Vaccine Effectiveness Against Severe Disease and Death for Patients With COVID-19 During the Delta-Dominant and Omicron-Emerging Periods: A K-COVE Study.

National cohort data collected during the coronavirus disease 2019 (COVID-19) delta and omicron periods in Korea revealed a lower risk of severe infection in recipients of three doses of the COVID-19 vaccine (adjusted odds ratio [aOR], 0.05-0.08). The risk of death was reduced during the omicron period compared to the delta period (aOR, 0.75; 95% confidence interval, 0.67-0.84).

Risk Factors Related to COVID-19 Reinfection and Fatality During the Omicron (BA.1/BA.2) Period in Korea.

BACKGROUND: This study aimed to investigate the deaths due to coronavirus disease 2019 (COVID-19) reinfection and related risk factors. METHODS: National cohort data were collected for a six-month period when omicron BA.1/BA.2 variant was dominant in South Korea. RESULTS: The long-term care facility residents (adjusted odds ratio, 3.11; 95% confidence interval [CI], 2.98-3.25) had significantly higher risk of reinfection than the general population. The risk of reinfection was significantly lower for persons with 2 or more vaccine doses compared to the unvaccinated. The risk of death was significantly higher in the reinfection group than in the primary infection group for persons in the 60-74 years age group (adjusted relative risk [aRR], 1.62; 95% CI, 1.19-2.20), and immunocompromised group (aRR, 4.56; 95% CI, 2.34-8.90). CONCLUSION: In these data, vaccination history was significantly related to reduced COVID-19 reinfection and severe progression, and scheduled vaccinations were important even with a history of infection.

Comparative Effectiveness of COVID-19 Bivalent Versus Monovalent mRNA Vaccines in the Early Stage of Bivalent Vaccination in Korea: October 2022 to January 2023.

BACKGROUND: This retrospective observational matched-cohort study of 2,151,216 individuals from the Korean coronavirus disease 2019 (COVID-19) vaccine effectiveness cohort aimed to evaluate the comparative effectiveness of the COVID-19 bivalent versus monovalent vaccines in providing additional protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, critical infection, and death in Korea. METHODS: Among individuals, those vaccinated with COVID-19 bivalent vaccines were matched in a 1:1 ratio with those who were vaccinated with monovalent vaccines (bivalent vaccines non-recipients) during the observation period. We fitted a time-dependent Cox proportional-hazards model to estimate hazard ratios (HRs) of COVID-19 outcomes for infection, critical infection, and death, and we defined vaccine effectiveness (VE) as 1-HR. RESULTS: Compared with the bivalent vaccination group, the incidence proportions in the monovalent vaccination group were approximately three times higher for infection, nine times higher for critical infection, and 11 times higher for death. In the early stage of bivalent vaccination, relative VE of bivalent vaccine against monovalent vaccine was 42.4% against SARS-CoV-2 infection, 81.3% against critical infection, and 85.3% against death. In addition, VE against critical infection and death according to the elapsed period after bivalent vaccination was maintained at > 70%. CONCLUSION: The bivalent booster dose provided additional protection against SARS-CoV-2 infections, critical infections, and deaths during the omicron variant phase of the COVID-19 pandemic.

Effectiveness of Heterologous COVID-19 Vaccine Booster in Korean Elderly Population, 2022.

We conducted a cohort study to assess vaccine effectiveness (VE) of coronavirus disease 2019 vaccine combinations on severe acute respiratory syndrome coronavirus 2 critical infection and death among elderly population in Korea. From January to August 2022, VE against death for 4 doses mRNA recipients was 96.1%, whereas 1-dose viral vector + 3-dose mRNA recipients had VE of 90.8%.

Household Secondary Attack Rates of SARS-CoV-2 Omicron Variant, South Korea, February 2022.

