An outbreak of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infections among hospital personnel with high mRNA vaccine uptake.

Real-world studies have demonstrated impressive effectiveness of the BNT162b2 COVID-19 vaccine in preventing symptomatic and asymptomatic SARS-CoV-2 infection. We describe an outbreak of SARS-CoV-2 infections in a hospital with high vaccine uptake. We found a low secondary attack rate (7%), suggesting low infectivity of vaccinated persons with vaccine breakthrough SARS-CoV-2 infections.

Invasive Fungal Diseases in Hospitalized Patients with COVID-19 in Israel: A Multicenter Cohort Study.

Highly variable estimates of COVID-19-associated fungal diseases (IFDs) have been reported. We aimed to determine the incidence of clinically important fungal diseases in hospitalized COVID-19 patients during the first year of the pandemic. We performed a multicenter survey of IFDs among patients hospitalized with COVID-19 in 13 hospitals in Israel between February 2020 and May 2021. COVID-19-associated pulmonary mold disease (PMD) and invasive candidiasis (IC) were defined using ECMM/ISHAM and EORTC/MSG criteria, respectively. Overall rates of IC and PMD among patients with critical COVID-19 were 10.86 and 10.20 per 1000 admissions, respectively, with significant variability among medical centers. PMD rates were significantly lower in centers where galactomannan was a send-out test versus centers with on-site testing (p = 0.035). The 30-day mortality rate was 67.5% for IC and 57.5% for PMD. Treatment with an echinocandin for IC or an extended-spectrum azole for PMD was associated with significantly lower mortality rates (adjusted hazard ratio [95% confidence interval], 0.26 [0.07-0.91] and 0.23 [0.093-0.57], respectively). In this multicenter national survey, variable rates of PMD were associated with on-site galactomannan testing, suggesting under-detection in sites lacking this capacity. COVID-19-related IFDs were associated with high mortality rates, which were reduced with appropriate antifungal therapy.

Drivers of adaptive evolution during chronic SARS-CoV-2 infections.

In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient's body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

Immunogenicity of a Third Dose of the BNT162b2 mRNA Covid-19 Vaccine in Patients with Impaired B Cell Reconstitution After Cellular Therapy-A Single Center Prospective Cohort Study.

Patients with delayed B-cell reconstitution/B-cell aplasia after cellular therapy show decreased immunogenicity to the BNT162b2 mRNA COVID-19 vaccine. We prospectively evaluated both humoral and cellular immune response to a third vaccine dose in patients after allogeneic HCT (n = 10) or CD19-based chimeric antigen receptor T cells (CAR-T) therapy (n = 6) with low absolute B cell numbers and who failed to mount a humeral response after 2 vaccine doses. Humoral response was documented in 40% and 17% after allogeneic HCT and CAR-T therapy, respectively. None of the patients with complete B-cell aplasia developed anti-vaccine antibodies. Cellular response was documented in all patients after allogeneic HCT and in 83% of the patients after CAR-T. T-cell subclasses levels were not predictive for response, while a longer duration from infusion of cells was associated with a better cellular response. We conclude that cellular response develops with repeated vaccine doses even in patients with B-cell aplasia or delayed B-cell reconstitution, and these patients should therefore be vaccinated. These results should be considered in future studies analyzing immunogenicity in this population. Larger and longer follow-up studies are required to confirm whether cellular immunogenicity translates into vaccine efficacy.

The effect of a third-dose BNT162b2 vaccine on anti-SARS-CoV-2 antibody levels in immunosuppressed patients.

