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An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.

ABSTRACT: The antigenic component of a common Lyme disease vaccine is recombinant outer surface protein A (rOspA) of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Coincidentally, patients with chronic, treatment-resistant Lyme arthritis develop an immune response against OspA, whereas those with acute Lyme disease usually do not. Treatment-resistant Lyme arthritis occurs in a subset of Lyme arthritis patients and is linked to HLA.DRB1*0401 (DR4) and related alleles. Recent work from our laboratory identified T cell crossreactivity between epitopes of OspA and lymphocyte function-associated antigen 1alpha(L) chain (LFA-1alpha(L)) in these patients. We generated a form of rOspA, FTK-OspA, in which the LFA-1alpha(L)/rOspA crossreactive T cell epitope was mutated to reduce the possible risk of autoimmunity in genetically susceptible individuals. FTK-OspA did not stimulate human or mouse DR4-restricted, WT-OspA-specific T cells, whereas it did stimulate antibody responses specific for WT-OspA that were similar to mice vaccinated WT-OspA. We show here that the protective efficacy of FTK-OspA is indistinguishable from that of WT-OspA in vaccination trials, as both C3H/HeJ and BALB/c FTK-OspA-vaccinated mice were protected from Bb infection. These data demonstrate that this rOspA-derived vaccine lacking the predicted cross-reactive T cell epitope, but retaining the capacity to elicit antibodies against infection, is effective in generating protective immunity.

SUBMITTER: Willett TA

PROVIDER: S-EPMC337048 | biostudies-literature | 2004 Feb

REPOSITORIES: biostudies-literature

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An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.

Willett Theresa A TA Meyer Abbie L AL Brown Eric L EL Huber Brigitte T BT

Proceedings of the National Academy of Sciences of the United States of America 20040123 5

The antigenic component of a common Lyme disease vaccine is recombinant outer surface protein A (rOspA) of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Coincidentally, patients with chronic, treatment-resistant Lyme arthritis develop an immune response against OspA, whereas those with acute Lyme disease usually do not. Treatment-resistant Lyme arthritis occurs in a subset of Lyme arthritis patients and is linked to HLA.DRB1*0401 (DR4) and related alleles. Recent work from our ...[more]

PMID: 14742868

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Project description:Outer surface protein C (OspC) plays a pivotal role in mediating tick-to-host transmission and infectivity of the Lyme disease spirochete, Borreliella burgdorferi. OspC is a helical-rich homodimer that interacts with tick salivary proteins, as well as components of the mammalian immune system. Several decades ago, it was shown that the OspC-specific monoclonal antibody, B5, was able to passively protect mice from experimental tick-transmitted infection by B. burgdorferi strain B31. However, B5's epitope has never been elucidated, despite widespread interest in OspC as a possible Lyme disease vaccine antigen. Here, we report the crystal structure of B5 antigen-binding fragments (Fabs) in complex with recombinant OspC type A (OspCA). Each OspC monomer within the homodimer was bound by a single B5 Fab in a side-on orientation, with contact points along OspC's α-helix 1 and α-helix 6, as well as interactions with the loop between α-helices 5 and 6. In addition, B5's complementarity-determining region (CDR) H3 bridged the OspC-OspC' homodimer interface, revealing the quaternary nature of the protective epitope. To provide insight into the molecular basis of B5 serotype specificity, we solved the crystal structures of recombinant OspC types B and K and compared them to OspCA. This study represents the first structure of a protective B cell epitope on OspC and will aid in the rational design of OspC-based vaccines and therapeutics for Lyme disease. IMPORTANCE The spirochete Borreliella burgdorferi is a causative agent of Lyme disease, the most common tickborne disease in the United States. The spirochete is transmitted to humans during the course of a tick taking a bloodmeal. After B. burgdorferi is deposited into the skin of a human host, it replicates locally and spreads systemically, often resulting in clinical manifestations involving the central nervous system, joints, and/or heart. Antibodies directed against B. burgdorferi's outer surface protein C (OspC) are known to block tick-to-host transmission, as well as dissemination of the spirochete within a mammalian host. In this report, we reveal the first atomic structure of one such antibody in complex with OspC. Our results have implications for the design of a Lyme disease vaccine capable of interfering with multiple stages in B. burgdorferi infection.

Dataset Information

An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.

Publications

An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.

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