We studied the effect of booster vaccinations on reducing household transmission of SARS-CoV-2 B.1.1529 (Omicron) variant in a February 2022 sampling of contacts in South Korea. The secondary attack rate was lower for vaccinated versus unvaccinated contacts, and booster vaccination resulted in a lower incidence rate ratio.

SARS-CoV-2 Breakthrough Infections after introduction of 4 COVID-19 Vaccines, South Korea, 2021.

We conducted a nationwide retrospective cohort study to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection among recipients of 4 different vaccines in South Korea. Age-adjusted breakthrough infection rate per month was highest for Janssen (42.6/100,000 population), followed by AstraZeneca (21.7/100,000 population), Pfizer-BioNTech (8.5/100,000 population), and Moderna (1.8/100,000 population).

Effectiveness of Second mRNA COVID-19 Booster Vaccine in Immunocompromised Persons and Long-Term Care Facility Residents.

We used a nationwide population registry in South Korea to estimate the effect of a second booster dose of mRNA COVID-19 vaccine on the risk for laboratory-confirmed SARS-CoV-2 infection, critical infection, and death in immunocompromised persons and long-term care facility (LTCF) residents. During February 16-May 7, 2022, among 972,449 eligible persons, 736,439 (75.7%) received a first booster and 236,010 (24.3%) persons received a second booster. Compared with the first booster group, at 30-53 days, the second booster recipients had vaccine effectiveness (VE) against all infections of 22.28% (95% CI 19.35%-25.11%), VE against critical infection of 56.95% (95% CI 29.99%-73.53%), and VE against death of 62.96% (95% CI 34.18%-79.15%). Our findings provide real-world evidence that a second booster dose of mRNA vaccine substantially increases protection against critical infection and death in these high-risk population groups.

Time from Exposure to Diagnosis among Quarantined Close Contacts of SARS-CoV-2 Omicron Variant Index Case-Patients, South Korea.

To determine optimal quarantine duration, we evaluated time from exposure to diagnosis for 107 close contacts of severe acute respiratory syndrome coronavirus 2 Omicron variant case-patients. Average time from exposure to diagnosis was 3.7 days; 70% of diagnoses were made on day 5 and 99.1% by day 10, suggesting 10-day quarantine.

Community Transmission of SARS-CoV-2 Omicron Variant, South Korea, 2021.

In South Korea, a November 2021 outbreak caused by severe acute respiratory syndrome coronavirus 2 Omicron variant originated from 1 person with an imported case and spread to households, kindergartens, workplaces, restaurants, and hospitals, resulting in 11 clusters within 3 weeks. An epidemiologic curve indicated rapid community transmission of the Omicron variant.

Reinfection with SARS-CoV-2 in general population, South Korea; nationwide retrospective cohort study.

To better understand the epidemiology of SARS-CoV-2 reinfections, we analyzed national data from South Korean who were followed longitudinally from January 2020 to April 2022. We conducted a nationwide retrospective cohort study to estimate possible SARS-CoV-2 reinfection rates in all residents in South Korea, with at least two episodes of laboratory-confirmed SARS-CoV-2 infection by reverse-transcriptase polymerase chain reaction or rapid antigen test (RAT) performed at least 45 or more days between both episodes, between January 2020 and April 2022. There were 16 130 855 laboratory-confirmed SARS-CoV-2 cases in South Korea, with 55 841 (346.2 per 100 000; or 0.3% of all infections) cases of possible reinfections. The reinfection rate has increased from 6.0 cases per 100 000 during Pre-Delta period to 128.0 cases per 100 000 and 355.1 cases per 100 000 during Delta and Omicron periods, respectively. Persons with one dose of vaccination had the highest reinfection rate of 642.2 per 100 000, followed by unvaccinated persons (536.2/100 000) and two-dose vaccinated persons (406.3/100 000). Our finding suggests that the majority of possible reinfections occurred following the emergence of new variants.

Importation and Transmission of SARS-CoV-2 B.1.1.529 (Omicron) Variant of Concern in Korea, November 2021.

