Biology subjects

Uwamino, Y.

Publications and source records attributed to Uwamino, Y..

7 recordsLinked to original sources

bioRxiv2025

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

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.

microbiology↗

bioRxiv2025

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

In the spring of 2025, multiple SARS-CoV-2 Omicron JN.1 subvariants were circulating, with LP.8.1 among the major variants. Pharmaceutical companies such as Pfizer/BioNTech, Moderna, and Novavax/Takeda adopted monovalent LP.8.1 for their 2025-2026 season vaccines, following recommendations issued by the WHO in May 2025. As of November 2025, SARS-CoV-2 variants including LP.8.1, XEC, NB.1.8.1, and XFG--all designated as variants under monitoring--were circulating. In terms of the spike gene, these recent variants as well as LP.8.1 are derived from JN.1. Moreover, BA.3.2, a BA.3 descendant with multiple mutations in the spike gene, has recently emerged and exhibits robust immune evasion. In Japan, the rollout of the LP.8.1-based vaccination has progressed since the end of September 2025. We previously reported the humoral immunity induced by the XBB.1.5-based monovalent vaccine in 2023 and the JN.1-based monovalent vaccine in 2024 in the Japanese population. Here, we investigated the efficiency of humoral immunity induced by two LP.8.1-based vaccines, the mRNA vaccine from Pfizer/BioNTech and the recombinant protein-based vaccine from Novavax/Takeda, in Japan. We performed neutralization assays using sera obtained from individuals who received the LP.8.1 mRNA vaccine from Pfizer/BioNTech (N=29) or the LP.8.1 recombinant protein vaccine from Novavax/Takeda (N=20) with pseudoviruses harboring spike proteins of B.1.1, BA.5, XBB.1.5, JN.1, LP.8.1, XEC, NB.1.8.1, XFG and BA.3.2. In both mRNA and protein-based vaccinee groups, the change in 50% neutralizing titer (NT50) against variants that were predominant before JN.1 (i.e., B.1.1, BA.5 and XBB.1.5) were smaller than those against JN.1 and its subvariants, including LP.8.1, XEC, NB.1.8.1 and XFG. Consistent with recent studies, neutralizing antibodies against BA.3.2 were induced by both vaccines. However, the induction fold change of BA.3.2 was smaller than those of JN.1 and its subvariants. Next, we tested humoral immune response of participants who received both JN.1-based vaccine in 2024 and LP.8.1-based vaccine in 2025 (N=15). Approximately a year after the JN.1-based vaccination, neutralization titer has waned against all variants tested. However, when we compare the NT50s of pre-vaccination sera between 2025 and 2024, those in 2025 against all variants except for B.1.1 were significantly higher than those last year. This suggests that the cross-neutralizing antibodies induced by JN.1-based vaccination were still maintained for a year. Furthermore, the neutralization abilities against the JN.1 sublineages tested and BA.3.2 were significantly reboosted after the LP.8.1-based vaccination. Our study shows immune boosting by the LP.8.1-based vaccine is effective in achieving cross-neutralization against a broad range of JN.1 sublineages in a JN.1-naive population and in recalling waning humoral immunity against these subvariants.

microbiology↗

bioRxiv2024

Robust antiviral humoral immunity induced by JN.1 monovalent mRNA vaccines against a broad range of SARS-CoV-2 Omicron subvariants including JN.1, KP.3.1.1 and XEC

