A multivalent CPS-CRM197 conjugate vaccine protects against severe/fatal Klebsiella pneumoniae disease in a mouse infection model

Klebsiella pneumoniae is an important cause of human infections and is often resistant to multiple antibiotics. Most infections occur in individuals with co-morbidities and/or those who have risk factors for infection. Although progress has been made, new therapeutics and preventive measures are needed. To that end, we developed a mouse model of severe/fatal K. pneumoniae infection (intraperitoneal inoculation that leads to bacteremia) to evaluate strain virulence and test protection conferred by a multivalent CPS-conjugate vaccine. We first compared the virulence of four clinical isolates representative of important K. pneumoniae clones globally (ST23/KL1, ST86/KL2, ST11/KL64, and ST147/KL64), each of which harbors a virulence plasmid. The ST11 and ST147 isolates are additionally multidrug resistant, including resistance to carbapenem antibiotics. Compared with ST23 and ST86 isolates, the ST11 and ST147 isolates were less virulent in the mouse infection model. Moreover, numbers of viable ST11 and ST147 organisms recovered from blood decreased over time, whereas those of ST23 and ST86 increased. As a step toward evaluating the ability of a CPS-CRM197 conjugate vaccine to protect against lethal infection, we immunized CD-1 outbred mice with a cocktail of eight selected CPS conjugates, boosted them twice, and then challenged those mice with one of the two most virulent isolates (ST23/KL1 or ST86/KL2) by intraperitoneal inoculation. Mice receiving the CPS-CRM197 conjugate vaccine were protected against lethal infection caused by KL1 and KL2 isolates, whereas all sham-immunized mice developed fatal disease within 96 h. These results underscore the potential of a standard CPS-conjugate approach for development of a multivalent K. pneumoniae vaccine.