LYMErix, and cited business reasons for abandoning the product. Fewer than 10,000 persons were projected to receive LYMErix in 2002, a sales level not considered sufficient to justify manufacture and marketing. Factors likely affecting GSK’s decision included continuing reports of adverse effects, particularly arthritis associated with LYMErix, the need for three inoculations over a full year period to develop only partial immunity, studies indicating that further booster shots would be needed to maintain immunity, studies indicating that Lyme disease is harder to contract and easier to treat than previously thought, and the vaccine being ineffective against tick strains in Europe and other potential major markets.
In July 2003, GSK agreed to settle a class-action lawsuit (that consolidated six such suits) alleging that LYMErix could cause an arthritic condition in some people. However, those who received the vaccine received nothing from the settlement. The product was taken off the market in Feb. 2002, the primary goal of the suit. The 34 lawyers for the plaintiffs’ were compensated slightly over $1 million for their fees and expenses.
Tech. transfer: Dr. M.M. Simon and colleagues cloned and expressed OspA from B. burgdorferi ZS7, and demonstrated its protective capacity to induce antibodies in passively immunized SCID mice (Proc. Nat. Acad. Sci., vol. 87, p. 3768-3772, 1990; Science, vol. 227, p. 645, 1985). U.S. patent 5,434,077 (a divisional of 5,178,859), “Borrelia burgdorferi strain 257,” assigned to the Max-Planck-Gesellschaft zur Forderung der Wissenschaften and the Deutsches Krebsforschungszentrum, has only one claim stating, “Isolated Borrelia burgdorferi strain ZS7, DSM 5527,” with the source strain used for L-OspA antigen deposited as DSM 5527. U.S. 5,686,267, “Nucleic acid molecule encoding antigen associated with lyme disease,” claims recombinant Borrelia burgdorferi ZS7 OspA
and expression methods. U.S. patent 5,942,236, “Osp A proteins of Borrelia burgdorferi subgroups, encoding genes and vaccines,” Aug. 24, 1999, is coassigned to GlaxoSmithKline Biologicals, Max-Planck-Gesellschaft zur Forderung der Wissenschaften, and Deutsches Krebsforschungszentrum. Cloning and expression of L-OspA are discussed, but this patent does not explicitly include the expression vectors and full-length protein associated with LYMErix. Presumably, SKB/GSK licensed these LYMErix-related patents.
U.S. patent 5,688,512, “Borrelia antigen,” Bergstrom, S. and Barbour, A.G., issued November 18, 1997, assigned to Symbicom AB, describes isolation of various antigen fractions (A through F) from Borrelia burgdorferi along with vectors and expression of Borrelia burgdorferi OspA useful for vaccines. The nucleotide sequence coding for the full-length, wild-type OspA was originally determined for B31, the North American strain of B. burgdorferi. See Bergstrom, S. (Symbicom AB), et al., “Molecular Analysis of linear plasmid-encoded major surface proteins, OspA and OspB of the Lyme disease spirochete Borrelia burgdorferi,” Mol. Microbiol., vol. 3, p. 479-486, 1989. An international patent application, WO90/04411, assigned to Symbicom AB, discloses the cloning and expression of Osp A protein derived from B. burgdorferi B31 and its use as a vaccine. Presumably, SKB/GSK licensed these LYMErix-related patents.
SmithKline Beecham Corp., now GlaxoSmithKline, exclusively licensed expression vector technology used for manufacture of LYMErix from the National Cancer Institute (NCI), National Institutes of Health (NIH), including U.S. 4,925,799 and 4,578,355, license no. L-006-85 (active as early as 10/93). The plasmid cloning vector pAS1 containing both transcriptional and translational regulatory sequences from the lambda bacteriophage genome is useful as an expression vector for high-level expression of prokaryotic and eukaryotic genes. Plasmid pAS1 (ATCC 39262) is particularly useful for expression of cloned sequences in E. coli. This plasmid cloning vector, containing both transcriptional and translational regulatory sequences derived from the bacteriophage lambda genome, was constructed to achieve high level expression of prokaryotic and eukaryotic genes.
Trials: The pivotal randomized, multi-centered, placebo-controlled Phase III trial of LYMErix involving almost 11,000 people between 15-70 years of age was conducted in the northeast U.S. and Wisconsin, where Lyme disease is endemic. Individuals received three doses of vaccine at 0, 1, and 12 months, and were followed for 20 months after the first injection or through two tick seasons. After two doses of the vaccine in the first year of the trial, the protection rate against definite Lyme Disease was 50%; and in the second year, after three doses, was 78%. The vaccine was given only to healthy individuals, and was generally well tolerated. Local injection site reactions, including redness, soreness, and swelling, were common. Most other adverse events, such as flu-like symptoms and muscle and joint pain, occurred less frequently and were mild to moderate. No data are available regarding safety and efficacy in persons <15 or >70 years of age.
Disease: Lyme disease is the most commonly diagnosed vector-borne disease in the U.S. Over 99,000 cases were reported to CDC from 1982-1996. During that period, the incidence of reported cases increased by over 32-fold, and incidence has continued to rise. In May 2004, CDC reported that Lyme disease cases reached an all time high in 2002, 23,763 cases with an incidence rate of 8.2 cases/100,000, up from 17,029 cases with an incidence of 6.0 cases/100,000 in 2001, with cases in 47 states. Preliminary data indicate no changes in 2003, while tick populations (and likely, Lyme disease cases) will be much higher in 2004. Most cases are reported from the Northeast, upper Midwest and Pacific coastal areas of the U.S. Incidence varies from state to state and within states at the county level. The trend is for increasing incidence in established endemic areas and geographic spread of the causative organism to new areas. Lyme disease has a bimodal age distribution, with the highest number of cases in children ages 2-15 and in adults ages 30-55.