As of November 2024, SARS-CoV-2 Omicron JN.1 subvariants, such as KP.2 (JN.1.11.1.2), KP.3 (JN.1.11.1.3), KP.3.1.1 (JN.1.11.1.3.1.1), and XEC -- a recombinant lineage between KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3) -- have been circulating in several countries. To control the infection with SARS-CoV-2 Omicron JN.1 subvariants, JN.1 monovalent mRNA vaccines have been developed. Some previous reports showed that the JN.1 monovalent mRNA vaccine of Pfizer/BioNTech (US/Germany) increased antiviral humoral immunity against JN.1 subvariants and XEC. However, the efficacy of other available JN.1 monovalent mRNA vaccines (e.g., Daiichi-Sankyo, Japan) remains unassessed. To validate the antiviral efficacy induced by JN.1 mRNA vaccines, sera were collected from individuals vaccinated with Pfizer/BioNTech JN.1 mRNA vaccine (N=15) or Daiichi-Sankyo JN.1 mRNA vaccine (N=19) before and 3-4 weeks after vaccination. We then performed a neutralization assay using these sera and pseudoviruses. Both Pfizer/BioNTech JN.1 vaccine (2.4-to 8.0-fold, P=0.0001) and Daiichi-Sankyo JN.1 vaccine (2.3-to 13-fold, P=0.0001) boosted antiviral humoral immunity against all variants tested with statistical significance. While the Pfizer/BioNTech mRNA vaccine encodes the full-length JN.1 spike (S), the Daiichi-Sankyo mRNA vaccine encodes the receptor-binding domain of JN.1 S. Our data suggest that the receptor-binding domain of JN.1 S can effectively induce antiviral humoral immunity against JN.1 subvariants and XEC comparable to the full-length JN.1 S. However, it should be considered that the sizes of our cohorts are relatively small (<20 donors per cohort), and donor characteristics, such as age, sex, underlying disease status, and previous SARS-CoV-2 infection, may critically affect the experimental results. Future investigations with larger cohorts will address this concern. When compared to vaccination with JN.1 mRNA vaccines, our previous investigations showed that the natural infection of JN.1 and KP.3.3 elicited poorer antiviral humoral immunity against JN.1 and its subvariants. Our results suggest that the JN.1 mRNA vaccination more robustly induces antiviral humoral immunity against recent JN.1 subvariants than the natural infection of JN.1 subvariants regardless of manufacturer. Moreover, as we reported last year, the humoral immunity induced by XBB.1.5 monovalent mRNA vaccine against XBB.1.5 was weaker than that against ancestral B.1.1. However, in the case of JN.1 monovalent mRNA vaccine, here we showed that the 50% neutralization titer against XBB.1.5 is greater than that against ancestral B.1.1. These observations imply that immune imprinting has shifted from that biased toward pre-Omicron to that biased toward Omicron, depending on the time and/or number of immune stimuli (e.g., infection and/or vaccination).

microbiology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 XEC variant

The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions (e.g., S:R346T, S:F456L, and S:Q493E), have emerged concurrently. As of October 2024, KP.3.1.1 (JN.1.11.1.3.1.1), which acquired S:31del, outcompeted other JN.1 subvariants including KP.2 and KP.3 and is the most predominant SARS-CoV-2 variant in the world. Thereafter, XEC, a recombinant lineage of KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3), was first identified in Germany on August 7, 2024. XEC acquired two S substitutions, S:T22N and S:F59S, compared with KP.3 through recombination, with a breakpoint at genomic position 21,738-22,599. We estimated the relative effective reproduction number (Re) of XEC using a Bayesian multinomial logistic model based on genome surveillance data from the USA, the United Kingdom, France, Canada, and Germany, where this variant has spread as of August 2024. In the USA, the Re of XEC is 1.13-fold higher than that of KP.3.1.1. Additionally, the other countries under investigation herein showed higher Re for XEC. These results suggest that XEC has the potential to outcompete the other major lineage including KP.3.1.1. We then assessed the virological properties of XEC using pseudoviruses. Pseudovirus infection assay showed that the infectivity of KP.3.1.1 and XEC was significantly higher than that of KP.3. Although S:T22N did not affect the infectivity of the pseudovirus based on KP.3, S:F59S significantly increased it. Neutralization assay was performed using three types of human sera: convalescent sera after breakthrough infection (BTI) with XBB.1.5 or KP.3.3, and convalescent sera after JN.1 infection. In all serum groups, XEC as well as KP.3.1.1 showed immune resistance when compared to KP.3 with statistically significant differences. In the cases of XBB.1.5 BTI sera and JN.1 infection sera, the 50% neutralization titers (NT50s) of XEC and KP.3.1.1 were comparable. However, we revealed that the NT50 of XEC was significantly (1.3-fold) lower than that of KP.3.1.1. Moreover, both S:T22N and S:F59S significantly (1.5-fold and 1.6-fold) increased the resistance to KP.3.3 BTI sera. Here we showed that XEC exhibited higher pseudovirus infectivity and higher immune evasion than KP.3. Particularly, XEC exhibited more robust immune resistance to KP.3.3 BTI sera than KP.3.1.1. Our data suggest that the higher Re of XEC than KP.3.1.1 is attributed to this property and XEC will be a predominant SARS-CoV-2 variant in the world in the near future.