In November 2021, 14 international travel-related severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant of concern (VOC) patients were detected in South Korea. Epidemiologic investigation revealed community transmission of the omicron VOC. A total of 80 SARS-CoV-2 omicron VOC-positive patients were identified until December 10, 2021 and 66 of them reported no relation to the international travel. There may be more transmissions with this VOC in Korea than reported.

KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism.

Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the early stage of the disease remains the only curative option, although only in 20% of patients with early stage disease. Clinical trials targeting the main oncogenic driver, KRAS, have largely been unsuccessful. Recently, global metabolic reprogramming has been identified in patients with pancreatic cancer and oncogenic KRAS mouse models. The newly reprogrammed metabolic pathways and oncometabolites affect the tumorigenic environment. The development of methods modulating metabolic reprogramming in pancreatic cancer cells might constitute a new approach to its therapy. In this review, we describe the major metabolic pathways providing acetyl-CoA and NADPH essential to sustain lipid synthesis and cell proliferation in pancreatic cancer cells.

The Cut-off Values of Surrogate Measures for Insulin Sensitivity in a Healthy Population in Korea according to the Korean National Health and Nutrition Examination Survey (KNHANES) 2007-2010.

BACKGROUND: This study aimed to identify the gender-specific characteristics of the surrogate measures of insulin resistance and to establish valid cut-off values for metabolic abnormalities in a representative sample in Korea. METHODS: Data were collected from the datasets of the Korean National Health and Nutrition Examination Survey between 2007 and 2010. The total number of eligible participants was 10,997. We used three measures of insulin resistance: the homeostasis model assessment-insulin resistance (HOMA-IR), McAuley index, and triglyceride and glucose (TyG) index. The estimated cut-off values were determined using the highest score of the Youden index. RESULTS: The area under the curve (AUC) of the HOMA-IR, McAuley index, and TyG index were 0.737 (95% confidence interval [CI], 0.725-0.750), 0.861 (95% CI, 0.853-0.870), and 0.877 (95% CI, 0.868-0.885), respectively. The cut-off values of the HOMA-IR were 2.20 in men, 2.55 in premenopausal women, and 2.03 in postmenopausal women, and those of the McAuley index were 6.4 in men and 6.6 in premenopausal and postmenopausal women. For the TyG index, the cut-off values were 4.76 in men and 4.71 in premenopausal and postmenopausal women. CONCLUSION: In conclusion, the present study provides the valid cut-off values of the indirect surrogate measures of insulin sensitivity. These values may be used as reference for insulin sensitivity in a clinical setting and may provide a simple and supplementary method for identifying populations at risk of insulin resistance.

Anti-inflammatory activity of chloroquine and amodiaquine through p21-mediated suppression of T cell proliferation and Th1 cell differentiation.

Chloroquine (CQ) and amodiaquine (AQ) have been used for treating or preventing malaria for decades, and their application has expanded into treating inflammatory disease in humans. CQ and AQ are applicable for controlling rheumatoid arthritis, but their molecular mechanisms of anti-inflammatory activity remain to be elucidated. In this study, we examined the effects of CQ and AQ on T cell activation and T cell-mediated immune response. CQ had no significant effect on T cell numbers, but decreased the population of T cells with a high division rate. However, AQ treatment significantly increased the number of cells with low division rates and eliminated cells with high division rates, resulting in the inhibition of T cell proliferation triggered by T cell receptor stimulation, of which inhibition occurred in developing effector T helper and regulatory T cells, regardless of the different exogenous cytokines. Interestingly, the cyclin-dependent kinase inhibitor p21 was significantly and dose-dependently increased by CQ, and more potently by AQ, while other cell cycle regulators were unchanged. Both CQ and AQ elevated the transcription level of p21 though the activation of p53, but also blocked p21 protein degradation in the presence of cycloheximide, causing p21 protein accumulation mainly in the nucleus. Sustained treatment of developing T cells with either CQ or AQ suppressed IFN-γ production in a dose dependent manner and potently inhibited the differentiation of IFN-γ-producing Th1 cells. These results demonstrate that CQ and AQ increase the expression level of p21 and inhibit T cell proliferation and the development of IFN-γ-producing Th1 cells, thereby revealing beneficial roles in treating a wide range of chronic inflammatory diseases mediated by inflammatory T cells.

