Why the study?
SARS-CoV-2 continues to evolve and emerging variants might escape immune responses generated by existing vaccines and therapeutic mAbs, making rapid neutralization analysis essential.
The optimized CPER reverse genetics system enables rapid evaluation of therapeutic mAbs against emerging SARS-CoV-2 variants, revealing that while some mAbs retain broad potency, others like S309 and C68.59 lose efficacy against recent Omicron subvariants.
SARS-CoV-2 continues to evolve, and its emerging variants might escape the immune responses generated by existing vaccines and therapeutic mAbs. Accordingly, rapid analysis of their possible neutralization phenotype is essential and can be facilitated by reverse genetics (RGs) systems to regenerate viruses with variant-specific substitutions. Here, we efficiently generate a panel of recent variants of SARS-CoV-2 (Omicron XBB.1.16, EG.5.1, BA.2.86, and JN.1) using a substantially optimized circular polymerase extension reaction (CPER) RGs system. Neutralization potency was analyzed for mAbs targeting different regions of spike protein. mAbs P4-J15, C68.61, S2X259, and IY-2A IgG were able to neutralize all recent viruses. However, S309, which was previously used to treat infection and targets the outer face of RBD, showed ∼75-fold reduction in potency versus JN.1. Moreover, C68.59, which targets the SD1 region of the CTD, was unable to neutralize either BA.2.86 or JN1, which share the E554K substitution in SD1. CPER RGs system and microneutralization assays can be adopted as effective tools to evaluate the efficacy of therapeutic mAbs against emerging variants in a time-responsive manner.
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Afzal et al. (2025) studied this question.
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