Development of an OspC-based tetravalent, recombinant, chimeric vaccinogen that elicits bactericidal antibody against diverse Lyme disease spirochete strains

Vaccine

Volumn 25, Issue 3, 2007, Pages 466-480

  Earnhart, Christopher G ^a   Buckles, Eric L ^a   Marconi, Richard T ^a  

^a VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Borrelia; Lyme disease vaccine; Outer surface protein C

Indexed keywords

BACTERIUM ANTIBODY; EPITOPE; LYME DISEASE VACCINE; OUTER SPACE PROTEIN C; RECOMBINANT VACCINE;

ANIMAL EXPERIMENT; ARTICLE; BACTERIAL STRAIN; BACTERIUM CULTURE; BORRELIA BURGDORFERI; COMPLEMENT DEPENDENT CYTOTOXICITY; CONTROLLED STUDY; EPITOPE MAPPING; IMMUNOGENICITY; IN VITRO STUDY; LYME DISEASE; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; SEQUENCE ANALYSIS; SPIROCHETE; VACCINATION;

AMINO ACID SEQUENCE; ANIMALS; BASE SEQUENCE; BORRELIA BURGDORFERI; CLONING, MOLECULAR; ENZYME-LINKED IMMUNOSORBENT ASSAY; EPITOPES; FLUORESCENT ANTIBODY TECHNIQUE; IMMUNOBLOTTING; LYME DISEASE; LYME DISEASE VACCINES; MALE; MICE; MICE, INBRED C3H; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PHOSPHATIDYLCHOLINES; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; SPECIES SPECIFICITY; VACCINES, SYNTHETIC;

EID: 33845212331     PISSN: 0264410X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.vaccine.2006.07.052     Document Type: Article

References (100)

