A new generation needle- and adjuvant-free trivalent plague vaccine utilizing adenovirus-5 nanoparticle platform

Abstract

A plague vaccine with a fusion cassette of YscF, F1, and LcrV encoding genes in an adenovirus-5 vector (rAd5-YFV) is evaluated for efficacy and immune responses in mice. Two doses of the vaccine provides 100% protection when administered intranasally against challenge with Yersinia pestis CO92 or its isogenic F1 mutant in short- or long- term immunization in pneumonic/bubonic plague models. The corresponding protection rates drop in rAd5-LcrV monovalent vaccinated mice in plague models. The rAd5-YFV vaccine induces superior humoral, mucosal and cell-mediated immunity, with clearance of the pathogen. Immunization of mice with rAd5-YFV followed by CO92 infection dampens proinflammatory cytokines and neutrophil chemoattractant production, while increasing Th1- and Th2-cytokine responses as well as macrophage/monocyte chemo-attractants when compared to the challenge control animals. This is a first study showing complete protection of mice from pneumonic/bubonic plague with a viral vector-based vaccine without the use of needles and the adjuvant.

Combinatorial viral vector-based and live-attenuated vaccines without an adjuvant to generate broader immune responses to effectively combat pneumonic plague

“…However, such a Tcell population was not detected in animals immunized with the Ad5-YFV vaccine (26). Further, the Th1 immune response was favored after vaccination of mice with the Ad5-YFV vaccine over Th2, possibly due to the Ad5 vector used, while the Th2 immune response was favored after immunization of animals with the LMA vaccine (26,28). In our past studies, the Ad5-YFV vaccine was always delivered intranasally (i.n.…”

“…The Ad5-YFV is a replication deficient adenovirus type 5 vector-based vaccine containing genes for three plague antigens: fraction 1 capsule-like antigen F1, tip protein of the T3SS LcrV, and YscF that forms the barrel structure of T3SS needle (25). Using a prime-boost immunization regimen (21 days apart), both vaccines when used individually, elicited robust humoral and cell-mediated immune responses in animals and conferred 100% protection against lethal Y. pestis CO92 challenge (26,27). Importantly, each of these vaccines has its own unique characteristics.…”

“…IL-17 production is an important correlate of protection against plague in the absence of protective antibodies (29,30). However, such a Tcell population was not detected in animals immunized with the Ad5-YFV vaccine (26). Further, the Th1 immune response was favored after vaccination of mice with the Ad5-YFV vaccine over Th2, possibly due to the Ad5 vector used, while the Th2 immune response was favored after immunization of animals with the LMA vaccine (26,28).…”

Plague Prevention and Therapy: Perspectives on Current and Future Strategies

“…Both vaccines, rF1 + rV and rV10, were tested and demonstrated efficacy against pneumonic plague infection in mice, guinea pigs and Cynomolgus macaques [176,177] but not in African green monkeys [125]. Further investigations of enhancing immunogenicity or delivery of these subunit vaccines have been attempted or are ongoing by several groups [178][179][180][181][182][183][184][185]. Y. pestis is a Gramnegative bacterium that expresses multiple potential targets that have been exploited for the development of novel medical countermeasures.…”

Optimised Heterologous Expression and Functional Analysis of the Yersinia pestis F1-Capsular Antigen Regulator Caf1R

“…The F1 capsule also has substantial applied value. Due to its surface location, high level of expression and the fact that the F1 polymer is unique to Y. pestis, F1 remains a primary target for plague diagnostics [11][12][13][14] and a key component of anti-plague vaccines [6,[15][16][17].…”