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Director, The Peter Doherty Institute for Infection and Immunity
Professor of Infectious Diseases
University of Melbourne
Consultant Infectious Diseases Physician
Alfred Hospital and Royal Melbourne Hospital
Sharon Lewin, AO, FRACP, PhD, FAAHMS, has disclosed that she has received consulting fees from AbbVie, Gilead Sciences, and ViiV Healthcare; funds for research support from Leidos; and other financial or material support from Gilead Sciences, Merck, and ViiV Healthcare.
Many countries, both low and high resource, still have low rates of vaccination because of low availability of vaccines or structural barriers to delivering COVID-19 vaccines. Furthermore, even when vaccines are widely available, there will always be some individuals who refuse vaccination for various reasons or who do not respond adequately to vaccination. The availability of alternate prevention strategies, therefore, remains of great interest, particularly for prevention of infection of the most vulnerable populations. This approach is commonly used for many infectious diseases, for example, in outbreaks of hepatitis A where vaccines or antibodies may be administered to contacts.
An example of a vulnerable population that could benefit from COVID-19 pre-exposure and postexposure prophylaxis is persons living in nursing homes or assisted living facilities, where outbreaks of COVID-19 have been associated with high rates of morbidity and mortality. In the Unites States as of June 2021, for example, long-term care facilities accounted for 5% of SARS-CoV-2 infections but 32% of COVID-19–related deaths. In Australia between late January 2020 and June 7, 2020 (before the widespread availability of vaccines), 685 of 910 (75%) deaths from COVID-19 occurred in nursing homes. Even with better vaccine availability, this setting will require alternative prevention strategies.
New Data on Bamlanivimab for Prevention of COVID-19
In a recent study published in JAMA by Cohen and colleagues, bamlanivimab, a neutralizing monoclonal antibody that recognizes the spike protein, was evaluated in a multipart, randomized, double-blind, placebo-controlled, single-dose phase III study to determine the efficacy and safety of preventing COVID-19 and SARS-CoV-2 infection. The BLAZE-2 trial participants were residents and staff at 74 US nursing and assisted living facilities with at least 1 confirmed SARS-CoV-2 index case and were negative at baseline for SARS-CoV-2 infection and serology. Participants were randomized to receive bamlanivimab or placebo before the results were available. Those who were negative at baseline for SARS-CoV-2 (nasopharyngeal and nasal swabs) and serology comprised the prevention population (N = 966).
The mean age was 53 years (range: 18-104) and 75% were women. The incidence of SARS-CoV-2 infections among those treated with bamlanivimab vs placebo was 8.5% vs 15.2%, respectively, with an odds ratio of 0.43 (95% CI: 0.28-0.68; P <.001). Although adverse events occurred in both the antibody and placebo arms, there were no statistically significant differences between the two. The incidence of moderate or worse severity of COVID-19 by Day 57 was reduced in the bamlanivimab group compared with placebo (8.3% vs 14.1%, respectively), with the greatest benefit seen in residents but not in staff. Bamlanivimab was also associated with lower incidence of SARS-CoV-2 infection of 17.9% at 4 weeks post randomization compared with 23.3% in the placebo group.
This intervention suggests an effective strategy to protect the most vulnerable populations from COVID-19. However, there are a few limitations to the study. First, the study was performed when there were no new variants of concern. More recently, multiple variants (including beta, gamma, delta, and kappa, which all contain a mutation at position E484) have demonstrated resistance to bamlanivimab. However, multiple other monoclonal antibodies are now approved, at least in the United States with Emergency Use Authorization, including casirivimab (REGN10933), imdevimab (REGN10987), and etesevimab (LY-CoV016). Whether these agents administered alone or in combination will have similar efficacy to bamlanivimab for prevention of COVID-19 remains to be demonstrated, but it is highly likely. Second, it remains to be determined whether passive immunotherapy has a role in highly vulnerable populations already vaccinated, for example, for recipients of vaccines that induce suboptimal protection against variants of concern. Finally, the need to administer antibodies by infusion remains an added complexity. Recent reports of topical administration of SARS-CoV-2 antibodies that protect against infection, including variants of concern, are very encouraging, although currently only demonstrated in animal models.
