HJAR Jan/Feb 2021

HEALTHCARE JOURNAL OF ARKANSAS I  JAN / FEB 2021 29 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 (public and patient safety being at the top of the list). Should the pub- lic and practitioners feel comfort- able injecting this first generation of “rushed” COVID-19 vaccines into so many as is being suggested? MORICI: The vaccine advisory committee and FDA will analyze the raw data accumu- lated from the initiation of phase 1 to the ongoing phase 3 clinical trials that enrolled between 30,000-44,000 participants. The data includes at least two months of follow- up after administration of the second vaccine dose in at least half of the phase 3 trial partic- ipants. As of now, there have been no serious adverse events associated with the vaccines. Notably, as stated previously, the mRNA vac- cine technology used in these vaccines has already been in human clinical trials in vari- ous forms prior to this one, albeit at a smaller scale. This should provide even greater con- fidence that these vaccines are safe over the longer term. While it is certainly a possibility that rare serious adverse events will only be identified once hundreds of millions of doses have been administered, the impact of the pandemic and the risks associated with SARS CoV-2 infection far outweigh the risks of the vaccines. Congratulations to your team on be- ing awarded a Fast Grant to develop bacteria-based adjuvants for the next-generation COVID-19 vaccine, 2.0, if you will. Will you please tell us about what you are working on and why it is important? MCLACHLAN: As mentioned above, the first generation of vaccines are extremely promising but may not be able to prevent as- ymptomatic transmission or may not be able to target the immune response to the portal of viral entry (in this case, the lung). Most vaccines include a component called an ad- juvant that essentially alerts the immune sys- tem to respond to the vaccine, which it might otherwise ignore. There are a variety of adju- vants currently approved for vaccines; how- ever, not all of these adjuvants are capable of eliciting the most complete of robust im- mune response. We have developed and uti- lized a new generation of adjuvants that we have found in our research to be capable of activating all parts of the immune response. More importantly, we have found that our adjuvants can target the appropriate immune response to the mucosal tissues such as the lung. Our Fast Grant proposes to test these new adjuvants in the next generation of CO- VID-19 vaccines to induce, long-term lung immunity against the virus. This would ulti- mately allow us to prevent both disease and transmission in people exposed to the virus as we go forward. Is SARS-Cov-2 evolving (like the flu)? MORICI: The introduction of SARS CoV-2 into the human population is a recent event, and mutations do appear to be accumulating as the virus spreads more widely among the human population. So far, these mutations do not appear to be altering its proteins in such a way that they would circumvent the current vaccines. This is in contrast to Influenza (flu) virus that exhibits both antigenic drift (minor changes in its surface proteins) and antigenic shift (major changes in composition) that forces us to modify the vaccine each year to match the most common flu strains circulat- ing in the population. Because SARS CoV-2 and the flu virus are so different, it is not really fair to compare the two in this way. While the type of genetic material inside of each is simi- lar (RNA), the way this material is arranged is very different, and this arrangement leads to flu acquiring far more, and more dangerous, mutations compared to SARS CoV-2. It is en-