The Immune Response to a Vesicular Stomatitis Virus Vaccine Vector Is Independent of Particulate Antigen Secretion and Protein Turnover Rate

Vesicular stomatitis virus (VSV) is a highly cytopathic virus being developed as a vaccine vector due to its ability to induce strong protective T cell and antibody responses after a single dose. However, little is known regarding the mechanisms underlying the potent immune responses elicited by VSV.We previously generated a VSV vector expressing the hepatitis B virus middle enve-lope surface glycoprotein (MS) that induces strongMS-specific T cell and antibody responses in mice. After synthesis in the cyto-plasm, the MS protein translocates to the endoplasmic reticulum, where it forms subviral particles that are secreted from the cell. To better understand the contributions of secreted and intracellular protein to the VSV-induced immune response, we pro-duced a vector expressing a secretion-deficient MSmutant (MSC69A) and compared the immunogenicity of this vector to that of the wild-type VSV-MS vector in mice. As expected, the MSC69A protein was not secreted from VSV-infected cells and displayed enhanced proteasome-mediated degradation. Surprisingly, despite these differences in intracellular protein processing, the T cell and antibody responses generated toMSC69A were comparable to those elicited by virus expressing wild-typeMS protein. Therefore, when it is expressed from VSV, the immune responses to MS are independent of particulate antigen secretion and the turnover rate of cytoplasmic protein. These results are consistent with a model in which the immune responses to VSV are strongly influenced by the replication cycle of the vector and demonstrate that characteristics of the vector have the capacity to affect vaccine efficacy more than do the properties of the antigen itself. Vesicular stomatitis virus (VSV) is a nonsegmented negative-strand RNA virus belonging to the Rhabdoviridae family tha