An ancestral SARS-CoV-2 vaccine induces anti-Omicron variants antibodies by hypermutation.

The immune escape of Omicron variants significantly subsides by the third dose of an mRNA vaccine. However, it is unclear how Omicron variant-neutralizing antibodies develop under repeated vaccination. We analyze blood samples from 41 BNT162b2 vaccinees following the course of three injections and analyze their B-cell receptor (BCR) repertoires at six time points in total. The concomitant reactivity to both ancestral and Omicron receptor-binding domain (RBD) is achieved by a limited number of BCR clonotypes depending on the accumulation of somatic hypermutation (SHM) after the third dose. Our findings suggest that SHM accumulation in the BCR space to broaden its specificity for unseen antigens is a counterprotective mechanism against virus variant immune escape.

Anti-SARS-CoV-2 nucleocapsid antibody positivity 3 years after COVID-19.

The accurate identification of individuals without prior infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is pivotal for seroepidemiological research and vaccine trials. Because of widespread COVID-19 vaccination, the anti-nucleocapsid antibody continues to serve as a valuable marker for individuals without a history of COVID-19. This study aimed to comprehensively assess anti-nucleocapsid antibody positivity using diverse commercial and in-house immunoassays among individuals who contracted COVID-19 more than 3 years ago. We enrolled 44 participants with laboratory-confirmed COVID-19 between January and May 2020 from Seoul National University Hospital and its community treatment centers. The results showed anti-nucleocapsid antibody positivities ranged from 45.5% to 87.9% depending upon the immunoassay used. The study highlights the importance of considering the limited anti-nucleocapsid antibody positivity in participants with a distant COVID-19 history in seroepidemiological or vaccine research.

Risk factors for resistant gram-positive bacteremia in febrile neutropenic patients with cancer.

BACKGROUND: Gram-positive bacteria are frequently resistant to empirical beta-lactams in febrile neutropenic patients with cancer. As microbiology and antibiotic susceptibility changes, we reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer. METHODS: Episodes of bacteremic febrile neutropenia in Seoul National University Hospital from July 2019 to June 2022 were reviewed. Resistant Gram-positive bacteria were defined as a pathogen susceptible only to glycopeptide or linezolid in vitro (e.g., methicillin-resistant staphylococci, penicillin-resistant viridans streptococci, and ampicillin-resistant enterococci). Episodes were compared to identify independent risk factors for resistant Gram-positive bacteremia. RESULTS: Of 225 episodes, 78 (34.7%) involved resistant Gram-positive bacteremia. Multivariate analysis revealed that breakthrough bacteremia while being administered antibiotics (adjusted odds ratio [aOR], 6.794; 95% confidence interval [95% CI], 3.130-14.749; P < 0.001) and catheter-related infection (aOR 4.039, 95% CI 1.366-11.946; P = 0.012) were associated with resistant Gram-positive bacteremia. Chronic liver disease (aOR 0.231, 95% CI 0.059-0.905; P = 0.035) and hypotension at bacteremia (aOR 0.454, 95% CI 0.218-0.945; P = 0.035) were inversely associated with resistant Gram-positive bacteremia. CONCLUSIONS: Resistant Gram-positive bacteria should be considered in breakthrough bacteremia and catheter-related infection in febrile neutropenic patients with cancer.

Prevention of Cytomegalovirus Infection in Solid Organ Transplant Recipients: Guidelines by the Korean Society of Infectious Diseases and the Korean Society for Transplantation.

Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV infection in SOT recipients was developed jointly by the Korean Society for Infectious Diseases and the Korean Society of Transplantation. CMV serostatus of both donors and recipients should be screened before transplantation to best assess the risk of CMV infection after SOT. Seronegative recipients receiving organs from seropositive donors face the highest risk, followed by seropositive recipients. Either antiviral prophylaxis or preemptive therapy can be used to prevent CMV infection. While both strategies have been demonstrated to prevent CMV infection post-transplant, each has its own advantages and disadvantages. CMV serostatus, transplant organ, other risk factors, and practical issues should be considered for the selection of preventive measures. There is no universal viral load threshold to guide treatment in preemptive therapy. Each institution should define and validate its own threshold. Valganciclovir is the favored agent for both prophylaxis and preemptive therapy. The evaluation of CMV-specific cell-mediated immunity and the monitoring of viral load kinetics are gaining interest, but there was insufficient evidence to issue recommendations. Specific considerations on pediatric transplant recipients are included.

