Abstract
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.
Highlights
Correlates of immunity for most human vaccines rely on antibodies for protection [1]
We previously showed that expressing secreted BAFF, but not a proliferating inducing ligand (APRIL), from a recombinant rabies virus (RABV)-based vaccine targets the extrafollicular pathway of B cell differentiation and improves rabies vaccinations [31, 32]
The membrane-anchored BAFF in this first experiment consisted of an IL-2 signal sequence fused in-frame with the ectodomain of murine BAFF and the RABV G transmembrane domain (TM) and cytoplasmic domain (CD) (RABV-mBAFF)
Summary
Correlates of immunity for most human vaccines rely on antibodies for protection [1]. In the context of preventing human RABV infections, the induction of rapid and long-lasting serum VNAs is critical for protection because RABV vaccines are administered for both pre- and post-exposure settings (reviewed in [2, 3]). Strategies aimed at enhancing the speed, magnitude and longevity of vaccine-induced antibody titers is critical to improve vaccines against human rabies infection and/or to develop vaccines against other infectious diseases where an effective vaccine is lacking. One strategy to improve vaccine immunity is to target antigen to cells of the immune system. Targeting antigen directly to B cells improves the efficacy of antibody-based vaccines by increasing the speed [8] and magnitude of T cell-independent (TI) and T cell-dependent (TD) B cell responses [reviewed in [9]]. Fusing secreted antigen to CD180 [8] or C3d [reviewed in [9]] targets the antigen to cognate B cells, promoting rapid and potent antibody responses against viruses [10,11,12,13,14,15], bacteria [16], or synthetic antigens [17]
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