A heterologous AZD1222 priming and BNT162b2 boosting regimen more efficiently elicits neutralizing antibodies, but not memory T cells, than the homologous BNT162b2 regimen.

BACKGROUND: Comparative analyses of SARS-CoV-2-specific immune responses elicited by diverse prime-boost regimens are required to establish efficient regimens for the control of COVID-19. METHOD: In this prospective observational cohort study, spike-specific immunoglobulin G (IgG) and neutralizing antibodies (nAbs) alongside spike-specific T-cell responses in age-matched groups of homologous BNT162b2/BNT162b2 or AZD1222/AZD1222 vaccination, heterologous AZD1222/BNT162b2 vaccination, and prior wild-type SARS-CoV-2 infection/vaccination were evaluated. RESULTS: Peak immune responses were achieved after the second vaccine dose in the naïve vaccinated groups and after the first dose in the prior infection/vaccination group. Peak titers of anti-spike IgG and nAb were significantly higher in the AZD1222/BNT162b2 vaccination and prior infection/vaccination groups than in the BNT162b2/BNT162b2 or AZD1222/AZD1222 groups. However, the frequency of interferon-γ-producing CD4+ T cells was highest in the BNT162b2/BNT162b2 vaccination group. Similar results were observed in the analysis of polyfunctional T cells. When nAb and CD4+T-cell responses against the Delta variant were analyzed, the prior infection/vaccination group exhibited higher responses than the groups of other homologous or heterologous vaccination regimens. CONCLUSION: nAbs are efficiently elicited by heterologous AZD1222/BNT162b2 vaccination, as well as prior infection/vaccination, whereas spike-specific CD4+T-cell responses are efficiently elicited by homologous BNT162b2 vaccination. Variant-recognizing immunity is more efficiently generated by prior infection/vaccination than the other homologous or heterologous vaccination regimens.

Vaccine Effect on Household Transmission of Omicron and Delta SARS-CoV-2 Variants.

BACKGROUND: We evaluated the household secondary attack rate (SAR) of the omicron and delta severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, according to the vaccination status of the index case and household contacts; further, in vaccinated index cases, we evaluated the effect of the antibody levels on household transmission. METHODS: A prospective cross-sectional study of 92 index cases and 197 quarantined household contacts was performed. Tests for SARS-CoV-2 variant type and antibody level were conducted in index cases, and results of polymerase chain reaction tests (during the quarantine period) were collected from contacts. Association of antibody levels in vaccinated index cases and SAR was evaluated by multivariate regression analysis. RESULTS: The SAR was higher in households exposed to omicron variant (42%) than in those exposed to delta variant (27%) (P = 0.040). SAR was 35% and 23% for unvaccinated and vaccinated delta variant exposed contacts, respectively. SAR was 44% and 41% for unvaccinated and vaccinated omicron exposed contacts, respectively. Booster dose immunisation of contacts or vaccination of index cases reduced SAR of vaccinated omicron variant exposed contacts. In a model with adjustment, anti-receptor-binding domain antibody levels in vaccinated index cases were inversely correlated with household transmission of both delta and omicron variants. Neutralising antibody levels had a similar relationship. CONCLUSION: Immunisation of household members may help to mitigate the current pandemic.

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.

The Potential Role of an Adjunctive Real-Time Locating System in Preventing Secondary Transmission of SARS-CoV-2 in a Hospital Environment: Retrospective Case-Control Study.

