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Commentary: mAbs and COVID-19
Monoclonal Antibodies Are Expanding SARS-CoV-2 Prevention and Treatment Strategies

Released: March 09, 2021

Expiration: March 08, 2022

Renslow Sherer
Renslow Sherer, MD
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At the IAS COVID-19 Conference: Prevention held in February 2021, Dr. Myron Cohen provided an informative review of the status of monoclonal antibodies (mAbs) in COVID-19 (“Active and passive vaccination to prevent COVID-19 infection and disease”) and noted that multiple mAbs are in development for the treatment and prevention of SARS-CoV-2 infection. The FDA has granted Emergency Use Authorizations for 2 spike protein mAbs: bamlanivimab (monotherapy or in combination with etesevimab) and the casirivimab/imdevimab combination. Bamlanivimab and etesevimab bind to different but overlapping epitopes in the receptor binding domain (RBD), and casirivimab/imdevimab bind to nonoverlapping epitopes of the RBD.

Preliminary Phase II Trials for COVID-19 Treatment
BLAZE-1 and REGN-COV-2, small phase II trials in outpatients with early symptomatic COVID-19, demonstrated reduced recovery of nasopharyngeal SARS-CoV-2 with bamlanivimab (with and without etesevimab) and with casirivimab/imdevimab, respectively. Both trials demonstrated trends toward clinical benefits of reduced hospitalizations or medical visits. In REGN-COV-2, baseline immune response predicted degree of benefit—that is, patients who were already making their own antibodies benefited less. Both agents were also studied in patients hospitalized with COVID-19 who were receiving remdesivir and other treatments, and in both cases, trials were stopped due to lack of benefit. These data suggest that administration of mAbs early in the course of disease is essential for efficacy and that they have no role in the management of moderate to severe disease. Larger treatment trials are now being enrolled to study mAbs in the setting of early initiation of therapy.

2 Large COVID-19 Prevention Studies in Unique Populations
Both bamlanivimab and casirivimab/imdevimab are being studied for prophylaxis in important populations. BLAZE-2 is a randomized, double-blind, placebo-controlled phase III trial to evaluate the efficacy and safety of bamlanivimab for prevention of SARS-CoV-2 infection in residents and staff of skilled nursing and assisted living facilities where at least 1 case of SARS-CoV-2 infection had been confirmed in the previous 7 days. Preliminary results after all participants reached 8 weeks of follow-up demonstrated significantly lower frequency of symptomatic COVID-19 (primary endpoint) in individuals treated with bamlanivimab compared with placebo (odds ratio: 0.43; P = .00021). In the subgroup of nursing home residents, there was a significantly lower frequency of symptomatic COVID-19 in individuals treated with bamlanivimab compared with placebo (odds ratio: 0.20; P = .00026), suggesting an 80% lower risk of symptomatic COVID-19 in this population. A small group of participants (N = 132) had asymptomatic SARS-CoV-2 infection at enrollment and are being included in an exploratory analysis for treatment. R10933-10987-COV-2069 study is a randomized, double-blind, placebo-controlled phase III trial assessing casirivimab/imdevimab for prevention of SARS-CoV-2 infection in asymptomatic household contacts of people with COVID-19 documented within the previous 4 days and returning home. Preliminary results (N = 409) demonstrated approximately 50% lower rates of overall infection and 100% lower rates of symptomatic infection compared with placebo. In addition, casirivimab/imdevimab compared with placebo was associated with a shortened time of viral shedding (44 weeks vs 9 weeks) and high (>104 copies/mL) viral shedding (22 weeks vs 0 weeks) suggesting a benefit for reduced transmission.  Similar to BLAZE-2, a cohort of patients were asymptomatic but SARS-CoV-2 positive at baseline. Thus, 2 prevention studies are also essentially studying very early treatment of COVID-19 with mAbs in asymptomatic and presymptomatic individuals in a randomized fashion.

How can mAbs be valuable for COVID-19 prevention, and what questions remain?
We need to better understand the best strategies for the effective use of COVID-19 vaccines and mAbs for prevention of SARS-CoV-2 infection and severe illness. mAbs can offer immediate protection for individuals exposed or unvaccinated in high-risk settings in contrast to vaccines that take a week for some benefit and several weeks for full benefit in 2-dose regimens, and nursing homes and other congregate living settings offer increased feasibility for patient identification, counseling, and treatment. mAbs also offer an alternative in the uncommon setting of COVID-19 vaccine allergy. In addition, mAbs may provide insights into the antibody concentrations required to prevent infection as well as early signals for variations in response to mAbs in the presence of SARS-CoV-2 variants. Other important questions include the optimal duration following mAb administration for safe vaccination, and the use of mAbs in the setting of a SARS-CoV-2 infection following vaccination.

Finally, ascertaining the impact of emerging variants on the efficacy of mAbs will be a critical determinant for their utility. Wang and colleagues studied resistance in recently emerging variants from the United Kingdom (B.1.1.7) and South Africa (B.1.351) and found that although B.1.1.7 demonstrated refractory neutralization to some mAbs targeting the RBD, activity of currently available agents was retained. By contrast, the E484K mutation of the B.1.351 variant appeared to be refractory to neutralization by many RBD mAbs including bamlanivimab and casirivimab, which bind to the receptor binding motif of the RBD as well as etesevimab. Of importance, imdevimab, which targets the “outer side” of the RBD, retained activity. In settings in which the variants B.1.351 and P.1 (that was identified in Brazil) are emerging or in which active surveillance of SARS-CoV-2 variants is not available, it may be prudent to choose the combination casirivimab/imdevimab to ensure full activity. All COVID-19 treaters are well advised to watch the epidemiologic trends of these and other variants over time. It has been challenging to persuade eligible people with a new diagnosis of SARS-CoV-2 and mild illness who are over age 65 and/or with significant co-morbidities to accept a one-time intravenous infusion that promises to reduce the incidence of severe illness or death from 9-10% to 2-3%, as these agents have been shown to do in susceptible patients. Additional challenges to prevent and treat people with COVID-19 will evolve with the success of our prevention efforts and the ongoing emergence of new variants.

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