Limited Cross-Neutralization of Emerging SARS-CoV-2 BA.3.2.2 After LP.8.1-Updated Vaccination.

The SARS-CoV-2 virus continues to evolve under immune selection pressure, leading to the emergence of antigenically distinct Omicron subvariants such as BA.3.2.2. This sublineage harbors extensive spike mutations, including numerous substitutions within the receptor-binding domain, suggesting potential immune escape from currently deployed vaccines. Given its increasing prevalence, we evaluated the neutralization capacity of variant-adapted vaccines against BA.3.2.2. Using Ad5/35-based adenoviral vaccines encoding JN.1 and LP.8.1 spike antigens, neutralizing antibody responses were assessed in murine and non-human primate models using a pseudotyped lentivirus assay. Antigenic cartography based on neutralization data demonstrated that BA.3.2.2 is antigenically distant from previously circulating variants. Although LP.8.1 vaccination broadened neutralization against multiple variants, neutralizing activity against BA.3.2.2 was markedly lower than that against LP.8.1 and other tested variants. Booster immunization further enhanced responses to matched variants but failed to restore neutralization against BA.3.2.2. These findings indicate that BA.3.2.2 exhibits substantial resistance to vaccine-induced neutralization, underscoring the urgent need for updated vaccine strategies to address newly emerging SARS-CoV-2 variants.