Immunogenicity and Safety of Vaccines against Coronavirus Disease in Actively Treated Patients with Solid Tumors: A Prospective Cohort Study.

PURPOSE: We aimed to assess the humoral response to and reactogenicity of coronavirus disease 2019 (COVID-19) vaccination according to the vaccine type and to analyze factors associated with immunogenicity in actively treated solid cancer patients (CPs). Materials and Methods: Prospective cohorts of CPs, undergoing anticancer treatment, and healthcare workers (HCWs) were established. The participants had no history of previous COVID-19 and received either mRNA-based or adenovirus vector-based (AdV) vaccines as the primary series. Blood samples were collected before the first vaccination and after 2 weeks for each dose vaccination. Spike-specific binding antibodies (bAbs) in all participants and neutralizing antibodies (nAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type, Delta, and Omicron variants in CPs were analyzed and presented as the geometric mean titer. RESULTS: Age-matched 20 HCWs and 118 CPs were included in the analysis. The bAb seroconversion rate and antibody concentrations after the first vaccination were significantly lower in CPs than in HCWs. After the third vaccination, antibody levels in CPs with a primary series of AdV were comparable to those in HCWs, but nAb titers against the Omicron variant did not quantitatively increase in CPs with AdV vaccine as the primary series. The incidence and severity of adverse reactions post-vaccination were similar between CPs and HCWs. CONCLUSION: CPs displayed delayed humoral immune response after SARS-CoV-2 vaccination. The booster dose elicited comparable bAb concentrations between CPs and HCWs, regardless of the primary vaccine type. Neutralization against the Omicron variant was not robustly elicited following the booster dose in some CPs, implying the need for additional interventions to protect them from COVID-19.

Reactogenicity and Immunogenicity of the ChAdOx1 nCOV-19 Coronavirus Disease 2019 Vaccine in South Korean Healthcare Workers.

PURPOSE: The association between reactogenicity and immunogenicity of the ChAdOx1 nCOV-19 is controversial. We aimed to evaluate this association among South Korean healthcare workers (HCWs). MATERIALS AND METHODS: Participants received two doses of the ChAdOx1vaccine 12 weeks apart. Blood samples were tested for anti-severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) spike protein receptor binding domain antibodies about 2 months after the first and second doses using the Elecsys Anti-SARS-CoV-2 S assay kits. Adverse events were noted using an online self-reporting questionnaire. RESULTS: Among the 232 HCWs, pain (85.78% after the first dose vs. 58.62% after the second dose, p<0.001) was the most prominent local reaction, and myalgia or fatigue (84.05% vs. 53.02%, p<0.001) was the most prominent systemic reaction. The frequency of all adverse events was significantly reduced after the second dose. After the first dose, the anti-SARS-CoV-2 S showed significantly higher titer in the group with swelling, itching, fever, and nausea. Also, the anti-SARS-CoV-2 S titer significantly increased as the grade of fever (p=0.007) and duration of fever (p=0.026) increased; however, there was no significant correlation between immunogenicity and adverse event after the second dose. The group with pain after the first dose showed a greater increase in the anti-SARS-CoV-2 S difference between the second and first doses compared to the group without pain (542.2 U/mL vs. 363.8 U/mL, p=0.037). CONCLUSION: The frequency of adverse events occurring after the first dose of the ChAdOx1 was significantly reduced after the second dose. Interestingly, the elevation of anti-SARS-CoV-2 S titer was significantly increased in the group with pain after the first dose.

Estimation of SARS-CoV-2 Neutralizing Activity and Protective Immunity in Different Vaccine Types Using Three Surrogate Virus Neutralization Test Assays and Two Semiquantitative Binding Assays Targeting the Receptor-Binding Domain.