Rise in broadly cross-reactive adaptive immunity against human ß-coronaviruses in MERS-recovered patients during the COVID-19 pandemic.

To develop a universal coronavirus (CoV) vaccine, long-term immunity against multiple CoVs, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, Middle East respiratory syndrome (MERS)-CoV, and future CoV strains, is crucial. Following the 2015 Korean MERS outbreak, we conducted a long-term follow-up study and found that although neutralizing antibodies and memory T cells against MERS-CoV declined over 5 years, some recovered patients exhibited increased antibody levels during the COVID-19 pandemic. This likely resulted from cross-reactive immunity induced by SARS-CoV-2 vaccines or infections. A significant correlation in antibody responses across various CoVs indicates shared immunogenic epitopes. Two epitopes-the spike protein's stem helix and intracellular domain-were highly immunogenic after MERS-CoV infection and after SARS-CoV-2 vaccination or infection. In addition, memory T cell responses, especially polyfunctional CD4+ T cells, were enhanced during the pandemic, correlating significantly with MERS-CoV spike-specific antibodies and neutralizing activity. Therefore, incorporating these cross-reactive and immunogenic epitopes into pan-CoV vaccine formulations may facilitate effective vaccine development.

Impact of T-Cell Engagers on COVID-19-Related Mortality in B-Cell Lymphoma Patients Receiving B-Cell Depleting Therapy.

PURPOSE: B-cell depleting therapies, including T-cell engager (TCE), are increasingly used for patients with hematologic malignancies, including during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to evaluate the relationship between TCE therapy and COVID-19-related outcomes among patients with COVID-19 and B-cell lymphomas receiving B-cell depleting therapy. MATERIALS AND METHODS: This retrospective cohort study included patients with B-cell lymphoma, who were admitted to Seoul Natio-nal University Hospital with COVID-19 between September 2021 and February 2023, and received B-cell depleting therapy before COVID-19 diagnosis. Multivariable logistic regression was used to identify factors associated with severe to critical COVID-19 and COVID-19-related mortality. RESULTS: Of 54 patients with B-cell lymphomas and COVID-19 who received B-cell depleting therapy, 14 were treated with TCE (TCE group) and 40 with rituximab (RTX group). COVID-19-related mortality was higher in the TCE group than in the RTX group (57.1% vs. 12.5%, p=0.002). In multivariable analyses, TCE therapy (adjusted odds ratio [aOR], 7.08; 95% confidence interval [CI], 1.29 to 38.76; p=0.024) and older age (aOR, 1.06; 95% CI, 1.00 to 1.13; p=0.035) were associated with severe to critical COVID-19. TCE therapy (aOR, 8.98; 95% CI, 1.48 to 54.40; p=0.017), older age (aOR, 1.13; 95% CI, 1.02 to 1.26; p=0.022), and prior bendamustine therapy (aOR, 7.78; 95% CI, 1.17 to 51.65; p=0.034) were independent risk factors for COVID-19-related mortality. CONCLUSION: B-cell lymphoma patients treated with TCE had significantly worse outcomes from COVID-19 than those treated with RTX. TCE therapy should be used with caution in B-cell lymphoma patients during the COVID-19 epidemic.

Clinical outcomes and immunological features of COVID-19 patients receiving B-cell depletion therapy during the Omicron era.

