HJBR Jan/Feb 2021

HEALTHCARE JOURNAL OF BATON ROUGE I  JAN / FEB 2021 31 mon mouse models (68). However, fur- ther studies on R848 adjuvanticity should stress more on vaccine formulation. A re- cent study by Gadd et al. indicated that only when R848 was conjugated with DOPE (1,2−di−(9Z−octadecenoyl)−sn−glycero−3− phosphoethanolamine):DDA (dimeth- yldioctadecylammonium bromide salt) multilamella liposomes rather than linear mixed, a high potency of immunostimula- tory activity was observed (69). Moreover, an R848-encapsulating PLGA nanopar- ticle can bring down the excessive level of inflammatory cytokines induced by free R848, which could be benefit to provide long-term safety and appropriate immune response (70). Although CpG had been shown to exhib- it considerable potential as a coronavirus- specific adjuvant, studies have found that it might be a poor inducer of long-term immune memory (46). A recent study indi- cated that single-stranded RNAs (ssRNAs) derived from the Cricket paralysis virus (CrPV) intergenic region (IGR) internal ri- bosome entry sites (IRES) could function as vaccine adjuvants endowing long-last- ing immunity. This adjuvant significantly activates innate immune response through activating TLR7 and enhancing the chemo- taxis of professional antigen-presenting cells (APC) (71). Moreover, some novel ad- juvants such as STING agonist, Advax, and AS01B, which is an adjuvant formulated in recombinant zoster vaccine Shingrix, ex- hibit advantages for long-lasting immune responses (46, 59, 72). Advax, a delta inu- lin microparticle adjuvant, augmented the induction of neutralizing antibodies along with the existence of memory B cells and a robust, long-lasting T-cell IFN- γ response when it was formulated in recombinant or inactivated SARS-CoV vaccines (46). Moreover, Matrix M1, a saponin-based ad- juvant, has been demonstrated to be more effective than alum adjuvant in inducing neutralizing antibodies to SARS S protein or MERS S protein (17). This might address the concern that S protein may lead to antibody-dependent enhancement (ADE), which is more likely to be triggered by mild antibody production (36). The SARS-CoV-2 infections occur at the mucosal surface of the upper respiratory tract (73). Thus, the elicitation of protective immune responses at the mucosa is criti- cal. TLR agonists, such as flagellin (74) and CpG ODN (62), have been used as muco- sal adjuvants. As discussed above, the CpG ODN can elicit neutralizing antibodies in mucosal compartments (62) when formu- lated with inactivated SARS-CoV. Addition- ally, the STING agonist, bis-(3´,5´)-cyclic dimeric guanosine monophosphate (c-di- GMP or cdGMP), has been reported as a potent mucosal vaccine adjuvant that in- ducesTh1 andTh17 cytokines in a plant-de- rived H5 influenza vaccine after intranasal vaccination (75). In a very recent study, it was demonstrated that pulmonary surfac- tant–biomimetic liposomes encapsulating STING agonists could be used as mucosal adjuvants for universal influenza vaccines that trigger rapid humoral and cellular immune responses and exhibit sustained cross-protection against influenza (76). Though cdGMP in polymeric nanoparticle formulations has been used as adjuvants with MERS-CoV S-RBD protein, its abil- ity to induce mucosal immunity was not specifically examined (72). Thus, further studies are warranted to examine both the efficacy and safety of mucosal adjuvants in coronavirus vaccines. Conclusion and Perspectives In this article, we provided an overview of previously studied adjuvants in candi- date inactivated and subunit coronavirus vaccines with a focus on the types of adju- vants in the vaccine formulations and the nature of immune responses to the formu- lated vaccines. These previous studies pro- vided a convenient basis for the screening of adjuvants required to develop coronavi- rus vaccines. In-depth reviews of the vari- ous adjuvants, a comprehensive under- standing of their impacts on the extent and types of immune responses, and an explo- ration of their combinations with various antigen types and vaccine platforms will facilitate the selection of adjuvants that provide the required immunological pro- tection of coronavirus vaccines. In the absence of a cure for COVID-19, effective and safe vaccines are urgently re- quired. Adjuvants such as aluminum-based salts, TLR agonists, emulsions, and other novel adjuvants have distinctive physico- chemical properties, which can be signifi- cant in regulating the strength, duration, and types of immune responses (19, 63, 77). Studies have suggested that neutralizing antibodies are critical for immune protec- tion (34, 42).While mechanistic studies are still being conducted, emerging evidence has suggested that SRAS-CoV-2-specific CD4+ and CD8+ T cells in coordination with neutralizing antibodies are required for generating protective immunity against SARS-CoV-2 (33). Thus, the appropriate adjuvants should be selected to formulate specific antigens that will achieve optimal immunogenicity profiles. Current available “In the absence of a cure for COVID-19, effective and safe vaccines are urgently required. Adjuvants such as aluminum- based salts, TLR agonists, emulsions, and other novel adjuvants have distinctive physicochemical properties, which can be significant in regulating the strength, duration, and types of immune responses.”