Vetnuus | September 2024 11 >>> 12 The methods, including cauterization, excision, and amputation, among others, were deemed inconsistent and eventually considered unsuitable as treatment methods. However, this understanding persisted until Louis Pasteur developed the first rabies vaccine in the nineteenth century [2]. The first generation of vaccines began in 1885 with Louis Pasteur, who used an infected rabbit spinal cord that was inactivated via sun drying to develop a vaccine [2]. The vaccine was able to provide success; however, there were many concerns. The consistency of inactivation of the virus in the vaccine was questioned, given that post-vaccine rabies cases were being reported. Given the development method, large-scale production of Pasteur’s vaccine was also challenging. Using Pasteur’s work, other researchers added their advancements, including adding phenol to inactivate the virus, using baby animal brains to create vaccines as they contained less myelin, using embryonated chicken and duck eggs to make a live attenuated vaccine, and using the cell culture system to enhance the production of a vaccine [2,4,5]. In the modern world, the vaccines used are the modified live vaccine, the inactivated rabies vaccine, and the adjuvanted rabies vaccine [2]. With the advancement of recombinant DNA technologies, new vaccination candidates may soon be available. Types of rabies vaccines The first vaccines created to immunize people against the rabies virus contained an inactivated form [6]. These vaccines were initially developed through the isolation of the virus from animals infected with rabies, followed by the inactivation of the virus through the addition of various chemicals [7]. However, this technique led to numerous issues, such as poor antigenicity of the virus and adverse reactions to different components in the vaccine [8]. To overcome these deficiencies, new methods were developed to generate superior vaccines. Improvements in cell culture techniques allowed for the growth of viruses in various cell lines in vitro [9]. After the viruses were cultured, they were extracted from the cells and inactivated via treatment with compounds such as beta-propiolactone and formalin [10]. The inactivated viruses were then administered to people or animals. This stimulates the innate and adaptive immune response, ultimately creating memory B and T cells, providing long-lasting immunological protection against the virus [11]. Vaccines containing the inactivated virus are typically administered via intramuscular injection. The vaccine may be given either pre-exposure or post-exposure, with multiple doses required to achieve maximum immunological protection [12]. Vaccines generated via virus culturing in vitro are safe and efficacious and allow for a high degree of control in growing the virus [9]. Unfortunately, there is a risk that some viruses may not be fully inactivated during development. Additionally, multiple doses of the vaccine are required, which may lead to issues regarding patient compliance [13]. Following the development of vaccines containing inactivated forms of the virus, vaccines for rabies were created containing a live-attenuated form of the rabies virus. These were initially created by passing the rabies virus through numerous cell cultures and selecting nonpathogenic forms of the virus [2]. When vaccines containing this product were administered via intramuscular injection to various animals, a robust immune response was generated, and high levels of antibody titers were recovered in the serum against the rabies virus. However, numerous adverse effects, such as severe tremors and paralysis, were reported [14]. The large number of adverse effects combined with a high sensitivity to fluctuations in temperature resulted in the modified live vaccine no longer being recommended for parenteral administration by the World Health Organization [2,14]. More recently, vaccines containing mutated forms of the rabies virus have been created, greatly reducing virulence [2]. The glycoprotein (g) is crucial for the rabies virus to be pathogenic [15]. Thus, mutations can be induced at sites in the gene that encodes for this protein, rendering the virus no longer pathogenic though still infectious, allowing for a strong immune response to be still generated against it [16]. Vaccines containing mutated forms of the rabies virus may be administered orally and are often given to animals that serve as a reservoir for the rabies virus, such as dogs [2]. The advantages of this vaccination method include the production of a vigorous immune response and few doses required to achieve a high degree of immunological protection. One study showed numerous antibodies against the rabies virus in dogs three years after receiving a single dose of the vaccine [17]. Limitations of the live attenuated vaccine form are a higher cost than other vaccination methods and a risk of reversion back to the pathogenic form of the virus through back mutations [18,19]. A third method of generating vaccines against the rabies virus involves using recombinant techniques to express proteins of the rabies virus in various vectors such as the vaccinia virus, canarypox virus, and the Orf virus [20-22]. This is done by creating attenuated viral vectors that express the rabies virus glycoprotein. This protein is generally chosen to be expressed in the vector because it is expressed on the surface of the rabies virus. This allows for the generation of antibodies that can bind to glycoprotein, thus preventing rabies virions from entering host cells, as this glycoprotein is critical in mediating cell entry [23,24]. Vaccines containing these recombinant virions are typically only used in animals, with most instances of human administration of this vaccine only being done in the context of clinical trials [21]. However, studies involving animals have shown that this vaccine produces a very strong B and T cell response that offers protection for an extended period, even after just a single administration of the vaccine [25]. Additionally, immunological solid reactions have been documented after both intramuscular and oral administration of this vaccine in animals [25]. The drawbacks of this type of vaccine include its high cost of production and a limited number of studies of its use in humans (Table 1) [13]. Article
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