BACKGROUND: There has been an increasing demand for new technologies regarding infection control in hospital settings to reduce the burden of contact tracing. OBJECTIVE: This study aimed to compare the validity of a real-time locating system (RTLS) with that of the conventional contact tracing method for identifying high-risk contact cases associated with the secondary transmission of SARS-CoV-2. METHODS: A retrospective case-control study involving in-hospital contact cases of confirmed COVID-19 patients, who were diagnosed from January 23 to March 25, 2022, was conducted at a university hospital in South Korea. Contact cases were identified using either the conventional method or the RTLS. The primary endpoint of this study was secondary transmission of SARS-CoV-2 among contact cases. Univariate and multivariable logistic regression analysis comparing test positive and versus negative contact cases were performed. RESULTS: Overall, 509 and 653 cases were confirmed by the conventional method and the RTLS, respectively. Only 74 contact cases were identified by both methods, which could be attributed to the limitations of each method. Sensitivity was higher for the RTLS tracing method (653/1088, 60.0%) than the conventional tracing method (509/1088, 46.8%) considering all contact cases identified by both methods. The secondary transmission rate in the RTLS model was 8.1%, while that in the conventional model was 5.3%. The multivariable logistic regression model revealed that the RTLS was more capable of detecting secondary transmission than the conventional method (adjusted odds ratio 6.15, 95% CI 1.92-28.69; P=.007). CONCLUSIONS: This study showed that the RTLS is beneficial when used as an adjunctive approach to the conventional method for contact tracing associated with secondary transmission. However, the RTLS cannot completely replace traditional contact tracing.

Neutralizing Activity Against SARS-CoV-2 Delta and Omicron Variants Following a Third BNT162b2 Booster Dose According to Three Homologous or Heterologous COVID-19 Vaccination Schedules.

With the emergence and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants, escaping vaccine-induced immunity is a concern. Three vaccination schedules, homologous or heterologous, have been initially applied due to an insufficient supply of vaccines in Korea. We investigated neutralizing activities against Omicron and Delta variants in each schedule. Three schedules using three doses of the BNT162b2 (BNT) or the ChAdOx1 (ChAd) vaccines include ChAd-ChAd-BNT, ChAd-BNT-BNT, and BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild type (WT) SARS-CoV-2, Delta variant, and Omicron variant. A total of 170 sera from 75 participants were tested, and the baseline characteristics of participants were not significantly different between groups. After the 2nd vaccine dose, geometric mean titers of PRNT ND50 against WT, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628). ChAd-BNT-BNT showed a slight increase of PRNT ND50 against WT, Delta, and Omicron (2,757, 1,279, and 230) compared to the 2nd dose. The results suggest that a 3rd BNT booster dose induced strengthened neutralizing activity against Delta and Omicron variants. The waning of cross-reactive neutralizing antibodies after the 3rd dose and the need for additional boosting should be further investigated.

Antibody Level Predicts the Clinical Course of Breakthrough Infection of COVID-19 Caused by Delta and Omicron Variants: A Prospective Cross-Sectional Study.

Background: Omicron variant viruses spread rapidly, even in individuals with high vaccination rates. This study aimed to determine the utility of the antibody against spike protein level as a predictor of the disease course of coronavirus disease 2019 (COVID-19) in vaccinated patients. Methods: Between December 11, 2021, and February 10, 2022, we performed a prospective observational cohort study in South Korea, which included patients infected with Delta and Omicron variants. A multivariable logistic regression analysis to determine the association between antibody levels and outcomes was conducted. The relationship between antibody levels and cycle threshold (Ct) values was confirmed using a generalized linear model. Results: From 106 vaccinated patients (39 Delta and 67 Omicron), the geometric mean titers of antibodies in patients with fever (≥37.5°C), hypoxia (≤94% of SpO2), pneumonia, C-reactive protein (CRP) elevation (>8 mg/L), or lymphopenia (<1100 cells/µL) were 1201.5 U/mL, 98.8 U/mL, 774.1 U/mL, 1335.1 U/mL, and 1032.2 U/mL, respectively. Increased antibody levels were associated with a decrease in the occurrence of fever (adjusted odds ratio [aOR], 0.23; 95% CI, 0.12-0.51), hypoxia (aOR, 0.23; 95% CI, 0.08-0.7), CRP elevation (aOR, 0.52; 95% CI, 0.29-0.0.94), and lymphopenia (aOR, 0.57; 95% CI, 0.33-0.98). Ct values showed a positive correlation between antibody levels (P = .02). Conclusions: Antibody levels are predictive of the clinical course of COVID-19 in vaccinated patients with Delta and Omicron variant infections. Our data highlight the need for concentrated efforts to monitor patients with severe acute respiratory syndrome coronavirus 2 infection who are at risk of low antibody levels.

