Vetnuus | September 2024 13 the need for timely administration immediately following exposure. In the same open-label, single-arm study of 12 healthy adult subjects, a total of 15 adverse events (AE) were noted, including gastrointestinal disorders, injection site pain/nodules, dizziness, and extremity pain, all of which were mild except for one subject who experienced moderate oropharyngeal pain [30]. The efficacy of rabies therapy decreases once clinical symptoms manifest, underscoring the importance of early intervention. Recent research has focused on developing novel treatment strategies composed of molecules that target viral replication at different stages of the rabies virus life cycle and molecules that inhibit some pathways of the innate host immune response [31]. In one study on mice, a cocktail regimen of six compounds was selected for use based on the results of previous studies: caspase-1 inhibitor, tumour necrosis factor (TNF)-α inhibitor, mitogenactivated protein (MAP)-kinase inhibitor, mouse interferon (IFN)- α/β, favipiravir, ribavirin and HRIG [31]. Mannitol was utilized as a blood-brain barrier opener [31]. The results of this study report a statistically significant extension of survival of mice treated with the drug cocktail compared to the survival of mice in the virus control group. They found a significant downregulation of proinflammatory molecules (caspase-1 and TNF-α) in the CNS in rhinovirus (RV)-infected mice treated with a combination of drugs, including IFN-α/β [31]. While the traditional combination therapy of RIG and vaccines remains the standard for PEP, ongoing research is uncovering new therapeutic avenues for treating rabies infections. One approach involves enhancing the immune response using adjuvants or novel vaccine formulations. Adjuvants can boost the immune response, potentially improving vaccine efficacy. A separate animal study on mice revealed that the absence of Toll-like receptor 7 (TLR7), an innate receptor sensing single-stranded viral RNA, led to lower antibody production in mice immunized with rabies virus (RABV) [32]. The results showed that TLR7 deficiency affected the recruitment of germinal center (GC) B cells and led to lessened GC formation, resulting in impaired RABV-neutralizing antibodies (VNA) and an inadequate Th1-based immune response [32]. Novel rabies infection treatments targeting the TLR7 signalling pathway for activation are promising strategies for improving the current efficacy of future rabies vaccines. Novel vaccine formulations, such as virus-like particles, are being explored for their ability to induce a more potent and more targeted immune response. Another animal study with rabies viruslike particles (RV-VLPs) in mice was conducted using stable cell lines for producing RV-VLPs via lentiviral-based transduction of human embryonic kidney (HEK)-293 cells [33]. This study developed a G protein-expressing cell line (HEK-G) to produce G-containing viruslike particles, evaluated the immunogenicity of these particles in mice, and found that the RV-VLPs were able to induce specific immune responses against rabies virus G protein [33]. These results encourage the study of new VLPs because these particles produced a specific antibody response. Other advancements in molecular biology and virology have paved the way for potential breakthroughs in more advanced rabies infections. Gene therapy, for example, holds promise for delivering antiviral genes directly to infected neurons by using rAAV-N796, a small interfering RNA (siRNA) that targets the nucleoprotein gene of rabies, preventing the virus from evading the host’s innate immune response [34]. Other forms of gene therapy being studied include clustered regularly interspaced short palindromic repeats (CRISPR) or CRISPR-associated protein (Cas9)-based technologies and induced pluripotent stem cells (iPSCs). The iPSC technique is proposed to target the editing of the rabies virus genome, potentially rendering it non-pathogenic, which is more helpful for disease modelling [35]. A combination therapy of the CRISPR/Cas9 system and iPSC method was found to correct erroneous strings in vitro. Gene delivery tools such as adeno-associated virus (AAV), Sendai virus, and episomes can then deliver corrected genes to target organs [35]. Furthermore, monoclonal antibodies specific to rabies virus proteins are being investigated for their therapeutic potential, offering a more targeted, precise, and time-sensitive approach to rabies treatment than HRIG [36]. From serum polyclonal antibodies to hybridoma monoclonal antibodies (mAbs) and from murine mAbs to human mAbs, considerable progress has been made in the urgent PEP of rabies [36]. RVC20, a broadly neutralizing mAb, was shown to neutralize all 35 tested RABV strains worldwide [36]. The efficiency of neutralizing mAb cocktails has been confirmed in clinical trials [36]. However, developing a neutralizing rabies cocktail binding to the nonoverlapping glycoprotein epitopes is a challenge, indicating the need for subsequent research. Eventually, safe, effective, and affordable rabies mAbs are presumed to replace HRIG in rabies PEP (Figures 1-3). Article FIGURE 1: Comparison of live attenuated and inactivated vaccines in rabies prevention. Live vaccines use weakened virus forms and are temperature sensitive, while inactivated vaccines require multiple doses and are globally used. Both stimulate the immune system against rabies and are used in post-exposure prophylaxis. FIGURE 2: Illustration of the differences and similarities between HRIG and monoclonal antibodies in rabies PEP. HRIG offers immediate immunity but has availability issues; monoclonal antibodies are advanced, broadly neutralizing, and may replace HRIG. Both are used with vaccines for immediate rabies immunity. HRIG: human rabies immunoglobulin; PEP: post-exposure prophylaxis >>> 14
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