Protective Immunity against Respiratory Tract Challenge withYersinia pestisin Mice Immunized with an Adenovirus‐Based Vaccine Vector Expressing V Antigen

Abstract

The aerosol form of the bacterium Yersinia pestis causes the pneumonic plague, a rapidly fatal disease. At present, no plague vaccines are available for use in the United States. One candidate for the development of a subunit vaccine is the Y. pestis virulence (V) antigen, a protein that mediates the function of the Yersinia outer protein virulence factors and suppresses inflammatory responses in the host. On the basis of the knowledge that adenovirus (Ad) gene-transfer vectors act as adjuvants in eliciting host immunity against the transgene they carry, we tested the hypothesis that a single administration of a replication-defective Ad gene-transfer vector encoding the Y. pestis V antigen (AdsecV) could stimulate strong protective immune responses without a requirement for repeat administration. AdsecV elicited specific T cell responses and high IgG titers in serum within 2 weeks after a single intramuscular immunization. Importantly, the mice were protected from a lethal intranasal challenge of Y. pestis CO92 from 4 weeks up to 6 months after immunization with a single intramuscular dose of AdsecV. These observations suggest that an Ad gene-transfer vector expressing V antigen is a candidate for development of an effective anti-plague vaccine.

A Replication-Defective Human Type 5 Adenovirus-Based Trivalent Vaccine Confers Complete Protection against Plague in Mice and Nonhuman Primates

“…The rAdsecV produced a secreted form of LcrV and elicited specific T-cell responses as well as high IgG titers in sera, which protected mice from a lethal intranasal challenge of Y. pestis CO92 in a single intramuscular immunization (44). Although there is no direct comparison, the AdsecV provided better protection (80 to 100%) in mice than our monovalent rAd5-LcrV vaccine (ϳ20%) (Fig.…”

“…The adenoviral vector system has been successfully used as a vaccine platform for a number of pathogens, including Y. pestis (44,45), with several advantages: (i) the adenoviral genome is well characterized, with the capability of integrating Ն6 kb of the potential insert size for delivering multiple antigens; (ii) the replication-defective Ad5 vector has been developed for gene therapeutic applications at a wide range of doses, with minimal side effects; and (iii) adenoviruses have a broad tropism, infecting a variety of dividing and nondividing cells. Studies have shown that adenoviruses transfer genes effectively to APCs in vivo to promote rapid and robust humoral and cellular immune responses to the transgene products (46)(47)(48)(49)(50)(51)(52)(53).…”

“…Previously, an rAd5 (designated rAdsecV) expressing a human Ig secretion (sec) signal fused to lcrV was reported (44). The rAdsecV produced a secreted form of LcrV and elicited specific T-cell responses as well as high IgG titers in sera, which protected mice from a lethal intranasal challenge of Y. pestis CO92 in a single intramuscular immunization (44).…”

“…1B and 2B), indicating that the secreted form of LcrV might be more immunogenic in mice. However, different species of mice (SwissWebster versus BALB/c) and challenge doses were used in these studies (44). In our initial study, an rAd5 expressing the Ig secretion signal fused to YFV was successfully created; however, we found that the secreted YFV (sYFV) was toxic to HEK293 cells, which prevented large-scale expansion of this construct (data not shown).…”

Adenovirus-Mediated Delivery of an Anti-V Antigen Monoclonal Antibody Protects Mice against a Lethal Yersinia pestis Challenge

“…2A). Pooled V antigen-specific hyperimmune serum from mice immunized multiple times with AdsecV, an Ad gene transfer vector encoding V antigen, was used as a positive control (8). Negative controls for this experiment included PBS and clone 1A10.14, a MAb that did not react with V antigen.…”