Effectiveness of REGEN-COV antibody combination in preventing severe COVID-19 outcomes.

REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, has been approved as a treatment for high-risk patients infected with SARS-CoV-2 within five days of their diagnosis. We performed a retrospective cohort study, and used data repositories of Israel's largest healthcare organization to determine the real-world effectiveness of REGEN-COV treatment against COVID-19-related hospitalization, severe disease, and death. We compared patients infected with Delta variant and treated with REGEN-COV (n = 289) to those infected but not-treated with REGEN-COV (n = 1,296). Demographic and clinical characteristics were used to match patients and for further adjustment as part of the C0x model. Estimated treatment effectiveness was defined as one minus the hazard ratio. Treatment effectiveness of REGEN-COV was 56.4% (95% CI: 23.7-75.1%) in preventing COVID-19 hospitalization, 59.2% (95% CI: 19.9-79.2%) in preventing severe COVID-19, and 93.5% (95% CI: 52.1-99.1%) in preventing COVID-19 death in the 28 days after treatment. In conclusion, REGEN-COV was effective in reducing the risk of severe sequelae in high-risk COVID-19 patients.

BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age.

BACKGROUND: Limited evidence is available on the real-world effectiveness of the BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) and specifically against infection with the omicron variant among children 5 to 11 years of age. METHODS: Using data from the largest health care organization in Israel, we identified a cohort of children 5 to 11 years of age who were vaccinated on or after November 23, 2021, and matched them with unvaccinated controls to estimate the vaccine effectiveness of BNT162b2 among newly vaccinated children during the omicron wave. Vaccine effectiveness against documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic Covid-19 was estimated after the first and second vaccine doses. The cumulative incidence of each outcome in the two study groups through January 7, 2022, was estimated with the use of the Kaplan-Meier estimator, and vaccine effectiveness was calculated as 1 minus the risk ratio. Vaccine effectiveness was also estimated in age subgroups. RESULTS: Among 136,127 eligible children who had been vaccinated during the study period, 94,728 were matched with unvaccinated controls. The estimated vaccine effectiveness against documented infection was 17% (95% confidence interval [CI], 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. The absolute risk difference between the study groups at days 7 to 21 after the second dose was 1905 events per 100,000 persons (95% CI, 1294 to 2440) for documented infection and 599 events per 100,000 persons (95% CI, 296 to 897) for symptomatic Covid-19. The estimated vaccine effectiveness against symptomatic Covid-19 was 18% (95% CI, -2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. We observed a trend toward higher vaccine effectiveness in the youngest age group (5 or 6 years of age) than in the oldest age group (10 or 11 years of age). CONCLUSIONS: Our findings suggest that as omicron was becoming the dominant variant, two doses of the BNT162b2 messenger RNA vaccine provided moderate protection against documented SARS-CoV-2 infection and symptomatic Covid-19 in children 5 to 11 years of age. (Funded by the European Union through the VERDI project and others.).

Comparing COVID-19-related hospitalization rates among individuals with infection-induced and vaccine-induced immunity in Israel.

With the COVID-19 pandemic ongoing, accurate assessment of population immunity and the effectiveness of booster and enhancer vaccine doses is critical. We compare COVID-19-related hospitalization incidence rates in 2,412,755 individuals across four exposure levels: non-recent vaccine immunity (two BNT162b2 COVID-19 vaccine doses five or more months prior), boosted vaccine immunity (three BNT162b2 doses), infection-induced immunity (previous COVID-19 without a subsequent BNT162b2 dose), and enhanced infection-induced immunity (previous COVID-19 with a subsequent BNT162b2 dose). Rates, adjusted for potential demographic, clinical and health-seeking-behavior confounders, were assessed from July-November 2021 when the Delta variant was predominant. Compared with non-recent vaccine immunity, COVID-19-related hospitalization incidence rates were reduced by 89% (87-91%) for boosted vaccine immunity, 66% (50-77%) for infection-induced immunity and 75% (61-83%) for enhanced infection-induced immunity. We demonstrate that infection-induced immunity (enhanced or not) provides more protection against COVID-19-related hospitalization than non-recent vaccine immunity, but less protection than booster vaccination. Additionally, our results suggest that vaccinating individuals with infection-induced immunity further enhances their protection.

Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.

BACKGROUND: With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose. METHODS: To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19-related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression. RESULTS: The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction-confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19-related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19-related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19-related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis. CONCLUSIONS: A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19-related outcomes among persons who had received a third dose at least 4 months earlier. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

An integrated framework for identifying clinical-laboratory indicators for novel pandemics: COVID-19 and MIS-C.

During the critical early stages of an emerging pandemic, limited availability of pathogen-specific testing can severely inhibit individualized risk screening and pandemic tracking. Standard clinical laboratory tests offer a widely available complementary data source for first-line risk screening and pandemic surveillance. Here, we propose an integrated framework for developing clinical-laboratory indicators for novel pandemics that combines population-level and individual-level analyses. We apply this framework to 7,520,834 clinical laboratory tests recorded over five years and find clinical-lab-test combinations that are strongly associated with SARS-CoV-2 PCR test results and Multisystem Inflammatory Syndrome in Children (MIS-C) diagnoses: Interleukin-related tests (e.g. IL4, IL10) were most strongly associated with SARS-CoV-2 infection and MIS-C, while other more widely available tests (ferritin, D-dimer, fibrinogen, alanine transaminase, and C-reactive protein) also had strong associations. When novel pandemics emerge, this framework can be used to identify specific combinations of clinical laboratory tests for public health tracking and first-line individualized risk screening.