Estimating neutralizing activity in vaccinees is crucial for predicting the protective effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As the plaque reduction neutralization test (PRNT) requires a biosafety level 3 facility, it would be advantageous if surrogate virus neutralization test (sVNT) assays and binding assays could predict neutralizing activity. Here, five different assays were evaluated with respect to the PRNT in vaccinees: three sVNT assays from GenScript, Boditech Med, and SD Biosensor and two semiquantitative binding assays from Roche and Abbott. The vaccinees were subjected to three vaccination protocols: homologous ChAdOx1, homologous BNT162b2, and heterologous administration. The ability to predict a 50% neutralizing dose (ND50) of ≥20 largely varied among the assays, with the binding assays showing substantial agreement (kappa, ~0.90) and the sVNT assays showing relatively poor performance, especially in the ChAdOx1 group (kappa, 0.33 to 0.97). The ability to predict an ND50 value of ≥118.25, indicating a protective effect, was comparable among different assays. Applying optimal cutoffs based on Youden's index, the kappa agreements were greater than 0.60 for all assays in the total group. Overall, relatively poor performance was demonstrated in the ChAdOx1 group, owing to low antibody titers. Although there were intra-assay differences related to the vaccination protocols, as well as interassay differences, all assays demonstrated fair performance in predicting the protective effect using the new cutoffs. This study demonstrates the need for a different cutoff for each assay to appropriately determine a higher neutralizing titer and suggests the clinical feasibility of using various assays for estimation of the protective effect. IMPORTANCE The coronavirus disease 2019 (COVID-19) pandemic continues to last, despite high COVID-19 vaccination rates. As many people experience breakthrough infection after prior infection and/or vaccination, estimating the neutralization activity and predicting the protective effect are major issues of concern. However, since standard neutralization tests are not available in most clinical laboratories, it would be beneficial if commercial assays could predict these aspects. In this study, we evaluated the performance of three sVNT assays and two semiquantitative binding assays targeting the receptor-binding domain with respect to the PRNT. Our results suggest that these assays could be used for predicting the protective effect by adjusting the cutoffs.

Kinetics of vaccine-induced neutralizing antibody titers and estimated protective immunity against wild-type SARS-CoV-2 and the Delta variant: A prospective nationwide cohort study comparing three COVID-19 vaccination protocols in South Korea.

Introduction: Despite vaccine development, the COVID-19 pandemic is ongoing due to immunity-escaping variants of concern (VOCs). Estimations of vaccine-induced protective immunity against VOCs are essential for setting proper COVID-19 vaccination policy. Methods: We performed plaque-reduction neutralizing tests (PRNTs) using sera from healthcare workers (HCWs) collected from baseline to six months after COVID-19 vaccination and from convalescent COVID-19 patients. The 20.2% of the mean PRNT titer of convalescent sera was used as 50% protective value, and the percentage of HCWs with protective immunity for each week (percent-week) was compared among vaccination groups. A correlation equation was deduced between a PRNT 50% neutralizing dose (ND50) against wild type (WT) SARS-CoV-2 and that of the Delta variant. Results: We conducted PRNTs on 1,287 serum samples from 297 HCWs (99 HCWs who received homologous ChAdOx1 vaccination (ChAd), 99 from HCWs who received homologous BNT162b2 (BNT), and 99 from HCWs who received heterologous ChAd followed by BNT (ChAd-BNT)). Using 365 serum samples from 116 convalescent COVID-19 patients, PRNT ND50 of 118.25 was derived as 50% protective value. The 6-month cumulative percentage of HCWs with protective immunity against WT SARS-CoV-2 was highest in the BNT group (2297.0 percent-week), followed by the ChAd-BNT (1576.8) and ChAd (1403.0) groups. In the inter-group comparison, protective percentage of the BNT group (median 96.0%, IQR 91.2-99.2%) was comparable to the ChAd-BNT group (median 85.4%, IQR 15.7-100%; P =0.117) and significantly higher than the ChAd group (median 60.1%, IQR 20.0-87.1%; P <0.001). When Delta PRNT was estimated using the correlation equation, protective immunity at the 6-month waning point was markedly decreased (28.3% for ChAd group, 52.5% for BNT, and 66.7% for ChAd-BNT). Conclusion: Decreased vaccine-induced protective immunity at the 6-month waning point and lesser response against the Delta variant may explain the Delta-dominated outbreak of late 2021. Follow-up studies for newly-emerging VOCs would also be needed.

Heterologous ChAdOx1 and Bnt162b2 vaccination induces strong neutralizing antibody responses against SARS-CoV-2 including delta variant with tolerable reactogenicity.