1. Burgdorfer W., Barbour A.G., Hayes S.F., Benach J.L., Grunwaldt E., and Davis J.P. Lyme disease-a tick-borne spirochetosis?. Science 216 (1982) 1317-1319
2. Benach J.L., Bosler E.M., Hanrahan J.P., Coleman J.L., Bast T.F., Habicht G.S., et al. Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med 308 (1983) 740-742
3. Fahrer H., van der Linden S.M., Sauvian M.J., Gern L., Zhioua E., and Aeschlimann A. The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk. J Infect Dis 163 (1991) 305-310
4. Steere A.C., Malawista S.E., Hardin J.A., Ruddy S., Askenase W., and Andiman W.A. Erythema chronicum migrans and Lyme arthritis. The enlarging clinical spectrum. Ann Intern Med 86 (1977) 685-698
5. Steere A.C., Malawista S.E., Snydman D.R., Shope R.E., Andiman W.A., Ross M.R., et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 20 (1977) 7-17
6. Eiffert H., Karsten A., Thomssen R., and Christen H.-J. Characterization of Borrelia burgdorferi strains in Lyme arthritis. Scand J Infect Dis 24 (1998) 437-439
7. Steere A.C., and Glickstein L. Elucidation of Lyme arthritis. Nat Rev Immunol 4 2 (2004) 143-152
8. Asch E.S., Bujak D.I., Weiss M., Peterson M.G., and Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 21 3 (1994) 454-461
9. Nagi K.S., Joshi R., and Thakur R.K. Cardiac manifestations of Lyme disease: a review. Can J Cardiol 12 5 (1996) 503-506
10. Barthold S.W., Persing D.H., Armstrong A.L., and Peeples R.A. Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice. Am J Pathol 139 2 (1991) 263-273
11. Nachman S.A., and Pontrelli L. Central nervous system Lyme disease. Semin Pediatr Infect Dis 14 2 (2003) 123-130
12. Coyle P.K., and Schutzer S.E. Neurologic aspects of Lyme disease. Med Clin North Am 86 2 (2002) 261-284
13. Meltzer M.I., Dennis D.T., and Orloski K.A. The cost effectiveness of vaccinating against Lyme disease. Emerg Infect Dis 5 (1999) 321-328
14. Shadick N.A., Liang M.H., Phillips C.B., Fossel K., and Kuntz K. The cost-effectiveness of vaccination against Lyme disease. Arch Intern Med 161 (2001) 554-561
15. Kalish R.A., Leong J.M., and Steere A.C. Association of treatment resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun 61 (1993) 2774-2779
16. Koide S., Yang X., Huang X., Dunn J.J., and Luft B.J. Structure-based design of a second-generation Lyme disease vaccine based on a C-terminal fragment of Borrelia burgdorferi OspA. J Mol Biol 350 2 (2005) 290-299
17. Willett T.A., Meyer A.L., Brown E.L., and Huber B.T. An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope. Proc Natl Acad Sci USA 101 5 (2004) 1303-1308
18. Gilmore Jr. R.D., Mbow M.L., and Stevenson B. Analysis of Borrelia burgdorferi gene expression during life cycle phases of the tick vector Ixodes scapularis. Microbes Infect 3 10 (2001) 799-808
19. Schwan T.G., Piesman J., Golde W.T., Dolan M.C., and Rosa P.A. Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc Natl Acad Sci USA 92 7 (1995) 2909-2913
20. de Silva A.M., Zeidner N.S., Zhang Y., Dolan M.C., Piesman J., and Fikrig E. Influence of outer surface protein A antibody on Borrelia burgdorferi within feeding ticks. Infect Immun 67 1 (1999) 30-35
21. Fuchs R., Jauris S., Lottspeich F., Preac-Mursic V., Wilske B., and Soutschek E. Molecular analysis and expression of a Borrelia burgdorferi gene encoding a 22 kDa protein (pC) in Escherichia coli. Mol Microbiol 6 (1992) 503-509
22. Marconi R.T., Samuels D.S., and Garon C.F. Transcriptional analyses and mapping of the ospC gene in Lyme disease spirochetes. J Bacteriol 175 (1993) 926-932
23. Sadziene A., Wilske B., Ferdows M.S., and Barbour A.G. The cryptic ospC gene of Borrelia burgdorferi B31 is located on a circular plasmid. Infect Immun 61 (1993) 2192-2195
24. Schwan T.G. Temporal regulation of outer surface proteins of the Lyme-disease spirochaete Borrelia burgdorferi. Biochem Soc Trans 31 Pt 1 (2003) 108-112
