Neutralizing Antibody Response of the Wild-Type/Omicron BA.1 Bivalent Vaccine as the Second Booster Dose against Omicron BA.2 and BA.5.

In addition to the original monovalent vaccines available for SARS-CoV-2, bivalent vaccines covering wild-type (WT) and Omicron BA.1 are also available. However, there is a lack of real-world data on the immunogenicity of bivalent vaccines as second boosters against the dominant Omicron sublineages, including BA.2 and BA.5. Healthcare workers (n = 565) who received the first booster vaccination were followed for 2 weeks after the second booster dose of the monovalent mRNA-1273 (WT group, n = 168) and bivalent BNT162b2 (WT+BA.1 group, n = 23) vaccines. Participants with previous SARS-CoV-2 infections were excluded from the study. The anti-receptor binding domain (RBD) antibody levels after the second booster dose in the WT and WT+BA.1 group were similar (median [interquartile range], 26,262.0 [16,951.0 to 38,137.0] U/mL versus 24,840.0 [14,828.0 to 41,460.0] U/mL, respectively). Although the neutralization activities of the pooled sera were lower against BA.5 than against other variants in both groups, the activities against BA.2 and BA.5 in the WT+BA.1 group were higher than those of the WT group in both pseudotyped and live virus assays. Vaccine-related symptoms, including systemic and local symptoms, were strongly correlated with anti-RBD antibody levels and neutralizing titers. In conclusion, the second booster dose of the bivalent (WT/Omicron BA.1) vaccine induced higher neutralizing activity against BA.2 and BA.5 than that of the original monovalent vaccine. IMPORTANCE Although Omicron BA.1-containing bivalent vaccines have been authorized, real-world data validating their safety and antibody responses remain scarce. We conducted a prospective longitudinal study to assess the safety, immunogenicity, and reactogenicity of the second booster dose with the Omicron BA.1 bivalent vaccine in health care workers. Compared with the original monovalent vaccine, the bivalent (WT+BA.1) vaccine elicited higher levels of neutralizing antibodies against the Omicron BA.2 and BA.5 subvariants. The frequency of adverse events after the second booster dose was similar to that of the monovalent vaccine. BA.5-neutralizing antibodies induced by the bivalent Omicron BA.1-containing vaccine were expected to decline. A prospective longitudinal study should be performed to determine the persistence of the humoral immunity.

Clinical Features of Hypoxemia Due to Infection Under Home-Based Medication During the COVID-19 Pandemic Period.

BACKGROUND: Despite the growing demand for home-based medication during the COVID-19 pandemic period, there remains scarce evidence of hypoxemic infection in home-care settings. In this study, we investigated the clinical features of hypoxemic respiratory failure due to infection during the period under home-based medication (defined as 'home-care-acquired infection'). METHODS: This retrospective observational study enrolled patients with home-care-acquired infection, other than COVID-19, in two home-care clinics in Sapporo, Japan, between April 2020 and May 2021 (the early phase of the COVID-19 pandemic). The participants were divided into two groups according to whether they required additional home oxygen therapy, and were compared to assess the predictors of hypoxemic respiratory failure. Furthermore, the clinical features were compared with those in patients aged >60 years with COVID-19 who were admitted to Toyama University Hospital during the same period. RESULTS: A total of 107 patients with home-care-acquired infections were included in the study (median age, 82 years). Twenty-two patients required home oxygen therapy, and 85 did not. Thirty-day mortality rates were 32% and 8%. Among the patients in the hypoxemia group, none had desired a care-setting transition, following the advanced care planning. Multivariable logistic regression analysis showed that initial antibiotic treatment failure and malignant disease were independently associated with hypoxemic respiratory failure (odds ratio, 7.28 and 7.10; p=0.023 and p<0.005, respectively). In comparison with hypoxemia in the COVID-19 cohort, the lower incidence of febrile co-habitants and earlier onset of hypoxemia were significant in those due to home-care-acquired infection. CONCLUSION: This study demonstrated that hypoxemia due to home-care-acquired infection was characterized by distinct features, possibly different from those due to COVID-19 in the early pandemic period.

