A Bivalent, Chimeric Rabies Virus Expressing Simian Immunodeficiency Virus Envelope Induces Multifunctional Antibody Responses

Dunkel, Amber; Shen, Shixue; LaBranche, Celia C.; Montefiori, David C.; McGettigan, James P.

doi:10.1089/aid.2014.0319

Cited by 8 publications

(7 citation statements)

References 104 publications

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“…To this end, we developed a novel, in vitro flow cytometry-based mouse ADCC assay to assess the ability of antibodies elicited by FILORAB3 to induce direct killing by NK cells (23). Purified IgG from the sera of mice immunized with 2 doses of adjuvanted FILORAB3 led to significantly higher levels of killing by NK cells than by purified IgG from the sera of mice immunized with the parental rabies vaccine alone plus adjuvant.…”

Section: Discussionmentioning

confidence: 99%

“…For filoviruses as well as other viruses, neutralization in vitro does not necessarily correlate with protection in vivo. Nonneutralizing antibodies are known to confer protection by ADCC, phagocytosis, prevention of virus budding, and other mechanisms (10,(23)(24)(25)(26)(27)(28)(29)(30). Through both an in vitro approach and an in vivo approach, we identified an important role for ADCC and other nonneutralizing antibody functions in vaccine-induced immunity by FILORAB3.…”

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confidence: 99%

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A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model

Keshwara

Hagen

Abreu-Mota

et al. 2019

J Virol

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Marburg virus (MARV) is a filovirus related to Ebola virus (EBOV) associated with human hemorrhagic disease. Outbreaks are sporadic and severe, with a reported case mortality rate of upward of 88%. There is currently no antiviral or vaccine available. Given the sporadic nature of outbreaks, vaccines provide the best approach for long-term control of MARV in regions of endemicity. We have developed an inactivated rabies virus-vectored MARV vaccine (FILORAB3) to protect against Marburg virus disease. Immunogenicity studies in our labs have shown that a Th1-biased seroconversion to both rabies virus and MARV glycoproteins (GPs) is beneficial for protection in a preclinical murine model. As such, we adjuvanted FILORAB3 with glucopyranosyl lipid adjuvant (GLA), a Toll-like receptor 4 agonist, in a squalene-in-water emulsion. Across two different BALB/c mouse challenge models, we achieved 92% protection against murine-adapted Marburg virus (ma-MARV). Although our vaccine elicited strong MARV GP antibodies, it did not strongly induce neutralizing antibodies. Through bothin vitroandin vivoapproaches, we elucidated a critical role for NK cell-dependent antibody-mediated cellular cytotoxicity (ADCC) in vaccine-induced protection. Overall, these findings demonstrate that FILORAB3 is a promising vaccine candidate for Marburg virus disease.IMPORTANCEMarburg virus (MARV) is a virus similar to Ebola virus and also causes a hemorrhagic disease which is highly lethal. In contrast to EBOV, only a few vaccines have been developed against MARV, and researchers do not understand what kind of immune responses are required to protect from MARV. Here we show that antibodies directed against MARV after application of our vaccine protect in an animal system but fail to neutralize the virus in a widely used virus neutralization assay against MARV. This newly discovered activity needs to be considered more when analyzing MARV vaccines or infections.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model

Keshwara

Hagen

Abreu-Mota

et al. 2019

J Virol

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“…On days 14 and 62 postimmunization, blood was collected and serum was isolated for analysis. RABV G-specific IgG antibodies were determined by ELISA as described previously (40,(71)(72)(73). Anti-dsDNA levels were determined by ELISA on pooled sera from each immunized group diluted 1:100 in 1ϫ PBS and plated in duplicate using a mouse anti-dsDNA Ig (total AϩGϩM) ELISA kit (Alpha Diagnostic International), run according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…On days 3, 5, 7, and 10 postimmunization, blood was collected and serum was isolated for analysis. RABV G-specific IgG and IgM antibodies were determined by ELISA and reported at a 1:50 dilution as described previously (40,(71)(72)(73). VNA titers of pooled, heat-inactivated sera were determined using the rapid fluorescent focus inhibition test (RFFIT) as described previously (40,71).…”

Section: Methodsmentioning

confidence: 99%

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

Haley

Tzvetkov

Meuwissen

et al. 2017

J Virol

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Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP.IMPORTANCE Effective RABV PEP is currently resource-and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality.

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“…On days 3, 5, 7, 10 and 56 post-immunization, blood was collected and serum was isolated for analysis. RABV G-specific IgG and IgM antibodies were determined by ELISA and reported at 1:50 serum dilution as described previously (Cenna et al, 2009, 2008; Dorfmeier et al, 2013b; Dunkel et al, 2015). VNA titers of pooled, heat-inactivated sera were determined using the RFFIT as described previously (Cenna et al, 2009, 2008).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)–expressed by B cells in various stages of maturation–with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent in response to rRABV-APRIL and the vector eight weeks after immunization. Moreover, APRIL is dispensable for the long-lived antibody-secreting PC response to rRABV vaccination as anti-RABV G IgG levels were similar in APRIL-deficient and wild-type mice six months after vaccination. Mice lacking the APRIL receptor TACI demonstrated primary anti-RABV G antibody responses similar to wild-type mice following immunization with the vaccine vector indicating that this response is independent of TACI-mediated signals. Collectively, our findings demonstrate that APRIL and associated TACI signaling is dispensable for the immune response to RABV-based vaccination.

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A Bivalent, Chimeric Rabies Virus Expressing Simian Immunodeficiency Virus Envelope Induces Multifunctional Antibody Responses

Cited by 8 publications

References 104 publications

A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model

A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

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

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