(-)-Epicatechin gallate (ECG) stimulates osteoblast differentiation via Runt-related transcription factor 2 (RUNX2) and transcriptional coactivator with PDZ-binding motif (TAZ)-mediated transcriptional activation.

Osteoporosis is a degenerative bone disease characterized by low bone mass and is caused by an imbalance between osteoblastic bone formation and osteoclastic bone resorption. It is known that the bioactive compounds present in green tea increase osteogenic activity and decrease the risk of fracture by improving bone mineral density. However, the detailed mechanism underlying these beneficial effects has yet to be elucidated. In this study, we investigated the osteogenic effect of (-)-epicatechin gallate (ECG), a major bioactive compound found in green tea. We found that ECG effectively stimulates osteoblast differentiation, indicated by the increased expression of osteoblastic marker genes. Up-regulation of osteoblast marker genes is mediated by increased expression and interaction of the transcriptional coactivator with PDZ-binding motif (TAZ) and Runt-related transcription factor 2 (RUNX2). ECG facilitates nuclear localization of TAZ through PP1A. PP1A is essential for osteoblast differentiation because inhibition of PP1A activity was shown to suppress ECG-mediated osteogenic differentiation. Taken together, the results showed that ECG stimulates osteoblast differentiation through the activation of TAZ and RUNX2, revealing a novel mechanism for green tea-stimulated osteoblast differentiation.

Uremic toxin p-cresol induces Akt-pathway-selective insulin resistance in bone marrow-derived mesenchymal stem cells.

We reported a functional incompetence in mesenchymal stem cells (MSCs) under uremia, but the mechanisms have not been explored. To study the mechanisms of dysfunctional MSCs induced by uremia, we characterized insulin signaling in MSCs and investigated the effect of uremic toxin, p-cresol, on the proangiogenic actions of insulin. In MSCs, insulin induced hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor, and stromal cell-derived factor 1α expressions via PI3K/Akt-dependent pathway. MSCs treated with p-cresol exhibited altered insulin signaling in a selective manner for insulin receptor substrate-1/PI3K/Akt pathway, whereas ERK pathway remained active. The insulin-induced increase of HIF-1α was blunted by p-cresol treatment. This Akt-selective insulin resistance was also observed in MSCs isolated from chronic kidney disease (CKD) mice. In mice model of hindlimb ischemia, blood flow recovery, capillary density, and local production of angiogenic factors in the ischemic limb treated with CKD MSCs were significantly inferior to those promoted by control MSCs. However, modifying CKD MSCs by overexpression of HIF-1α restored all of these changes. Taken together, these data suggest that p-cresol contributes to insulin resistance in a selective manner for Akt pathway. This might be a biological explanation for the functional incompetence of MSCs under uremia through defects in the insulin-induced elevation of HIF-1α protein expression.

Lysine 313 of T-box is crucial for modulation of protein stability, DNA binding, and threonine phosphorylation of T-bet.

