Characterization of a single-cycle rabies virus-based vaccine vector.
Recombinant rabies virus (RV)-based vectors have demonstrated their efficacy in generating long-term, antigen-specific immune responses in murine and monkey models. However, replication-competent viral vectors pose significant safety concerns due to vector pathogenicity. RV pathogenicity is largely attributed to its glycoprotein (RV-G), which facilitates the attachment and entry of RV into host cells. We have developed a live, single-cycle RV by deletion of the G gene from an RV vaccine vector expressing HIV-1 Gag (SPBN-DeltaG-Gag). Passage of SPBN-DeltaG-Gag on cells stably expressing RV-G allowed efficient propagation of the G-deleted RV. The in vivo immunogenicity data comparing single-cycle RV to a replication-competent control (BNSP-Gag) showed lower RV-specific antibodies; however, the overall isotype profiles (IgG2a/IgG1) were similar for the two vaccine vectors. Despite this difference, mice immunized with SPBN-DeltaG-Gag and BNSP-Gag mounted similar levels of Gag-specific CD8(+) T-cell responses as measured by major histocompatibility complex class I Gag-tetramer staining, gamma interferon-enzyme-linked immunospot assay, and cytotoxic T-cell assay. Moreover, these cellular responses were maintained equally at immunization titers as low as 10(3) focus-forming units for both RV vaccine vectors. CD8(+) T-cell responses were significantly enhanced by a boost with a single-cycle RV complemented with a heterologous vesicular stomatitis virus glycoprotein. These findings demonstrate that single-cycle RV is an effective alternative to replication-competent RV vectors for future development of vaccines for HIV-1 and other infectious diseases.
Gomme
Emily A
EA
Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Faul
Elizabeth J
EJ
Flomenberg
Phyllis
P
McGettigan
James P
JP
Schnell
Matthias J
MJ
D000818:Animals; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011818:Rabies / Q000276:immunology / Q000517:prevention & control*; D011819:Rabies Vaccines / Q000235:genetics / Q000276:immunology; D011820:Rabies virus / Q000276:immunology* / Q000472:pathogenicity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053586:Virus Internalization; D014779:Virus Replication / Q000502:physiology
D000914:Antibodies, Viral; D015683:Gene Products, gag; D011819:Rabies Vaccines; D007371:Interferon-gamma