key: cord-0869525-b6axdask
authors: O’Horo, John C.; Challener, Douglas W.; Speicher, Leigh; Bosch, Wendelyn; Seville, Maria Teresa; Bierle, Dennis M.; Ganesh, Ravindra; Wilker, Caroline G.; Arndt, Richard F.; Arndt, Lori L.; Tulledge-Scheitel, Sidna M.; Hanson, Sara N.; Razonable, Raymund R.
title: Effectiveness of Monoclonal Antibodies in Preventing Severe COVID-19 with Emergence of the Delta Variant
date: 2021-12-16
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2021.12.002
sha: 39c7ff69712fc641faf1b185fe9c4ef93bf5fdef
doc_id: 869525
cord_uid: b6axdask

Anti-spike monoclonal antibodies have proven invaluable in preventing severe outcomes from COVID-19, including hospitalization and death. The rise of the SARS-CoV-2 Delta variant begs the question of whether monoclonal antibodies maintain similar efficacy now as they had when the alpha and beta variants predominated, when they were first assessed and approved. We used a retrospective cohort to compare rates of severe outcomes in an epoch where alpha and beta were predominant compared to delta. A total of 5,356 patients were infused during the alpha/beta variant predominant (N=4,874) and delta variant predominant (N=482) era. Overall, odds of severe infection were 3.0% of patients in the alpha/beta predominant era, compared to 4.9% in the delta predominant cohort. The unadjusted odds ratio was higher for severe disease in the delta era (OR 1.67, 95% CI 0.96-2.89), particularly when adjusted for Charlson Comorbidity Index (adjusted OR 2.04, 95% CI 1.30 – 3.08). The higher odds of severe infection could be due to a more virulent delta variant, although the possibility of decreased anti-spike monoclonal antibody effectiveness in the clinical setting cannot be excluded. Research into the most effective strategies for utilizing and improving anti-spike monoclonals for the treatment of emerging variants is warranted.

Anti-spike monoclonal antibodies have proven invaluable in preventing severe outcomes from COVID- 19 , including hospitalization and death. The rise of the SARS-CoV-2 Delta variant begs the question of whether monoclonal antibodies maintain similar efficacy now as they had when the alpha and beta variants predominated, when they were first assessed and approved. We used a retrospective cohort to compare rates of severe outcomes in an epoch where alpha and beta were predominant compared to delta. A total of 5,356 patients were infused during the alpha/beta variant predominant (N=4,874) and delta variant predominant (N=482) era. Overall, odds of severe infection were 3.0% of patients in the alpha/beta predominant era, compared to 4.9% in the delta predominant cohort. The unadjusted odds ratio was higher for severe disease in the delta era (OR 1.67, 95% CI 0.96-2.89), particularly when adjusted for Charlson Comorbidity Index (adjusted OR 2.04, 95% CI 1.30 -3.08). The higher odds of severe infection could be due to a more virulent delta variant, although the possibility of decreased antispike monoclonal antibody effectiveness in the clinical setting cannot be excluded. Research into the most effective strategies for utilizing and improving anti-spike monoclonals for the treatment of emerging variants is warranted.

Anti-spike monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have provided some of the first highly effective treatments for outpatients with mild to moderate coronavirus disease 2019 . These therapies have convincingly demonstrated reductions in progression to severe disease and hospitalization 1-3 and more recent data suggests mortality reduction. 4, 5 Mayo Clinic and the Mayo Clinic Health System established infusion centers for anti-spike monoclonal antibody therapy in Arizona, Florida, Minnesota, and Wisconsin. As of 10/28/2021, the program has infused over 14 thousand patients since the first product, bamlanivimab, was made available in 11/19/2020 under Food and Drug Administration (FDA) emergency use authorization (EUA). 6 In the analysis of initial real-world experience, bamlanivimab monotherapy was associated with 40-60% reductions in hospitalization, along with significant reductions in the rates of intensive care unit admissions and mortality. 7 Treatments have evolved over time due to the evolution of SARS-CoV-2 variants. Currently, our centers are infusing casirivimab/imdevimab to outpatients with mild to moderate COVID-19 that meet the FDA EUA eligibility criteria. In another analysis, there was a 70% reduction in hospitalization among high-risk patients who received casirivimab-imdevimab therapy when compared to propensity-matched untreated control group. 8 There was no significant difference in the rates of hospitalization between patients treated with bamlanivimab monotherapy compared to those who received casirivimab-imdevimab combination. 7

