Protection against lethal pneumonic plague by intramuscular F1V vaccine incorporating a colloidal TLR4-TLR7 dual adjuvant

Yersinia pestis is a facultative intracellular bacterium that causes plague, which manifests in bubonic form and the more severe pneumonic and septicemic forms. There is no FDA-approved vaccine for plague, and those used in the past for human prophylaxis were suboptimal against aerosol infection or nonencapsulated strains. To provide broad protection against Y. pestis , further optimization of vaccine formulations is essential. In a lethal aerosol challenge model using nonencapsulated Y. pestis in BALB/c mice, we compared an existing benchmark vaccine to a similar formulation using novel TLR4-TLR7 dual adjuvant KUP101A in place of TLR9 adjuvant CpG 2006. In addition, we compared vaccination through the subcutaneous (SC) and intramuscular (IM) routes, and we compared vaccination using KUP101A with or without additional alum adjuvant. Two vaccine doses were given four weeks apart, and four weeks later mice were challenged via whole-body aerosol exposure. KUP101A compared favorably to CpG for conferring protection after Y. pestis challenge and led to significantly lower bacterial burden in tissues. This was observed despite similar humoral immunity and Th1/Th2 phenotype, and less evidence of splenic T cell memory than was seen with CpG. Alum was necessary for the protective effect of KUP101A, similarly to CpG. Finally, we saw evidence that IM vaccination was preferable to SC for inducing Th1 polarization, based on the ratio of serum IgG2a to IgG1 and splenocyte cytokine secretion. This study demonstrates that KUP101A is a promising adjuvant with a favorable safety profile for future Y. pestis vaccine development.