Therapeutic passive vaccination against chronic Lyme disease in mice

Abstract

Passive and active immunization against outer surface protein A (OspA) has been successful in protecting laboratory animals against subsequent infection with Borrelia burgdorferi. Antibodies (Abs) to OspA convey full protection, but only when they are present at the time of infection. Abs inactivate spirochetes within the tick and block their transmission to mammals, but do not affect established infection because of the loss of OspA in the vertebrate host. Our initial finding that the presence of high serum titers of anti-OspC Abs (5 to 10 g͞ml) correlates with spontaneous resolution of disease and infection in experimentally challenged immunocompetent mice suggested that therapeutic vaccination with OspC may be feasible. We now show that polyclonal and monospecific mouse immune sera to recombinant OspC, but not to OspA, of B. burgdorferi resolve chronic arthritis and carditis and clear disseminated spirochetes in experimentally infected C.B.-17 severe combined immunodeficient mice in a dose-dependent manner. This was verified by macroscopical and microscopical examination of affected tissues and recultivation of spirochetes from ear biopsies. Complete resolution of disease and infection was achieved, independent of whether OspC-specific immune sera (10 g OspC-specific Abs) were repeatedly given (4؋ in 3-to 4-day intervals) before the onset (day 10 postinfection) or at the time of fully established arthritis and carditis (days 19 or 60 postinfection). The results indicate that in mice spirochetes constitutively express OspC and are readily susceptible to protective OspC-specific Abs throughout the infection. Thus, an OspC-based vaccine appears to be a candidate for therapy of Lyme disease.

Artificial‐infection protocols allow immunodetection of novel Borrelia burgdorferi antigens suitable as vaccine candidates against Lyme disease

“…As shown in Table 3, passive transfer of rabbit IS specific for ZS7.A68 and, with one exception each, also those with specificity for ZS7.A36 or ZS7.A66 into recipients before experimental challenge led to complete protection against disease and infection. Rabbit and mouse IS to OspC served as positive controls and normal rabbit serum as a negative control [11,20]. In essence similar results were obtained with mouse IS (data not shown).…”

“…), resulted in resolution of joint swelling and clearance of spirochetes. Previous experiments [11,20,22] and our initial experiments (data not shown) had already demonstrated that § 10 3 IS or normal mouse sera had no or only minimal effects on established B. burgdorferi infection in SCID mice.…”

“…However, the previous finding that a fraction of experimentally challenged AKR/N mice with high levels of OspC-specific Ab was able to resolve infection [20] and that IS from tick-or needle-infected mice prevent subsequent infection in naive recipients [4,5] suggested that inherent spirochetal defense mechanisms can be breached by more-potent and/or morewell-timed Ab responses. This has been most convincingly documented for Ab to OspA and OspC [10,16,20]. These two lipoproteins are known to be differentially expressed on spirochetes in the vector and mammalian hosts [9,14].…”

“…Ab induced by the OspA vaccine are unable to resolve B. burgdorferi infection within the mammalian host for reasons given above [9,20]. However, our recent observation of a close correlation between high titers of serum Ab to OspC and resolution of infection in susceptible AKR/N mice suggested that spirochetes were susceptible to Ab in vivo as long as sufficient amounts of relevant Ab are available [20].…”

“…However, our recent observation of a close correlation between high titers of serum Ab to OspC and resolution of infection in susceptible AKR/N mice suggested that spirochetes were susceptible to Ab in vivo as long as sufficient amounts of relevant Ab are available [20]. This is supported by the finding that passive transfer of OspC-specific Ab prevents and resolves experimental and tick-borne B. burgdorferi infections in immunodeficient mice and in immunocompetent mice [11,20]. Thus, eradication of spirochetes during chronic infection may be feasible by artificially enhancing Ab responses to in-vivo-expressed B. burgdorferi antigens.…”