The SARS-CoV-2 alpha (B. proportion of cases by early spring. Since July 2021, the delta (B.1.617.2) variant has rapidly become the predominant lineage, associated with higher rates of hospitalization and healthcare utilization than prior strains. 9 As the delta variant demonstrates a greater ability to evade neutralizing antibodies, 10 this leads to the question of whether the clinical benefits of reduced hospitalization associated with anti-spike monoclonal antibodies are maintained. We compared the clinical outcomes of monoclonal antibody infusion during two time periods -an earlier period where alpha and beta were the predominant variants, and a later period where delta was predominant.

We conducted a retrospective cohort study analyzing the outcomes of patients infused with anti-spike monoclonal antibodies in two broad epochs stratified by geography for times and spaces when the delta variant was predominant versus when it was less common. The Mayo Clinic Institutional Review Board determined the study was exempt. Eligible study subjects both received an anti-spike monoclonal antibody infusion for COVID-19 at a Mayo Clinic site prior to 7/31/2021 and had not opted out of inclusion of their medical records for research purposes.

Patients were eligible to receive anti-spike monoclonal antibody if they were diagnosed with mild to moderate COVID-19, were within 10 days of symptom onset, and met the FDA EUA criteria.

These state that patients should have characteristics that put them at high risk for severe COVID-19, including age >65 years, body mass index (BMI) >35, diabetes, chronic kidney disease, immunosuppressive therapy or condition, or among patients over 55 years if they have hypertension, cardiovascular disease or chronic lung disease. A Monoclonal Antibody Screening Score (MASS) was developed using these criteria to stratify patients based on their risk of hospitalization, as previously described. 7 On 5/14/2021, the FDA EUA criteria expanded to include all patients with a BMI >25, the J o u r n a l P r e -p r o o f removal of age restriction for hypertension, cardiovascular disease and pulmonary diseases, and the inclusion of liver disease, neurodevelopmental disorders, and dependence on medical devices among other criteria.

This study employed an Electronic Health Record (EHR) based registry tool to identify patients with COVID-19 and determine pertinent demographic characteristics (age, sex, race, ethnicity) and comorbidities defined by the Charlson comorbidity index (CCI) and MASS. EHR data was used to abstract date and type of monoclonal antibody infusions and the region in which the infusion was performed. (Figure 1) . Notably, Arizona started infusions in December, later than other sites and during a local peak in admissions.

After excluding patients infused in May and June, a total of 5,356 patients were infused during the alpha/beta variant predominant (N=4,874) and delta variant predominant (N=482) era. Although there were some demographic differences at baseline between sites when alpha and beta were predominant, these were not significant in the delta era (Table and supplement) Patients during the delta variant predominant era had a lower average BMI (due to changes in the EUA criteria that reduced the BMI eligibility from >35 to >25) and possessed more comorbidity (as assessed by higher CCI) but did not differ in terms of age or sex characteristics. Fewer Whites and more African Americans were infused in the delta era, which was notable given the worse outcomes reported in African Americans infected with COVID-19. Interestingly, despite the higher CCI, the median MASS score was lower in the delta cohort (P< 0.01). This may result from the expanded criteria for eligibility in May 2021 allowing for younger and less comorbid patients to be infused. COVID-19 vaccination was expectedly higher in the delta than alpha/beta era (46.9% versus 2.1%). The period between PCR testing and antibody infusion was similar in the delta predominant era compared to the alpha/beta predominant era. In the delta predominant era, casirivimab/imdevimab was the only anti-spike monoclonal antibody being infused.