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.

Transfer of virtual reality endoscopy training to live animal colonoscopy: a randomized control trial of proficiency vs. repetition-based training.

BACKGROUND: Low first-time pass rates of the Fundamentals of Endoscopic Surgery (FES) exam stimulated development of virtual reality (VR) simulation curricula for test preparation. This study evaluates the transfer of VR endoscopy training to live porcine endoscopy performance and compares the relative effectiveness of a proficiency-based vs repetition-based VR training curriculum. METHODS: Novice endoscopists completed pretesting including the FES manual skills examination and Global Assessment of GI Endoscopic Skills (GAGES) assessment of porcine upper and lower endoscopy. Participants were randomly assigned one of two curricula: proficiency-based or repetition-based. Following curriculum completion, participants post-tested via repeat FES examination and GAGES porcine endoscopy assessments. The two cohorts pre-to-post-test differences were compared using ANCOVA. RESULTS: Twenty-two residents completed the curricula. There were no differences in demographics or clinical endoscopy experience between the groups. The repetition group spent significantly more time on the simulator (repetition: 242.2 min, SD 48.6) compared to the proficiency group (proficiency: 170.0 min, SD 66.3; p = 0.013). There was a significant improvement in porcine endoscopy (pre: 10.6, SD 2.8, post: 16.6, SD 3.4; p < 0.001) and colonoscopy (pre: 10.4, SD 2.7, post: 16.4, SD 4.2; p < 0.001) GAGES scores as well as FES manual skills performance (pre: 270.9, SD 105.5, post: 477.4, SD 68.9; p < 0.001) for the total cohort. There was no difference in post-test GAGES performance or FES manual skills exam performance between the two groups. Both the proficiency and repetition group had a 100% pass rate on the FES skills exam following VR curriculum completion. CONCLUSION: A VR endoscopy curriculum translates to improved performance in upper and lower endoscopy in a live animal model. VR curricula type did not affect FES manual skills examination or live colonoscopy outcomes; however, a proficiency curriculum is less time-consuming and can provide a structured approach to prepare for both the FES exam and clinical endoscopy.

Effect of a hospital-wide campaign on COVID-19 vaccination uptake among healthcare workers in the context of raised concerns for life-threatening side effects.

BACKGROUND: All healthcare workers (HCWs) in Yongin Severance Hospital were allocated to receive the ChAdOx1 nCov-19 vaccine according to national policy. A report of thrombosis and thrombocytopenia syndrome (TTS) associated with ChAdOx1 nCoV-19 led to hesitancy about receiving the second dose among HCWs who had received the first dose. METHODS: From 7 to 14 May, 2021, we performed a survey to identify the factors associated with hesitancy about receiving the second vaccine dose among HCWs at the hospital who had received the first dose of the vaccine. Based on survey results, a hospital-wide campaign was implemented on 18 May 2021 to improve vaccine coverage. HCWs who completed the second dose completed a self-administered questionnaire to evaluate the effect of the campaign. FINDINGS: Of 1,171 HCWs who had received the first dose of the vaccine, 71.5% completed the online survey, of whom 3.7% refused to take the second dose and 22.3% showed hesitancy. Hesitancy to receive a second dose was significantly associated with age under 30 years and concerns about TTS, and was less common among those who trusted effectiveness and safety of the vaccine. Among HCWs who received the first dose, 96.2% completed vaccination with the second dose between 27 May and 4 June, 2021. Of those who answered the questionnaire asked about the timing of their decision to receive the second dose, 57.1% reported that they were motivated by the hospital-wide campaign. CONCLUSION: A tailored intervention strategy based on a survey can improve COVID-19 vaccination uptake among HCWs.

