Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting

Abstract

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.

Waning immunity and IgG4 responses following bivalent mRNA boosting

“…This phenomenon has also been recently described in studies where immunization with monovalent or bivalent mRNA vaccines induced limited NAbs against BA.5 and XBB variants (37)(38)(39). Moreover, boosting with monovalent BA.5 or XBB vaccines as well as breakthrough infections resulted in superior NAb responses against these variants (37,38). Together, these data suggest that future COVID-19 boosters should exclude the ancestral WA1/2020 spike immunogen, which is the current plan for the 2023 booster.…”

“…Immune imprinting likely contributed to NAb responses being directed primarily against the ancestral WA1/2020 strain following bivalent mRNA boosting (34)(35)(36). This phenomenon has also been recently described in studies where immunization with monovalent or bivalent mRNA vaccines induced limited NAbs against BA.5 and XBB variants (37)(38)(39). Moreover, boosting with monovalent BA.5 or XBB vaccines as well as breakthrough infections resulted in superior NAb responses against these variants (37,38).…”

Antigenicity assessment of SARS-CoV-2 saltation variant BA.2.87.1

“…Subsequently, we evaluated the neutralizing potency of a collection of BA.2-effective monoclonal antibodies (mAbs) derived from repetitive Omicron infections that target various epitopes of RBD, as defined in our previous studies, to further interrogate BA.2.87.1's immune escape capability and mechanism (Figure 2A) 4,[18][19][20][21] . Most of the mAbs involved remain reactive to XBB.1.5 as well.…”

Risk of subsequent SARS‐CoV‐2 infection among vaccinated employees with or without hybrid immunity acquired early in the Omicron‐predominant era of the COVID‐19 pandemic

“…13,14 Recent evidence suggests that optimal vaccination strategies for mitigating such negative imprinting going forward may differ depending on the degree of hybrid immunity present. 17 There are potential limitations of our study. While our analysis assumes 100% of the workforce was vaccinated, we can only verify that 98% of the SFDPH employees working regularly at the ZSFG medical center received a primary vaccination series six or more weeks before the Omicron variant became the predominant circulating SARS-CoV-2 variant in the United States.…”