microbiology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 KP.2 variant

The JN.1 variant (BA.2.86.1.1), arising from BA.2.86(.1) with the S:L455S substitution, exhibited increased fitness and outcompeted the previous dominant XBB lineage by the biggening of 2024. JN.1 subsequently diversified, leading to the emergence of descendants with spike (S) protein substitutions such as S:R346T and S:F456L. Particularly, the KP.2 (JN.1.11.1.2) variant, a descendant of JN.1 bearing both S:R346T and S:F456L, is rapidly spreading in multiple regions as of April 2024. Here, we investigated the virological properties of KP.2. KP.2 has three substitutions in the S protein including the two above and additional one substitution in non-S protein compared with JN.1. We estimated the relative effective reproduction number (Re) of KP.2 based on the genome surveillance data from the USA, United Kingdom, and Canada where >30 sequences of KP.2 has been reported, using a Bayesian multinomial logistic model. The Re of KP.2 is 1.22-, 1.32-, and 1.26-times higher than that of JN.1 in USA, United Kingdom, and Canada, respectively. These results suggest that KP.2 has higher viral fitness and potentially becomes the predominant lineage worldwide. Indeed, as of the beginning of April 2024, the estimated variant frequency of KP.2 has already reached 20% in United Kingdom. The pseudovirus assay showed that the infectivity of KP.2 is significantly (10.5-fold) lower than that of JN.1. We then performed a neutralization assay using monovalent XBB.1.5 vaccine sera and breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections. In all cases, the 50% neutralization titer (NT50) against KP.2 was significantly lower than that against JN.1. Particularly, KP.2 shows the most significant resistance to the sera of monovalent XBB.1.5 vaccinee without infection (3.1-fold) as well as those who with infection (1.8-fold). Altogether, these results suggest that the increased immune resistance ability of KP.2 partially contributes to the higher Re more than previous variants including JN.1.

microbiology↗

bioRxiv2023

Antiviral humoral immunity against SARS-CoV-2 Omicron subvariants induced by XBB.1.5 monovalent vaccine in infection-naive and XBB-infected individuals

To control infection with SARS-CoV-2 Omicron XBB subvariants, the XBB.1.5 monovalent mRNA vaccine has been available since September 2023. However, we have found that natural infection with XBB subvariants, including XBB.1.5, does not efficiently induce humoral immunity against the infecting XBB subvariants. These observations raise the possibility that the XBB.1.5 monovalent vaccine may not be able to efficiently induce humoral immunity against emerging SARS-CoV-2 variants, including a variety of XBB subvariants (XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and HK.3) as well as BA.2.86. To address this possibility, we collected two types of sera from individuals vaccinated with the XBB.1.5 vaccine; those who had not been previously infected with SARS-CoV-2 and those who had been infected with XBB subvariants prior to XBB.1.5 vaccination. We collected sera before and 3-4 weeks after vaccination, and then performed a neutralization assay using these sera and pseudoviruses.

microbiology↗

bioRxiv2022

Memory B cells and memory T cells induced by SARS-CoV-2 booster vaccination or infection show different dynamics and efficacy to the Omicron variant.

Although BNT162b2 vaccination was shown to prevent infection and reduce COVID-19 severity, and the persistence of immunological memory generated by the vaccination has not been well elucidated. We evaluated memory B and T cell responses to the SARS-CoV-2 spike protein before and after the third BNT162b2 booster. Although the antibody titer against the spike receptor-binding domain (RBD) decreased significantly 8 months after the second vaccination, the number of memory B cells continued to increase, while the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the antibody titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, while memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- cTfh1 was positively correlated with RBD-specific antibody-secreting B cells. Furthermore, T cell-dependent antibody production from reactivated memory B cells in vitro was correlated to the Tfh-like cytokine levels. For the response to variant RBDs, although 60%-80% of memory B cells could bind to the Omicron RBD, their binding affinity was low, while memory T cells show an equal response to the Omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate antibody production and T cell responses after Omicron strain infection, which prevents severe illness and death due to COVID-19.

immunology↗