HJAR Jan/Feb 2021

26 JAN / FEB 2021  I  HEALTHCARE JOURNAL OF ARKANSAS COVID-19 VACCINE 2.0 aluminum oxyhydroxide (43), aluminum hydroxide (11), aluminum phosphate (22), and Imject™ Alum (23), which is a mixture of aluminum hydroxide and magnesium hydroxide. Even though there is no spe- cific description regarding the aluminum hydroxide in reported literature (11, 18, 21), it can also be referred to Aluminum oxyhy- droxide (44). However, these studies lacked systematic comparisons with regards to their adjuvanticity and how various alum- based adjuvants differed in their ability to induce neutralizing antibodies. It is worth noting that inactivated SARS- CoV or S protein-based vaccines are as- sociated with Th2-type immunopathology, which is characterized by an increase in eosinophils and inflammatory infiltrates (14, 30, 37, 45). Moreover, the addition of alum adjuvant exacerbated the immu- nopathologic reactions (14, 45). In alum- adjuvanted SARS-CoV double-inactivated vaccine (DIV), there was a skew in the N or S protein-specific antibodies toward IgG1, when compared with the more bal- anced antibody production in the nonad- juvanted DIV vaccine (14). These observa- tions raise significant concerns regarding the safety of adjuvanted coronavirus vac- cines. On the other hand, it has been shown that alum can reduce immunopathology in SARS-CoV vaccines containing either a double-inactivated virus or S protein (11). Furthermore, in a recent study, a purified inactivated SARS-CoV-2 vaccine (PiCo- Vacc) adjuvanted with aluminum hydrox- ide conferred complete protection in non- human primates (rhesus macaques) with potent humoral responses but without lung immunopathology (15). This finding raises the question of the mechanism of eosino- philic immunopathology. While commonly thought of as the product of Th2 respons- es, recent studies have indicated that tis- sue eosinophilia can also be controlled by Th17 responses (46). Thus, the proper selection of CoV antigens and adjuvants that can shift host responses away from a Th17-bias appears to be critical. In addi- tion, other studies have demonstrated that the Th2 immunopathology may be associ- ated with SARS N or S protein that results in enhanced eosinophilic immunopathol- ogy (11, 37, 47). However, more studies are required, as the preliminary data is limited. Additionally, the Th-2–biased immune re- sponses may raise the concern on vaccine- enhanced respiratory disease (VAERD) (38, 48), however, there are no evidences that alum-adjuvanted CoV vaccines show the effect. When alum was used as an adjuvant in CoV vaccines (Table 1), there was a lack of Th1 CD4+ T cell and cytotoxic CD8+ T cell immune responses, which is typical for alum-adjuvanted vaccines (49). However, recent study has demonstrated that the SARS-CoV-2–specific adaptive immune re- sponse correlated with milder disease, in- dicating that coordinated CD4+ and CD8+ T cell responses play a synergistic effect in the protective immunity of COVID-19 (33). Several other adjuvants, which are capable of inducing more balanced Th1/Th2 or Th1-biased immune responses, have been formulated in CoV vaccines and will be dis- cussed in the following sections. Emulsion Adjuvants The emulsion adjuvants, MF59, and AS03 have already been used in licensed human vaccines to improve the immuno- genicity of the antigens (50, 51). Compared with alum that lacks the capability to medi- ate cell-mediated immunity (49), MF59 and AS03 can elicit more balanced immunity, possibly by improving antigen uptake, re- cruiting immune cells, and promoting the migration of activated antigen-presenting cells (28, 50, 52). Emulsion adjuvants have already been used in preclinical studies of vaccines against coronavirus. MF59 used in inactivated SARS and MERS vaccines, as well as vaccines containing the RBD do- main of the MERS-CoV spike (S) protein, has exhibited excellent adjuvanticity, with potent humoral immune responses, i.e., high titers of neutralizing antibodies, and cell-mediated immunity in the coronavi- rus vaccines (53–55). In addition, depend- ing on the types of antigen, cell-mediated immunity induced by MF59 differs. When formulated with the MERS-CoV S protein, MF59 enhanced both effective CD4+ and CD8+ T-cell immune responses. In com- parison, when combined with inactivated SARS CoV, MF59 induced significant CD4+ T cell, but not CD8+ T cell responses (56, 57). However, in another study by Zhang et al., it was demonstrated that when MERS S protein was adjuvanted with MF59, it induced higher IgG1 and IgG2a antibod- ies with a slightly Th2-biased response (54). Subsequent studies also showed that ferritin-based MERS-CoV S protein, adju- vanted with MF59, promoted multiple an- tibody responses, including high levels of IgA antibody titers that resulted in potent mucosal immune responses (58). A study by Tang et al. has indicated that there are no significant differences in the neutraliz- ing activity of the serum derived frommice “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.”