Background: The clinical outcomes and immunological features of coronavirus disease 2019 (COVID-19) patients receiving B-cell depletion therapy (BCDT), especially in Omicron variant era, have not been fully elucidated. We aimed to investigate the outcomes and immune responses of COVID-19 patients receiving BCDT during the Omicron period.Methods: We retrospectively compared clinical outcomes between COVID-19 patients treated with BCDT (the BCDT group) and those with the same underlying diseases not treated with BCDT (the non-BCDT group). For immunological analyses, we prospectively enrolled COVID-19 patients receiving BCDT and immunocompetent COVID-19 patients as controls. We measured humoral and cellular immune responses using the enzyme-linked immunosorbent assay and flow cytometry.Results: Severe to critical COVID-19 was more frequent in the BCDT group than in the non-BCDT group (41.9% vs. 28.3%, p = .030). BCDT was an independent risk factor for severe to critical COVID-19 (adjusted odds ratio [aOR] 2.21, 95% confidence interval [CI] 1.21-4.04, p = .010) as well as for COVID-19-related mortality (aOR 4.03, 95% CI 1.17-13.86, p = .027). Immunological analyses revealed that patients receiving BCDT had lower anti-S1 IgG titres and a tendency to higher proportions of activated CD4+ T-cells than the controls.Conclusions: BCDT was associated with worse COVID-19 outcomes in the Omicron period. Humoral immune response impairment and T-cell hyperactivation were the main immunological features of COVID-19 patients treated with BCDT, which may have contributed to the worse outcomes of COVID-19 in this population.

Tracking antigen-specific TCR clonotypes in SARS-CoV-2 infection reveals distinct severity trajectories.

Despite the importance of antigen-specific T cells in infectious disease, characterizing and tracking clonally amplified T cells during the progression of a patient's symptoms remain unclear. Here, we performed a longitudinal, in-depth single-cell multiomics analysis of samples from asymptomatic, mild, usual severe, and delayed severe patients of SARS-CoV-2 infection. Our in-depth analysis revealed that hyperactive or improper T-cell responses were more aggressive in delayed severe patients. Interestingly, tracking of antigen-specific T-cell receptor (TCR) clonotypes along the developmental trajectory indicated an attenuation in functional T cells upon severity. In addition, increased glycolysis and interleukin-6 signaling in the cytotoxic T cells were markedly distinct in delayed severe patients compared to usual severe patients, particularly in the middle and late stages of infection. Tracking B-cell receptor clonotypes also revealed distinct transitions and somatic hypermutations within B cells across different levels of disease severity. Our results suggest that single-cell TCR clonotype tracking can distinguish the severity of patients through immunological hallmarks, leading to a better understanding of the severity differences in and improving the management of infectious diseases by analyzing the dynamics of immune responses over time.

Possibility of Decreasing Incidence of Human Immunodeficiency Virus Infection in Korea.

BACKGROUND: The number of newly diagnosed cases of human immunodeficiency virus (HIV) infection in Korea, which had increased until 2019, has markedly decreased since the coronavirus disease 2019 pandemic started. This study evaluated whether the decrease is due to a reduction in the incidence of HIV infection and/or delayed diagnosis during the pandemic. MATERIALS AND METHODS: We reviewed the medical records of 587 newly diagnosed patients with HIV infection between February 2018 and January 2022 from four general hospitals, and their characteristics were compared between the pre-pandemic and pandemic periods. The lapse time from infection to diagnosis was estimated using an HIV modeling tool. RESULTS: The estimated mean times to diagnosis were 5.68 years (95% confidence interval [CI]: 4.45 - 6.51 years) and 5.41 years (95% CI: 4.09 - 7.03 years) before and during the pandemic, respectively (P = 0.016). The proportion of patients with acquired immunodeficiency syndrome-defining illnesses, expected to visit hospitals regardless of the pandemic, decreased from 17.2% before the pandemic to 11.9% during the pandemic (P = 0.086). CONCLUSION: The decrease in the number of newly diagnosed cases of HIV infection in Korea might have resulted from an actual decrease in the incidence of HIV infection rather than a worsening of underdiagnosis or delayed diagnosis.

Empirical vs pre-emptive broad-spectrum antifungal therapy for acute myelogenous leukaemia in the era of antimould prophylaxis.