The language of crisis: spatiotemporal effects of COVID-19 pandemic dynamics on health crisis communications by political leaders.

In times of crisis, communication by leaders is essential for mobilizing an effective public response. During the COVID-19 pandemic, compliance with public health guidelines has been critical for the prevention of infections and deaths. We assembled a corpus of over 1500 pandemic-related speeches, containing over 4 million words, delivered by all 50 US state governors during the initial months of the COVID-19 pandemic. We analyzed the semantic, grammatical and linguistic-complexity properties of these speeches, and examined their relationships to COVID-19 case rates over space and time. We found that as COVID-19 cases rose, governors used stricter language to issue guidance, employed greater negation to defend their actions and highlight prevailing uncertainty, and used more extreme descriptive adjectives. As cases surged to their highest levels, governors used shorter words with fewer syllables. Investigating and understanding such characteristic responses to stress is important for improving effective public communication during major health crises.

Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy.

To evaluate the effectiveness of the BNT162b2 messenger RNA vaccine in pregnant women, we conducted an observational cohort study of pregnant women aged 16 years or older, with no history of SARS-CoV-2, who were vaccinated between 20 December 2020 and 3 June 2021. A total of 10,861 vaccinated pregnant women were matched to 10,861 unvaccinated pregnant controls using demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. Estimated vaccine effectiveness from 7 through to 56 d after the second dose was 96% (95% confidence interval 89-100%) for any documented infection, 97% (91-100%) for infections with documented symptoms and 89% (43-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group and no deaths were observed in either group. In summary, the BNT162b2 mRNA vaccine was estimated to have high vaccine effectiveness in pregnant women, which is similar to the effectiveness estimated in the general population.

Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study.

BACKGROUND: Many countries are experiencing a resurgence of COVID-19, driven predominantly by the delta (B.1.617.2) variant of SARS-CoV-2. In response, these countries are considering the administration of a third dose of mRNA COVID-19 vaccine as a booster dose to address potential waning immunity over time and reduced effectiveness against the delta variant. We aimed to use the data repositories of Israel's largest health-care organisation to evaluate the effectiveness of a third dose of the BNT162b2 mRNA vaccine for preventing severe COVID-19 outcomes. METHODS: Using data from Clalit Health Services, which provides mandatory health-care coverage for over half of the Israeli population, individuals receiving a third vaccine dose between July 30, 2020, and Sept 23, 2021, were matched (1:1) to demographically and clinically similar controls who did not receive a third dose. Eligible participants had received the second vaccine dose at least 5 months before the recruitment date, had no previous documented SARS-CoV-2 infection, and had no contact with the health-care system in the 3 days before recruitment. Individuals who are health-care workers, live in long-term care facilities, or are medically confined to their homes were excluded. Primary outcomes were COVID-19-related admission to hospital, severe disease, and COVID-19-related death. The third dose effectiveness for each outcome was estimated as 1 - risk ratio using the Kaplan-Meier estimator. FINDINGS: 1 158 269 individuals were eligible to be included in the third dose group. Following matching, the third dose and control groups each included 728 321 individuals. Participants had a median age of 52 years (IQR 37-68) and 51% were female. The median follow-up time was 13 days (IQR 6-21) in both groups. Vaccine effectiveness evaluated at least 7 days after receipt of the third dose, compared with receiving only two doses at least 5 months ago, was estimated to be 93% (231 events for two doses vs 29 events for three doses; 95% CI 88-97) for admission to hospital, 92% (157 vs 17 events; 82-97) for severe disease, and 81% (44 vs seven events; 59-97) for COVID-19-related death. INTERPRETATION: Our findings suggest that a third dose of the BNT162b2 mRNA vaccine is effective in protecting individuals against severe COVID-19-related outcomes, compared with receiving only two doses at least 5 months ago. FUNDING: The Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.

Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.

BACKGROUND: Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. METHODS: We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. RESULTS: In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. CONCLUSIONS: In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

Internet search patterns reveal clinical course of COVID-19 disease progression and pandemic spread across 32 countries.

Effective public health response to novel pandemics relies on accurate and timely surveillance of pandemic spread, as well as characterization of the clinical course of the disease in affected individuals. We sought to determine whether Internet search patterns can be useful for tracking COVID-19 spread, and whether these data could also be useful in understanding the clinical progression of the disease in 32 countries across six continents. Temporal correlation analyses were conducted to characterize the relationships between a range of COVID-19 symptom-specific search terms and reported COVID-19 cases and deaths for each country from January 1 through April 20, 2020. Increases in COVID-19 symptom-related searches preceded increases in reported COVID-19 cases and deaths by an average of 18.53 days (95% CI 15.98-21.08) and 22.16 days (20.33-23.99), respectively. Cross-country ensemble averaging was used to derive average temporal profiles for each search term, which were combined to create a search-data-based view of the clinical course of disease progression. Internet search patterns revealed a clear temporal pattern of disease progression for COVID-19: Initial symptoms of fever, dry cough, sore throat and chills were followed by shortness of breath an average of 5.22 days (3.30-7.14) after initial symptom onset, matching the clinical course reported in the medical literature. This study shows that Internet search data can be useful for characterizing the detailed clinical course of a disease. These data are available in real-time at population scale, providing important benefits as a complementary resource for tracking pandemics, especially before widespread laboratory testing is available.