The results of the present study showed a better outcome, in terms of supplemental oxygen requirement for COVID-19 and all-cause mortality, in high-risk inpatients with hospital-acquired SARS-CoV-2 infection receiving early treatment with REGEN-COV, compared to those receiving standard care alone. None of patients treated with the casirivimab/imdevimab cocktail experienced disease progression or death within 28 days, despite all having multiple risk factors for development of severe COVID-19. Conversely, 60% of patients receiving standard care experienced acute hypoxemic respiratory failure requiring oxygen support, and almost 35% of them died within 28 days of SARS-CoV-2 infection diagnosis, a finding consistent with results of previous investigations on HA-COVID-19 [1, 4, 7, 8]. Administration of REGEN-COV was well tolerated and no serious adverse events were registered in treated patients during hospital stay.
Of note, patients in the REGEN-COV group received the mAb cocktail in the early phases of the SARS-CoV-2 infection, as supported by the low severity of the disease at diagnosis and the absence of an endogenous immune response against SARS-CoV-2 in all 7 patients who underwent serology assay (4 patients were not tested for serum antibodies against SARS-CoV-2). A prompt diagnosis of nosocomial SARS-CoV-2 infection was favored by the institutional protocol for COVID-19 prevention and control, which provided for symptom-oriented testing and serial universal screening of all hospitalized patients by RT-PCR on nasopharyngeal swab. As shown by previous studies, a timely infusion of mAb therapy in the early phases of COVID-19 is needed in order to achieve beneficial effects, as mAbs appears ineffective if administered late in the disease course, when severe symptoms have developed [16, 24–26].
Our findings appear in line with the results of the large phase 1-3 randomized controlled trials by Weinreich and colleagues, which assessed REGEN-COV treatment in non-hospitalized COVID-19 patients [27, 28]. In the final analysis of this trial, including 4057 ambulatory patients with early diagnosis of symptomatic COVID-19 and at least 1 risk factors for severe disease, REGEN-COV, both in the 2400mg and 1200mg dosage, was safe and significantly reduced COVID-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.001] and 70.4% reduction [1.0% vs 3.2%; p=0.002], respectively) .
To date, few data are available on the use of mAbs in the special population of patients acquiring COVID-19 during hospital admission for other medical illnesses. Koehler and colleagues have described the outcome of 11 asymptomatic patients with HA-COVID-19 admitted to a German hospital, who received a treatment with different mAbs (bamlanivimab in 8 patients, and casirivimab/imdevimab in 3 patients) early after infection diagnosis. Compared to 32 HA-COVID-19 asymptomatic patients receiving standard care alone, a lower rate of COVID-19-associated radiological changes and a remarkably lower rate of ICU admission and death were detected in subjects receiving mAbs . The results of our study corroborate these findings and offer support to the use of REGEN-COV in high-risk inpatients who acquire asymptomatic to mild nosocomial COVID-19.
One notable ancillary finding of our study is the shorter time required to obtain a negative RT-PCR test on nasopharyngeal swab in patients treated with REGEN-COV compared to those treated with standard care. This result may appear not clinically relevant; however, it should be considered that faster viral clearance shortens the duration of isolation measures, thus accelerating the return of COVID-19 patients to community life. In addition, a reduced time to negative RT-PCR test could be especially important in COVID-19 patients admitted to hospital for underlying diseases requiring surgery or rehabilitation care, as a positive result of SARS-CoV-2 testing could preclude access to these services.
Although neutralizing mAbs have been validated as therapeutic option against COVID-19, circulating SARS-CoV-2 variants may show resistance to these antiviral agents, due to mutations that affect the targeted epitopes in the spike protein reducing or preventing antibody binding . On April 2021, the FDA revoked the EUA for the bamlanivimab mAb monotherapy due to resistance in several major virus variants, including Delta variant and, more recently, it recommended against the use of the bamlanivimab/etesevimab cocktail in several US territories, due to high prevalence of variants with reduced susceptibility to both antibodies in the combination [29–32]. Although we have not ascertained the presence of infections by SARS-CoV-2 variants of concern (VOC) in our study, multiple analyses have shown that the combination of antibodies in REGEN-COV retains potency against major circulating VOCs, including Delta (B.1.617.2), which remains, to date, the dominant strain worldwide (source: GISAID) [30, 31]. Regarding the new Omicron (B.1.1.529) variant, recently identified in South Africa, there is no direct evidence to support resistance or susceptibility to mAb therapies, including REGEN-COV. Prior in vitro analyses and structural modeling regarding the individual mutations present in the Omicron variant indicate a potential reduced neutralization activity of REGEN-COV antibodies; however, further analyses are needed to confirm and quantify this preliminary finding .
REGEN-COV and other neutralizing mAbs have been authorized based on studies conducted at a time in which SARS-CoV-2 vaccination was poorly widespread. As a consequence, we have little information on the benefits of mAbs in vaccinated patients who acquire SARS-CoV-2 infection. Casirivimab/imdevimab cocktail and the other authorized mAbs could be useful for the treatment of breakthrough COVID-19 in high-risk individuals with poor immune response to the vaccine or waning immunity, and in patients infected by SARS-CoV-2 variants for whom the immune response elicited by vaccination might be sub-optimal. Recently, Bierle and colleagues have assessed the efficacy of mAb treatment in a cohort of 1395 fully vaccinated persons with breakthrough COVID-19. In this cohort 107 (7.7%) patients required hospital admission by day 28; the risk of hospitalization was significantly lower in patients who were treated with mAb therapy, most of whom received casirivimab/imdevimab (OR 0.227, CI 0.128 - 0.403, p<0.001) .
The strenghts of this retrospective, real-world study are the assessment of a unique type of neutralizing mAb combination (casirivimab/imdevimab), and the exploration of its effect in a special cohort of inpatients affected by nosocomial COVID-19. Patients who acquire SARS-CoV-2 infection during hospital admission for reasons other than COVID-19 are often characterized by advanced age and a high burden of comorbidities; in addition, they have an underlying acute illness that could further increase vulnerability to complications and death from SARS-CoV-2 infection . Our findings shed light on the possible therapeutic management of such high-risk patients.
This research has several limitations. The limited number of patients enrolled, the retrospective and monocentric design affect the validity, reliability and generalizability of the study results. Another limitation is that we were unable to accurately assess minor symptoms of SARS-CoV-2 infection (e.g., change in smell or taste, cough), which were not systematically reported in medical records. Finally, we were unable to identify the SARS-CoV-2 variants responsible for infection in the study population, as enrolled patients did not undergo viral genome sequencing, and we could not assess the presence of a correlation between viral variants responsible for infection and REGEN-COV treatment effects.