INTRODUCTION: This study compared clinical outcomes in patients with acute myelogenous leukaemia (AML) who developed prolonged (≥4 days) febrile neutropenia (FN) and received either empirical or pre-emptive antimould prophylaxis in order to evaluate the need for routine empirical antifungal therapy. METHODS: This retrospective study reviewed adult patients (aged ≥18 years) with AML who developed prolonged FN and received antimould prophylaxis during induction or re-induction chemotherapy at a single centre between September 2016 and December 2020. Patients were categorized into pre-emptive or empirical groups based on whether or not there was clinical evidence of invasive fungal infection (IFI) at the start of antifungal treatment, respectively. Clinical outcomes were compared between the two groups after propensity score matching (PSM). RESULTS: In total, 229 chemotherapy episodes (36 and 193 in the empirical and pre-emptive groups, respectively) were analysed. In the pre-emptive group, broad-spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 PSM, there were no significant differences between the empirical and pre-emptive groups in terms of the incidence of proven or probable IFI [0/36 (0%) vs 5/97 (5.2%); P=0.323], all-cause mortality [3/36 (8.3%) vs 4/97 (4.1%); P=0.388] and IFI-related mortality [0/36 (0.0%) vs 1/45 (2.2%); P=0.556]. CONCLUSION: The differences in clinical outcomes between empirical and pre-emptive antifungal therapy in patients with AML who received antimould prophylaxis were not significant. Therefore, broad-spectrum antifungal therapy in patients receiving antimould prophylaxis may be delayed until there is clear evidence of IFI.

Impact of routine brain imaging on the prognosis of patients with left-sided valve infective endocarditis without neurological manifestations.

BACKGROUND: There are limited data on the impact of routine use of brain magnetic resonance imaging (MRI) on the prognosis of neurologically asymptomatic patients with left-sided infective endocarditis (IE). METHODS: Among patients diagnosed with possible or definite IE in two tertiary referral centers between January 2005 and March 2019, we identified 527 left-sided IE patients without neurological symptoms or signs at the time of diagnosis. Patients who underwent brain MRI within 1 week after the IE diagnosis were classified as the routine brain imaging group (n = 216), and the rest were categorized as the control group (n = 311). All-cause mortality at 3 months, attributable mortality (defined as death directly related to IE), and fatal neurological events compared after adjustment using inverse probability of treatment weighting (IPTW). RESULTS: During a median follow-up of 57 months, the routine brain imaging group had a similar risk of 3-month all-cause mortality to the control group in the multivariate analysis (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.24-1.14) and IPTW-adjusted cohort (HR, 0.59; 95% CI, 0.25-1.42). The risks of attributable mortality and fatal neurological events were also similar between the two groups in the multivariable analysis and IPTW-adjusted cohort. In the subgroup analysis, the routine brain imaging group showed more favorable outcomes in cases of large vegetation (> 10 mm) or acute-onset microorganisms. CONCLUSIONS: Routine use of brain MRI in left-sided IE patients without neurological manifestations is not associated with improved clinical outcomes. However, routine brain imaging in appropriate clinical settings could improve clinical outcomes.

Effect of Wearing Personal Protective Equipment (PPE) for COVID-19 Treatment on Blood Culture Contamination: Implication for Optimal PPE Strategies.

The personal protective equipment (PPE) used to minimize exposure to hazards can hinder healthcare workers from performing sophisticated procedures. We retrospectively reviewed 77,535 blood cultures (202,012 pairs) performed in 28,502 patients from January 2020 to April 2022. The contamination rate of all blood cultures was significantly elevated in the coronavirus disease 2019 ward at 4.68%, compared to intensive care units at 2.56%, emergency rooms at 1.13%, hematology wards at 1.08%, and general wards at 1.07% (All of P < 0.001). This finding implies that wearing PPE might interfere with adherence to the aseptic technique. Therefore, a new PPE policy is needed that considers the balance between protecting healthcare workers and medical practices.

Low humoral and cellular immune responses early after breakthrough infection may contribute to severe COVID-19.

