APRIL:TACI axis is dispensable for the immune response to rabies vaccination

Haley, Shannon; Tzvetkov, Evgeni P.; Lytle, Andrew; Alugupalli, Kishore R.; Plummer, Joseph R; McGettigan, James P.

doi:10.1016/j.antiviral.2017.06.004

Cited by 4 publications

(3 citation statements)

References 50 publications

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“…Furthermore, cytomegalovirus also increases human tonsillar B cell survival by stimu-lating the expression of BAFF and BAFF-R on these cells (137). In contrast to cytomegalovirus, the involvement of the APRIL-TACI axis in host resistance appears to be questionable because while rabies virus induces APRIL expression in murine B cells, immunization with a recombinant rabies vaccine expressing APRIL does not improve antibody responses, and virus-specific plasma cell generation is not diminished in immunized TACI-deficient mice (138).…”

Section: Viral Infections Of the Central Nervous Systemmentioning

confidence: 99%

The Role of BAFF System Molecules in Host Response to Pathogens

Sakai

Akkoyunlu

2017

Clin Microbiol Rev

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The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.

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Section: Viral Infections Of the Central Nervous Systemmentioning

confidence: 99%

The Role of BAFF System Molecules in Host Response to Pathogens

Sakai

Akkoyunlu

2017

Clin Microbiol Rev

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“…In immunization studies for rabies virus, RABV viral vector immunogens expressing membrane-anchored BAFF have been shown to be capable of inducing faster and higher titers of neutralizing antibodies toward RABV antigens without adversely affecting the longevity of the immune response [122]. Conversely, in a separate study, anchoring of APRIL to RABV viral vectors had no effect on antibody responses, and APRIL co-engagement did not improve the generation of LLPCs [123]. These studies are some of the first to assess whether the addition of molecular adjuvants can affect the longevity of the induced memory response through the generation of LLPCs.…”

Section: Tumor Necrosis Family (Tnf) Receptorsmentioning

confidence: 96%

B cell targeting by molecular adjuvants for enhanced immunogenicity

Sicard

Kassardjian

Julien

2020

Expert Review of Vaccines

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Introduction: Adjuvants are critical components of vaccines to improve the quality and durability of immune responses. Molecular adjuvants are a specific subclass of adjuvants where ligands of known immune-modulatory receptors are directly fused to an antigen. Co-stimulation of the B cell receptor (BCR) and immune-modulatory receptors through this strategy can augment downstream signaling to improve antibody titers and/or potency, and survival in challenge models. Areas covered: C3d has been the most extensively studied molecular adjuvant and shown to improve immune responses to a number of antigens. Similarly, tumor necrosis superfamily ligands, such as BAFF and APRIL, as well as CD40, CD180, and immune complex ligands can also improve humoral immunity as molecular adjuvants. Expert opinion: However, no single strategy has emerged that improves immune outcomes in all contexts. Thus, systematic exploration of molecular adjuvants that target B cell receptors will be required to realize their full potential as next-generation vaccine technologies.

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“…We previously showed that expressing secreted BAFF, but not a proliferating inducing ligand (APRIL), from a recombinant RABV-based vaccine targets the extrafollicular pathway of B cell differentiation and improves rabies vaccinations [31, 32]. However, this approach requires viral gene expression in-vivo to produce BAFF, eliminating its potential as an inactivated vaccine.…”

Section: Introductionmentioning

confidence: 99%

Incorporating B cell activating factor (BAFF) into the membrane of rabies virus (RABV) particles improves the speed and magnitude of vaccine-induced antibody responses

Plummer

McGettigan

2019

PLoS Negl Trop Dis

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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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APRIL:TACI axis is dispensable for the immune response to rabies vaccination

Cited by 4 publications

References 50 publications

The Role of BAFF System Molecules in Host Response to Pathogens

The Role of BAFF System Molecules in Host Response to Pathogens

B cell targeting by molecular adjuvants for enhanced immunogenicity

Incorporating B cell activating factor (BAFF) into the membrane of rabies virus (RABV) particles improves the speed and magnitude of vaccine-induced antibody responses

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