4  Polysaccharide adjuvant for antiviral vaccine
Vaccination is the most successful and effective medical intervention to prevent infectious diseases, which can reduce mortality, prolong life expectancy and improve quality of life [106]. The development of a vaccine for coronavirus is a critical step in prevention, but it may not be effective for future strains, and we must be ready for the next epidemic [3]. Polysaccharide adjuvant can enhance the immune effect of a vaccine, thus promoting body-specific immunity and non-specific immunity, cellular immunity, humoral immunity and mucosal immunity [107]. Chitosan is effective in stimulating humoral and cell-mediated immune responses with a proven safety record in animals and humans, which has been used as adjuvant for improving vaccine efficacy, especially in RNA virus vaccines [13,108,109]. Chitosan can only modestly protect animals against RSV infection when given post-infection, while it can significantly reduce RSV infection in mice when combined with inactivated RSV vaccine before infection. This study suggested that chitosan can be applied as a potential treatment/adjuvant for RSV infection [13]. Chitosan-adjuvanted vaccines can enhance antibody titers against A- and B-type human influenza viruses 4 to 6 times compared with the vaccines without chitosan. Inactivated AIV A/H5N2 admixed with chitosan, when administered to mice challenged afterwards with the same virus, showed higher immunogenicity and protective efficacy compared with the antigen without chitosan [110]. Chitosan adjuvanted vaccine stored at 4 °C can preserve its adjuvant properties for at least 8 months. Chitosan can stimulate proliferative and cytotoxic activity of splenic mononuclear leukocytes in mice [111]. Thus, chitosan is a promising adjuvant candidate for inactivated influenza vaccines, which provides a reference for the development of anti-novel coronavirus vaccines.
Although SARS-CoV vaccines can protect against lethal infection, the addition of delta inulin-based polysaccharide adjuvant on day 3 post-challenge can significantly increase serum neutralizing-antibody titers and reduce lung virus titers. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. This suggests that delta inulin polysaccharide adjuvants have the potential to develop more effective coronavirus vaccines [20]. In addition, some Chinese herbal medicinal polysaccharides have been used as safe and effective adjuvants [77,107,112,113]. APS as an adjuvant combined with influenza vaccine can improve the immune response and systemic humoral response to H5N1 virus infection [46,114]. APS can potentially be used as an immunomodulator for a foot-and-mouth disease virus (FMDV), which is an RNA virus vaccine, and provide better protection against FMDV [115]. APS is also a potent adjuvant for hepatitis B DNA vaccine, and can enhance the immune responses of HBV DNA vaccine via promoting dendritic cells maturation and inhibit the regulatory T cells frequency [116]. Polysaccharide extract from RI exerts potent anti-IAV activity against human seasonal influenza viruses (H1N1 and H3N2) and AIV (H6N2 and H9N2) in vitro [49]. The polysaccharides also significantly reduced the expression of pro-inflammatory cytokines (IL-6) and strongly inhibited the protein expression of TLR-3 induced by PR8. The polysaccharide extract from RI, therefore, has the potential to be used as an adjunct to antiviral therapy for the treatment of IAV infection [49].
Additionally, peptide-based vaccines have become as a potentially important strategy for the development of therapeutic vaccination [117,118]. They do not require in vitro culture, making them biologically safe, and their selectivity can accurately activate the immune responses [119,120]. For example, a hydrocarbon-stapled short α-helical peptide can effectively inhibit MERS-CoV infection and its S protein-mediated cell-cell fusion [121]. The epitopes selected from the S glycoprotein of SARS-COV-2 can be used to design and prepare immunogenic multi-epitopic peptide vaccine against novel coronavirus disease caused by SARS-CoV-2 [122,123]. The T cell multi epitopes-based peptide vaccine was designed for COVID-19 using the envelope protein of SARS-CoV-2 as an immunogenic target [124]. Carrageenan and its structurally related compounds may serve as innovative adjuvants for enhancing peptide-based vaccine potency through immune enhancement [118]. The glycopeptides prepared by the combination of selected polysaccharides with peptides, and the peptide vaccines with polysaccharide adjuvants, will have important application prospects for inhibiting coronaviruses.