Preinfection Neutralizing Antibodies, Omicron BA.5 Breakthrough Infection, and Long COVID: A Propensity Score-Matched Analysis.

BACKGROUND: Data are limited on the role of preinfection humoral immunity protection against Omicron BA.5 infection and long coronavirus disease (COVID) development. METHODS: We conducted nested case-control analysis among tertiary hospital staff in Tokyo who donated blood samples in June 2022 (1 month before Omicron BA.5 wave), approximately 6 months after receiving a third dose of COVID-19 mRNA vaccine. We measured live virus-neutralizing antibody titers against wild type and Omicron BA.5, and anti-receptor-binding domain (RBD) antibody titers at preinfection, and compared them between cases and propensity-matched controls. Among the breakthrough cases, we examined association between preinfection antibody titers and incidence of long COVID. RESULTS: Preinfection anti-RBD and neutralizing antibody titers were lower in cases than controls. Neutralizing titers against wild type and Omicron BA.5 were 64% (95% confidence interval [CI], 42%-77%) and 72% (95% CI, 53%-83%) lower, respectively, in cases than controls. Individuals with previous Omicron BA.1/BA.2 infections were more frequent among controls than cases (10.3% vs 0.8%), and their Omicron BA.5 neutralizing titers were 12.8-fold higher than infection-naive individuals. Among cases, preinfection antibody titers were not associated with incidence of long COVID. CONCLUSIONS: Preinfection immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may play a role in protecting against the Omicron BA.5 infection but not preventing long COVID.

Dyslipidemia and SARS-CoV-2 spike antibody titres after the second and third doses of the BNT162b2 vaccine among healthcare workers in Japan.

OBJECTIVE: This study aimed to examine the sex-associated differences in the relationship between dyslipidemia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike immunoglobulin (Ig)G antibodies among BNT162b2 vaccine recipients. METHODS: Participants were staff members (aged 21-75 years) of a medical and research institution who underwent an anti-SARS-CoV-2 spike IgG antibody test after the second (n = 1872) and third doses (n = 1075) of the BNT162b2 vaccine. Dyslipidemia was defined as triglyceride level ≥150 mg/dl, high-density lipoprotein-cholesterol level <40 mg/dl, low-density lipoprotein-cholesterol level ≥140 mg/dl, or lipid-lowering medication use. Multivariable linear regression was used to calculate the ratio of means for SARS-CoV-2 spike IgG titre according to dyslipidemia status. RESULTS: The prevalence of dyslipidemia was 38.0% in men and 19.6% in women. The relationship between dyslipidemia and SARS-CoV-2 spike IgG titres after the second dose differed markedly by sex (P for interaction <0.001). In men, dyslipidemia was associated with significantly lower IgG titres: the ratio of means (95% confidence interval) was 0.82 (0.72-0.93). However, this association disappeared after the third dose (0.96 [0.78-1.18]). Of the dyslipidemia components, hypertriglyceridemia was inversely associated with SARS-CoV-2 spike IgG antibody titre after both the second and third doses (ratio of means: 0.82 [0.70-0.95] and 0.73 [0.56-0.95], respectively). In women, IgG titres did not differ according to dyslipidemia or hypertriglyceridemia status after either dose. CONCLUSIONS: These results suggest a detrimental role of hypertriglyceridemia in the humoral immune response to the BNT162b2 vaccine for COVID-19 in men but not in women.

Cumulative and undiagnosed SARS-CoV-2 infection among the staff of a medical research centre in Tokyo after the emergence of variants.

To describe the trend of cumulative incidence of coronavirus disease 19 (COVID-19) and undiagnosed cases over the pandemic through the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants among healthcare workers in Tokyo, we analysed data of repeated serological surveys and in-house COVID-19 registry among the staff of National Center for Global Health and Medicine. Participants were asked to donate venous blood and complete a survey questionnaire about COVID-19 diagnosis and vaccine. Positive serology was defined as being positive on Roche or Abbott assay against SARS-CoV-2 nucleocapsid protein, and cumulative infection was defined as either being seropositive or having a history of COVID-19. Cumulative infection has increased from 2.0% in June 2021 (pre-Delta) to 5.3% in December 2021 (post-Delta). After the emergence of the Omicron, it has increased substantially during 2022 (16.9% in June and 39.0% in December). As of December 2022, 30% of those who were infected in the past were not aware of their infection. Results indicate that SARS-CoV-2 infection has rapidly expanded during the Omicron-variant epidemic among healthcare workers in Tokyo and that a sizable number of infections were undiagnosed.

