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

ABSTRACT: 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.

SUBMITTER: Haley SL

PROVIDER: S-EPMC5375675 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Haley Shannon L SL Tzvetkov Evgeni P EP Meuwissen Samantha S Plummer Joseph R JR McGettigan James P JP

Journal of virology 20170329 8

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 ac ...[more]

PMID: 28148792

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Project description:Introduction Each year, an estimated 25000 rabies death occurs in Africa. Post-exposure prophylaxis (PEP) remains the only proven approach in preventing rabies deaths. Most of rabies deaths occur among those who delayed, did not receive, or complete rabies PEP. The aim of this study was to determine the pattern of animal bite, factors associated with delays in initiating, and nonadherence to rabies PEP regimen. Method Data on clients reporting for rabies PEP in a tertiary hospital setting in Ghana were collected from 2013 to 2016. Demographics, place, and source of exposure were collected. Other information obtained included adherence to the PEP protocol and GPS coordinates of the town of animal bites. The shortest distance between the GPS coordinates of town of animal bite and the site of administration of the rabies PEP was calculated. A total of 1030 individuals received rabies PEP over the period. Results Overall, 52.9% (545) were males while 47.1% (485) were females. Majority of the cases were between the age group 1–10 years accounting for 29.2%. Dog bites accounted for 96.5% (n?=?994). Cats, nonhuman primates, human bites, respectively, accounted for 1.8% (n?=?18), 1.2% (n?=?12), and 0.6% (n?=?6) of all bites. Majority of bites occurred at home (66.2% (n?=?646)). Also, 31.6% (n??=?308) and 2.3% (n?=?22) of bites occurred on the streets and neighbors/friends' homes, respectively. Only, 18.7% initiated PEP within 24 hours of bite. Rabies PEP regimen completion rate was 95.2% (n?=?976). The median distance travelled to access rabies PEP was 7.87?km (IQR, 3.58–16.27) km. Overall, 34.7% (n?=?344) had the animal bite within 4.99?km radius of the treatment room of KBTH. Clients who delayed in initiating rabies PEP were 2.6 (95% CI, 1.3–5.1) times more likely to be males and 2.0 (1.1–3.9) times more likely to receive bites in a location more than 5?km radius from the KBTH treatment room. Gender, age, and distance of bite from the treatment room were not associated with the likelihood of not completing rabies PEP schedule. Discussion. Bites from suspected rabies infected animals remain a problem in southern Ghana. There are significant delays in initiating PEP for rabies prevention. Most animal bite victims are children ten years and below. Male gender and bites more than 5?km radius from the site of rabies PEP administration were most significant factors associated with delays in initiating rabies PEP. There is the need for adopting strategies to encourage prompt initiation and adherence to PEP.

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

Publications

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

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