OBJECTIVES: We assessed humoral responses and reactogenicity following the heterologous vaccination compared to the homologous vaccination groups. METHODS: We enrolled healthcare workers (HCWs) who were either vaccinated with ChAdOx1 followed by BNT162b2 (heterologous group) or 2 doses of ChAdOx1 (ChAdOx1 group) or BNT162b2 (BNT162b2 group). Immunogenicity was assessed by measuring antibody titers against receptor-binding domain (RBD) of SARS-CoV-2 spike protein in all participants and neutralizing antibody titer in 100 participants per group. Reactogenicity was evaluated by a questionnaire-based survey. RESULTS: We enrolled 499 HCWs (ChAdOx1, n = 199; BNT162b2, n = 200; heterologous ChAdOx1/BNT162b2, n = 100). The geometric mean titer of anti-receptor-binding domain antibody at 14 days after the booster dose was significantly higher in the heterologous group (11 780.55 binding antibody unit (BAU)/mL [95% CI, 10 891.52-12 742.14]) than in the ChAdOx1 (1561.51 [95% CI, 1415.03-1723.15]) or BNT162b2 (2895.90 [95% CI, 2664.01-3147.98]) groups (both p < 0.001). The neutralizing antibody titer of the heterologous group (geometric mean ND50, 2367.74 [95% CI, 1970.03-2845.74]) was comparable to that of the BNT162b2 group (2118.63 [95% CI, 1755.88-2556.32]; p > 0.05) but higher than that of the ChAdOx1 group (391.77 [95% CI, 326.16-470.59]; p < 0.001). Compared with those against wild-type SARS-CoV-2, the geometric mean neutralizing antibody titers against the Delta variant at 14 days after the boosting were reduced by 3.0-fold in the heterologous group (geometric mean ND50, 872.01 [95% CI, 685.33-1109.54]), 4.0-fold in the BNT162b2 group (337.93 [95% CI, 262.78-434.57]), and 3.2-fold in the ChAdOx1 group (206.61 [95% CI, 144.05-296.34]). The local or systemic reactogenicity after the booster dose in the heterologous group was higher than that of the ChAdOx1 group but comparable to that of the BNT162b2 group. DISCUSSION: Heterologous ChAdOx1 followed by BNT162b2 vaccination with a 12-week interval induced a robust humoral immune response against SARS-CoV-2, including the Delta variant, that was comparable to the homologous BNT162b2 vaccination and stronger than the homologous ChAdOx1 vaccination, with a tolerable reactogenicity profile.

Safety and immunogenicity of two recombinant DNA COVID-19 vaccines containing the coding regions of the spike or spike and nucleocapsid proteins: an interim analysis of two open-label, non-randomised, phase 1 trials in healthy adults.

BACKGROUND: We assessed the safety and immunogenicity of two recombinant DNA vaccines for COVID-19: GX-19 containing plasmid DNA encoding the SARS-CoV-2 spike protein, and GX-19N containing plasmid DNA encoding the SARS-CoV-2 receptor-binding domain (RBD) foldon, nucleocapsid protein, and plasmid DNA encoding the spike protein. METHODS: Two open-label non-randomised phase 1 trials, one of GX-19 and the other of GX-19N were done at two hospitals in South Korea. We enrolled healthy adults aged 19-49 years for the GX-19 trial and healthy adults aged 19-54 years for the GX-19N trial. Participants who tested positive by serological testing for SARS-CoV-2 were excluded. At 4-week intervals, the GX-19 trial participants received two vaccine doses (either 1·5 mg or 3·0 mg), and the GX-19N trial participants received two 3·0 mg doses. The vaccines were delivered intramuscularly using an electroporator. The participants were followed up for 52 weeks after first vaccination. Data collected up to day 57 after first vaccination were analysed in this interim analysis. The primary outcome was safety within 28 days after each vaccination measured in the intention-to-treat population. The secondary outcome was vaccine immunogenicity using blood samples collected on day 43 or 57 after first vaccination measured in the intention-to-treat population. The GX-19 (NCT044445389) and GX-19N (NCT04715997) trials are registered with ClinicalTrials.gov. FINDINGS: Between June 17 and July 30, 2020, we screened 97 individuals, of whom 40 (41%) participants were enrolled in the GX-19 trial (20 [50%] in the 1·5 mg group and 20 [50%] in the 3·0 mg group). Between Dec 28 and 31, 2020, we screened 23 participants, of whom 21 (91%) participants were enrolled on the GX-19N trial. 32 (52%) of 61 participants reported 80 treatment-emergent adverse events after vaccination. All solicited adverse events were mild except one (2%) case of moderate fatigue in the 1·5 mg GX-19 group; no serious vaccine-related adverse events were detected. Binding antibody responses increased after second dose of vaccination in all groups (p=0·0002 in the 1·5 mg GX-19 group; p<0·0001 in the 3·0 mg GX-19; and p=0·0004 for the spike protein and p=0·0001 for the RBD in the 3·0 mg GX-19N group). INTERPRETATION: GX-19 and GX-19N are safe and well tolerated. GX-19N induces humoral and broad SARS-CoV-2-specific T-cell responses. GX-19N shows lower neutralising antibody responses and needs improvement to enhance immunogenicity. FUNDING: The Korea Drug Development Fund, funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare.

No Change of Pneumocystis jirovecii Pneumonia after the COVID-19 Pandemic: Multicenter Time-Series Analyses.