25. Gilmore Jr. R.D., Kappel K.J., Dolan M.C., Burkot T.R., and Johnson B.J. Outer surface protein C (OspC), but not P39 is a protective immunogen against a tick-transmitted Borrelia burgdorferi challenge: evidence for a conformational protective epitope in OspC. Infect Immun 64 6 (1996) 2234-2239
26. Bockenstedt L.K., Hodzic E., Feng S., Bourrel K.W., de Silva A., Montgomery R.R., et al. Borrelia burgdorferi strain-specific OspC mediated immunity in mice. Infect Immun 65 (1997) 4661-4667
27. Gilmore Jr. R.D., and Mbow M.L. Conformational nature of the Borrelia burgdorferi B31 outer surface protein C protective epitope. Infect Immun 67 10 (1999) 5463-5469
28. Mathiesen M.J., Holm A., Christiansen M., Blom J., Hansen K., Ostergard S., et al. The dominant epitope of Borrelia garinii outer surface protein C recognized by sera from patients with neuroborreliosis has a surface exposed conserved structural motif. Infect Immun 66 (1998) 4073-4079
29. Scheiblhofer S., Weiss R., Durnberger H., Mostbock S., Breitenbach M., Livey I., et al. A DNA vaccine encoding the outer surface protein C from Borrelia burgdorferi is able to induce protective immune responses. Microbes Infect 5 11 (2003) 939-946
30. Jobe D.A., Lovrich S.D., Schell R.F., and Callister S.M. C-terminal region of outer surface protein C binds borreliacidal antibodies in sera from patients with Lyme disease. Clin Diagn Lab Immunol 10 (2003) 573-578
31. Rousselle J.C., Callister S.M., Schell R.F., Lovrich S.D., Jobe D.A., Marks J.A., et al. Borreliacidal antibody production against outer surface protein C of Borrelia burgdorferi. J Infect Dis 178 (1998) 733-741
32. Wallich R., Siebers A., Jahraus O., Brenner C., Stehle T., and Simon M.M. DNA vaccines expressing a fusion product of outer surface proteins A and C from Borrelia burgdorferi induce protective antibodies suitable for prophylaxis but not for resolution of Lyme disease. Infect Immun 69 4 (2001) 2130-2136
33. Mbow M.L., Gilmore Jr. R.D., and Titus R.G. An OspC-specific monoclonal antibody passively protects mice from tick-transmitted infection by Borrelia burgdorferi B31. Infect Immun 67 10 (1999) 5470-5472
34. Probert W.S., Crawford M., Cadiz R.B., and LeFebre R.B. Immunization with outer surface protein (Osp) A but not OspC provides cross-protection of mice challenged with North American isolates of Borrelia burgdorferi. J Infect Dis 175 (1997) 400-405
35. Brown E.L., Kim J.H., Reisenbichler E.S., and Hook M. Multicomponent Lyme vaccine: three is not a crowd. Vaccine 23 28 (2005) 3687-3696
36. Probert W.S., and LeFebvre R.B. Protection of C3H/HeN mice from challenge with Borrelia burgdorferi through active immunization with OspA, OspB, or OspC, but not with OspD or the 83-kilodalton antigen. Infect Immun 62 5 (1994) 1920-1926
37. Seinost G., Dykhuizen D.E., Dattwyler R.J., Golde W.T., Dunn J.J., Wang N., et al. Four clones of Borrelia burgdorferi sensu stricto cause invasive infection in humans. Infect Immun 67 (1999) 3518-3524
38. Wang I.N., Dykhuizen D.E., Qiu W., Dunn J.J., Bosler E.M., and Luft B.J. Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto. Genetics 151 1 (1999) 15-30
39. Theisen M., Borre M., Mathiesen M.J., Mikkelsen B., Lebech A.M., and Hansen K. Evolution of the Borrelia burgdorferi outer surface protein OspC. J Bacteriol 177 (1995) 3036-3044
40. Brisson D. Dykhuizen DE. ospC diversity in Borrelia burgdorferi: Different hosts are different niches. Genetics 168 (2004) 713-722
41. Hodzic E., Feng S., and Barthold S.W. Stability of Borrelia burgdorferi outer surface protein C under immune selection pressure. J Infect Dis 181 2 (2000) 750-753
42. Stevenson B., Bockenstedt L.K., and Barthold S.W. Expression and gene sequence of outer surface protein C of Borrelia burgdorferi reisolated from chronically infected mice. Infect Immun 62 8 (1994) 3568-3571
43. Earnhart C.G., Buckles E.L., Dumler J.S., and Marconi R.T. Demonstration of OspC type diversity in invasive human Lyme disease isolates and identification of previously uncharacterized epitopes that define the specificity of the OspC antibody response. Infect Immun 73 (2005) 7869-7877