A T-box-containing protein expressed in T cells (T-bet) is a key transcription factor involved in the regulation of Th cell differentiation. Although T-bet-deficient CD4(+) T cells fail to produce IFN-γ and typically differentiate into Th2 cells in vitro, ectopic overexpression of T-bet elevates IFN-γ and suppresses production of IL-2 and Th2 cytokines through different mechanisms. Despite the importance of the T-bet protein level, the regulatory mechanisms that control T-bet protein stability are largely unknown. In this study, we found that T-bet underwent proteasomal degradation via ubiquitination at Lys-313. Despite its robust accumulation following lysine mutation, T-bet(K313R) failed to increase IFN-γ production because of diminished DNA binding activity, as demonstrated in the crystal structure of T-bet-DNA complex. Strikingly, T-bet(K313R) entirely lost the ability to suppress IL-2 production and Th2 cell development; this was due to loss of its interaction with NFAT1. We further identified that the T-bet(K313R) reduced the phosphorylation of T-bet at Thr-302, and that threonine phosphorylation was essential for T-bet interaction with NFAT1 and suppression of NFAT1 activity. Retroviral transduction of T-bet(T302A) into T-bet-deficient cells restored IFN-γ levels compared with those induced by wild-type T-bet, but this mutant failed to inhibit IL-2 and Th2 cytokine production. Collectively, these data show that Lys-313 in the T-box domain is essential for controlling T-bet protein stability via ubiquitin-dependent degradation, T-bet binding to the IFN-γ promoter, and for the interaction with and suppression of NFAT1. Thus, multiple posttranslational modifications of T-bet are involved in fine-tuning cytokine production during Th cell development.

Ablation of peroxiredoxin II attenuates experimental colitis by increasing FoxO1-induced Foxp3+ regulatory T cells.

Peroxiredoxin (Prx) II is an intracellular antioxidant molecule that eliminates hydrogen peroxide, employing a high substrate-binding affinity. PrxII deficiency increases the levels of intracellular reactive oxygen species in many types of cells, which may increase reactive oxygen species-mediated inflammation. In this study, we investigated the susceptibility of PrxII knockout (KO) mice to experimentally induced colitis and the effects of PrxII on the immune system. Wild-type mice displayed pronounced weight loss, high mortality, and colon shortening after dextran sulfate sodium administration, whereas colonic inflammation was significantly attenuated in PrxII KO mice. Although macrophages were hyperactivated in PrxII KO mice, the amount of IFN-γ and IL-17 produced by CD4(+) T cells was substantially reduced. Foxp3(+) regulatory T (Treg) cells were elevated, and Foxp3 protein expression was increased in the absence of PrxII in vitro and in vivo. Restoration of PrxII into KO cells suppressed the increased Foxp3 expression. Interestingly, endogenous PrxII was inactivated through hyperoxidation during Treg cell development. Furthermore, PrxII deficiency stabilized FoxO1 expression by reducing mouse double minute 2 homolog expression and subsequently activated FoxO1-mediated Foxp3 gene transcription. PrxII overexpression, in contrast, reduced FoxO1 and Foxp3 expression. More interestingly, adoptive transfer of naive CD4(+) T cells from PrxII KO mice into immune-deficient mice attenuated T cell-induced colitis, with a reduction in mouse double minute 2 homolog expression and an increase in FoxO1 and Foxp3 expression. These results suggest that inactivation of PrxII is important for the stability of FoxO1 protein, which subsequently mediates Foxp3(+) Treg cell development, thereby attenuating colonic inflammation.

Anti-adipogenic activity of the naturally occurring phenanthroindolizidine alkaloid antofine via direct suppression of PPARγ expression.

Antofine (ANTF) is a phenanthroindolizidine alkaloid isolated from the root of Cynanchum paniculatum Kitagawa (Asclepiadaceae), which is used as an herbal remedy for pain and inflammation. ANTF also possesses antiviral and antitumorigenic activities. In this study, we investigated the role of ANTF in adipogenesis. Chronic ABTF administration suppressed adipocyte differentiation and marker expression in a dose-dependent manner. Furthermore, acute administration of ANTF at early stages of differentiation process inhibited lipid droplet formation and adipogenic gene expression. ANTF Treatment decreased expression of PPARγ protein, a master transcription factor in the regulation of adipocyte differentiation, leading to a suppression of aP2 promoter activity. These results suggest that ANTF exerts potent anti-adipogenic effects via direct suppression of PPARγ protein expression, with consequent downregulation of adipogenic gene expression.