Background: Little is known about the immune determinants for severe coronavirus disease 2019 (COVID-19) in individuals vaccinated against severe acute respiratory syndrome coronavirus 2. We therefore attempted to identify differences in humoral and cellular immune responses between patients with non-severe and severe breakthrough COVID-19. Methods: We prospectively enrolled hospitalized patients with breakthrough COVID-19 (severe and non-severe groups) and uninfected individuals who were vaccinated at a similar time (control group). Severe cases were defined as those who required oxygen therapy while hospitalized. Enzyme-linked immunosorbent assays and flow cytometry were used to evaluate humoral and cellular immune responses, respectively. Results: Anti-S1 IgG titers were significantly lower in the severe group than in the non-severe group within 1 week of symptom onset and higher in the non-severe group than in the control group. Compared with the control group, the cellular immune response tended to be diminished in breakthrough cases, particularly in the severe group. In multivariate analysis, advanced age and low anti-S1 IgG titer were associated with severe breakthrough COVID-19. Conclusions: Severe breakthrough COVID-19 might be attributed by low humoral and cellular immune responses early after infection. In the vaccinated population, delayed humoral and cellular immune responses may contribute to severe breakthrough COVID-19.

Anti-Alpha-Toxin Antibody Responses and Clinical Outcomes of Staphylococcus aureus Bacteremia.

BACKGROUND: Alpha-toxin (AT), a major virulence factor of Staphylococcus aureus, is an important immunotherapeutic target to prevent or treat invasive S. aureus infections. Previous studies have suggested that anti-AT antibodies (Abs) may have a protective role against S. aureus bacteremia (SAB), but their function remains unclear. Therefore, we aimed to investigate the association between serum anti-AT Ab levels and clinical outcomes of SAB. METHODS: Patients from a prospective SAB cohort at a tertiary-care medical center (n = 51) were enrolled in the study from July 2016 to January 2019. Patients without symptoms or signs of infection were enrolled as controls (n = 100). Blood samples were collected before the onset of SAB and at 2- and 4-weeks post-bacteremia. Anti-AT immunoglobin G (IgG) levels were measured using an enzyme-linked immunosorbent assay. All clinical S. aureus isolates were tested for the presence of hla using polymerase chain reaction. RESULTS: Anti-AT IgG levels in patients with SAB before the onset of bacteremia did not differ significantly from those in non-infectious controls. Pre-bacteremic anti-AT IgG levels tended to be lower in patients with worse clinical outcomes (7-day mortality, persistent bacteremia, metastatic infection, septic shock), although the differences were not statistically significant. Patients who needed intensive care unit care had significantly lower anti-AT IgG levels at 2 weeks post-bacteremia (P = 0.020). CONCLUSION: The study findings suggest that lower anti-AT Ab responses before and during SAB, reflective of immune dysfunction, are associated with more severe clinical presentations of infection.

COVID-19 Vaccination in Korea.

Since December 2020, various coronavirus disease 2019 (COVID-19) vaccines have been developed and approved. As of February 2023, mRNA vaccines including bivalent vaccines (Pfizer/BioNTech, Moderna), recombinant protein vaccines (Novavax, SK Bioscience), and viral vector vaccines (AstraZeneca, Janssen) have been approved in Korea. COVID-19 vaccination can effectively reduce hospitalization and deaths due to symptomatic COVID-19, especially severe and critical COVID-19. The primary series vaccination against COVID-19 is recommended for all adults aged ≥18 years in Korea. Booster vaccination with the bivalent mRNA vaccine is available for those ≥12 years who have completed the primary series vaccination, regardless of the type of vaccine previously received, and is recommended for all adults. Booster vaccination can be administered since 90 days after the last dose. Localized and systemic adverse events following COVID-19 vaccination are relatively common and more frequently documented in younger age groups. Rare but potentially serious specialized adverse reactions include anaphylaxis, thrombosis with thrombocytopenia syndrome, myocarditis, and Guillain-Barré syndrome. Previous severe allergic reactions, such as anaphylaxis, to any COVID19 vaccine or vaccine component are considered a contraindication for vaccination. The indications and schedule for COVID-19 vaccination are subject to change based on further research results and the COVID-19 pandemic.

Different degree of cytokinemia and T-cell activation according to serum IL-6 levels in critical COVID-19.

