Browse the corpus

To the Editor: In March 2024, pemivibart (Invivyd) was authorized for emergency use as preexposure prophylaxis against coronavirus disease 2019 (Covid-19) for immunocompromised patients who might not have a robust response to vaccines.1 This human monoclonal antibody was derived from ADG-2, an antibody directed at the receptor-binding domain class 1/4 region in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This antibody had previously shown protective efficacy against SARS-CoV-2 infection.2 However, ADG-2 lost virus-neutralizing activity against the omicron variant and its subsequent subvariants. Nine mutations (five in the heavy chain and four in the light chain) were introduced to create pemivibart, which showed greater breadth in neutralizing recent SARS-CoV-2 strains.3 The JN.1 subvariant of SARS-CoV-2 emerged in late 2023 and rapidly became dominant globally. In the past 6 months, JN.1 has continued to evolve, giving rise to multiple sublineages with unique spike mutations (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org). KP.2 was a JN.1 progeny that appeared, but it was later outcompeted by KP.3, with both sublineages gradually displacing the original JN.1 (Fig. S1B). More recently, KP.3.1.1, KP.2.3, and LB.1 have emerged, each with independent development of a deletion of S31 in the N-terminal domain of the spike protein; KP.3.1.1 is now a fast-growing sublineage worldwide.

ut it was later outcompeted by KP.3, with both sublineages gradually displacing the original JN.1 (Fig. S1B). More recently, KP.3.1.1, KP.2.3, and LB.1 have emerged, each with independent development of a deletion of S31 in the N-terminal domain of the spike protein; KP.3.1.1 is now a fast-growing sublineage worldwide. In this study, we assessed the effect of recent SARS-CoV-2 evolution on the neutralizing activity of a version of pemivibart that we synthesized in our laboratory. We constructed pseudoviruses for JN.1, KP.2, KP.3, KP.2.3, KP.3.1.1, and LB.1 and subjected them to neutralization assays, as described previously.4 Our laboratory-synthesized pemivibart neutralized both JN.1 and KP.2 in vitro with similar activity, whereas its potency was decreased modestly against LB.1, KP.2.3, and KP.3 and substantially against KP.3.1.1 (Figure 1A). The 50% inhibitory concentration (IC50) of our laboratory-synthesized pemivibart against KP.3.1.1 was approximately 4.0 μg per milliliter or approximately 25 times as high as that against JN.1 (Figure 1B), an increase that could reduce the protective efficacy of pemivibart against this subvariant. The factor changes in the 90% inhibitory concentration (IC90) mirrored those observed for IC50, but 99% neutralization of KP.3.1.1 and KP.2.3 could not be achieved up to a concentration of 250 μg per milliliter. Pemivibart is authorized to be administered intravenously at a dose of 4500 mg every 3 months. The trough geometric mean serum concentration of pemivibart has been reported to be 175 μg per milliliter,3 which is well above the IC50 and IC90 values against KP.3.1.1. However, the mucosal concentrations of pemivibart that are needed to confer protection against infection (typically, a fraction of serum levels) are unknown. Meanwhile, we note that our virus neutralization assays against multiple SARS-CoV-2 strains yielded results similar to those reported by Invivyd (Fig. S2).

3.1.1. However, the mucosal concentrations of pemivibart that are needed to confer protection against infection (typically, a fraction of serum levels) are unknown. Meanwhile, we note that our virus neutralization assays against multiple SARS-CoV-2 strains yielded results similar to those reported by Invivyd (Fig. S2). Comparing the results of the neutralization of KP.2 versus KP.3 (Figure 1B), it is apparent that the Q493E mutation has a greater effect on the activity of our pemivibart than the R346T mutation. Although Q493E does not reside within the epitope of ADG-22 (nor, presumably, of pemivibart), the mutation may increase resistance to pemivibart because of an enhanced binding affinity for the ACE2 receptor facilitated by an epistatic effect with the F456L mutation.5 The precise structural mechanism notwithstanding, our findings show a substantial loss of activity of our pemivibart against KP.3.1.1, the most rapidly expanding SARS-CoV-2 sublineage worldwide. Close monitoring of the clinical efficacy of this newly authorized monoclonal antibody is warranted.