Effectiveness of the third dose of BNT162b2 vaccine on neutralizing Omicron variant in the Japanese population.

INTRODUCTION: The vaccine against SARS-CoV-2 provides humoral immunity to fight COVID-19; however, the acquired immunity gradually declines. Booster vaccination restores reduced humoral immunity; however, its effect on newly emerging variants, such as the Omicron variant, is a concern. As the waves of COVID-19 cases and vaccine programs differ between countries, it is necessary to know the domestic effect of the booster. METHODS: Serum samples were obtained from healthcare workers (20-69 years old) in the Pfizer BNT162b2 vaccine program at the Toyama University Hospital 6 months after the second dose (6mA2D, n = 648) and 2 weeks after the third dose (2wA3D, n = 565). The anti-SARS-CoV-2 antibody level was measured, and neutralization against the wild-type and variants (Delta and Omicron) was evaluated using pseudotyped viruses. Data on booster-related events were collected using questionnaires. RESULTS: The median anti-SARS-CoV-2 antibody was >30.9-fold elevated after the booster (6mA2D, 710.0 U/mL [interquartile range (IQR): 443.0-1068.0 U/mL]; 2wA3D, 21927 U/mL [IQR: 15321.0->25000.0 U/mL]). Median neutralizing activity using 100-fold sera against wild-type-, Delta-, and Omicron-derived variants was elevated from 84.6%, 36.2%, and 31.2% at 6mA2D to >99.9%, 99.1%, and 94.6% at 2wA3D, respectively. The anti-SARS-CoV-2 antibody levels were significantly elevated in individuals with fever ≥37.5 °C, general fatigue, and myalgia, local swelling, and local hardness. CONCLUSION: The booster effect, especially against the Omicron variant, was observed in the Japanese population. These findings contribute to the precise understanding of the efficacy and side effects of the booster and the promotion of vaccine campaigns.

Effect of Casirivimab/Imdevimab Treatment on Serum Type I Interferon Levels in SARS-CoV-2 Infection.

The effects of casirivimab and imdevimab (C/I) on the innate immune response against SARS-CoV-2 infection remain unclear. We evaluated the effect of C/I on type I interferon (IFN-I) and cytokines in patients with SARS-CoV-2 infection. This prospective observational study recruited consecutive patients hospitalized with SARS-CoV-2 infection. Blood levels of IFN-I and cytokines before and after C/I administration were assessed using enzyme-linked immunoassay. The study enrolled 29 patients in the C/I group. In addition, 11 patients who received remdesivir and dexamethasone (R/D group) during the early phase (≤5 days after the onset of symptoms) were included as a comparator group. After treatment, IFN-α and IFN-ß levels decreased significantly in both the C/I group and R/D group, whilst the post-treatment neutrophil-to-lymphoid ratio increased in the early C/I group but not the R/D group. In the C/I group, temporal temperature elevation and hypoxemia were observed after treatment in 58.6% and 41.4% of the cohort, respectively. However, most patients recovered by 5 days after treatment. This study could demonstrate the high therapeutic effect of C/I with an antibody-dependent enhancement-like response and decreased IFN-I production, which was likely due to the immediate induction of an antibody-dependent immune response against SARS-CoV-2.

Circulating Type I Interferon Levels in the Early Phase of COVID-19 Are Associated With the Development of Respiratory Failure.

