Vaccination against Lyme disease caused by diverse Borrelia burgdorferi.

Abstract

SummaryDiversity and mutations in the genes for outer surface proteins (Osps) A and B ofBorrelia burgdorferi sensu lato (13, burgdorferi), the spirochetal agent of Lyme disease, suggests that a monovalent OspA or OspB vaccine may not provide protection against antigenically variable naturally occurring B, burgdorferi. We now show that OspA or OspB immunizations protect mice from tick-borne infection with heterogeneous/g burgdorferi from different geographic regions. This result is in distinct contrast to in vitro killing analyses and in vivo protection studies using syringe injections of/g burgdorferi as the challenge inoculum. Evaluations of vaccine efficacy against Lyme disease and other vector-borne infections should use the natural mode of transmission and not be predicated on classification systems or assays that do not rely upon the vector to transmit infection.V accination with outer surface proteins (Osps)lA or B from a Borrelia burgdorferi sensu law (13, burgdorferi) isolate (designated N40) protected C3H/HeJ mice from infection when challenged with the same strain (1, 2). Humoral immunity was sufficient for protection as the passive transfer of OspA or OspB antibodies protected C.B.-17 scid or C3H mice from/3; burgdorferi infection (1-4). OspA and OspB variability, including amino acid differences or truncations of the COOH terminus of the Osps, however, allowed/~ burgdorferi to survive in the presence of protective antibody in vitro and in vivo, predicting a lack of vaccine efficacy (2, 5-11). In addition, spirochetes have been identified that lack the 49-kb plasmid encoding ospA and ospB or have chimeric Osps due to homologous recombination between ospA and ospB, suggesting that OspA or OspB mediated immunity would not be protective in the event of infection by these mutants (7,12). The infectivity of these mutant spirochetes in selected hosts has not yet been delineated. RFLP, multilocus enzyme electrophoresis, or nucleic acid hybridization studies distinguished as many as four groups of/t burgdorferi, with the 1 Abbreviation used in this paper: Osp, outer surface protein. 215description of three new proposed species-/g burgdorferi sensu stricto, Borrelia afzelii, and Borrelia garinii (13)(14)(15)(16)(17). Similarly, reactivity with OspA mAbs divided/g burgdorferi into seven serogroups which upon detailed analysis (several of the serotypes were variants of the three species that arose from osp recombination) corresponded to the three new species (13). lg burgdo~feri sensu stricto is prevalent in North America whereasEuropean sites may contain all three species. In vivo passive immunization studies demonstrated that antiserum against spirochetes from individual groups protected scid mice or hamsters against challenge with homologous, but not heterologous/~ burgdorferi (8,18).The in vivo protection studies used single isolates of/~ burgdorferi, and syringe inoculations as the method of spirochete challenge, and therefore do not mimic natural transmission of the agent. Accordingly, we have shown that v...

Vector Competence of Ixodes scapularis and Ixodes ricinus (Acari: Ixodidae) for Three Genospecies of Borrelia burgdorferi

“…Most vaccine trials have used ticks infected in the laboratory with only B. burgdorferi sensu stricto (Gern et al 1994. One vaccine trial used a combination of ticks collected in the field in the northeast United States, California, Sweden, and Germany, as well as ticks exposed to characterized strains (Fikrig et al 1995). Fikrig et al (1995) showed that a single antigen produced from the OspA gene derived from B. burgdoiferi sensu stricto could afford protection against both B. burgdorferi sensu stricto and B. afzelii.…”

“…One vaccine trial used a combination of ticks collected in the field in the northeast United States, California, Sweden, and Germany, as well as ticks exposed to characterized strains (Fikrig et al 1995). Fikrig et al (1995) showed that a single antigen produced from the OspA gene derived from B. burgdoiferi sensu stricto could afford protection against both B. burgdorferi sensu stricto and B. afzelii. These researchers failed, however, to infect rodents with B. gflrinu-infected ticks.…”

“…Thus, evaluation of vaccine efficacy should be assessed using tick transmission (Fikrig et al 1995). Moreover, ticks infected with each of the 3 genospecies would allow for a heterologous tick challenge to assess comprehensively protection afforded by candidate antigens.…”

Specific Issues in the Design and Implementation of an Efficacy Trial for a Lyme Disease Vaccine

“…Tick transmission studies have also indicated a annular rash with central clearing that occurs at the site of the significant degree of vaccine-induced cross-protection between tick bite in Ç60% -80% of cases. Late-stage disease, which can spirochetes from different regions of the U.S. [9]. Following the initial phase I studies, a double-blind, placebocontrolled dose-range study was conducted in 350 healthy adult residents of three New England islands on which LD is highly vations: all doses were well tolerated, although mild local reac-10 states were selected for the pivotal trial.…”

“…In istered 1 year later. Prolonged surveillance was employed because of the long latency period for the appearance of some 1993, a total of 8,285 cases of LD were reported to the CDC by 44 states, 15% less than the number of LD cases (9,677) of the symptoms (e.g., rheumatological and neurological manifestations) and because it will assist in addressing the issue of reported in the continental United States during 1992 [14].…”