44. Buckles EL, Earnhart CG, Marconi RT. Analysis of the antibody response in humans to the type A OspC loop 5 domain and assessment of the potential utility of the loop 5 epitope in Lyme disease vaccine development. Clin Vaccine Immunol, in press.
45. Kumaran D., Eswaramoorthy S., Luft B.J., Koide S., Dunn J.J., Lawson C.L., et al. Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete Borrelia burgdorferi. EMBO J 20 5 (2001) 971-978
46. Eicken C., Sharma C., Klabunde T., Owens R.T., Pikas D.S., Hook M., et al. Crystal structure of Lyme disease antigen outer surface protein C from Borrelia burgdorferi. J Biol Chem 276 (2001) 10010-10015
47. Zuckert W.R., Kerentseva T.A., Lawson C.L., and Barbour A.G. Structural conservation of neurotropism-associated VspA within the variable Borrelia Vsp-OspC lipoprotein family. J Biol Chem 276 1 (2001) 457-463
48. Sung S.Y., McDowell J., Carlyon J.A., and Marconi R.T. Mutation and recombination in the upstream homology box flanked ospE related genes of the Lyme disease spirochetes results in the development of new antigenic variants during infection. Infect Immun 68 3 (2000) 1319-1327
49. Crasto C.J., and Feng J.A. LINKER: a program to generate linker sequences for fusion proteins. Protein Eng 13 5 (2000) 309-312
50. Alghaferi M.Y., Anderson J.M., Park J., Auwaerter P.G., Aucott J.N., Norris D.E., et al. Borrelia burgdorferi ospC heterogeneity among human and murine isolates from a defined region of Northern Maryland and Southern Pennsylvania: Lack of correlation with invasive and non-invasive genotypes. J Clin Microbiol 43 4 (2005) 1879-1884
51. Gasteiger E., Hoogland C., Gattiker A., Duvaud S., Wilkins M.R., Appel R.D., et al. Protein identification and analysis tools on the ExPASy server. In: Walker J.M. (Ed). The proteomics protocols handbook (2005), Humana Press, Totowa, NJ 571-608
52. Kneller D.G., Cohen F.E., and Langridge R. Improvements in protein secondary structure prediction by an enhanced neural network. J Mol Biol 214 1 (1990) 171-182
53. Guruprasad K., Reddy B.V., and Pandit M.W. Correlation between stability of a protein and its dipeptide composition: a novel approach for predicting in vivo stability of a protein from its primary sequence. Protein Eng 4 2 (1990) 155-161
54. Tilly K., Elias A.F., Errett J., Fischer E., Iyer R., Schwartz I., et al. Genetics and regulation of chitobiose utilization in Borrelia burgdorferi. J Bacteriol 183 19 (2001) 5544-5553
55. Ledin K.E., Zeidner N.S., Ribeiro J.M., Biggerstaff B.J., Dolan M.C., Dietrich G., et al. Borreliacidal activity of saliva of the tick Amblyomma americanum. Med Vet Entomol 19 1 (2005) 90-95
56. Elias A.F., Bono J.L., Carroll J.A., Stewart P., Tilly K., and Rosa P. Altered stationary-phase response in a Borrelia burgdorferi rpoS mutant. J Bacteriol 182 10 (2000) 2909-2918
57. Montgomery R.R., Schreck K., Wang X., and Malawista S.E. Human neutrophil calprotectin reduces the susceptibility of Borrelia burgdorferi to penicillin. Infect Immun 74 4 (2006) 2468-2472
58. Elias A.F., Stewart P.E., Grimm D., Caimano M.J., Eggers C.H., Tilly K., et al. Clonal polymorphism of Borrelia burgdorferi strain B31 MI: implications for mutagenesis in an infectious strain background. Infect Immun 70 4 (2002) 2139-2150
59. Shin J.J., Bryksin A.V., Godfrey H.P., and Cabello F.C. Localization of BmpA on the exposed outer membrane of Borrelia burgdorferi by monospecific anti-recombinant BmpA rabbit antibodies. Infect Immun 72 4 (2004) 2280-2287
60. Gilmore Jr. R.D., Bacon R.M., Carpio A.M., Piesman J., Dolan M.C., and Mbow M.L. Inability of outer-surface protein C (OspC)-primed mice to elicit a protective anamnestic immune response to a tick-transmitted challenge of Borrelia burgdorferi. J Med Microbiol 52 Pt 7 (2003) 551-556
61. Hanson M.S., and Edelman R. Vaccines against Lyme disease. In: Levine M., Kaper J.B., Rappuoli R., Liu M.A., and Good M.F. (Eds). New generation vaccines (2004), Marcel Dekker AG, New York
