In this issue of the JCI, Gupta et al. (1) report the systematic emergence of SARS-CoV-2 variants expressing Spike mutations in immunocompromised patients treated with different anti-Spike monoclonal antibodies (mAbs) across different pandemic waves. Antibody-based antiviral therapies largely work by neutralizing virions. Resistance to neutralization can be either basal or develop after treatment. Gupta et al. (1) show that the majority of such mutations were treatment specific and conferred specific treatment resistance. These findings closely parallel and confirm previous case reports and small case series reporting that mAb therapy, such as sotrovimab (2), can select for treatment-resistant variants in immunosuppressed patients. Although the immediate clinical importance of the findings by Gupta et al. (1) has been dulled by the withdrawal of all anti-Spike mAb therapies due to the emergence of resistant Omicron sublineages, their experience has valuable implications for other and future antiviral mAbs. mAb treatment–emergent resistance in immunocompromised patients could have been anticipated given what we know from the history of antibody-based therapies, the mechanism of action of mAbs, and the mutation-prone nature of SARS-CoV-2. The evidence that this resistance has occurred with notable incidence has tremendous implications for future therapy and public health policies in response to the pandemic.

Since many viral infections, including SARS-CoV-2, produce a quasi-species swarm in vivo because of the error-prone viral replication, there is always the concern that therapies will select for escape variants. Each mAb recognizes a single epitope on viral surface antigenic determinants, and immunocompromised patients typically have higher baseline viral loads and delayed viral clearance (as the authors demonstrate for SARS-CoV-2). Such a conundrum creates an ideal landscape for treatment-emergent resistance (Figure 1).

mAb therapies select for escape variants in SARS-CoV-2 infection. (A) SARS-CoV-2 infection with susceptible viral strains (blue squares and diamonds) has several potential outcomes after mAb therapy, including the emergence of antibody-resistant strains (orange circles). (B) Infection with a mAb-resistant virus (orange circles) can further diversify viral strains (orange squares and diamonds), yielding strains with the potential for evading vaccine immunity and initiating additional infection waves within the population.

It is relatively easy to select for antibody escape variants in vitro by incubating specific mAbs with replicating virus, and this process has been carried out for Chikungunya virus (3), respiratory syncytial virus (RSV) (4), and SARS-CoV (5). Escape variants can emerge during mAb therapy of RSV experimental infection in Cotton rats (6), or through prophylactic mAb pre-exposure in humans (7). Hence, the findings of Gupta et al. (1) are not surprising, but they are of great importance given the implications for immunocompromised patients with COVID-19 and for potential directions of the pandemic.