Introduction: Tocilizumab, a humanized anti-interleukin-6 receptor (IL-6R) antibody, is recommended for the treatment of severe to critical coronavirus diseases 2019 (COVID-19). However, there were conflicting results on the efficacy of tocilizumab. Therefore, we hypothesized that the differences in tocilizumab efficacy may stem from the different immune responses of critical COVID-19 patients. In this study, we described two groups of immunologically distinct COVID-19 patients, based on their IL-6 response. Methods: We prospectively enrolled critical COVID-19 patients, requiring oxygen support with a high flow nasal cannula or a mechanical ventilator, and analyzed their serial samples. An enzyme-linked immunosorbent assay and flow cytometry were used to evaluate the cytokine kinetics and cellular immune responses, respectively. Results: A total of nine patients with critical COVID-19 were included. The high (n = 5) and low IL-6 (n = 4) groups were distinguished by their peak serum IL-6 levels, using 400 pg/mL as the cut-off value. Although the difference of flow cytometric data did not reach the level of statistical significance, the levels of pro-inflammatory cytokines and the frequencies of intermediate monocytes (CD14+CD16+), IFN-γ+ CD4+ or CD8+ T cells, and HLA-DR+PD-1+ CD4+ T cells were higher in the high IL-6 group than in the low IL-6 group. Conclusion: There were distinctive two groups of critical COVID-19 according to serum IL-6 levels having different degrees of cytokinemia and T-cell responses. Our results indicate that the use of immune modulators should be more tailored in patients with critical COVID-19.

Comparable humoral and cellular immunity against Omicron variant BA.4/5 of once-boosted BA.1/2 convalescents and twice-boosted COVID-19-naïve individuals.

The fourth vaccination dose confers additional protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with no prior coronavirus disease-19 (COVID-19). However, its immunological benefit against currently circulating BA.4/5 is unclear in individuals who have received a booster shot and been infected with Omicron variant BA.1/2. We analyzed immune responses in whom had been boosted once and did not have COVID-19 (n = 16), boosted once and had COVID-19 when BA.1/2 was dominant in Korea (Hybrid-6M group, n = 27), and boosted twice and did not have COVID-19 (Vx4 group, n = 15). Antibody binding activities against RBDo BA.1 and RBDo BA.4/5 , antigen-specific memory CD4+ and CD8+ T-cell responses against BA.4/5, and B-cell responses against SARS-CoV-2 wild-type did not differ statistically between the Hybrid-6M and Vx4 groups. The humoral and cellular immune responses of the Hybrid-6M group against BA.4/5 were comparable to those of the Vx4 group. Individuals who had been boosted and had an Omicron infection in early 2022 may not have high priority for an additional vaccination.

How We Have Treated Severe to Critically Ill Patients With Coronavirus Disease 2019 in Korea.

Since 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide, and the coronavirus disease 2019 (COVID-19) pandemic currently continues. In response to this unprecedented pandemic, several researchers and medical staff have struggled to find appropriate treatments for COVID-19. Patients with mild symptoms can recuperate with symptomatic care, however establishing treatment for severe to critically ill patients who can have a high mortality has been essential. Accordingly, the guidelines for COVID-19 treatment have evolved through numerous trials and errors and have been relatively well established to date. In the Republic of Korea, several evidence-based guidelines for COVID-19 treatment were released and revised, reflecting various research and regional medical conditions. To date, approximately 3 years after the beginning of the COVID-19 pandemic, we are reflecting on the changes in the guidelines thus far and have summarized the treatment experience of severe to critically ill patients with COVID-19. The Korean guidelines for COVID-19 treatment have been updated continuously as the National Institutes of Health (NIH) guidelines have changed. Dexamethasone is currently used as the backbone for the treatment of severe to critically ill patients with COVID-19, and remdesivir, baricitinib, and tocilizumab can be added depending on a patient's situation. In addition, venous thromboembolism prophylaxis is one of the important adjunctive therapies for patients with severe COVID-19. In the clinical field, treatment of severely ill patients with COVID-19 based on guidelines is widely practiced by medical staff and established currently.