Omicron BA.1 neutralizing antibody response following Delta breakthrough infection compared with booster vaccination of BNT162b2.

BACKGROUND: Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus third vaccine dose on neutralizing antibodies (NAb) against Omicron. METHODS: Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during follow-up. One control matched to each case was selected from boosted and unboosted individuals. We compared live-virus NAb against Wild-type, Delta, and Omicron BA.1 across groups. RESULTS: Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. CONCLUSIONS: Symptomatic Delta breakthrough infection increased NAb against Wild-type, Delta, and Omicron BA.1, similar to the third vaccine. Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.

Clostridium ramosum bacteremia: A case series at a general acute care hospital.

Clostridium ramosum infections have been rarely reported, probably due to underestimating in clinical practice. Seven patients with bacteremia from gastrointestinal sources and skin and soft tissue were recognized between 2009 and 2020. Most of them were older and in compromised status, and they had risk factors including cancer, diabetes, liver cirrhosis, gangrene, and pressure ulcers. The source of infections was considered bacterial translocation from the gastrointestine and the skin and soft tissue infections. All patients were treated with antimicrobials, and two received surgical interventions. Four patients died secondary to sepsis due to C. ramosum. The bacteremia of C. ramosum should be appropriately evaluated and treated, especially in compromised hosts.

Vitamin D deficiency during the coronavirus disease 2019 (COVID-19) pandemic among healthcare workers.

BACKGROUND & AIMS: Vitamin D deficiency is a common nutritional problem worldwide that may have worsened during the coronavirus disease 2019 (COVID-19) pandemic. The present study sought to examine the prevalence and correlates of vitamin D deficiency among healthcare workers three years after the start of the COVID-19 pandemic. METHODS: Participants comprised 2543 staff members from a medical research institute, who completed a questionnaire and donated blood samples in June 2023. 25-hydroxyvitamin D (25[OH]D) levels were measured using an electrochemiluminescence immunoassay. Logistic regression was used to calculate the odds ratio and its 95% confidence interval while adjusting for covariates. RESULTS: The proportions of participants with vitamin D insufficiency (25[OH]D 20-29 ng/mL) and deficiency (25[OH]D < 20 ng/mL) were 44.9% and 45.9%, respectively. In a multivariable-adjusted model, factors associated with a higher prevalence of vitamin D deficiency included younger age, female sex, fewer hours of daytime outdoor physical activity during leisure time (without regular use of sunscreen), lower intake of fatty fish, no use of vitamin D supplements, smoking, and no alcohol consumption. Occupational factors, including shift work, were not independently associated with vitamin D deficiency. CONCLUSIONS: Our results suggest that vitamin D insufficiency and deficiency are highly prevalent among healthcare workers. Health education regarding lifestyle modifications for this occupational group are warranted to improve their vitamin D status in the COVID-19 era.

High diagnostic accuracy of quantitative SARS-CoV-2 spike-binding-IgG assay and correlation with in vitro viral neutralizing activity.

