Enhancement of immune response to an antigen delivered by vaccinia virus by displaying the antigen on the surface of intracellular mature virion

Abstract

Vaccinia virus (VACV) is the vaccine for smallpox and a widely-used vaccine vector for infectious diseases and cancers. The majority of the antibodies elicited by live VACV vaccination respond to virion structural proteins, including many integral membrane proteins on the intracellular mature virion (MV). Here, we showed that antibody response to an exogenous antigen delivered by VACV was greatly enhanced by incorporating the antigen as an integral membrane protein of MV. We constructed recombinant VACV expressing a Y. pestis protective antigen, LcrV, unmodified or fused with either a signal peptide or with the transmembrane domain of VACV D8 protein (LcrV-TM). Electron microscopy showed that LcrV-TM was displayed on the surface of MV. Importantly, VACV expressing LcrV-TM elicited a significantly higher titer of anti-LcrV antibody in mice than viruses expressing other forms of LcrV. Only mice immunized with LcrV-TM-expressing VACV were protected from lethal Y. pestis and VACV WR challenges. Antigen engineering through fusion with D8 transmembrane domain may be broadly applicable for enhancing the immune response to antigens delivered by a VACV vector. The recombinant virus described here could also serve as the basis for developing a vaccine against both smallpox and plague.

Utilizing poxviral vectored vaccines for antibody induction—Progress and prospects

“…Intriguingly though, the study with recombinant vaccinia also assessed the merits of membrane-binding versus secretion of the encoded P. falciparum MSP1 antigen and reported the highest levels of functional antibody induction when the antigen was designed to anchor in the membrane. Similar observations were made by showing that targeting a protective antigen from Yersinia pestis to the IMV membrane of vaccinia virus led to enhanced and protective antibody responses in mice [78]. The benefits of membrane anchoring versus secretion may be antigen-dependent, as well as determined by the cell type infected, but such observations may warrant further investigation as new poxviral vectors are designed for optimal antibody induction.…”

Safety and immunogenicity of mammalian cell derived and Modified Vaccinia Ankara vectored African swine fever subunit antigens in swine

“…The lack of antibody response may be related to a defect in antigen presentation, e.g., the retention of the MVA expressed ASFV antigens inside infected cells may have limited their presentation to B-cells (Borrego et al, 2006;Ganges et al, 2005). The use of molecular elements such as tPA to enhance intracellularly expressed antigen secretion for B-cell recognition and MHC II presentation for priming of helper CD4 T-cells (Brewoo et al, 2010;Embry et al, 2011) has been previously reported. Since the administered MVA-ASFV constructs lacked the secretory tPA signal, the absence of observed antibody response may be due to limited B-cell presentation.…”

Plague Vaccines: Status and Future

“…The secreted LcrV was a more potent vaccine that the previous vaccine that encoded the non-secreted form and the authors showed that a high level of protection was dependent on CD4 + but not CD8 + cells and correlated with increased anti-LcrV antibody and a bias toward IgG2a and away from IgG1 isotypes [194, 195]. In addition, Vaccinia virus (VACV) is the vaccine for smallpox and a widely-used vaccine vector for infectious diseases and cancers [196]. Several groups demonstrated that a vaccinia viral vector expressing either lcrV or caf1 (gene encoding F1) as vaccines which are highly immunogenic in BALB/c mice and safe in immunocompromised SCID mice [196–198].…”

“…In addition, Vaccinia virus (VACV) is the vaccine for smallpox and a widely-used vaccine vector for infectious diseases and cancers [196]. Several groups demonstrated that a vaccinia viral vector expressing either lcrV or caf1 (gene encoding F1) as vaccines which are highly immunogenic in BALB/c mice and safe in immunocompromised SCID mice [196–198]. …”