62. Caro-Aguilar I., Lapp S., Pohl J., Galinski M.R., and Moreno A. Chimeric epitopes delivered by polymeric synthetic linear peptides induce protective immunity to malaria. Microbes Infect 7 13 (2005) 1324-1337
63. McNeil S.A., Halperin S.A., Langley J.M., Smith B., Warren A., Sharratt G.P., et al. Safety and immunogenicity of 26-valent group a streptococcus vaccine in healthy adult volunteers. Clin Infect Dis 41 8 (2005) 1114-1122
64. Dale J.B., Penfound T., Chiang E.Y., Long V., Shulman S.T., and Beall B. Multivalent group A streptococcal vaccine elicits bactericidal antibodies against variant M subtypes. Clin Diagn Lab Immunol 12 7 (2005) 833-836
65. Hu M.C., Walls M.A., Stroop S.D., Reddish M.A., Beall B., and Dale J.B. Immunogenicity of a 26-valent group A streptococcal vaccine. Infect Immun 70 4 (2002) 2171-2177
66. Dale J.B. Multivalent group A streptococcal vaccine designed to optimize the immunogenicity of six tandem M protein fragments. Vaccine 17 2 (1999) 193-200
67. Kotloff K.L.C.M., Palmer K., Campbell J.D., Reddish M.A., Hu M.C., Wasserman S.S., and Dale J.B. Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial. JAMA 292 (2005) 738-739
68. Horvath A.O.C., Karpati L., Sun H.K., Good M., and Toth I. Toward the development of a synthetic group A streptococcal vaccine of high purity and broad protective coverage. J Med Chem 47 (2005) 4100-4104
69. Apt D., Raviprakash K., Brinkman A., Semyonov A., Yang S., Skinner C., et al. Tetravalent neutralizing antibody response against four dengue serotypes by a single chimeric dengue envelope antigen. Vaccine 24 3 (2006) 335-344
70. Fan C.F., and Mei X.G. Co-immunization of BALB/c mice with recombinant immunogens containing G protein fragment and chimeric CTL epitope of respiratory syncytial virus induces enhanced cellular immunity and high level of antibody response. Vaccine 23 (2005) 4453-4461
71. Wang X.N., Zhang G.P., Zhou J.Y., Feng C.H., Yang Y.Y., Li Q.M., et al. Identification of neutralizing epitopes on the VP2 protein of infectious bursal disease virus by phage-displayed heptapeptide library screening and synthetic peptide mapping. Viral Immunol 18 (2005) 549-557
72. Bouche F.B., Steinmetz A., Yanagi Y., and Muller C.P. Induction of broadly neutralizing antibodies against measles virus mutants using a polyepitope vaccine strategy. Vaccine 23 17-18 (2005) 2074-2077
73. Lovrich S.D., Jobe D.A., Schell R.F., and Callister S.M. Borreliacidal OspC antibodies specific for a highly conserved epitope are immunodominant in human Lyme disease and do not occur in mice or hamsters. Clin Diagn Lab Immunol 12 6 (2005) 746-751
74. Ruzic-Sabljic E., Lotric-Furlan S., Maraspin V., Cimperman J., Logar M., Jurca T., et al. Comparison of isolation rate of Borrelia burgdorferi sensu lato in MKP and BSK-II medium. Int J Med Microbiol 296 Suppl. 40 (2006) 267-273
75. Hofmeister E.K., Glass G.E., Childs J.E., and Persing D.H. Population dynamics of a naturally occurring heterogeneous mixture of Borrelia burgdorferi clones. Infect Immun 67 11 (1999) 5709-5716
76. Guttman D.S., Wang P.W., Wang I.N., Bosler E.M., Luft B.J., and Dykhuizen D.E. Multiple infections of Ixodes scapularis ticks by Borrelia burgdorferi as revealed by single-strand conformation polymorphism analysis. J Clin Microbiol 34 3 (1996) 652-656
77. Rijpkema S.G., Tazelaar D.J., Molkenboer M.J., Noordhoek G.T., Plantinga G., Schouls L.M., et al. Detection of Borrelia afzelii, Borrelia burgdorferi sensu stricto, Borrelia garinii and group VS116 by PCR in skin biopsies of patients with erythema migrans and acrodermatitis chronica atrophicans. Clin Microbiol Infect 3 1 (1997) 109-116
78. Dale J.B., Chiang E.Y., and Lederer J.W. Recombinant tetravalent group A streptococcal M protein vaccine. J Immunol 151 4 (1993) 2188-2194
79. Dale J.B., Simmons M., Chiang E.C., and Chiang E.Y. Recombinant, octavalent group A streptococcal M protein vaccine. Vaccine 14 10 (1996) 944-948
