T he prototypical vaccine used in postexposure settings was developed over a century ago for use following exposure to a potentially rabid animal (9, 14). Postexposure vaccination remains the worldwide standard for the prevention of rabies infections of humans. Despite the long history of rabies vaccine use as a postexposure treatment and the facts that over two-thirds of the world population live in regions where rabies is endemic and that over 55,000 people die every year due to RV infections, little information is available regarding the development of effective B cell responses early postvaccination, which may influence the outcome of postexposure vaccine efficacy. Current vaccines for human use are based on inactivated RV strains. Therefore, vaccineinduced protection against RV has long been described as being dependent solely on CD4 ϩ T cell help for the induction of protective antibody responses (9). These observations are supported by experiments carried out in RV-vaccinated nude mice that did not develop anti-RV antibody responses and were not protected against pathogenic challenge in preexposure settings (29). Similarly, Mifune et al. (16) showed that vaccinated athymic nude mice did not produce anti-RV antibodies in postexposure experiments. Furthermore, neutralizing antibodies directed against RV antigens were shown to be produced only with the assistance of Thelper cells (1). Finally, T cell depletion studies further showed the importance of CD4 ϩ T cells in generating neutralizing, protective antibodies in mice after RV infection (21). Together, these experiments showed that current inactivated RV-based vaccines rely on T cell help for the elicitation of effective antibody responses associated with protection against pathogenic challenge.Vaccine-induced immunity is a complex process involving innate and adaptive immune responses. During the development of typical vaccine-induced immunity, antigen-primed T cells migrate to the T and B cell borders of secondary lymphoid organs, where they interact with their cognate antigen-specific B cells. After activation, B cells differentiate into early, short-lived extrafollicular plasma cells, germinal center (GC) B cells, or early unswitched memory B cells that can recirculate (7). Within GCs, B cells differentiate into memory B cells or long-lived plasma cells that secrete high-affinity, postswitched antibodies. In most cases, fully formed GC-derived memory B cells and plasma cells can take from days to weeks to develop. From a traditional vaccination standpoint, this lag time between vaccination and GC B cell development is required and usually acceptable, since GC B cells are critical for long-term B cell responses to protect against future exposure to the pathogen. However, vaccines are also used in postexposure settings after exposure to pathogens, such as for RV. Since the lag time between vaccination and the generation of effective GC B cell responses might be too long, administration of postexposure vaccines for the prevention of rabies infection may...

We previously showed that a matrix (M) gene-deleted rabies virus (RABV)-based vaccine (RABV-DM) is highly immunogenic and induces potent B cell responses in the context of RABV infection. We speculated that RABV-DM expressing HIV proteins would also induce potent B cell responses against HIV antigens. As a prerequisite to future studies in nonhuman primates, we completed immunogenicity studies in mice to confirm the ability of RABV-DM to induce polyfunctional B cell responses in the context of HIV. To that end, the envelope protein from the mac239 strain of SIV (SIVmac239Env) was cloned into RABV-DM, resulting in RABV-DM-Env. Infectious virus was recovered following standard methods and propagated on baby hamster kidney cells stably expressing RABV M [ > 10 7 focus forming units (ffu)/ml]. Western blot analysis of cell lysates or of purified virions confirmed Env expression on the surface of infected cells and within virus particles, respectively. Positive neutralization activity against a neutralization-sensitive SIV strain and to a lesser extent against a neutralization-resistant SIV strain was detected in mice after a single intramuscular inoculation with RABV-DM-Env. The quality, but not quantity, of the antibody response was enhanced via boosting with recombinant gp130 or RABV-DM-Env as measured by an increase in antibody avidity and a skewing toward a Th1-type antibody response. We also show that an intradermal inoculation induces higher antibodies than an intramuscular or intranasal inoculation. An intradermal inoculation of RABV-DM-Env followed by a boost inoculation with recombinant gp130 produced anti-SIV antibodies with neutralizing and nonneutralizing antibody (nNAb) effector functions. Together, RABV-DM-Env induces B cells to secrete antibodies against SIV with the potential to clear both ''free'' and cell-associated virus. Strategies capable of eliciting both NAbs as well as nNAbs might help to improve the efficacy of HIV-1 vaccines.