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Passive immunotherapy has played an essential role in the prevention and treatment of infectious diseases since Emil von Behring’s Nobel Prize–winning work in the 1890s on the use of antiserum raised in horses to treat diphtheria. This work paved the way for use of antiserum to treat tetanus and prevent rabies, and for Rufus Cole’s development of type-specific immune serum to treat pneumococcal pneumonia, published in 1913.1 By the mid-20th century, advances in clinical immunology led to the use of immune globulins, comprising primarily immunoglobulin G, harvested from persons with high-titer antibodies to provide postexposure prophylaxis against varicella-zoster virus (varicella-zoster immune globulin), hepatitis B virus (hepatitis B immune globulin), and other viral infections. Convalescent plasma, obtained from individuals who have recovered from a particular viral infection, has been used to varying effect in the treatment of influenza during the 1918 pandemic and for Ebola, severe acute respiratory syndrome, and COVID-19.2,3
A limitation in the use of convalescent plasma and immune globulin is the need to recruit donors with high-titer neutralizing antibody directed against the pathogen of interest in sufficient numbers to maintain a steady supply. Technological advances now permit the identification and characterization of individual B cells from these donors that produce virus-specific neutralizing monoclonal antibodies (mAbs).4 The immunoglobulin genes of such B cells can be cloned and expressed to produce high-titer neutralizing mAbs. This approach has led to the identification of numerous mAbs with neutralizing activity against the spike protein of SARS-CoV-2, the etiologic agent of COVID-19. Four of these mAbs (bamlanivimab plus etesevimab and casirivimab plus imdevimab) have received an Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) for treatment of early-stage COVID-19.
Preclinical studies showed that intravenous administration of bamlanivimab reduces viral replication in the upper and lower respiratory tract of rhesus macaques in a dose-dependent manner.5 Results of the BLAZE-1 study provided preliminary evidence for the antiviral activity and potential clinical benefit of bamlanivimab alone and in combination with etesevimab in outpatients with symptomatic COVID-19.6,7
In this issue of JAMA, the study by Cohen and colleagues8 provides further evidence for the preventive potential of bamlanivimab. The authors report results of a randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of a single intravenous 4200-mg dose of bamlanivimab for preventing SARS-CoV-2 infection and COVID-19 among residents and staff of skilled nursing and assisted living facilities in the US. Residents and staff from 74 facilities in which at least 1 confirmed index case of COVID-19 had occurred within the preceding 7 days were eligible if they were aged 18 years or older and had no known history of COVID-19. Nasal and nasopharyngeal swabs for SARS-CoV-2 testing were obtained at study entry along with blood for SARS-CoV-2 serology. Participants were randomized and dosed prior to availability of baseline test results. Those who tested negative for SARS-CoV-2 infection at entry constituted the prevention population, which included 666 staff and 300 residents (966 total participants); an additional 132 participants with positive nasal swab results and negative serology at baseline were followed up as the treatment population (and according to the authors will be reported on separately). The primary outcome was incidence of COVID-19, defined as detection of SARS-CoV-2 by nasal swab accompanied by mild or worse disease occurring within 21 days of detection and within 8 weeks of randomization.
In the overall prevention population, bamlanivimab significantly reduced the incidence of mild or worse COVID-19 compared with placebo (8.5% vs 15.2%, respectively; odds ratio, 0.43; 95% CI, 0.28-0.68); the protective effect was greater in prespecified analyses limited to the resident prevention population (n = 300; 8.8% vs 22.5%; odds ratio, 0.20; 95% CI, 0.08-0.49). A significant reduction in the incidence of mild or worse COVID-19 was not observed when analyzed for the staff (n = 666) in the prevention population (8.4% vs 12.2%; odds ratio, 0.58; 95% CI, 0.33-1.02).
