Abstract
Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R−/−) to characterize the role for IL-21 in RABV vaccine-induced immunity. IL-21R−/− mice immunized with a low dose of a live recombinant RABV-based vaccine (rRABV) produced only low levels of primary or secondary anti-RABV antibody response while wild-type mice developed potent anti-RABV antibodies. Furthermore, IL-21R−/− mice immunized with low-dose rRABV were only minimally protected against pathogenic RABV challenge, while all wild-type mice survived challenge, indicating that IL-21R signaling is required for antibody production in response to low-dose RABV-based vaccination. IL-21R−/− mice immunized with a higher dose of vaccine produced suboptimal anti-RABV primary antibody responses, but showed potent secondary antibodies and protection similar to wild-type mice upon challenge with pathogenic RABV, indicating that IL-21 is dispensable for secondary antibody responses to live RABV-based vaccines when a primary response develops. Furthermore, we show that IL-21 is dispensable for the generation of Tfh cells and memory B cells in the draining lymph nodes of immunized mice but is required for the detection of optimal GC B cells or plasma cells in the lymph node or bone marrow, respectively, in a vaccine dose-dependent manner. Collectively, our preliminary data show that IL-21 is critical for the development of optimal vaccine-induced primary but not secondary antibody responses against RABV infections.
Highlights
rabies virus (RABV) is a single-stranded negative sense RNA virus of the genus lyssavirus in the Rhabdoviridae family that kills approximately 55,000 people annually
We show that IL-21 is critical for the induction of primary vaccine-induced antiRABV G antibody titers and that the effects of IL-21 are highly dependent on the dose of vaccine administered
In our model of rabies immunogenicity and protection, the lack of IL-21 receptor influenced the detection of B cells in germinal centers in lymph nodes or of plasma cells in bone marrow after immunization with low or high doses of vaccine, respectively
Summary
RABV is a single-stranded negative sense RNA virus of the genus lyssavirus in the Rhabdoviridae family that kills approximately 55,000 people annually. Up to 60% of rabies cases are in children, making rabies the seventh most important infectious disease in terms of years lost [1]. Except for cattle and foxes, the incidence of rabies in domesticated or wildlife remained unchanged or significantly increased in the US in 2011 compared to the five-year average for each species [4], exemplifying the difficulty in containing zoonotic viral infections even in industrialized nations. Rabies is considered a neglected global zoonotic infectious disease that disproportionately affects children and, understanding how B cells develop in response to experimental RABV-based vaccination may help to support efforts to develop a single-dose human rabies vaccine for use in both developing and industrialized countries
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