Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections: The ORCHESTRA Prospective Cohort Study

Abstract

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p < 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05–0.27, p < 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08–5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03–1.08, p < 0.001), and male gender (aOR:1.97, 95%CI: 1.04–3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p < 0.001) in immunocompromised and elderly patients >75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.

Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments

“…The H2020-funded ORCHESTRA project (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) includes work package 2 (WP2), prospectively enrolling high-risk patients receiving early treatment for symptomatic COVID-19. Clinical efficacies of bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab in 740 mild-to-moderate non-hospitalized COVID-19 patients have been described (19, 20) (for eligibility criteria, see Supplementary Table 1 ). From the WP2 cohort, patients were prospectively invited to a sub-study assessing immunological and virological responses to mAbs.…”

“…As several studies have shown that immunocompromised individuals show a prolonged carriage of SARS-CoV-2 (5, 7), we investigated whether these patients receiving mAb therapy also carried higher viral loads. Immunocompromised status was defined clinically on the basis of patients on active immunosuppressive treatment for cancer or immunological diseases, as described (19, 20). We showed that immunocompromised patients had higher viral loads at the time of enrolment within the mAb treatment groups (ΔCt 3.03 and 2.76 for ORF1ab and N , respectively; p < 0.001).…”

“…All outpatients aged ≥ 18 years, presenting with mild-to-moderate COVID-19 (confirmed by quantitative real-time Reverse Transcription (RT-q)PCR or a positive antigenic 3 rd generation test) at high risk for clinical worsening in accordance with Italian Medicine Agency indications (for definition see ref. 7,8 ) were offered monoclonal antibody therapy and enrolled in this study prior collection of written informed consent. All enrolled patients received treatment with either bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or tixagevimab/cilgavimab.…”

“…Early therapy with synthetic anti-SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) targeting the Spike protein has been shown to reduce the risk of severe COVID-19 in high-risk outpatients including vaccinated subjects 1-8 . Recent studies showed that immunocompromised individuals are deficient in clearing the virus and developing sufficient antibody titers after the administration of SARS-CoV-2 vaccines 9,10 .…”

“…Immunocompromised individuals are also unable to develop sufficient antibody titers after the administration of SARS-CoV-2 vaccines. To tackle this, synthetic anti-SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) targeting the Spike protein have been developed that demonstrate clinical benefit for mild-to-moderately ill, high-risk COVID-19 patients (13)(14)(15)(16)(17)(18)(19)(20). For example, the first widely available mAb, bamlanivimab that targets an epitope on the receptor-binding domain (RBD), showed a reduced rate of hospitalization, ICU admission, and mortality compared with usual care (21).…”