SARS-CoV-2 (COVID-19): Beginning to Understand a New Virus.

Within the last two decades, several members of the Coronaviridae family demonstrated epidemic potential. In late 2019, an unnamed genetic relative, later named SARS-CoV-2 (COVID-19), erupted in the highly populous neighborhoods of Wuhan, China. Unchecked, COVID-19 spread rapidly among interconnected communities and related households before containment measures could be enacted. At present, the mortality rate of COVID-19 infection worldwide is 6.6%. In order to mitigate the number of infections, restrictions or recommendations on the number of people that can gather in a given area have been employed by governments worldwide. For governments to confidently lift these restrictions as well as counter a potential secondary wave of infections, alternative medications and diagnostic strategies against COVID-19 are urgently required. This review has focused on these issues.

Patterns of viral clearance in the natural course of asymptomatic COVID-19: Comparison with symptomatic non-severe COVID-19.

OBJECTIVES: The aim of this study was to elucidate patterns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in the natural course of asymptomatic coronavirus disease 2019 (COVID-19). METHODS: Consecutive patients with non-severe COVID-19 were included retrospectively. Asymptomatic patients with a normal body temperature and no evidence of pneumonia throughout the disease course were assigned to the asymptomatic group. The reverse transcription PCR (RT-PCR) assay was repeated every two to five days after the first follow-up RT-PCR assay. Negative conversion was defined as two consecutive negative RT-PCR assay results within a 24-h interval. Rebound of the cycle threshold (Ct) value was defined as negative from the single RT-PCR assay and positive from the following assay. RESULTS: Among a total of 396 patients identified (median age 42.5 years (interquartile range (IQR) 25.0-55.0 years), 35.6% male), 68 (17.2%) were assigned to the asymptomatic group and 328 (82.8%) to the symptomatic group. The time until negative conversion was significantly shorter in the asymptomatic group than in the symptomatic group: median 14.5 days (IQR 11.0-21.0 days) and 18.0 days (IQR 15.0-22.0 days), respectively (p = 0.001). Rebound of Ct values was observed in 78 patients (19.7%). CONCLUSIONS: Time until negative conversion is shorter in asymptomatic COVID-19 than in symptomatic COVID-19. Rebound of Ct values is not uncommon.

Additional diagnostic testing of the 2019 novel coronavirus (SARS-CoV-2).

PURPOSE OF REVIEW: Within the last two decades several members of the Coronaviridae family namely Severe Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) have demonstrated epidemic potential. In late, 2019 an unnamed genetic relative, later named SARS-CoV-2 realized its potential in the highly populous neighborhoods of Wuhan, China. Unchecked, the virus rapidly spread among interconnected communities and related households before containment measures could be in acted. "Appropriate" diagnostic testing in response to the SARS-CoV-2 outbreak should be urgently considered. This perspective review gives particular attention to the potential diagnostic testing of the virus in semen and seminal fluids due to its high levels of angiotensin converting enzyme 2 (ACE2) precursor. RECENT FINDINGS: As many infectious viruses are stable in semen and have transmitted the respective diseases, the presence of SARS-CoV-2 should be tested in semen to assess their stabilities and half-life. As in case of Ebola virus, it was present in semen for longer period in a carrier man without any symptom. Additional hypothesis is that since ACE2 could serve as a mediator for the endocytosis of the previously SARS coronavirus, SARS-CoV-2 may enter the cells through similar mechanism. From the protein expression atlas, high levels of ACE2 precursor were found in intestines and testis. Hence, the testis and seminal fluids could be the host cell and/or reservoir. The results could be used as a suggestive guideline for the sexual activities after the discharge or declaration of disease free.