HJBR Jan/Feb 2021

30 JAN / FEB 2021  I  HEALTHCARE JOURNAL OF BATON ROUGE COVID-19 VACCINE 2.0 rapid activation of innate immunity, and subsequently, effective adaptive immunity. TLR agonists have been extensively studied as vaccine adjuvants (60, 61). CpG, Poly I:C, glucopyranosyl lipid A (GLA), and resiqui- mod (R848) are agonists for TLR9, TLR3, TLR4, and TLR7/8, respectively. These ad- juvants have been evaluated in candidate vaccines against SARS CoV (62, 63). In addition to neutralizing antibod- ies and CD4+ T cells, optimal protection against coronavirus probably involves the synergistic effect of CD8+ T cells (64). Memory CD8+ T cells solve the problem of neutralizing antibodies only existing for short periods and providing long-term protective cellular immunity (64). Among the TLR agonists, CpG significantly aug- ments the CD8+ T cell immune response higher than the others (63). Indeed, it has been demonstrated that CpG can also stim- ulate enhanced IgG production in animals immunized with an inactivated SARS-CoV vaccine (62). In addition to IgG, IgA pro- duction was also enhanced, only when CpG was administered via intranasal (i.n.) administration (62), indicating immune activation in the mucosal compartment. Although CpG is capable of inducing both cellular and humoral immune responses, it preferentially induces responses that are Th1-biased. Moreover, CpG can divert pre-existing Th2 responses to a Th1 phe- notype, which has laid a foundation for the combination of CpG with other adjuvants, most commonly alum (65). In SARS-CoV or MERS-CoV subunit vaccines, studies have found that the combination of alum and CpG elicited higher neutralization an- tibody titers and a more robust cellular immune response compared with alum alone or alum with other TLR agonists (18, 19). In addition to alum, CpG is combined with Montanide ISA-51, a type of water-in- oil emulsion adjuvant. When the combined adjuvants were formulated with SARS S or N protein, they were capable of promot- ing robust neutralizing antibody produc- tion (66). However, vaccinated with only SARS N protein, animals showed immune responses biased dramatically toward Th1 (67). In addition, it is reported that R848 could enhance antigen-specific CTL re- sponse and induce a fast, robust and du- rable IFN- α production in vivo among humanized mice, which is distinct from the experimental findings based on com- likely to recommend use in children under 18 until the vaccines have been evaluated in that group. Further, it is expected that the most susceptible people (health care workers and nursing home residents) will be the first in line to receive the vaccines as they become avail- able. How long do you expect to be work- ing on this particular project, and, if successful, what is the expected timetable for it to hit market? MCLACHLAN: We expect to be working on this particular project for the next six months to one year. If successful, we hope to move the research forward into a competitive fed- eral grant that would allow us to test these products in larger animal models and po- tentially humans. The move into the market is lengthy, despite the current warp-speed pandemic vaccine production. It is notable that the current first-generation vaccine tech- nology has been in the pipeline in one form or another for at least a decade. We predict that our vaccine product will potentially move faster than that, but it remains important to test any product for safety and efficacy, es- pecially in its early stages. We do expect that our vaccine adjuvants, as they proceed for- ward into potential clinical trials, will have the capacity to enhance future vaccines against the next potential pandemic. Do you think COVID-19 will change the way future vaccines are devel- oped? MORICI: We believe the plug-n-play vaccine platforms, such as mRNA and viral vectors, have shown tremendous promise to respond quickly to new or emerging viral threats. As such, we are likely to see huge investments in these technologies going forward. We do not yet know the limitations of these vaccines, such as whether they eliminate viral carriage or transmission or whether they provide long-term protection, because it is too soon to answer these questions. In addition, fur- ther improvements in stability of the mRNA vaccines could reduce the requirements for cold storage and enable broader global distribution. Nonetheless, these newer vac- cine technologies are a great addition to an ever-increasing diversity of licensed vaccine platforms. It is important to stress that while these specific mRNA COVID-19 vaccines are new, the mRNA technology itself used in these vaccines is not and that the rapid move into clinical trials was not truly as rapid as per- ceived by the public. Future vaccine design and implementation is unlikely to proceed at this pace, particularly against other types of pathogens (e.g., bacteria) or if they make use of new components that must be rigorously tested in animal models before small imple- mentation studies in humans. It is also nota- ble that the sheer amount of worldwide fund- ing for implementation of the first generation of COVID-19 vaccines is extraordinary and unlikely to be a routine process in the future. Once this pandemic passes, what is the next project your team would like to focus on? MORICI: Our team focuses on the devel- opment of next-generation vaccines by tai- loring vaccines with new adjuvants that can enhance protection in the mucosa, the major portal of entry for infectious agents. In ad- dition to a vaccine for SARS CoV-2 virus, we are currently working on vaccines to elimi- nate respiratory bacterial infections, such as those caused by Pseudomonas aeruginosa and Bordetella pertussis. In addition to these studies, we have recently turned our atten- tion to the global public health crisis caused by the opioid epidemic and are working with collaborators at Scripps Institute in La Jolla, CA to design an effective adjuvanted vaccine that can prevent overdose with heroin and fentanyl . n