Borrelia spirochetes are responsible for a variety of human disorders including Lyme borreliosis and relapsing fevers. Borrelia burgdorferi is transmitted primarily by infected ixodes ticks that are part of the Ixodes ricinus complex, including the common deer tick. B. burgdorferi has also been shown to be carried in other species of ticks and by mosquitoes and deer flies, but it appears that only ticks of the I. ricinus complex are able to transmit the disease to humans.
Lyme disease generally occurs in three stages. Stage one involves a localized characteristic “bull’s eye” rash (erythema miarans) from which the spirochete may be cultured more readily than at any other time during infection. Flu-like or meningitis-like symptoms are common at this time. Stage two occurs within days or weeks, and involves spread of the spirochete through the patient’s blood or lymph to many different sites in the body including the brain and joints. Varied symptoms of this disseminated infection occur in the skin, nervous system, and musculoskeletal system, although symptoms are typically intermittent. Stage three, or late infection, is defined as persistent infection, and can be severely disabling. This includes chronic arthritis and syndromes of the central and peripheral nervous system appear during this stage as a result of the ongoing infection and perhaps resulting autoimmune disease. Infection often leads to relapsing fever characterized by repeated episodes of illness and fever separated by periods of well being. Lyme disease, named after Lyme, CT, where is was first identified, is rarely fatal.
Medical: The standard vaccination regimen involved inoculation at 0, 1, and 12 months. See, “Recommendations for the Use of Lyme Disease Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP),” in Morbidity and Mortality Weekly Report (MMWR), June 04, 1999; vol. 48(RR07); p. 1-17. LYMErix vaccine is effective in North America, but it targets a subspecies of the Borrelia burgdorferi that only accounts for 1% of European cases.
Statistical analyses show that a total titer of IgG antibody to L-OspA ≥ 40 EU/Ml before the start of the tick season should provide protection for at least one tick season (i.e., that antibody titer ≥ 400 EU/mL appears to be the minimum titer that assures protection at the moment of exposure).
Recent studies have indicated that Lyme disease is more difficult to contract and easier to treat than had previously been thought, e.g., that intensive and prolonged antibiotic treatment is not effective for symptomatic patients, while a single dose of the antibiotic doxycycline may be an effective treatment.
Market: The Average Wholesale Price (AWP) in 2002 was $67.40/vial. A full course of the vaccine (three doses) generally cost consumers about $150-$200.
GSK reported that sales of LYMErix peaked in 1999 at $40 million, and that demand then declined. A total of about 1.4 million doses of LYMErix were distributed.
SKB’s/GSK’s marketing in the U.S. included considerable direct-to-consumer (DTC) marketing, including television, print, outdoor, and other advertising, especially in high-risk areas. SKB spent $118 million on ads for the vaccine in 1999. SKB significantly increased its marketing through the end of the Lyme disease season in the fall of 2000. This included “guerrilla marketing,” e.g., sending lime green Volkswagen Beetles painted with the slogan, “Prevent Lyme disease. Call your doctor now,” to county fairs, horse shows, etc., along with informational teams. The ads did not explicitly mention LYMErix by name, allowing SKB to avoid disclosing the potential side effects of the drug. Cohn & Wolfe (New York, NY) handled public relations for LYMErix.
R&D: Successful safety studies have been reported for two new Lyme disease vaccines being developed by GlaxoSmithKline (GSK) and Baxter Hyland Immuno. These are expected to extend better coverage for European use. Baxter Healthcare has licensed patents from the State University of New York (SUNY; Stony Brook, NY) and Brookhaven National Laboratory (BNL; Upton, NY) concerning recombinant forms of OspA and Lyme vaccines designed to protect against all known species of the bacterium. SUNY and BNL researchers used the National Synchrotron Light Source at BNL, a particle acellerator, to examine the crystal structures of OspA proteins.
Companies involvement:
Full monograph
230 Lyme Vaccine, rDNA/GSK
Nomenclature:
Lyme Vaccine, rDNA/GSK [BIO]
Lyme Disease Vaccine (Recombinant OspA) [FDA]
LYMErix [TR]
Borrelia burgdorfi outer surface protein A (OspA), recombinant [SY]
L-OspA with aluminum hydryoxide adjuvant [SY]
Lyme Vaccine, recombinant [SY]
molecular weight (kDa) = 27.8
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19981221
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
lipoproteins
recombinant DNA
vaccines, bacterial
vaccines, subunit
antifoam agent
AR58, Escherichia coli (E. coli)
ATCC 20705
bacterial culture <!-- bacterialculture -->
Borellia burgdorferi, sensu stricto ZS7 strain
Escherichia coli (E. coli)
kanamycin sulfate
Park-William no. 8, Corynebacterium diphtheriae
plasmid p7E3VkappahCkappa
plasmid pOA15
pOA15 plasmid
ZS7, Borellia burgdorferi
2-phenoxyethanol
aluminum hydroxide
phosphate buffered saline (PBS)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US011 Approved Formerly in US/withdrawn
EM999 Not Available/Not Marketed in EU
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