Background: The role of type I interferons (IFNs) in the early phase of COVID-19 remains unclear. Objectives: To evaluate the relationship between IFN-I levels in patients with COVID-19 and clinical presentation, SARS-CoV-2 viral load, and other major pro-inflammatory cytokines. Methods: This prospective observational study recruited patients hospitalized with COVID-19. The levels of interferon-alpha (IFN-α), interferon-beta (IFN-ß), interleukin-6 (IL-6), and C-X-C motif chemokine ligand (CXCL10) within 5 days after symptom onset were measured using an ELISA, in serum from blood collected within 5 days after the onset of symptoms. The SARS-CoV-2 viral load was determined via qPCR using nasal-swab specimens and serum. Results: The study enrolled 50 patients with COVID-19. IFN-α levels were significantly higher in patients who presented with pneumonia or developed hypoxemic respiratory failure (p < 0.001). Furthermore, IFN-α levels were associated with viral load in nasal-swab specimens and RNAemia (p < 0.05). In contrast, there was no significant association between IFN-ß levels and the presence of pneumonia or RNAemia, despite showing a stronger association with nasal-swab viral load (p < 0.001). Correlation analysis showed that the serum levels of IFN-α significantly correlated with those of IFN-ß, IL-6, and CXCL10, while the levels of IFN-ß did not correlate with those of IL-6 or CXCL10. Conclusions: Serum IFN-I levels in the early phase of SARS-CoV-2 infection were higher in patients who developed hypoxemic respiratory failure. The association between IFN-α, IL-6, and CXCL10 may reflect the systemic immune response against SARS-CoV-2 invasion into pulmonary circulation, which might be an early predictor of respiratory failure due to COVID-19.

Effectiveness of the third dose of BNT162b2 vaccine on neutralizing Omicron variant in the Japanese population☆

Introduction The vaccine against SARS-CoV-2 provides humoral immunity to fight COVID-19;however, the acquired immunity gradually declines. Booster vaccination restores reduced humoral immunity;however, its effect on newly emerging variants, such as the Omicron variant, is a concern. As the waves of COVID-19 cases and vaccine programs differ between countries, it is necessary to know the domestic effect of the booster. Methods Serum samples were obtained from healthcare workers (20–69 years old) in the Pfizer BNT162b2 vaccine program at the Toyama University Hospital 6 months after the second dose (6mA2D, n = 648) and 2 weeks after the third dose (2wA3D, n = 565). The anti-SARS-CoV-2 antibody level was measured, and neutralization against the wild-type and variants (Delta and Omicron) was evaluated using pseudotyped viruses. Data on booster-related events were collected using questionnaires. Results The median anti-SARS-CoV-2 antibody was >30.9-fold elevated after the booster (6mA2D, 710.0 U/mL [interquartile range (IQR): 443.0–1068.0 U/mL];2wA3D, 21927 U/mL [IQR: 15321.0–>25000.0 U/mL]). Median neutralizing activity using 100-fold sera against wild-type-, Delta-, and Omicron-derived variants was elevated from 84.6%, 36.2%, and 31.2% at 6mA2D to >99.9%, 99.1%, and 94.6% at 2wA3D, respectively. The anti-SARS-CoV-2 antibody levels were significantly elevated in individuals with fever ≥37.5 °C, general fatigue, and myalgia, local swelling, and local hardness. Conclusion The booster effect, especially against the Omicron variant, was observed in the Japanese population. These findings contribute to the precise understanding of the efficacy and side effects of the booster and the promotion of vaccine campaigns.

Age-Dependent Reduction in Neutralization against Alpha and Beta Variants of BNT162b2 SARS-CoV-2 Vaccine-Induced Immunity.