Analysis of key secondary end points showed significant decreases in the incidence of COVID-19 of moderate or worse severity by day 57 (8.3% vs 14.1%; odds ratio, 0.46; 95% CI, 0.29-0.73) and the incidence of SARS-CoV-2 infection within 4 weeks of randomization (17.9% vs 23.3%; odds ratio, 0.66; 95% CI, 0.46-0.94) for the bamlanivimab vs control groups. By day 57, there were no COVID-19–related deaths among participants who received bamlanivimab, whereas 5 COVID-19–related deaths occurred among participants in the placebo group (including 1 death in the treatment population). Among those who acquired SARS-CoV-2 infection (n = 282), viral loads at the time of the first positive test result were lower in the bamlanivimab group compared with the placebo group (2.44 vs 3.64 log10, respectively). Moreover, by 3 weeks after diagnosis, more participants in the bamlanivimab group than in the placebo group achieved viral clearance (93.0% vs 78.0%, respectively). Adverse events occurred in 20.1% of the bamlanivimab group and 18.9% of the control group, with serious adverse events were reported in 3.7% and 3.2%, respectively. Hypersensitivity reactions occurred in 3 bamlanivimab recipients (0.5%) but no placebo recipients.
The report by Cohen et al8 provides compelling proof of concept that mAbs directed against the SARS-CoV-2 spike protein can have clinically important benefits when used as postexposure prophylaxis. The study represents a logistical tour de force that required deploying mobile vans capable of transporting study personnel and all necessary supplies to implement the trial at skilled nursing and assisted living facilities housing vulnerable older populations across the country.9 The investigation also illustrates the strengths of harnessing the capacity of existing federally funded clinical trials networks (here coalesced into the COVID-19 Prevention Network), the pharmaceutical industry, and the National Institute of Allergy and Infectious Diseases in response to a public health crisis. Even as increasing proportions of residents of assisted living and long-term care facilities are vaccinated, establishing the principle that passive immune prophylaxis can prevent outbreaks of COVID-19 in these settings is an important advance. Inevitably, not all residents will be vaccinated nor will all vaccinees have protective responses. It is easy to conceive of situations in which SARS-CoV-2 mAbs might be used to abort outbreaks of COVID-19 in residential facilities similar to how oseltamivir is used to prevent influenza.10 Lower viral loads and faster clearance of SARS-CoV-2 among recipients of mAbs who do become infected could reduce the risk of onward transmission. However, a weakness of the study by Cohen et al was the limited racial and ethnic diversity of the participants; the study population included a relatively small proportion of Black or African American individuals (range, 7.8%-8.8% across the study groups) and Hispanic or Latino individuals (range, 1.9%-6.1%).
The study by Cohen et al also highlights the challenges of developing novel therapeutic and preventive interventions in the setting of a rapidly evolving pandemic. Since completion of this trial in January 2021, novel variants carrying spike protein mutations that reduce susceptibility to bamlanivimab (notably the E484K and L452R mutations) have emerged11; these variants currently constitute more than 20% of viral lineages circulating in the US.12 Consequently, the FDA has withdrawn the EUA for bamlanivimab13; although this monoclonal antibody is no longer available as a single treatment agent for prophylaxis or treatment of COVID-19, as was used in this clinical trial, the EUA for bamlanivimab plus etesevimab remains in place. Given the absence of any clinical trial data on etesevimab alone, the future clinical utility of this combination in the context of spreading SARS-CoV-2 resistance to bamlanivimab is uncertain.
Corresponding Author: Daniel R. Kuritzkes, MD, Division of Infectious Diseases, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (firstname.lastname@example.org).
Published Online: June 3, 2021. doi:10.1001/jama.2021.7515
Conflict of Interest Disclosures: Dr Kuritzkes reported receiving consulting honoraria from GlaxoSmithKline.
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Kuritzkes DR. Bamlanivimab for Prevention of COVID-19. JAMA. Published online June 03, 2021. doi:10.1001/jama.2021.7515
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