Therapeutic passive vaccination against chronic Lyme disease in mice - PubMed (original) (raw)

Therapeutic passive vaccination against chronic Lyme disease in mice

W Zhong et al. Proc Natl Acad Sci U S A. 1997.

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 microg/ml) 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 microg OspC-specific Abs) were repeatedly given (4x 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.

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Figures

Figure 1

Western blot analysis of NMS and IS used for passive immunization of C.B.-17 SCID mice. Lane 1, standard consisting of mouse mAbs to Hsp-70 (70 kDa), Hsp-60 (60 kDa), flagellin (41 kDa), OspB (34 kDa), OspA (31 kDa), OspC (24 kDa), pLA7 (20 kDa), and p7.5 (7.5 kDa). Lane 2, NMS, pooled from naive BALB/c mice. Lane 3, polyclonal IS generated in BALB/c mice immunized with rLip-OspA in ABM2 adjuvant. Lane 4, polyclonal IS generated in BALB/c mice immunized with rOspC in ABM2 adjuvant, as described in Materials and Methods.

Figure 2

Kinetics of appearance of _B. burgdorferi_-specific (IgG) or OspC-specific (IgM/IgG) Abs (A) and correlation analysis of serum levels of either total _B. burgdorferi_-specific or OspC-specific Abs (IgG) and elimination of spirochetes from infected mice (B). AKR/N, C57BL/6, and BALB/c mice (6–8 weeks old) were infected by syringe injection with 103 spirochetes into the base of the tail (s.c.). The amounts of _B. burgdorferi_-specific (IgG) and OspC-specific Abs (IgM and IgG) in sera from individual mice were tested with ELISA by using either whole-cell lysates (B. burgdorferi strain ZS7) or rOspC (ZS7) as substrates. The data represent the mean of individual serum samples tested (AKR/N and C57BL/c: 10 mice per group; BALB/c: seven mice per group). (A) Correlation between serum levels of total _B. burgdorferi_-specific IgG Abs, OspC-specific IgG Abs (day 23 p.i.), and the ability to recultivate spirochetes from ear biopsies (day 90 p.i.) was analyzed by ranking correlation assay (B).

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Therapeutic passive vaccination against chronic Lyme disease in mice - PubMed (original) (raw)