Background We studied humoral responses after COVID-19 vaccination across varying causes of immunodeficiency. Methods Prospective study of fully-vaccinated immunocompromised adults (solid organ transplant (SOT), hematologic malignancy, solid cancers, autoimmune conditions, HIV infection) versus non-immunocompromised healthcare-workers (HCW). The primary outcome was the proportion with a reactive test (seropositive) for IgG to SARS-CoV-2 receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. Results 1271 participants enrolled: 1,099 immunocompromised and 172 HCW. Compared to HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (p<0.01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus mRNA-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines, after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r=0.89, p<0.0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. Conclusion Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCW. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

Background Monoclonal antibody treatment may prevent complications of COVID-19. We sought to quantify the impact of bamlanivimab monoclonal antibody monotherapy on hospitalization and mortality among outpatients at high risk of COVID-19 complications. Methods In this observational study we compared outpatients who received bamlanivimab monoclonal antibody from December 9, 2020 to March 3, 2021 to non-treated patients with a positive polymerase chain reaction or antigen test for SARS-CoV-2 during the same period who were eligible for monoclonal antibody treatment. The primary outcome was 28-day hospitalization or all-cause mortality, and the secondary outcome was hospitalization or emergency department visit without hospitalization. The risk-adjusted odds of study outcomes comparing bamlanivimab treated and untreated patients was determined using 1:5 propensity matching and multivariable logistic regression. Results Among 232 patients receiving bamlanivimab matched with 1,160 comparator patients, the mean age was 67 years, 56% were female, and 196 (14%) of patients experienced hospitalization or mortality. After adjustment for propensity to receive treatment, bamlanivimab treatment was associated with a significantly reduced risk-adjusted odds of hospitalization or mortality within 28 days (OR 0.40, 95% confidence interval [95% CI] 0.24 to 0.69; p<.001). Bamlanivimab treatment was also associated with a significantly lower risk adjusted odds of hospitalization or emergency department visit without hospitalization (OR 0.54, 95% CI 0.35 to 0.82; p=.004). The results were most strongly associated with patients age 65 years and older. Conclusions Bamlanivimab monoclonal antibody monotherapy was associated with reduced hospitalizations and mortality within 28 days among outpatients with mild-moderate COVID-19.

Background: Monoclonal antibody (mAb) treatment may prevent complications of COVID-19. We sought to quantify the impact of bamlanivimab monotherapy on hospitalizations and mortality, as well as Emergency Department (ED) visits without hospitalization, among outpatients at high risk of COVID-19 complications. Methods: We compared patients receiving mAb to patients who met criteria but did not receive mAb from December 2020 through March 2021. The study population selection used propensity scores to match 1:1 by likelihood to receive mAb. The primary outcome was hospitalization or all-cause mortality within 28 days; the secondary outcome was hospitalization or ED visit without hospitalization within 28 days. Odds ratios (OR) calculation used logistic regression modeling including propensity score and mAb receipt predictors. Results: The study population included 234 patients receiving mAb and 234 matched comparator patients not receiving mAb. Patients receiving mAb were less likely to experience hospitalization or mortality (OR 0.31, 95% confidence interval [95%CI] 0.17-0.56, p=0.00001) and hospitalization or ED visit without hospitalization (OR 0.50, 95%CI 0.43-0.83, p=0.007). The impact of mAb was more pronounced in prevention of hospitalization (among all age groups, OR 0.35, 95%CI 0.19-0.66, p=0.001) than mortality or ED visit without hospitalization, and most strongly associated with patients age 65 years and older (primary outcome OR 0.28, 95%CI 0.14-0.56, p=0.0003). Conclusions: Bamlanivimab monotherapy was associated with reduction in the composite outcome of hospitalizations and mortality in patients with mild-moderate COVID-19. The benefit may be strongest in preventing hospitalization in patients ages 65 years or older.

Key Points Question Is subcutaneous treatment with casirivimab and imdevimab associated with improved 28-day clinical outcomes compared with nontreatment, and is it clinically similar to intravenously administered casirivimab and imdevimab for outpatients with COVID-19? Findings In this cohort study of 1959 propensity-matched outpatients with mild to moderate COVID-19 symptoms, the 28-day rate of hospitalization or death was 3.4% vs 7.0% for those receiving subcutaneous treatment vs nontreatment. In a second cohort analysis of 2185 outpatients, the 28-day rate of hospitalization or death was 2.8% vs 1.7% for subcutaneous vs intravenous treatment. Meaning Subcutaneous casirivimab and imdevimab was associated with reduced hospitalization and death compared with nontreatment and showed similar outcomes compared with intravenous casirivimab and imdevimab in outpatients with COVID-19.

