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The continuing emergence of SARS-CoV-2 variants highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by vaccination based on the ancestral (hereafter referred to as WT) strain would compromise the antibody response to Omicron-based boosters1–5. Vaccination strategies to counter immune imprinting are critically needed. Here we investigated the degree and dynamics of immune imprinting in mouse models and human cohorts, especially focusing on the role of repeated Omicron stimulation. In mice, the efficacy of single Omicron boosting is heavily limited when using variants that are antigenically distinct from WT—such as the XBB variant—and this concerning situation could be mitigated by a second Omicron booster. Similarly, in humans, repeated Omicron infections could alleviate WT vaccination-induced immune imprinting and generate broad neutralization responses in both plasma and nasal mucosa. Notably, deep mutational scanning-based epitope characterization of 781 receptor-binding domain (RBD)-targeting monoclonal antibodies isolated from repeated Omicron infection revealed that double Omicron exposure could induce a large proportion of matured Omicron-specific antibodies that have distinct RBD epitopes to WT-induced antibodies. Consequently, immune imprinting was largely mitigated, and the bias towards non-neutralizing epitopes observed in single Omicron exposures was restored. On the basis of the deep mutational scanning profiles, we identified evolution hotspots of XBB.1.5 RBD and demonstrated that these mutations could further boost the immune-evasion capability of XBB.1.5 while maintaining high ACE2-binding affinity. Our findings suggest that the WT component should be abandoned when updating COVID-19 vaccines, and individuals without prior Omicron exposure should receive two updated vaccine boosters.Exposure to early variants of SARS-CoV-2 results in immune imprinting in mouse models and in humans, reducing neutralizing antibody titres against Omicron variants, which could be mitigated with multiple updated boosters. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening1,2 to determine the profiles of RBD escaping mutations for 247 human anti-RBD neutralizing antibodies and show that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A–F)—a grouping that is highly concordant with knowledge-based structural classifications3–5. Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups. Specifically, neutralizing antibodies in groups A–D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Antibodies in group E (for example, S309)6 and group F (for example, bibr3022)7, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes. In total, over 85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was greatly undermined by Omicron, whereas VIR-7831 and DXP-604 still functioned at a reduced efficacy. Together, our data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus conserved region will remain most effective. Our results inform the development of antibody-based drugs and vaccines against Omicron and future variants.A high-throughput yeast display platform is used to analyse the profiles of mutations in the SARS-CoV-2 receptor-binding domain (RBD) that enable escape from antibodies, and suggests that most anti-RBD antibodies can be escaped by the Omicron variant. [ABSTRACT FROM AUTHOR]

The continuous evolution of SARS-CoV-2, particularly the emergence of BA.2.86/JN.1 lineage replacing XBB, necessitates re-evaluation of vaccine compositions 1-3 . Here, we provide a comprehensive analysis of the humoral immune response to XBB and JN.1 human exposure. We demonstrate the antigenic distinctiveness of XBB and JN.1 lineages in SARS-CoV-2-naive individuals, and JN.1 infection elicits superior plasma neutralization against its subvariants. We highlight KP.3's strong immune evasion and receptor binding capability, supporting its foreseeable prevalence. Extensive analysis of the BCR repertoire, isolating ~2000 RBD-specific antibodies with their targeting epitopes characterized by deep mutational scanning (DMS), underscores the superiority of JN.1-elicited memory B cells 4,5 . Class 1 IGHV3-53/3-66-derived neutralizing antibodies (NAbs) contribute majorly within wildtype-reactive NAbs against JN.1. However, KP.2 and KP.3 evade a substantial subset, even those induced by JN.1, advocating for booster updates to KP.2/KP.3. JN.1-induced Omicron-specific antibodies also demonstrate high potency across Omicron. Escape hotspots of these NAbs have already been mutated, resulting in higher immune barrier to escape, considering probable recovery of escaped NAbs. Additionally, the prevalence of IGHV3-53/3-66-derived antibodies, and their capability of competing with all Omicron-specific NAbs suggests their inhibitory role on the activation of Omicron-specific naive B cells, potentially explaining the heavy immune imprinting in mRNA-vaccinated individuals 6-8 . These findings delineate the evolving antibody response to Omicron antigenic shift from XBB to JN.1, and highlight the importance of developing JN.1-lineage, especially KP.2/KP.3-based vaccine boosters., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)