Humoral immunity induced by XEC monovalent vaccines against SARS-CoV-2 variants including XEC, LP.8.1, NB.1.8.1, XFG, and BA.3.2

Abstract After the emergence of SARS-CoV-2 Omicron variant at the end of 2021, Omicron has highly diverged into various sublineages: e.g., BA.5 in 2022, XBB.1.5 in 2023, JN.1 in 2024. Currently, several JN.1 subvariants including XEC, LP.8.1, NB.1.8.1 and XFG are circulating worldwide. Additionally, recent studies show that BA.3.2, a descendant of Omicron BA.3, exhibits profound immune evasion potential. On December 5, 2025, BA.3.2, was designated a variant under monitoring by the WHO. To prevent COVID-19, several countries including Japan have continuously developed and approved variant-adapted vaccines: e.g., ancestral/BA.5 bivalent vaccine in 20223, XBB.1.5-based monovalent vaccine in 20234, JN.1-based monovalent vaccine in 2024, and LP.8.1-based monovalent vaccine in 2025. Since XEC was more prevalent than LP.8.1 at the beginning of 2025 in Japan, two Japanese pharmaceutical companies, Daiichi Sankyo and Meiji Seika Pharma, have produced XEC-based vaccines. Here, we investigated the antiviral immunity induced by XEC-based monovalent vaccines against recently circulating SARS-CoV-2 variants, as well as BA.3.2, in the Japanese population. To assess the neutralizing antibody response induced by XEC-based vaccines, we obtained sera from individuals who had been vaccinated with the XEC-based mRNA monovalent vaccine produced by Daiichi Sankyo (N=22) or the XEC-based self-amplifying replicon vaccine produced by Meiji Seika Pharma (N=20). We collected sera before and 3–4 weeks after vaccination and then performed a neutralization assay using these sera with lentivirus-based pseudoviruses harboring spike proteins of B.1.1, BA.5, XBB.1.5, JN.1, XEC, LP.8.1, NB.1.8.1, XFG and BA.3.2. The 50% neutralization titers of the sera against all variants tested were significantly increased in after vaccination in both Daiichi Sankyo cohort (2.1-fold to 11.9-fold, P<0.0001) and Meiji Seika Pharma cohort (1.4-fold to 3.9-fold, P<0.0005). Consistent with our recent study using the sera from LP.8.1-based vaccinees, the humoral immunity induced by XEC-based vaccines against JN.1 and its subvariants (XEC, LP.8.1, NB.1.8.1 and XFG) was greater than that against other variants (B.1.1, BA.5, XBB.1.5 and BA.3.2). Notably, our result showed that the XEC-based mRNA vaccine induces a stronger humoral immunity compared to the XEC-based replicon vaccine, and even the LP.8.1-adapted vaccines. However, it should be noted that our cohorts are relatively small and may include confounding factors that affect the results, such as age, sex, history of natural infection and vaccination status. Future investigations with larger cohorts are required to better understand this possibility. To compare the immune status induced by XEC- and LP.8.1-based vaccines, we analyzed the cross-neutralization induced by these vaccines using antigenic cartography. The antigenic map was depicted based on the 50% neutralization titers values obtained from this study and our recent study using LP.8.1-based vaccine sera. The cartography showed that the immune status induced by XEC-based vaccines was similar to that induced by LP.8.1-based vaccines against the nine SARS-CoV-2 variant antigens tested. In sum, our investigations, including the recent one8, suggest that all 4 of the JN.1 subvariants-based vaccines that we tested induce profound humoral immunity against a broad range of SARS-CoV-2 variants. Competing Interest Statement N.I. has received lecture fees outside of the submitted work from Asahi Kasei Pharma Corporation, AstraZeneca K.K., bioMerieux Japan Ltd., BD Co., Ltd., Gilead Sciences Inc., GlaxoSmithKline, Meiji Seika Pharma Co., Ltd., MSD K.K., Pfizer, Shionogi Co., Ltd., and Shimadzu Corporation. N.I. has also received research funding from Shimadzu Corporation. K.S. has consulting fees from Moderna Japan Co., Ltd., Takeda Pharmaceutical Co. Ltd. and Shionogi & Co., Ltd and honoraria for lectures from Gilead Sciences, Inc., Moderna Japan Co., Ltd., and Shionogi & Co., Ltd. The other authors declare no competing interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Footnotes Conflict of interest: The authors declare that no competing interests exist.