4. Discussion
PROLIFERATION, INFLAMMATION
In this study, vaccine-induced humoral responses in both the KRG and control groups significantly increased two weeks after the second administration of all vaccines; then, a decrease was observed until 12 weeks or just before booster vaccination. However, after booster vaccination, humoral responses increased again; this trend was similar to the data in previous studies [Poor vaccine responses, such as reduced humoral responses and delayed T-cell responses after vaccination, including COVID-19 vaccines, in the elderly due to immunosenescence are well established [There are several possible factors related to this unique outcome regarding the maintenance of a higher vaccine-induced humoral response in the KRG group. First, KRG can help to enhance the effectiveness of COVID-19 vaccines through cytokine and chemokine regulation and immune cell proliferation and activity increase. Chemokines and cytokines are critical factors in innate immunity and inflammation, and they play essential roles in developing and maintaining adaptive immunity in response to vaccination [COVID-19 vaccination also induces SARS-CoV-2-specific CD8+ and CD4+ T cell responses, which might confer long-term immune memory against SARS-CoV-2 [We further examined the effect of the micronutrients in KRG. Previous studies showed that the host’s nutritional status influences immune response, and recent comprehensive review papers demonstrated the importance of individual micronutrients for immune response and the various mechanisms of action [Conversely, Chillon et al. [This study has several limitations. First, the participants in the KRG group were those who took KRG per day for four weeks or were taking KRG continuously. For those taking KRG continuously, it was difficult to determine the dosage of KRG accurately. However, continuous KRG intake was checked at each visit through a questionnaire. The KRG group maintained a relatively high vaccine-induced immune response compared with the control group at the end of this study, suggesting that KRG provides sufficient vaccine benefits at an indirect level. Second, during the clinical trial period, to minimize the effects of nutrients other than KRG, we told participants to stop all nutritional supplements, including vitamin D, which could affect vaccine-induced immune responses. Although nutritional supplement intake was checked through a questionnaire at each visit, the possibility of unobserved bias could not be excluded because it was a self-reported questionnaire. Third, vaccines based on different immunogenicity principles were included, including mRNA-based vaccines (Pfizer and Moderna) and recombinant adenoviral vector vaccines (AstraZeneca). However, this study was not a randomized clinical trial comparing antibody titers and KRG intake between vaccines. Regardless of KRG intake, the overall vaccine effectiveness of our study was confirmed to be consistent with the results of the previous studies, in which the antibody titers peaked two weeks after the second vaccination and then decreased after that [Moreover, the study population could not choose a vaccine and were given vaccines according to the vaccine protocols defined by the Korean government (KDCC). This study was performed in a single center; however, our study had the benefit of observing the same subjects longitudinally. Last, the effect of KRG on cellular immunity after COVID-19 vaccination was not tested; however, KRG modulated or enhanced immune response in previous in vitro and in vivo studies [