@article {1162171,
	title = {Glycoconjugate vaccine using a genetically modified O antigen induces protective antibodies to <em>Francisella tularensis</em>},
	journal = {Proc Natl Acad Sci U S A},
	volume = {2019 Mar 14},
	year = {2019},
	month = {2019 Mar 14},
	abstract = {<i>Francisella tularensis\&nbsp;</i>is the causative agent of tularemia, a category A bioterrorism agent. The lipopolysaccharide (LPS) O antigen (OAg) of has been considered for use in a glycoconjugate vaccine, but conjugate vaccines tested so far have failed to confer protection necessary against aerosolized pulmonary bacterial challenge. When OAg was purified under standard conditions, the antigen had a small molecular size [25 kDa, low molecular weight (LMW)]. Using milder extraction conditions, we found the native OAg had a larger molecular size [80 kDa, high molecular weight (HMW)], and in a mouse model of tularemia, a glycoconjugate vaccine made with the HMW polysaccharide coupled to tetanus toxoid (HMW-TT) conferred better protection against intranasal challenge than a conjugate made with the LMW polysaccharide (LMW-TT). To further investigate the role of OAg size in protection, we created an live vaccine strain (LVS) mutant with a significantly increased OAg size [220 kDa, very high molecular weight (VHMW)] by expressing a heterologous chain-length regulator gene () from the related species Immunization with VHMW-TT provided markedly increased protection over that obtained with TT glycoconjugates made using smaller OAgs. We found that protective antibodies recognize a length-dependent epitope better expressed on HMW and VHMW antigens, which bind with higher affinity to the organism.},
	issn = {1091-6490},
	doi = {10.1073/pnas.1900144116},
	author = {Stefanetti, Giuseppe and Okan, Nihal and Fink, Avner and Gardner, Erica and Kasper, Dennis L}
}