IMPORTANCE The effectiveness of monoclonal antibodies (mAbs), casirivimab and imdevimab, and sotrovimab, for patients with mild to moderate Covid-19 from the Delta variant is unknown. OBJECTIVE To evaluate the effectiveness of mAbs for the Delta variant compared to no treatment, and the comparative effectiveness between mAbs. DESIGN, SETTING, AND PARTICIPANTS Two parallel studies among patients who met Emergency Use Authorization criteria for mAbs from July 14, 2021 to September 29, 2021: i.) prospective observational cohort study comparing mAb treatment to no mAb treatment and, ii.) Bayesian adaptive randomized trial comparing the effectiveness of casirivimab-imdevimab versus sotrovimab. In the observational study, we compared eligible patients who received mAb at an outpatient infusion center at UPMC, to nontreated patients with a positive SARS-CoV-2 test. In the comparative effectiveness trial, we randomly allocated casirivimab-imdevimab or sotrovimab to patients presenting to infusion centers and emergency departments, per system therapeutic interchange policy. EXPOSURE Intravenous mAb per their EUA criteria. MAIN OUTCOMES AND MEASURES For the observational study, risk ratio estimates for hospitalization or death by 28 days were compared between mAb treatment to no mAb treatment using propensity matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day) in a Bayesian cumulative logistic model, adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio <1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound. RESULTS Among 3,558 patients receiving mAb, the mean age was 54 (SD 18 years), 1,511 (43%) were treated in an infusion center, and 450 (13%) were hospitalized or died by day 28. In propensity matched models, mAb treatment was associated with reduced risk of hospitalization or death compared to no treatment (risk ratio (RR)=0.40, 95% CI: 0.28-0.57). Both casirivimab and imdevimab (RR=0.31, 95% CI: 0.20-0.50), and sotrovimab (RR=0.60, 95% CI: 0.37-1.00) reduced hospitalization or death compared to no mAb treatment. Among patients allocated randomly to casirivimab and imdevimab (n=2,454) or sotrovimab (n=1,104), the median hospital-free days were 28 (IQR 28-28) for both groups, 28-day mortality was 0.5% (n=12) and 0.6% (n=7), and hospitalization by day 28 was 12% (n=291) and 12% (n=140), respectively. Compared to casirivimab and imdevimab, the median adjusted odds ratio for hospital-free days was 0.88 (95% credible interval, 0.70-1.11) for sotrovimab. This odds ratio yielded 86% probability of inferiority of sotrovimab versus casirivimab and imdevimab, and 79% probability of equivalence. CONCLUSIONS AND RELEVANCE In non-hospitalized patients with mild to moderate Covid-19 due to the Delta variant, casirivimab and imdevimab and sotrovimab were both associated with a reduced risk of hospitalization or death. The comparative effectiveness of mAbs appeared similar, though prespecified criteria for statistical inferiority or equivalence were not met. TRIAL REGISTRATION ClinicalTrials.gov: NCT04790786

DESIGN, SETTING, AND PARTICIPANTSThis study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria.EXPOSURE For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. MAIN OUTCOMES AND MEASURESFor the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned −1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. RESULTSA total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both (continued)

Objectives: Immunocompromised patients were excluded from COVID-19 vaccine clinical trials. The objectives of the study were to measure antibody responses, levels, and neutralization capability after COVID-19 vaccination among immunocompromised patients and compare these variables to those of immunocompetent healthcare workers. Methods This is an interim analysis of an ongoing observational, prospective cohort study which launched on April 14, 2021 across Western Pennsylvania. Participants were healthy healthcare workers (HCW) and immunocompromised patients who had completed their COVID-19 vaccination series. Individuals with a history of COVID-19 were not eligible. Serum was collected to measure for the presence of IgG against the SARS-CoV-2 Spike protein using a semi-quantitative assay; antibody levels were available for comparisons. A quasi-random subset of patients was selected for pseudovirus neutralization assays. Seropositivity with 95% Clopper-Pearson exact confidence intervals and distribution of antibody levels were measured. To identify risk factors for seronegativity, clinical characteristics were univariately compared between antibody reactive and non-reactive individuals within the immunocompromised group. Results: 107 HCW and 489 immunocompromised patients were enrolled. Compared to HCWs, seropositivity was significantly lower (p<.001) among immunocompromised patients with Solid organ transplant (SOT), autoimmune, hematological malignancies, and solid tumors (HCW=98.1%; SOT=37.2%; autoimmune=83.8%; hematological malignancies=54.7%; and solid tumor=82.4%, p < 0.05). Over 94% of patients with Human Immunodeficiency Virus were seropositive. Among seropositive patients, antibody levels were much lower among SOT (4.5 [2.1,13.1], p=.020). Neutralization titers tightly correlated with antibody levels (Spearman r = 0.91, p < 0.0001). Conclusion: Our findings demonstrate the heterogeneity of the humoral immune response to COVID-19 vaccines based on underlying immunosuppressive condition and highlight an urgent need to optimize and individualize COVID-19 prevention in these patients. These findings also have implications on public health guidance, particularly given revised Centers for Disease Control and Prevention recommendations permitting vaccinated individuals to abandon masking and social distancing in most settings. Future studies are warranted to determine assessment of cellular immunity, longitudinal measurement of immune responses, and the safety and efficacy of revaccination.

Treatment guidelines and emergency use authorizations for monoclonal antibodies (mAbs) for treatment of COVID-19 have changed frequently as different SARS-CoV-2 variants have emerged. This study evaluated whether early outpatient treatment with mAbs is associated with reduced risk for hospitalization or death at 28 days.