Consolidated infection control measures imposed by the government and hospitals during COVID-19 pandemic resulted in a sharp decline of respiratory viruses. Based on the issue of whether Pneumocystis jirovecii could be transmitted by airborne and acquired from the environment, we assessed changes in P. jirovecii pneumonia (PCP) cases in a hospital setting before and after COVID-19. We retrospectively collected data of PCP-confirmed inpatients aged ≥18 years (N = 2922) in four university-affiliated hospitals between January 2015 and June 2021. The index and intervention dates were defined as the first time of P. jirovecii diagnosis and January 2020, respectively. We predicted PCP cases for post-COVID-19 and obtained the difference (residuals) between forecasted and observed cases using the autoregressive integrated moving average (ARIMA) and the Bayesian structural time-series (BSTS) models. Overall, the average of observed PCP cases per month in each year were 36.1 and 47.3 for pre- and post-COVID-19, respectively. The estimate for residuals in the ARIMA model was not significantly different in the total PCP-confirmed inpatients (7.4%, p = 0.765). The forecasted PCP cases by the BSTS model were not significantly different from the observed cases in the post-COVID-19 (-0.6%, 95% credible interval; -9.6~9.1%, p = 0.450). The unprecedented strict non-pharmacological interventions did not affect PCP cases.

Optimal Triage for COVID-19 Patients Under Limited Health Care Resources With a Parsimonious Machine Learning Prediction Model and Threshold Optimization Using Discrete-Event Simulation: Development Study.

BACKGROUND: The COVID-19 pandemic has placed an unprecedented burden on health care systems. OBJECTIVE: We aimed to effectively triage COVID-19 patients within situations of limited data availability and explore optimal thresholds to minimize mortality rates while maintaining health care system capacity. METHODS: A nationwide sample of 5601 patients confirmed with COVID-19 until April 2020 was retrospectively reviewed. Extreme gradient boosting (XGBoost) and logistic regression analysis were used to develop prediction models for the maximum clinical severity during hospitalization, classified according to the World Health Organization Ordinal Scale for Clinical Improvement (OSCI). The recursive feature elimination technique was used to evaluate the maintenance of model performance when clinical and laboratory variables were eliminated. Using populations based on hypothetical patient influx scenarios, discrete-event simulation was performed to find an optimal threshold within limited resource environments that minimizes mortality rates. RESULTS: The cross-validated area under the receiver operating characteristic curve (AUROC) of the baseline XGBoost model that utilized all 37 variables was 0.965 for OSCI ≥6. Compared to the baseline model's performance, the AUROC of the feature-eliminated model that utilized 17 variables was maintained at 0.963 with statistical insignificance. Optimal thresholds were found to minimize mortality rates in a hypothetical patient influx scenario. The benefit of utilizing an optimal triage threshold was clear, reducing mortality up to 18.1%, compared with the conventional Youden index. CONCLUSIONS: Our adaptive triage model and its threshold optimization capability revealed that COVID-19 management can be achieved via the cooperation of both the medical and health care management sectors for maximum treatment efficacy. The model is available online for clinical implementation.

Characteristics of community-acquired respiratory viruses infections except seasonal influenza in transplant recipients and non-transplant critically ill patients.

BACKGROUND/PURPOSE: Transplant recipients are vulnerable to life-threatening community-acquired respiratory viruses (CA-RVs) infection (CA-RVI). Even if non-transplant critically ill patients in intensive care unit (ICU) have serious CA-RVI, comparison between these groups remains unclear. We aimed to evaluate clinical characteristics and mortality of CA-RVI except seasonal influenza A/B in transplant recipients and non-transplant critically ill patients in ICU. METHODS: We collected 37,777 CA-RVs multiplex real-time reverse transcription-polymerase chain reaction test results of individuals aged ≥18 years from November 2012 to November 2017. The CA-RVs tests included adenovirus, coronavirus 229E/NL63/OC43, human bocavirus, human metapneumovirus, parainfluenza virus 1/2/3, rhinovirus, and respiratory syncytial virus A/B. RESULTS: We found 286 CA-RVI cases, including 85 solid organ transplantation recipients (G1), 61 hematopoietic stem cell transplantation recipients (G2), and 140 non-transplant critically ill patients in ICU (G3), excluding those with repeated isolation within 30 days. Adenovirus positive rate and infection cases were most prominent in G2 (p < 0.001). The median time interval between transplantation and CA-RVI was 30 and 20 months in G1 and G2, respectively. All-cause in-hospital mortality was significantly higher in G3 than in G1 or G2 (51.4% vs. 28.2% or 39.3%, p = 0.002, respectively). The mechanical ventilation (MV) was the independent risk factor associated with all-cause in-hospital mortality in all three groups (hazard ratio, 3.37, 95% confidence interval, 2.04-5.56, p < 0.001). CONCLUSIONS: This study highlights the importance of CA-RVs diagnosis in transplant recipients even in long-term posttransplant period, and in non-transplant critically ill patients in ICU with MV.