80. Kraiczy P., Hunfeld K.P., Peters S., Wurzner R., Ackert G., Wilske B., et al. Borreliacidal activity of early Lyme disease sera against complement-resistant Borrelia afzelii FEM1 wild-type and an OspC-lacking FEM1 variant. J Med Microbiol 49 10 (2000) 917-928
81. Widhe M., Jarefors S., Ekerfelt C., Vrethem M., Bergstrom S., Forsberg P., et al. Borrelia-specific interferon-gamma and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome. J Infect Dis 189 10 (2004) 1881-1891
82. Keane-Myers A., and Nickell S.P. Role of IL-4 and IFN-gamma in modulation of immunity to Borrelia burgdorferi in mice. J Immunol 155 4 (1995) 2020-2028
83. Keane-Myers A., Maliszewski C.R., Finkelman F.D., and Nickell S.P. Recombinant IL-4 treatment augments resistance to Borrelia burgdorferi infections in both normal susceptible and antibody-deficient susceptible mice. J Immunol 156 7 (1996) 2488-2494
84. Keane-Myers A., and Nickell S.P. T cell subset-dependent modulation of immunity to Borrelia burgdorferi in mice. J Immunol 154 4 (1995) 1770-1776
85. Rammensee H., Bachmann J., Emmerich N.P., Bachor O.A., and Stevanovic S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50 3-4 (1999) 213-219
86. Zhang G.L., Khan A.M., Srinivasan K.N., August J.T., and Brusic V. MULTIPRED: a computational system for prediction of promiscuous HLA binding peptides. Nucleic Acids Res 33 (W) (2005) 172-179
87. Jiang Y., Lin C., Yin B., He X., Mao Y., Dong M., et al. Effects of the configuration of a multi-epitope chimeric malaria DNA vaccine on its antigenicity to mice. Chin Med J (Engl) 112 8 (1999) 686-690
88. Ahlborg N., Nardin E.H., Perlmann P., Berzins K., and Andersson R. Immunogenicity of chimeric multiple antigen peptides based on Plasmodium falciparum antigens: impact of epitope orientation. Vaccine 16 1 (1998) 38-44
89. Kjerrulf M., Lowenadler B., Svanholm C., and Lycke N. Tandem repeats of T helper epitopes enhance immunogenicity of fusion proteins by promoting processing and presentation. Mol Immunol 34 8-9 (1997) 599-608
90. Theisen D.M., Bouche F.B., El Kasmi K.C., von der Ahe I., Ammerlaan W., Demotz S., et al. Differential antigenicity of recombinant polyepitope-antigens based on loop- and helix-forming B and T cell epitopes. J Immunol Methods 242 1-2 (2000) 145-157
91. ten Hagen T.L., Sulzer A.J., Kidd M.R., Lal A.A., and Hunter R.L. Role of adjuvants in the modulation of antibody isotype, specificity and induction of protection by whole blood-stage Plasmodium yoelii vaccines. J Immunol 151 12 (1993) 7077-7085
92. Lindblad E.B. Aluminium compounds for use in vaccines. Immunol Cell Biol 82 5 (2004) 497-505
93. Petrovsky N., and Aguilar J.C. Vaccine adjuvants: current state and future trends. Immunol Cell Biol 82 5 (2004) 488-496
94. Brewer J.M., Conacher M., Hunter C.A., Mohrs M., Brombacher F., and Alexander J. Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4- or IL-13-mediated signaling. J Immunol 163 12 (1999) 6448-6454
95. McNeela E.A., and Mills K.H. Manipulating the immune system: humoral versus cell-mediated immunity. Adv Drug Deliv Rev 51 1-3 (2001) 43-54
96. Tongren J.E., Corran P.H., Jarra W., Langhorne J., and Riley E.M. Epitope-specific regulation of immunoglobulin class switching in mice immunized with malarial merozoite surface proteins. Infect Immun 73 12 (2005) 8119-8129
97. Cai Q.L., Wei F., Lin Y.H., Shao D.D., and Wang H. Immunogenicity of polyepitope libraries assembled by epitope shuffling: an approach to the development of chimeric gene vaccination against malaria. Vaccine 23 2 (2004) 267-277
98. Zhong W., Stehle T., Museteanu C., Siebers A., Gern L., Kramer M., et al. Therapeutic passive vaccination against chronic Lyme disease in mice. Proc Natl Acad Sci USA 94 23 (1997) 12533-12538
99. Schwan T.G., and Piesman J. Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice. J Clin Microbiol 38 1 (2000) 382-388
100. Hu C.M., Simon M., Kramer M.D., and Gern L. Tick factors and in vitro cultivation influence the protein profile, antigenicity and pathogenicity of a cloned Borrelia garinii isolate from Ixodes ricinus hemolymph. Infection 24 3 (1996) 251-257