Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis.
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.IMPORTANCEEffective 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.
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Shannon L
SL
Haley
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Evgeni P
EP
Tzvetkov
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Samantha
S
Meuwissen
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Joseph R
JR
Plummer
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA James.McGettigan@jefferson.edu.|Jefferson Vaccine Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
James P
JP
McGettigan
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002454:Cell Differentiation; D051379:Mice; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D011818:Rabies / Q000517:prevention & control*; D011819:Rabies Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D000914:Antibodies, Viral; D053264:B-Cell Activating Factor; D011819:Rabies Vaccines; C505720:Tnfsf13b protein, mouse; D014614:Vaccines, Synthetic
B cell activating factor (BAFF); antibody-based vaccine; extrafollicular B cell response; postexposure prophylaxis; rabies; vaccines; virus neutralizing antibodies