Background: Antibody testing can easily evaluate the clinical status of patients, aid in the diagnosis of multisystem inflammatory syndrome, and monitor the immunity level in the population. However, the applicability of serological tests in detecting antibodies against the severe acute respiratory syndrome 2 (SARS-CoV-2) spike-binding protein remains limited. This study aimed to quantify both serum-derived neutralizing immunoglobulin-G (IgG) antibody activity and the amount of anti-SARS-CoV-2 Spike-IgG (S-IgG) in convalescent sera/plasmas and evaluate the direct correlation between the in vitro IgG-EC50 values and S-IgG values. Methods: We evaluated the neutralizing activity of purified IgG (IgG-EC50), quantified S-IgG in the serum/plasma of consecutive COVID-19 convalescent individuals using a cell-based virus-neutralizing assay, and determined the correlation between IgG-EC50 and S-IgG. In addition, we evaluated rational cut-off values using the receiver operating characteristic (ROC) curve and calculated the sensitivity and specificity of the quantitative S-IgG assay for moderate and high IgG-EC50. Results: A high correlation was observed between S-IgG and IgG-EC50 with a Spearman's ρ value of -0.748 (95 % confidence interval [CI]: -0.804-0.678). Using an IgG-EC50 of 50 µg/mL and 20 µg/mL as the cut-off values for moderate and high in vitro neutralizing activity, respectively, the Youden's index values of 287.5 binding antibody units (BAU)/mL and 454.1 BAU/mL determined from the ROC curve showed the highest diagnostic accuracy, with Kappa values of 0.884 (95 % CI: 0.823-0.946) and 0.920 (95 % CI: 0.681-0.979), respectively. Conclusions: Quantitative S-IgG tests are a useful and convenient tool for estimating in vitro virus-neutralizing activity, with a high correlation with IgG-EC50 when the rational cut-off value is carefully determined.

Durability and determinants of anti-SARS-CoV-2 spike antibodies following the second and third doses of mRNA COVID-19 vaccine.

OBJECTIVES: To examine the differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination. METHODS: Throughout the pandemic, we evaluated the anti-spike IgG antibody titers of 2- and 3-dose mRNA vaccine recipients over time among the staff of a medical and research center in Tokyo. Linear mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last immune-conferred event (vaccination or infection) and compare antibody waning rates across prior infection and vaccination status, and across background factors in infection-naïve participants. RESULTS: A total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were analyzed. Antibody waning rate (percentage per 30 days [95% CI]) was slower after 3 doses (25% [23-26]) than 2 doses (36% [35-37]). Participants with hybrid immunity (vaccination and infection) had further slower waning rates: 2-dose plus infection (16% [9-22]); 3-dose plus infection (21% [17-25]). Older age, male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were associated with lower antibody titers, whereas these associations disappeared after 3 doses, except for sex (lower in female participants) and immunosuppressant use. Antibody waned slightly faster in older participants, females, and alcohol drinkers after 2 doses, whereas it did not differ after 3 doses across except sex. DISCUSSION: The 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection modestly enhanced its durability. The antibody levels at a given time point and waning speed after 2 doses differed across background factors; however, these differences mostly diminished after 3 doses.

Neutralizing antibodies after three doses of the BNT162b2 vaccine, breakthrough infection, and symptoms during the Omicron-predominant wave.

OBJECTIVES: To investigate the role of immunogenicity after the third vaccine dose against Omicron infection and COVID-19-compatible symptoms of infection. METHODS: First, we examined vaccine effectiveness (VE) of the third dose against the second dose during the Omicron wave among the staff at a tertiary hospital in Tokyo. In a case-control study of third vaccine recipients, we compared the preinfection live-virus neutralizing antibodies (NAb) against Omicron between breakthrough cases and their controls who had close contact with patients with COVID-19. Among these cases, we examined the association between NAb levels and the number of COVID-19-compatible symptoms. RESULTS: Among the 1456 participants for VE analysis, 60 breakthrough infections occurred during the Omicron wave. The third dose VE for infection was 54.6%. Among the third dose recipients, NAb levels against Omicron did not differ between the cases (n = 22) and controls (n = 21). Among the cases, those who experienced COVID-19-compatible symptoms had lower NAb levels against Omicron than those who did not. CONCLUSION: The third vaccine dose was effective in decreasing the risk of SARS-CoV-2 infection during Omicron wave compared with the second dose. Among third dose recipients, higher preinfection NAb levels may not be associated with a lower risk of Omicron infection. Contrarily, they may be associated with fewer symptoms of infection.

Trends of participants in convalescent plasma donation for COVID-19 in Japan as the pandemic evolved.

