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ImportanceThere is a dearth of comparative immunologic durability data after COVID-19 vaccinations. ObjectiveTo compare antibody responses and vaccine effectiveness 8.4 months post-primary COVID-19 vaccination. DesignSetting and Participants: In this cohort study of 903 healthcare workers who completed surveys about baseline characteristics and COVID-19 vaccine/infection history, 647 had antibody assays completed and were included herein. ExposureCOVID-19 vaccination with mRNA-1273 (n=387); BNT162b2 (n=212); or Ad26.COV2.S (n=10); unvaccinated (n=10); or boosted (n=28). Main Outcomes and MeasuresThe primary outcome was IgG anti-spike titer. Secondary/tertiary outcomes included IgG spike receptor-binding domain competitive antibody blocking ELISA pseudoneutralization against the USA-WA1/2020 strain, and vaccine effectiveness against COVID-19 infection. Antibody levels were compared using ANOVA and multiple linear regression. ResultsMean age was 49.7, 75.3% were female, and mean comorbidities/patient was 0.7. Baseline variables were balanced (p>.05) except for immunosuppression (higher in boosted, p=.047), prior COVID-19 infections (higher with Ad26.COV2.S and unvaccinated, p<.001), and time since primary vaccination (higher with mRNA-1273 and BNT162b2 than Ad26.COV2.S, p<.001). Unadjusted median (IQR) IgG anti-spike titers (AU/mL) were 1539.5 (876.7-2626.7) for mRNA-1273, 751.2 (422.0-1381.5) for BNT162b2, 451.6 (103.0-2396.7) for Ad26.COV2.S, 113.4 (3.7-194.0) for unvaccinated, and 31898.8 (21347.1-45820.1) for boosted (mRNA-1273 vs. BNT162b2, p<.001; mRNA-1273, BNT162b2, or boosted vs. unvaccinated, p<.006; mRNA-1273, BNT162b2, Ad26.COV2.S, or unvaccinated vs. boosted, p<.001; all other comparisons, p>.05). Unadjusted median (IQR) pseudoneutralization percentages were 90.9% (80.1-95.0) for mRNA-1273, 77.2% (59.1-89.9) for BNT162b2, 57.9% (36.6-95.8) for Ad26.COV2.S, 40.1% (21.7-60.6) for unvaccinated, and 96.4% (96.1-96.6) for boosted (mRNA-1273 vs. BNT162b2, p<.001; mRNA-1273, BNT162b2, or boosted vs. unvaccinated, p<.028; mRNA-1273, BNT162b2, Ad26.COV2.S, or unvaccinated vs. boosted, p<.001; all other comparisons, p>.05). Adjusted anti-spike and pseudoneutralization comparisons of mRNA-1273 and BNT162b2 showed similar patterns (p<.001). Vaccine effectiveness was 87-89% for mRNA-1273, BNT162b2, and boosted, and 33% for Ad26.COV2.S; no group differences were statistically significant. Conclusions and RelevanceDurability of antibody responses 8.4 months after COVID-19 primary vaccination was significantly higher with mRNA-1273 than with BNT162b2, however, vaccine effectiveness was equivalent. Antibody responses and vaccine effectiveness were lower but not significantly different for Ad26.COV2.S; given statistical uncertainty in the small Ad26.COV2.S group, clinically important effects cannot be excluded.
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BackgroundACEi/ARB medications have been hypothesized to have potential benefit in COVID-19. Despite concern for increased ACE-2 expression in some animal models, preclinical and observational-retrospective and uncontrolled trials suggested possible benefit. Two RCTs of the ARB losartan from University of Minnesota showed no benefit yet safety signals for losartan in outpatient and hospitalized COVID-19 patients. COVID MED, started early in the pandemic, also assessed losartan in a RCT in hospitalized patients with COVID-19. MethodsCOVID MED was a double-blinded, placebo-controlled, multicenter, platform randomized clinical trial (RCT). Hospitalized COVID-19 patients were randomized to receive standard care and hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued after RCTs showed no benefit. We report data from the losartan arm compared to combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint, the mean COVID-19 Ordinal Severity Score (COSS) slope of change, was compared with the Students t-test. Slow enrollment prompted early termination. ResultsOf 448 screened patients, 15 (3.5%) were randomized/enrolled, 9 to receive losartan and 6 to receive control (lopinavir/ritonavir [N=2], placebo [N=4]); 1 patient who withdrew prior to study drug was excluded yielding 14 patients for analysis (losartan [N=9] vs. control [N=5] [lopinavir/ritonavir [N=2], placebo [N=3]]). Most baseline parameters were balanced. Treatment with losartan was not associated with a difference in mean COSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan. ConclusionsIn this small blinded RCT in hospitalized COVID-19 patients, losartan did not improve outcome vs. control comparisons and was associated with adverse safety signals.
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BackgroundIn the beginning of the COVID-19 pandemic, many hospitalized patients received empiric hydroxychloroquine/chloroquine (HC/CQ). Although some retrospective-observational trials suggested potential benefit, all subsequent randomized clinical trials (RCTs) failed to show benefit and use generally ceased. Herein, we summarize key studies that clinicians advising patients on HC/CQs efficacy:safety calculus in hospitalized COVID-19 patients would want to know about in a practical one-stop-shopping source. MethodsPubmed and Google were searched on November 4, 2021. Search words included: COVID-19, hydroxychloroquine, chloroquine, in vitro, animal studies, clinical trials, and meta-analyses. Studies were assessed for import and included if considered impactful for benefit:risk assessment. ResultsThese searches led to inclusion of 12 in vitro and animal reports; 12 retrospective-observational trials, 19 interventional clinical trials (17 RCTs, 1 single-arm, 1 controlled but unblinded), and 51 meta-analyses in hospitalized patients. Inconsistent efficacy was seen in vitro and in animal studies for coronaviruses and nil in SARS-CoV-2 animal models specifically. Most retrospective-observational studies in hospitalized COVID-19 patients found no efficacy; QT prolongation and increased adverse events and mortality were reported in some. All RCTs and almost all meta-analyses provided robust data showing no benefit in overall populations and subgroups, yet concerning safety issues in many. ConclusionsHC/CQ have inconsistent anti-coronavirus efficacy in vitro and in animal models, and no convincing efficacy yet substantial safety issues in the overwhelming majority of retrospective-observational trials, RCTs, and meta-analyses in hospitalized COVID-19 patients. HC/CQ should not be prescribed for hospitalized COVID-19 patients outside of clinical trials. Key Summary PointsPreclinical hydroxychloroquine/chloroquine in vitro studies found inconsistent activity against coronaviruses including SARS-CoV-2. Preclinical hydroxychloroquine/chloroquine animals studies found inconsistent efficacy for coronaviruses in general and none for SARS-CoV-2. The overhwelming majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in hospitalized COVID-19 patients, and many found concerning safety signals. The majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in COVID-19 outpatients or for pre- or post-exposure prophylaxis, and some found concerning safety signals. The overwhelming majority of meta-analyses found no benefit for hydroxychloroquine/chloroquine in COVID-19 inpatients, outpatients, or for prophylaxis, and many found concerning safety signals.
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BackgroundResults from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. MethodsWe searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. ResultsEight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). ConclusionsThe findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.
