HJAR Jan/Feb 2021

28 JAN / FEB 2021  I  HEALTHCARE JOURNAL OF ARKANSAS COVID-19 VACCINE 2.0 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- 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) rently in the pipeline from Moderna and Bi- oNTech/Pfizer seem new to the public, they have been extensively studied and advanced in animal models for more than 20 years. Through these scientific endeavors, vast im- provements were made in terms of their sta- bility and immunogenicity (ability to induce an immune response), which ultimately has led to increased efficacy in humans as we are currently witnessing. Furthermore, the mRNA technology used by Moderna and BioNTech/ Pfizer were already being evaluated in human clinical trials for vaccines against other infec- tious diseases, such as Zika and Cytomega- lovirus, which is one of the reasons why the mRNA platform could be adapted so quickly to address the urgent need for a COVID-19 vaccine. Do you think this first generation of vaccines will halt the pandemic? Why or why not? JAMES MCLACHLAN: No, but we be- lieve it will certainly slow the pandemic by limiting the greatest loss of life through im- munization of the most exposed population (health care workers) and the most vulnerable (the elderly). A number of issues affect actu- ally halting the pandemic, even with the first generation of vaccines. The first is the role for herd immunity and vaccine uptake. In order to achieve herd immunity, where the unim- munized population is generally protected from infection by being surround by a “herd” of immunized people, the estimates are that at least 65% of the population must be im- munized. This estimate depends on the level of transmissibility of the virus and its mode of transmission, although the herd percentage required may actually be higher than this. A recent poll put the percent of people in the U.S. willing to get the vaccine at 58%, which is not quite what is needed for herd immunity. This is one reason that the first generation of vaccines may not halt the pandemic – the up- take by the population may just not be high enough. The second reason is, while we are learning vast amounts rapidly about this vi- rus, we still do not completely understand it. It may be that while a good vaccine, as the first-generation vaccines appear to be, can prevent severe disease in people who are ex- posed to the virus, these vaccines may not be able to prevent transmission of the virus from vaccinated people to unvaccinated people. A similar phenomenon exists with the child- hood vaccine for whooping cough (Called DTaP or TDaP). While the whooping cough vaccine can prevent disease in immunized people, it often doesn’t prevent transmission of the bacteria that causes whooping cough from immunized people to unimmunized people. It is possible this will occur with the virus that causes COVID-19 and the first gen- eration of vaccines as well. This leads to the final reason these vaccines mat not halt the pandemic, and that it is likely important for the most potent vaccines to induce mucosal immunity. Every part of the body can display an immune response, but most vaccine-me- diated immune responses are concentrated in the blood or in the lymphatic system. These types of immune response are often perfectly adequate for preventing and even eliminating some infectious diseases. Others require that the mucosa, the so called “ports of entry” for the disease, be specifically pro- tected by the immune response. In the ex- ample of COVID-19, the virus infects via the lungs or the respiratory mucosa. Inducing an immune response directly in these tissues would likely greatly enhance the efficacy of a vaccine against COVID-19 and should be the goal of second-generation vaccines and beyond. Testing/clinical trial protocols were supposably established for a reason