OBJECTIVES: The recent surge in coronavirus disease 2019 cases led to the consideration of a booster vaccine in previously vaccinated immunosuppressed individuals. However, the immunogenic effect of a third-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in immunosuppressed patients is still unknown. METHODS: This was an observational cohort study of 279 previously vaccinated immunosuppressed patients followed at a single tertiary hospital in Israel. Patients were administered a third dose of the Pfizer-BioNTech mRNA vaccine (BNT162b2) between July 14 and July 21, 2021. Levels of IgG antibodies against the spike receptor-binding domain of SARS-CoV-2 were measured 3 to 4 weeks after vaccination. RESULTS: Of the cohort of 279 patients, 124 (44.4%) had haematologic malignancies, 57 (20.4%) had rheumatologic diseases, and 98 (35.1%) were solid organ-transplant recipients. Anti-SARS-CoV-2 antibody levels increased in 74.9% of cases. Across the entire cohort, the median absolute antibody levels (expressed in AU/mL) increased from 7 (interquartile range (IQR), 0.1-69) to 243 (IQR, 2-4749) after the booster dose. The response significantly varied across subgroups: The transplant cohort showed the greatest increase in absolute antibody levels (from 52 (IQR, 7.25-184.5) to 1824 (IQR, 161-9686)), followed by the rheumatology (from 22 (IQR, 1-106) to 1291 (IQR, 6-6231)) and haemato-oncology (from 1 (IQR, 0.1-7) to 7.5 (IQR, 0.1-407.5)) cohorts. The χ2 test was 8.30 for difference in fold change (p = 0.016). Of the 193 patients who were seronegative at baseline, 76 became seropositive after vaccination, corresponding to a 39.4% (95% CI, 32.8%-46.4%) seroconversion rate. Transplant patients had the highest seroconversion rate (58.3% (95% CI, 44.3%-71.2%)), followed by rheumatology (44.1% (95% CI, 28.9%-60.5%)) and haemato-oncology (29.7% (95% CI, 22%-38.8%); χ2 = 11.87; p = 0.003) patients. DISCUSSION: A third dose of BNT162b2 is immunogenic in most immunosuppressed individuals, although antibody response may differ based on the type of disease and immunosuppression. The antibody level that correlates with protection is still unknown; thus, future studies are needed to evaluate clinical outcomes.

Short-Term Safety of Booster Immunization With BNT162b2 mRNA COVID-19 Vaccine in Healthcare Workers.

This study demonstrated a favorable short-term safety profile after a third dose of the BNT162b2 vaccine among healthcare workers (HCWs). There were more frequent local reactions and less systemic reactions compared to the second dose. The HCWs who reported reactions had higher prebooster titer of anti-S1 antibodies compared to those who reported no reactions.

Unraveling a Nosocomial Outbreak of COVID-19: The Role of Whole-Genome Sequence Analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic poses many epidemiological challenges. The investigation of nosocomial transmission is usually performed via thorough investigation of an index case and subsequent contact tracing. Notably, this approach has a subjective component, and there is accumulating evidence that whole-genome sequencing of the virus may provide more objective insight. METHODS: We report a large nosocomial outbreak in 1 of the medicine departments in our institution. Following intensive epidemiological investigation, we discovered that 1 of the patients involved was suffering from persistent COVID-19 while initially thought to be a recovering patient. She was therefore deemed to be the most likely source of the outbreak. We then performed whole-genome sequencing of the virus of 14 infected individuals involved in the outbreak. RESULTS: Surprisingly, the results of whole-genome sequencing refuted our initial hypothesis. A phylogenetic tree of the samples showed multiple introductions of the virus into the ward, 1 of which led to a cluster of 10 of the infected individuals. Importantly, the results pointed in the direction of a specific index patient that was different from the 1 that arose from our initial investigation. CONCLUSIONS: These results underscore the important added value of using whole-genome sequencing in epidemiological investigations as it may reveal unexpected connections between cases and aid in understanding transmission dynamics, especially in the setting of a pandemic where multiple possible index cases exist simultaneously.

Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.

BACKGROUND: Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance. METHODS: We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. RESULTS: Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637. CONCLUSIONS: The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.

Antibiotic Use during the COVID-19 Pandemic in a Tertiary Hospital with an Ongoing Antibiotic Stewardship Program.

During the recent pandemic, the fact that the clinical manifestation of COVID-19 may be indistinguishable from bacterial infection, as well as concerns of bacterial co-infection, have been associated with an increased use of antibiotics. The objective of this study was to assess the effect of targeted antibiotic stewardship programs (ASP) on the use of antibiotics in designated COVID-19 departments and to compare it to the antibiotic use in the equivalent departments in the same periods of 2018 and 2019. Antibiotic consumption was assessed as days of treatment (DOT) per 1000 patient days (PDs). The COVID-19 pandemic was divided into three periods (waves) according to the pandemic dynamics. The proportion of patients who received at least one antibiotic was significantly lower in COVID-19 departments compared to equivalent departments in 2018 and 2019 (Wave 2: 30.2% vs. 45.6% and 44.9%, respectively; Wave 3: 30.5% vs. 47.8% and 50.1%, respectively, p < 0.001). The DOT/1000PDs in every COVID-19 wave was lower than during similar periods in 2018 and 2019 (179-282 DOT/1000PDs vs. 452-470 DOT/1000PDs vs. 426-479 DOT/1000PDs, respectively). Moreover, antibiotic consumption decreased over time during the pandemic. In conclusion, a strong ASP is effective in restricting antibiotic consumption, particularly for COVID-19 which is a viral disease that may mimic bacterial sepsis but has a low rate of concurrent bacterial infection.

Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers.

IMPORTANCE: Randomized clinical trials have provided estimates of the effectiveness of the BNT162b2 vaccine against symptomatic SARS-CoV-2 infection, but its effect on asymptomatic infections remains unclear. OBJECTIVE: To estimate the association of vaccination with the Pfizer-BioNTech BNT162b2 vaccine with symptomatic and asymptomatic SARS-CoV-2 infections among health care workers. DESIGN, SETTING, AND PARTICIPANTS: This was a single-center, retrospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. Data were collected on symptomatic and asymptomatic SARS-CoV-2 infections confirmed via polymerase chain reaction (PCR) tests in health care workers undergoing regular screening with nasopharyngeal swabs between December 20, 2020, and February 25, 2021. Logistic regression was used to calculate incidence rate ratios (IRRs) comparing the incidence of infection between fully vaccinated and unvaccinated participants, controlling for demographics and the number of PCR tests performed. EXPOSURES: Vaccination with the BNT162b2 vaccine vs unvaccinated status was ascertained from the employee health database. Full vaccination was defined as more than 7 days after receipt of the second vaccine dose. MAIN OUTCOMES AND MEASURES: The primary outcome was the regression-adjusted IRR for symptomatic and asymptomatic SARS-CoV-2 infection of fully vaccinated vs unvaccinated health care workers. The secondary outcomes included IRRs for partially vaccinated health care workers (days 7-28 after first dose) and for those considered as late fully vaccinated (>21 days after second dose). RESULTS: A total of 6710 health care workers (mean [SD] age, 44.3 [12.5] years; 4465 [66.5%] women) were followed up for a median period of 63 days; 5953 health care workers (88.7%) received at least 1 dose of the BNT162b2 vaccine, 5517 (82.2%) received 2 doses, and 757 (11.3%) were not vaccinated. Vaccination was associated with older age compared with those who were not vaccinated (mean age, 44.8 vs 40.7 years, respectively) and male sex (31.4% vs 17.7%). Symptomatic SARS-CoV-2 infection occurred in 8 fully vaccinated health care workers and 38 unvaccinated health care workers (incidence rate, 4.7 vs 149.8 per 100 000 person-days, respectively, adjusted IRR, 0.03 [95% CI, 0.01-0.06]). Asymptomatic SARS-CoV-2 infection occurred in 19 fully vaccinated health care workers and 17 unvaccinated health care workers (incidence rate, 11.3 vs 67.0 per 100 000 person-days, respectively, adjusted IRR, 0.14 [95% CI, 0.07-0.31]). The results were qualitatively unchanged by the propensity score sensitivity analysis. CONCLUSIONS AND RELEVANCE: Among health care workers at a single center in Tel Aviv, Israel, receipt of the BNT162b2 vaccine compared with no vaccine was associated with a significantly lower incidence of symptomatic and asymptomatic SARS-CoV-2 infection more than 7 days after the second dose. Findings are limited by the observational design.

Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

Concordance between the results of randomized and non-randomized interventional clinical trials assessing the efficacy of drugs for COVID-19: a cross-sectional study.

OBJECTIVES: To assess whether results of observational studies of potential anti-COVID-19 drugs were reproduced in subsequent randomized controlled trials (RCTs). METHODS: This was a retrospective cross-sectional study, including studies published online between 1 January and 27 October 2020 that evaluated potential COVID-19 treatments and reported all-cause mortality. RESULTS: Of 133 comparisons included in 117 studies, most were non-randomized (104/133, 78%). Hydroxychloroquine was the most common drug type, combined with azithromycin (n = 27, 20%) or alone (n = 22, 16%), followed by IL-6 inhibitors (n = 36, 27%) and corticosteroids (n = 26, 20%). Seventy-one percent (74/104) of non-randomized studies reported adjusted survival results and only 8% (8/104) adjusted for immortal time bias. Only two RCTs (2/29, 7%) reported significant survival benefit, both reporting treatment with corticosteroids, while 32/104 (31%) non-randomized studies showed statistically significant survival benefit associated with the intervention arm. The results of the majority (28/32, 88%) of non-randomized studies reporting survival benefit were not replicated by large-scale RCTs. CONCLUSIONS: The results of most non-randomized studies reporting survival benefit of potential anti-COVID-19 drugs were not replicated by large RCTs. Regulators and healthcare professionals should exercise caution and resist the pressure to approve and prescribe drugs of unproven efficacy and potential toxicity to optimize patient care and maintain public trust in medical science.