Incorporating B cell activating factor (BAFF) into the membrane of rabies virus (RABV) particles improves the speed and magnitude of vaccine-induced antibody responses.
B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) superfamily of cytokines that links innate with adaptive immunity. BAFF signals through receptors on B cells, making it an attractive molecule to potentiate vaccine-induced B cell responses. We hypothesized that a rabies...
| Published in: | PLOS Neglected Tropical Diseases |
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| Main Authors: | , |
| Format: | Article in Journal/Newspaper |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019
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| Subjects: | |
| Online Access: | https://doi.org/10.1371/journal.pntd.0007800 https://doaj.org/article/81b59be30bd94004b30c862e035b1903 |
| Summary: | B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) superfamily of cytokines that links innate with adaptive immunity. BAFF signals through receptors on B cells, making it an attractive molecule to potentiate vaccine-induced B cell responses. We hypothesized that a rabies virus (RABV)-based vaccine displaying both antigen and BAFF on the surface of the same virus particle would target antigen-specific B cells for activation and improve RABV-specific antibody responses. To test this hypothesis, we constructed a recombinant RABV-based vector expressing virus membrane-anchored murine BAFF (RABV-ED51-mBAFF). BAFF was incorporated into the RABV particle and determined to be biologically functional, as demonstrated by increased B cell survival of primary murine B cells treated ex-vivo with RABV-ED51-mBAFF. B cell survival was inhibited by pre-treating RABV-ED51-mBAFF with an antibody that blocks BAFF functions. RABV-ED51-mBAFF also activated primary murine B cells ex-vivo more effectively than RABV as shown by significant upregulation of CD69, CD40, and MHCII on the surface of infected B cells. In-vivo, RABV-ED51-mBAFF induced significantly faster and higher virus neutralizing antibody (VNA) titers than RABV while not adversely affecting the longevity of the vaccine-induced antibody response. Since BAFF was incorporated into the virus particle and genome replication was not required for BAFF expression in-vivo, we hypothesized that RABV-ED51-mBAFF would be effective as an inactivated vaccine. Mice immunized with 250 ng/mouse of β-propriolactone-inactivated RABV-ED51-mBAFF showed faster and higher anti-RABV VNA titers compared to mice immunized with inactivated RABV. Together, this model stands as a potential foundation for exploring other virus membrane-anchored molecular adjuvants to make safer, more effective inactivated RABV-based vaccines. |
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