Background: We aimed to investigate chronological changes in the characteristics of participants in a coronavirus disease 2019 convalescent plasma donation study that may benefit optimal collection methods in the future. Methods: Data from a convalescent plasma donation study from April 30, 2020 to November 5, 2021 were collected and analyzed. After August 23, 2021, an interim analysis of factors linked to higher antibody titers led us to restrict our participant recruitment criteria to participants who were within 4 months of disease onset and to patients who were otherwise most likely to have sufficiently high antibody titers. Overall, 1299 samples from 1179 patients were analyzed. Results: Over the duration of the study, 35.9% of the samples were deemed eligible for convalescent plasma collection. The overall eligibility rate initially declined, dipping to <20% after one year. During this period, the proportion of enrolled samples from patients who had severe illness also declined, and the proportion of samples from participants who were >120 days post disease onset increased. After the addition of days from onset and vaccination status to our participant recruitment criteria, the eligibility rate improved significantly. Conclusions: As outbreaks of emerging infectious disease occur, it is desirable to construct and implement a scheme for convalescent plasma donation promptly and to monitor the eligibility rate over time. If it declines, promptly analyze and resolve the associated factors. Additionally, vaccine development and infection prevalence are likely to influence the effective recruitment of participants with high antibody titers.

Association of Impaired Fasting Glucose and Diabetes with SARS-CoV-2 Spike Antibody Titers after the BNT162b2 Vaccine among Health Care Workers in a Tertiary Hospital in Japan.

Background: Hyperglycemia can alter the activation of innate and acquired immunity, but epidemiological evidence linking hyperglycemia to post-vaccination immunogenicity is limited. Objective: To examine the association between SARS-CoV-2 spike antibody titers after the COVID-19 vaccine and impaired fasting glucose (IFG) and diabetes. Methods: Participants were 953 health care workers aged 21−75 years who were tested for SARS-CoV-2 spike IgG antibodies and underwent a health checkup two months after their second dose of the BNT162b2 vaccine. IFG was defined as a fasting plasma glucose (FPG) level of 100−125 mg/dL, and diabetes was defined as an FPG level ≥ 126 mg/dL or being under medical care for diabetes. Multivariable linear regression was used to calculate the ratio of the mean. Result: Spike IgG antibody titers were lower in the presence of hyperglycemia; the ratios of the means (95% CI) were 1.00, 0.79 (0.60−1.04), and 0.60 (0.42−0.87) for individuals with normoglycemia, IFG, and diabetes, respectively (p trend < 0.001). Restricted cubic spline regression analysis showed that IgG spike antibody titers decreased linearly with increasing concentrations of FPG. Conclusion: Diabetes and, to a lesser extent, IFG may be associated with poor humoral immune response after BNT162b2 vaccination.

Sex-associated differences between BMI and SARS-CoV-2 antibody titers following the BNT162b2 vaccine.

OBJECTIVE: This study investigated the sex-associated difference in the impact of obesity on antibody response to a COVID-19 vaccine. METHODS: This study included 2,435 health care workers who received two doses of the BioNTech, Pfizer (BNT162b2) vaccine and participated in a serological survey, during which they were tested for anti-SARS-CoV-2 spike immunoglobin G (IgG) antibodies and asked for information on height, weight, and vaccination history via a questionnaire. Multivariable linear regression analysis was used to estimate the geometric mean titers (GMT) of antibodies for each sex and BMI category. RESULTS: The relationship between BMI and anti-SARS-CoV-2 spike IgG titers markedly differed by sex (p value for interaction = 0.04). Spike IgG antibody titers tended to decrease with increasing BMI in men (p value for trend = 0.03); GMT (95% CI) were 6,093 (4,874-7,618) and 4,655 (3,795-5,708) for BMI < 18.5 and ≥30 kg/m2 , respectively. In contrast, spike IgG antibody titers did not significantly differ across BMI categories in women (p value for for trend = 0.62); GMT (95% CI) were 6,171 (5,714-6,665) and 5,506 (4,404-6,883) for BMI <18.5 and ≥30, respectively. CONCLUSIONS: Higher BMI was associated with lower titers of SARS-CoV-2 spike antibodies in men, but not in women, suggesting the need for careful monitoring of vaccine efficacy in men with obesity, who are at high risk of severe COVID-19 outcomes.

Association between γ-Glutamyl Transpeptidase and SARS-CoV-2 Spike Antibody Titers among BNT162b2 Vaccine Recipients.

