Vetnews | September 2024 18 « BACK TO CONTENTS microcarrier beads and can be cultured in fermentation tanks to produce a large amount of tissue culture medium containing the RABV. Clinical studies have shown that the RABV neutralizing antibody (RVNA) response after initial and intensified injections of PVRV is comparable with that after preexposure prophylaxis (PrEP) or PEP vaccination with HDCV.22 New rabies vaccines Currently, commercially available rabies vaccines are mainly CCV; however, the immunization process is complex, with multiple visits and long visit cycles, which objectively hinders the implementation of complete PEP, resulting in occasional reports of vaccine failure.23 In addition, vaccine production and immunization costs are high and immunization procedures are complex, making it far beyond the reach of using a single immunization regimen to expand PrEP and include it in children’s immunization plans in high-risk areas.24 Therefore, the development of vaccines with good immunogenicity, faster production of effective protective neutralizing antibodies, better compliance, low cost, and stronger protection while ensuring safety is an important direction for new rabies vaccine research and development. In recent years, novel adjuvant vaccines, protein and peptide vaccines, genetically modified vaccines, virus-like particle vaccines (VLPs), viral vector vaccines, and nucleic acid vaccines (DNA and RNA vaccines) have been the focus of search for new rabies vaccines. The rabies vaccine is not only effective in preventing rabies but also a therapeutic vaccine that requires the production of sufficient antibodies and immune defence in the shortest possible time after exposure to prevent RABV infection. Although Alum has been approved as the first adjuvant for human use and is widely used, some believe that it delays the early production of antibodies and cannot effectively induce cellular immunity,25–27 which is detrimental to the post-exposure preventive effect against rabies. On 30 June 2005, the China Food and Drug Administration banned the use of aluminium hydroxide (Al (OH)3) adjuvants in human rabies vaccines.28 Efficient, safe, and low-cost rabies adjuvant vaccines must not only reduce vaccine injection volume, but also enhance the immediate immune response, produce higher and more persistent levels of antibodies, and trigger strong cellular and humoral immunity by enhancing antigen presentation to antigenspecific immune cells, which is crucial27,29–31 Second generation adjuvants based on ligands for Toll-like receptors (TLR) appear to perform better.27 One adjuvanted rabies vaccine called the PIKA vaccine, composed of Rabipur and a polyinosinic-polycytidylic acid-based TLR-3-activating adjuvant, has completed a phase II clinical trial.32 This vaccine is composed of Rabipur and a TLR-3 activation adjuvant based on polyinosine cytidine. The vaccine was administered in an accelerated regimen, with two doses on day 0, two doses on day 3, and one dose on day 7, and was compared with the conventional Rabipur regimen administered on days 0, 3, 7, and 14. The results showed that the PIKA rabies vaccine acceleration regimen triggered a protective immune response as early as day 7. All subjects in the PIKA group reached a protective rabies virus-neutralizing antibody titers (0.5 IU/ml) on day 14, and the antibody titer increased faster than that in response to the control vaccine,33–35 The rabies virus glycoprotein (RABV-G) is the only protein that exists on the surface of viral particles and is responsible for the binding of the virus to host cells. It stimulates humoral immunity to produce RVNA and T cells to induce cellular immunity. It assembles into homologous trimeric proteins on the surface of viral particles. Many expression systems have been explored for glycoprotein expression, such as mammalian expression systems based on human embryonic kidney (HEK) 293,36 juvenile hamster kidney (BHK) 21,37 or Chinese hamster ovary (CHO)38 cell lines, which have been successfully tested to varying degrees. Depending on the cell medium and culture conditions,39 they can glycosylate G proteins to varying degrees. Insect cell expression systems based on recombinant rod-shaped viruses40 or transfected Schneider’s Drosophila 2 cells41 can express proteins at higher production sites, but typically only add shorter polysaccharides, fucose, and xylose residues. Yeast expression systems are also cost-effective; however, they undergo glycosylation with only mannose-containing polysaccharides, which is very different from glycosylation in mammalian cells. Therefore, yeast-derived RABV-G exhibit poor immunogenicity.42 RABV-G has also been expressed in plants such as tomatoes,43 carrots,44 and corn,45 with the aim of developing an edible rabies vaccine. Although the production of exogenous proteins in plants is cost-effective, it is hindered by purification issues. To date, the immune response triggered by oral immunization with plantderived RABV glycoproteins has been variable and is usually weaker than the immune response required to achieve reliable protection.46 The RABV can be modified through reverse genetics47 by deleting genes encoding phosphoprotein (P)48 or matrix protein (M),49 thereby weakening the virus virulence. This modified RABV does not replicate in animals (including immunodeficient animals); therefore, it may be safe. Rabies viruses with a matrix protein deficiency are more immunogenic than wild-type viruses with a phosphate protein deficiency or inactivation.50 However, the modified virus has less reproductive power in cell culture than the wild-type virus, which may increase the cost of vaccine production. Researchers have also developed vaccine viruses carrying two or three copies of glycoprotein genes.51 In mouse studies, inactivated multi-G-protein RABV vaccines showed stronger immunogenicity than wild-type viruses. The safest and most immunogenic of the different types of viral vector vaccines are adenoviruses, based on E1 deficiency.52 Adenoviruses cause replication defects by inserting sequences into the deleted E1 domain, which encodes proteins necessary for the transcription of other viral genes. Removing the adenoviral vector E1 induces a strong immune response in T and B cells. Due to the low persistence of the viral vector, this response can last for a long time.53 Because of the strong innate immune response induced by adenoviruses, high doses can cause serious side effects. The main disadvantage of adenoviral vectors is that their immunogenicity and efficacy are disrupted by neutralizing antibodies targeting the vector in the body54,55 Adenoviruses are widely present, and most people are infected with different adenoviral serotypes in early childhood. The presence of neutralizing antibodies in the body depends on the serotype and geographical location of the virus. Viruses isolated from non-human primates such as chimpanzees have been used as vectors. The serotypes of these viruses are extremely similar to those of human adenoviruses, but they do not spread among humans.56 Therefore, most adults lack neutralizing antibodies against monkey adenovirus, and even those with antibodies often have low titers. An E1-deficient chimpanzee adenovirus, SAdV-25 (also known as AdC68), expressing the RABV-G, has been widely tested in mice and nonhuman primates,56,57 After a single intramuscular injection, the virus can induce an effective and sustained neutralizing antibody response. Animals (including non-human primates) achieve complete protection against the RABV 1 year after vaccination. The adenovirus vector vaccine for the RABV will be highly cost-effective, as it is estimated that the cost of a single-dose vaccine is only $1. mRNA vaccines Nucleic acid vaccines contain both DNA and RNA. The principle involves connecting antigen genes with eukaryotic expression vectors and introducing them into the body to induce an immune response against the expressed proteins. Its advantage is that it can simultaneously activate both humoral and cellular immunity, and the body produces only an immune response to the inserted antigen, thereby reducing side effects. DNA vaccines are highly efficient and inexpensive, which makes them a good choice for use in developing countries. Human clinical trials have been disappointing in terms of their immunogenicity, although various efforts have been made to improve the efficacy of these vaccines. Several DNA vaccines have been licensed for veterinary use, such as the vaccines against the West Nile virus in horses and infectious hematopoietic necrosis virus in salmon, but no DNA vaccines have been licensed for human use; thus, the focus of nucleic acid vaccine research and development has shifted to RNA vaccines.58 mRNA vaccines have been the most popular nucleic acid technology, particularly Article
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