Differential ability of novel attenuated targeted deletion mutants of Francisella tularensis subspecies tularensis strain SCHU S4 to protect mice against aerosol challenge with virulent bacteria: effects of host background and route of immunization.
Francisella tularensis subspecies tularensis is a highly virulent facultative intracellular pathogen of humans and a potential biological weapon. A live vaccine strain, F. tularensis LVS, was developed more than 50 years ago by pragmatic attenuation of a strain of the less virulent holarctica subspecies. LVS was demonstrated to be highly effective in human volunteers who were exposed to intradermal challenge with fully virulent subsp. tularensis, but was less effective against aerosol exposure. LVS faces regulatory hurdles that to date have prevented its licensure for general use. Therefore, a better defined and more effective vaccine is being sought. To this end we have created gene deletion mutants in the virulent subsp. tularensis strain and tested them for their ability to elicit a protective immune response against systemic or aerosol challenge with the highly virulent wild-type subsp. tularensis strain, SCHU S4. Both oral and intradermal (ID) primary vaccination routes were assessed in BALB/c and C3H/HeN mice as was oral boosting. One SCHU S4 mutant missing the heat shock gene, clpB, was significantly more attenuated than LVS whereas a double deletion mutant missing genes FTT0918 and capB was as attenuated as LVS. In general mice immunized with SCHU S4DeltaclpB were significantly better protected against aerosol challenge than mice immunized with LVS. A single ID immunization of BALB/c mice with SCHU S4DeltaclpB was at least as effective as any other regimen examined. Mice immunized with SCHU S4Delta0918DeltacapB were generally protected to a similar degree as mice immunized with LVS. A preliminary examination of immune responses to vaccination with LVS, SCHU S4DeltaclpB, or SCHU S4Delta0918DeltacapB provided no obvious correlate to their relative efficacies.
Conlan
J Wayne
JW
National Research Council Canada, Institute for Biological Sciences, Ottawa, Ontario K1A 0R6, Canada. wayne.conlan@nrc-cnrc.gc.ca
Shen
Hua
H
Golovliov
Igor
I
Zingmark
Carl
C
Oyston
Petra C F
PC
Chen
Wangxue
W
House
Robert V
RV
Sjöstedt
Anders
A
D000284:Administration, Oral; D000336:Aerosols; D000818:Animals; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology*; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D007117:Immunization, Secondary; D007271:Injections, Intradermal; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D017384:Sequence Deletion; D014406:Tularemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology
D000336:Aerosols; D001428:Bacterial Vaccines; D014613:Vaccines, Attenuated