New Data on Sotrovimab as Treatment of COVID-19
Sotrovimab, formerly known as VIR-7831, is a pan-sarbecovirus monoclonal antibody that was reported in a recent preprint to maintain neutralization capacity against many variants of concern, including alpha, beta, and gamma strains, although neutralization capacity was reduced with some variants. Sotrovimab also contains a 2–amino acid Fc modification (termed LS) to increase half-life and potentially improve bioavailability in the respiratory mucosa through enhanced engagement with the neonatal Fc receptor.
Sotrovimab is being evaluated as a treatment for COVID-19 in a high-risk outpatient population in the COMET-ICE study, and results of a preplanned interim analysis of were recently made available. COMET-ICE is a multicenter, double-blind phase III trial in which nonhospitalized patients with symptomatic COVID-19 and at least 1 risk factor for disease progression (defined as hospitalization longer than 24 hours or death, through Day 29) were randomized 1:1 to receive sotrovimab 500 mg or placebo. At the time of interim analysis, 868 patients were randomized, and the most common risk factors for severe COVID-19 were obesity, aged 55 years or older, and diabetes requiring medication. In an intent-to-treat analysis, the risk of COVID-19 hospitalization was significantly reduced by 85% (97.24% CI: 44% to 96%; P = .002) with a total of 3 (1%) patients progressing to the primary endpoint in the sotrovimab group vs 21 (7%) patients in the placebo group. All 5 patients admitted to intensive care, including one who died by Day 29, received placebo.
As a result of the efficacy of sotrovimab in this setting, an independent data monitoring committee recommended that enrollment on the study be stopped on March 10, 2021, at which time 1057 patients had been randomized. On Friday May 21, 2021, the European Medicines Agency issued advice on use of sotrovimab for treating COVID-19. The Agency concluded that “sotrovimab can be used to treat confirmed COVID-19 in adults and adolescents (aged 12 years and above and weighing at least 40 kg) who do not require supplemental oxygen therapy and who are at risk of progressing to severe COVID-19.” These results are very encouraging for a potentially efficacious intervention for nonhospitalized, high-risk populations with COVID-19. Given that the target of sotrovimab is not involved in receptor binding, the possibility of emerging resistance is low and to date has not been reported.
In summary, potent neutralizing antibodies are an attractive strategy for the prevention and treatment of a new pandemic virus, as antibodies can be generated quickly and have a faster path to the clinic than small molecules. Hope was high in early 2020 that antibodies would be a major advance in both treatment and prevention of COVID-19. The 2 papers presented here show a clear role for monoclonal antibodies in preventing infection (providing the antibody can neutralize the relevant outbreak strain) and in treating to prevent severe COVID-19 in nonhospitalized patients with COVID-19 and at least 1 comorbidity. However, we have learned that many challenges remain in using SARS-CoV-2 monoclonal antibodies, including resistance to monoclonal antibodies with variants of concern, the need for intravenous administration, significant cost, and understanding the best timing for administration in people with established infection. In relation to the role of antibodies for prevention, despite the availability and widespread uptake of vaccines, passive immunotherapy will still likely have an important role in high-risk settings such as residential facilities when there is a high number of unvaccinated individuals or in the setting of an outbreak with a new variant that is resistant to available vaccines. Recent data from the United Kingdom regarding the rapid spread of the delta variant in a population with high rates of COVID-19 vaccination is a sober reminder that vaccination alone may not be sufficient to end SARS-CoV-2 infections and COVID-19–related deaths.
How do new data on monoclonal antibodies influence your thinking about COVID-19 treatment and prevention? Answer the polling question and join the conversation by posting in the discussion section. Then, see more from this ongoing series spotlighting exciting new and clinically significant data on COVID-19.