Overall, 184 of 5356 patients (3.4%) progressed to severe infection after monoclonal antibody infusion. The odds of severe infection were 3.0% of patients in the alpha/beta predominant era, compared to 4.9% in the delta predominant cohort. (Figure 2) The unadjusted odds ratio was not J o u r n a l P r e -p r o o f significantly higher for severe disease in the delta era compared to alpha/beta era (OR 1.67, 95% CI 0.96-2.89), however, this became significant when adjusted for CCI (adjusted OR 2.04, 95% CI 1.30 -3.08).

Restricting the analysis to only those who received casirivimab/imdevimab in both eras did not change the directionality or significance of results (unadjusted OR 1.74 95% CI 1.02-2.96, adjusted OR 2.09, 95% CI 1.19-3.66) (Supplement Table) . The overall number of patients who required admission to the ICU was 22 (0.4%), which was not significantly different across the epochs.

We observed increased risk of severe disease and poor outcomes post anti-spike antibody infusion during the period where the delta variant predominated compared to the earlier strains. While the absolute difference is slight, it remained significant after adjusting for pertinent covariates. This finding suggests that despite anti-spike monoclonal antibody treatment, delta variant infection remains more virulent than alpha/beta variant infection. This observation is in line with data from other countries that suggests increased virulence of delta variant infection compared to other variants, noting an increased risk of hospitalization, Intensive Care Unit stay and death with delta variant, primarily in unvaccinated persons. 16 17,18 The difference in outcomes is particularly notable in the context of the more liberal nature of the revised EUA, which allowed for infusion of patients with fewer comorbidities than the previous version. Despite a lower MASS score, there was a significant increase in the CCI in the delta cohort. This is surprising, though the conditions accounted for in the MASS score are limited to those in the original EUA eligibility, while the CCI provided a more global assessment and considered other comorbidities not in MASS. MASS score elements were also developed and validated in the pre-vaccine era, and some elements overlapped with earlier vaccine eligibility, a potential confounder. Nonetheless, more cases J o u r n a l P r e -p r o o f with severe outcomes were observed despite this lower MASS score and similar time to infusion in the delta predominant era.

Our study has several limitations. First, we used epochs and geography to correlate with circulating strains, as opposed to linking delta variant cases to specific outcomes. While the omission of May and June data meant the predominant circulating strains in the periods assessed were considerably more homogenous, this may not fully account for regional variation. Second, we did not account for the impact of specific anti-spike monoclonal antibody used. The shifts in practice towards the use of casirivimab/imdevimab meant we necessarily compared to bamlanivimab/etesivimab and bamlanivimab in prior eras. In our subset analysis, however, restricting the analysis only to those who received casirivimab/imdevimab in both periods did not change the overall results. Moreover, our previous work that compared bamlanivimab versus casirivimab/imdevimab outcomes during the alpha/beta predominant era did not show any significant difference in efficacy. 19 Third, the FDA EUA criteria for eligibility for anti-spike monoclonal antibody was expanded between the two eras, but the outcome should favor the delta period since the criteria was expanded to allow infusion of patients with lower comorbidity scores (as indicated by MASS). Despite this, we observed higher comorbidity scoring by the CCI in the delta period. Finally, the comparisons of different epochs and locations reflect different practices with regard to hospital admission policies, as well as vaccination rates which may have reduced the need for hospitalization in the delta cohort. However, the proportion of vaccinated persons were expectedly higher during the delta period. As the directionality was reversed (i.e., more patients in the later period required hospital admission and were thus classified as severe disease), these factors, including vaccination status, did not appear to have decreased severe outcomes in our study population. 

Ganesh 

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