BACKGROUND: Increased γ-glutamyl transpeptidase (GGT) levels can deplete plasma glutathione, which in turn impairs immune regulation; however, evidence on GGT levels and post-vaccine immunogenicity is lacking. OBJECTIVE: To examine the association between GGT and SARS-CoV-2 spike IgG antibodies. METHODS: Participants were 1479 medical staff (aged 21 to 75 years) who received a SARS-CoV-2 antibody test after their second vaccine and whose GGT levels were measured before the vaccine rollout. Elevated and highly elevated GGT levels were defined as 51-80 and ≥81 U/L, respectively. Multivariable linear regression was used to calculate the means of SARS-CoV-2 spike IgG. RESULTS: In a basic model, both elevated and highly elevated GGT levels were associated with significantly lower antibody titers. The ratio of mean (95% CI) was 0.83 (0.72-0.97) and 0.69 (0.57-0.84) for elevated and highly elevated GGT levels, respectively. However, these associations were largely attenuated after additional adjustment for potential confounders. An inverse association between GGT levels and antibody titers was found in women [0.70 (0.51-0.97)], normal-weight adults [0.71 (0.51-0.98)], and non-drinkers [0.73 (0.46-1.14)] but not in men, overweight adults, and alcohol drinkers. CONCLUSIONS: Circulating GGT concentrations were associated with the humoral immune response after COVID-19 vaccination, but this relationship could be ascribed to confounders such as sex, BMI, and alcohol drinking rather than GGT per se.

Inpatient antibiotic prescribing patterns using the World Health Organization (WHO) Access Watch and Reserve (AWaRe) classification in Okinawa, Japan: A point-prevalence survey.

Using point-prevalence methodology and the World Health Organization (WHO) Access, Watch, and Reserve Classification, we measured antibiotic use in 5 hospitals in Okinawa, Japan, on October 1, 2020. Overall, 29% of patients were prescribed an antibiotic on the survey date and the 3 most used antibiotics in the "Watch" category were cefazolin, ampicillin-sulbactam, and ampicillin.

Consistency of the results of rapid serological tests for SARS-CoV-2 among healthcare workers in a large national hospital in Tokyo, Japan.

We assessed the consistency of seropositive results of three rapid immunoassays (Kits A, B, and C) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to highly accurate serological tests (Abbott and Roche) among healthcare workers in a hospital in Tokyo. The seroprevalence of SARS-CoV-2 immunoglobulin G was 0.41%, 2.36%, and 0.08% using Kits A, B, and C, respectively. Of the 51 samples that were seropositive on any rapid test, all were seronegative on both the Abbott and the Roche assays. Given that the seroprevalence of SARS-CoV-2 immunoglobulin G varied widely according to the choice of rapid test and the rapid test results were inconsistent with the results of highly accurate tests, the diagnostic accuracy of rapid serological tests for SARS-CoV-2 should be assessed before introducing these tests for point-of-care testing or surveillance.

Community-acquired liver abscess caused by capsular genotype K2-ST375 hypervirulent Klebsiella pneumoniae isolates.

Hypervirulent Klebsiella pneumoniae has been associated with community-acquired liver abscesses in relatively healthy subjects since the 1990s, occasionally accompanied by disseminated disease. While isolates of capsular genotype K1 belonging to sequence type (ST) 23 have been the most prominent causative pathogen of this syndrome, other virulent clones have been implicated sporadically in recent years. A 68-year-old woman with diabetes in Okinawa, Japan suffered from a K. pneumoniae liver abscess, which recurred after a prolonged antibacterial treatment. The clinical course was further complicated with multiple sites of dissemination. Another 45-year-old woman living in Okinawa without underlying conditions was also diagnosed with a community-acquired K. pneumoniae liver abscess, which was cured with antibacterial treatment alone. Both of the causative isolates carried rmpA and aerobactin genes, and were confirmed as capsular genotype K2 and ST375. K. pneumoniae K2-ST375 is a hypervirulent clone of epidemiological significance causing severe community-acquired infections in relatively healthy subjects. More information about clinical characteristics and molecular epidemiology of hypervirulent K. pneumoniae clones other than K1-ST23 should be accumulated.