Vaccines against severe acute respiratory syndrome coronavirus-2 have been introduced. To investigate the relationship between vaccine-induced humoral immunity and patient age, we measured antibody levels and neutralization in vaccinated sera. Sera from 13 to 17 days after the second dose of the BNT162b2 vaccine were collected from health care workers at the University of Toyama (n = 740). Antibody levels were measured by the anti-receptor binding domain antibody test (anti-RBD test), and neutralization against wild-type (WT), α- and ß-variant pseudotyped viruses were assayed using a high-throughput chemiluminescent reduction neutralizing test (htCRNT; positivity cutoff, 50% neutralization at serum dilution 1:100). Basic clinical characteristics were obtained from questionnaires. Antibodies were confirmed in all participants in both the anti-RBD test (median, 2,112 U/ml; interquartile range [IQR], 1,275 to 3,390 U/ml) and the htCRNT against WT (median % inhibition, >99.9; IQR, >99.9 to >99.9). For randomly selected sera (n = 61), 100.0% had positive htCRNT values against the α- and ß-derived variants. Among those who answered the questionnaire (n = 237), the values of the anti-RBD test were negatively correlated with age in females (P < 0.01). An age-dependent decline in neutralization was observed against the variants but not against the wild-type virus (wild type, P = 0.09; α, P < 0.01; ß, P < 0.01). The neutralizing activity induced by BNT162b2 was obtained not only against the wild-type virus, but also against the variants; however, there was an age-dependent decrease in the latter. Age-related heterogeneity of vaccine-acquired immunity is a concern in preventive strategies in the era dominated by variants. IMPORTANCE Since mRNA vaccines utilize wild-type SARS-CoV-2 spike protein as an antigen, there are potential concerns about acquiring immunity to variants of this virus. The neutralizing activity in BNT162b2-vaccinated individuals was higher against the wild-type virus than against its variants; this effect was more apparent in older age groups. This finding suggests that one of the weaknesses of the mRNA vaccine is the high risk of variant infection in the elderly population. Because the elderly are at a higher risk of SARS-CoV-2 infection, the age-dependent decline of neutralization against viral variants should be considered while planning vaccination programs that include boosters.

Correlation of the Commercial Anti-SARS-CoV-2 Receptor Binding Domain Antibody Test with the Chemiluminescent Reduction Neutralizing Test and Possible Detection of Antibodies to Emerging Variants.

Serological tests are beneficial for recognizing the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). To identify protective immunity, optimization of the chemiluminescent reduction neutralizing test (CRNT) is critical. Whether commercial antibody tests have comparable accuracy is unknown. Serum samples were obtained from COVID-19 patients (n = 74), SARS-CoV-2 PCR-negative (n = 179), and suspected healthy individuals (n = 229) before SARS-CoV-2 variants had been detected locally. The convalescent phase was defined as the period after day 10 from disease onset or the episode of close contact. The CRNT using pseudotyped viruses displaying the wild-type (WT) spike protein and a commercial anti-receptor-binding domain (RBD) antibody test were assayed. Serology for the B.1.1.7 and B.1.351 variants was also assayed. Both tests concurred for symptomatic COVID-19 patients in the convalescent phase. They clearly differentiated between patients and suspected healthy individuals (sensitivity: 95.8% and 100%, respectively; specificity: 99.1% and 100%, respectively). Anti-RBD antibody test results correlated with neutralizing titers (r = 0.31, 95% confidence interval [CI] 0.22-0.38). Compared with the WT, lower CRNT values were observed for the variants. Of the samples with ≥100 U/mL by the anti-RBD antibody test, 77.8% and 88.9% showed ≥50% neutralization against the B.1.1.7 and the B.1.351 variants, respectively. Exceeding 100 U/mL in the anti-RBD antibody test was associated with neutralization of variants (P < 0.01). The CRNT and commercial anti-RBD antibody test effectively classified convalescent COVID-19 patients. Strong positive results with the anti-RBD antibody test can reflect neutralizing activity against emerging variants. IMPORTANCE This study provides a diagnostic evidence of test validity, which can lead to vaccine efficacy and proof of recovery after COVID-19. It is not easy to know neutralization against SARS-CoV-2 in the clinical laboratory because of technical and biohazard issues. The correlation of the quantitative anti-receptor-binding domain antibody test, which is widely available, with neutralizing test indicates that we can know indirectly the state of acquisition of functional immunity against wild and variant-type viruses in the clinical laboratory.