Analysis of active live immunization versus passive humoral immunotherapy against attenuated and virulent strains of Francisella tularensis

J. J. Drabick, A. H. Fortier, I. Golovliov, D. Shoemaker, G. Sandstrom

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Abstract

Evidence suggests that cellular immunity plays the dominant role in protection against tularemia, although humoral immunity appears to play a role in infections caused by Francisella tularensis strains of reduced virulence. To verify this, we tested immune human sera (from vaccination) and murine IgM and IgG3 monoclonal antibodies (both reactive against the dominant lipopolysaccharide antigen of the organism) for protective efficacy in a lethal murine model of tularemia, comparing an attenuated strain, the live vaccine strain (LVS), with a virulent strain, FSC041, for challenge. Whole immune serum (200 μl), the IgM (1000 μg), or the IgG3 (100 μg) monoclonal antibodies, but not isotype antibody controls, delivered 2 h before intraperitoneal challenge protected against various lethal inocula of the attenuated strain, LVS. In contrast, none of these antibodies protected animals challenged with as few as two colony-forming units of the highly virulent strain. Active immunization was performed using the LVS, a rifampicin-resistant mutant LVS (Rif(r) 7), and strain 38, all highly attenuated strains at two immunizing doses per strain. Mycobacterium bovis BCG strain served as a negative control. Immunization with BCG did not protect against infection with either strain. Only the highest dose of strain 38 protected against a challenge with the attenuated strain, LVS. Immunization with either the LVS or the rifampicin-resistant mutant, even at low doses, protected fully against a 200 LD50 challenge with the attenuated strain. In contrast, only active immunization with LVS afforded protection against a 20 LD50 challenge with the virulent strain. This protection was dose related and incomplete. Low immunizing dose protected 1 of 5 of the challenged mice from death, and high immunizing dose protected 2 of 5 mice from death. Specific antibody to F. tularensis, whether in polyclonal serum or as a purified monoclonal IgG or IgM, protects against infection with the attenuated strain, LVS, but plays no role in protection against a fully virulent tularemia strain. Only active immunization with LVS was found to be protective against infection with a highly virulent strain. Efforts to induce effective immunity against such fully virulent tularemia strains should focus on induction of cellular immune mechanisms of protection by active immunization with live attenuated organisms. Testing should only employ challenge with fully virulent strains. Live attenuated strains of Francisella tularensis vary in their capabilities to induce protection against such challenge.

Original languageEnglish (US)
Pages (from-to)67-74
Number of pages8
JournalVaccine Research
Volume6
Issue number2
StatePublished - Jan 1 1997

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All Science Journal Classification (ASJC) codes

  • Immunology
  • Microbiology (medical)

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