By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Subcutaneous administration of a combination of anti-SARS-COV-2 antibodies effectively prevented COVID-19 in most household contacts of cases.

SOURCE: O’Brien MP, Forleo-Neto E, Musser BJ, et al; Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med 2021; Aug 4. doi: 10.1056/NEJMoa2109682. [Online ahead of print].

O’Brien and colleagues examined the efficacy of REGEN-COV administration as post-exposure prophylaxis (PEP) for prevention of asymptomatic and symptomatic COVID-19 in adult and adolescent household contacts of SARS-CoV-2-infected individuals. REGEN-COV is a combination of two monoclonal antibodies, casirivimab and imdevimab, that each bind distinct epitopes in the receptor binding domain of the viral spike protein and have neutralizing activity.

Participants were asymptomatic, 12 years of age, and were enrolled within 96 hours of a household contact being found infected with SARS-CoV-2. They were randomized to receive a single subcutaneous administration of either placebo or 1,200 mg of the monoclonals (600 mg of each). All were screened for evidence of current or past COVID-19 by polymerase chain reaction (PCR) and antibody testing, with the latter including anti-spike immunoglobulin G (IgG) and immunoglobulin A (IgA) as well as antinucleoprotein antibodies. Although all participants continued in the study, only the 1,505 who were PCR and antibody negative were included in the assessment of the primary endpoint analysis for purposes of this report the percentage who developed symptomatic PCR-documented infection within 28 days.

The mean age was 42.9 years. Approximately one-third of patients had a body mass index (BMI) 30 and in one-eighth it was 35. Overall, 30.5% had any high-risk factor. Symptomatic SARS-CoV-2 infection occurred in 11/753 (1.5%) REGEN-COV recipients and 59/752 (7.8%) of those given placebo, for a relative risk reduction of 84% (P < 0.001). During weeks 2-4, two (0.3%) and 27 (3.6%) patients, respectively, developed symptomatic infection, with a relative risk reduction of 92.6%.

In combining documented asymptomatic infection with symptomatic infections, these occurred in 36/753 (4.8%) of REGEN-COV recipients and 107/752 (14.2%) of those given placebo, providing a relative risk reduction of 66.4% (P < 0.001). Monoclonal antibody administration also was associated with an 85.8% relative risk reduction of having a high nasopharyngeal viral load, defined as >104 ribonucleic acid (RNA) copies/mL, and the duration of having a high viral load was almost one week shorter. In patients who developed symptomatic infection, the time to resolution of symptoms was two weeks shorter in those who had received REGEN-COV.

Although monoclonals were administered subcutaneously rather than intravenously, the mean serum concentrations of casirivimab and imdevimab one day later were 22.1 mg/L and 25.8 mg/L, respectively — both above the estimated target dose for SARS-CoV-2 neutralization of 20 mg/L. The monoclonals reached peak concentrations at seven to eight days, and their mean elimination half-lives were 32.4 days and 27.0 days, respectively. At 28 days, the mean serum concentration of casirivimab was 30.4 mg/L and that of imdevimab was 24.6 mg/L.


Administration of the combination of casirivimab and imdevimab to at-risk outpatients with symptomatic COVID-19 has been demonstrated previously to result in an approximately 70% reduction in the incidence of hospitalization or death, rapidly reduce the viral load, and shorten the duration of symptoms.1 That study, which clearly demonstrated therapeutic benefit, resulted in the issuance of an Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA).2,3 Of note is that this remains the only unequivocally effective therapeutic for use in symptomatic outpatients. The study reviewed here similarly shows clear benefit in the prevention of symptomatic COVID-19 in household contacts of cases, and this resulted in the addition of this indication to the EUA.

Although the emergence of variants of SARS-CoV-2 has rendered some monoclonals ineffective, those with current significant circulation in the United States, including the delta variant, remain susceptible to neutralization by the components of REGEN-COV. Delta also remains susceptible to neutralization by another monoclonal, sotrovimab, which similarly has received EUA for treatment of at-risk symptomatic outpatients. However, it is likely that novel variants resistant to these monoclonals will emerge eventually.

In a study evaluating the therapeutic efficacy of REGEN-COV in hospitalized patients with COVID-19, benefit was limited to those seronegative at enrollment.4 As a consequence, it was stated by the investigators that “therapeutic use of REGEN-COV in the hospital setting may be best restricted to seronegative patients.” This observation and conclusion regarding therapy of COVID-19 inpatients naturally raises the question of whether outpatient post-exposure prophylaxis also should be limited to seronegative individuals — a distinction that would require point-of-care antibody testing. However, O’Brien and colleagues stated in the discussion portion of their report that, based on an analysis that included participants who were seropositive at entry and together with the safety profile of REGEN-COV, such testing is not necessary to inform decisions about its administration in the clinic setting. That analysis is based on data presented only in the supplementary appendix. The primary endpoint of development of symptomatic COVID-19 was reached in 5/222 (2.3%) seropositive placebo recipients and 1/235 (0.4%) of those given the monoclonal combination, yielding a relative risk reduction of 81.1%.

The recent EUA allows prophylactic administration of REGEN-COV to individuals at high risk of exposure because of SARS-CoV-2 infection in other individuals residing in the same institutional settings, such as nursing homes and prisons.2,3 It also provides for monthly administration, albeit at a reduced dose, for those not expected to mount an adequate immune response to vaccination and who have ongoing exposure. Monthly administration is consistent with the pharmacokinetic data presented by O’Brien et al and summarized earlier. Although there are no publicly available data regarding prophylaxis with sotrovimab, this monoclonal is believed to have a more prolonged serum half-life as a consequence of modification of its Fc fragment, thus potentially allowing less frequent administration. The EUA allowance for REGEN-COV raises the issue of whether non-institutionalized individuals, such as organ transplant recipients, who fail to respond to vaccination also may be candidates for receipt of ongoing prophylaxis.


  • REGEN-COV has a high degree of efficacy as post-exposure prophylaxis for symptomatic illness in seronegative and seropositive household contacts of patients with COVID-19. 
  • REGEN-COV is effective in the treatment of seronegative, but not seropositive, patients hospitalized because of COVID-19.


  1. Weinreich DM, Sivapalasingam S, Norton T, et al; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med 2021;384:238-251.
  2. U.S. Food and Drug Administration. Emergency Use Authorization 100.
  3. U.S. Food and Drug Administration. Fact Sheet for Healthcare Providers Emergency Use Authorization (EUA) of Sotrovimab.
  4. RECOVERY Collaborative Group; Horby PW, Mafham M, Peto L, et al. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. medRxiv 2021. doi: