Biology subjects

Kaku, Y.

Publications and source records attributed to Kaku, Y..

10 recordsLinked to original sources

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.3.1.1 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. Thereafter, JN.1 subvariants, such as LB.1 (JN.1.9.2.1), KP.2.3 (JN.1.11.1.2.3), and KP.3.1.1 (JN.1.11.1.3.1.1), which convergently acquired a deletion of Serine at the 31st position in S (S:S31del) in addition to the above substitutions, have emerged and spread as of June 2024. We recently reported the virological features of JN.1 subvariants including KP.2, KP.3, LB.1, and KP.2.3.2,3 Here, we investigated the virological properties of KP.3.1.1. First, we estimated the relative effective reproduction number (Re) of KP.3.1.1 using a Bayesian multinomial logistic model4 based on genome surveillance data from Spain, the USA, France, Canada, and the UK, where this variant has spread as of June 2024. In Spain, the Re of KP.3.1.1 is over 1.2-fold higher than that of JN.1 and even higher than those of KP.2, KP.3, LB.1, and KP.2.3. Additionally, the other countries under investigation herein show higher Re for KP.3.1.1. However, it must be noted there is the possibility of overestimation in these countries due to more limited KP.3.1.1 sequence numbers. These results suggest that KP.3.1.1 will spread worldwide along with other JN.1 sublineages. We then assessed the virological properties of KP.3.1.1 using pseudoviruses. The pseudovirus of KP.3.1.1 had significantly higher infectivity than that of KP.3. Neutralization of KP.3.1.1 was tested using i) convalescent sera after breakthrough infection (BTI) with XBB.1.5 or EG.5, ii) convalescent sera after the infection with HK.3 or JN.1, and iii) sera after monovalent XBB.1.5 vaccination. The 50% neutralization titer (NT50) against KP.3.1.1 was significantly lower than KP.3 (1.4-1.6-fold) in all four groups of convalescent sera tested. KP.3.1.1 also showed a 1.3-fold lower NT50 against XBB.1.5 vaccine sera than KP.3. Moreover, KP.3.1.1 showed stronger resistance with a 1.3-fold lower NT50 with statistical significances to the convalescent sera infected with EG.5 and HK.3 than KP.2.3. Altogether, KP.3.1.1 exhibited a higher Re, higher pseudovirus infectivity, and higher neutralization evasion than KP.3. These results align with our recent report that the JN.1 subvariants with S:S31del (e.g., KP.2.3 and LB.1) exhibited enhanced Re and immune evasion compared to the other JN.1 subvariants without S:S31del (e.g., JN.1, KP.2, and KP.3), highlighting the evolutionary significance of S:S31del in the JN.1 lineages.

microbiology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 KP.3, LB.1 and KP.2.3 variants

The SARS-CoV-2 JN.1 variant, arising from BA.2.86.1 with a substitution in the spike (S) protein, S:L455S, exhibited increased fitness and outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 and KP.3, which convergently acquired S protein substitutions such as S:R346T, S:F456L, and S:Q493E, have emerged concurrently. Furthermore, JN.1 subvariants such as LB.1 and KP.2.3, which convergently acquired S:S31del in addition to the above substitutions, have emerged and spread as of June 2024. Here we investigated the virological properties of KP.3, LB.1 and KP.2.3. We estimated the relative effective reproduction number (Re) of KP.3, LB.1, and KP.2.3 using a Bayesian multinomial logistic model based on the genome surveillance data from Canada, the UK, and the USA, where these variants have spread from March to April 2024. The Re of KP.3 is more than 1.2-fold higher than that of JN.1 and higher than or comparable to that of KP.2 in these countries. Importantly, the Re values of LB.1 and KP.2.3 are even higher than those of KP.2 and KP.3. These results suggest that the three variants we investigated herein, particularly LB.1, and KP.2.3, will become major circulating variants worldwide in addition to KP.2 and KP.3. The pseudovirus infectivity of KP.2 and KP.3 was significantly lower than that of JN.1. On the other hand, the pseudovirus infectivity of LB.1 and KP.2.3 was comparable to that of JN.1. Neutralization assay was conducted by using four types of breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections as well as monovalent XBB.1.5 vaccine sera. In all four groups of BTI sera tested, the 50% neutralization titers (NT50) against LB.1 and KP.2.3 were significantly lower than those against JN.1 (2.2-3.3-fold and 2.0-2.9-fold) and even lower than those against KP.2 (1.6-1.9-fold and 1.4-1.7 fold). Although KP.3 exhibited neutralization resistance against all BTI sera tested than JN.1 (1.6-2.2-fold) with statistical significance, there were no significant differences between KP.3 and KP.2. In the case of infection-naive XBB.1.5 vaccine sera, the NT50 values of JN.1 subvariants were very low. In the case of XBB.1.5 vaccine sera after natural XBB infection, the NT50 values against KP.3, LB.1 and KP.2.3 were significantly lower than those of JN.1 (2.1-2.8-fold) and even lower than KP.2 after infection (1.4-2.0-fold). Overall, our results suggest that the S substitutions convergently acquired in the JN.1 subvariants contribute to immune evasion, and therefore, increase their Re when compared to parental JN.1. More importantly, LB.1 and KP.2.3 exhibited higher pseudovirus infectivity and more robust immune resistance than KP.2. These data suggest that S:S31del is critical to exhibit increased infectivity, increased immune evasion, and therefore, potentially contributes to increased Re.

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

Virological characteristics of the SARS-CoV-2 JN.1 variant

The SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the currently circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. Comparing to XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike (S) protein, indicating a high potential for immune evasion. BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbors S:L455S and three mutations in non-S proteins. S:L455S is a hallmark mutation of JN.1: we have recently shown that HK.3 and other "FLip" variants carry S:L455F, which contributes to increased transmissibility and immune escape ability compared to the parental EG.5.1 variant. Here, we investigated the virological properties of 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↗

bioRxiv2023

Virological characteristics of the SARS-CoV-2 Omicron HK.3 variant harboring the "FLip" substitution

In November 2023, SARS-CoV-2 XBB descendants, including EG.5.1 (XBB.1.9.2.5.1), the currently predominant lineage, are circulating worldwide according to Nextstrain. EG.5.1 has a characteristic amino acid substitution in the spike protein (S), S:F456L, which contributes to its escape from humoral immunity. EG.5.1 has further evolved, and its descendant lineage harboring S:L455F (i.e., EG.5.1+S:L455F) emerged and was named HK.3 (XBB.1.9.2.5.1.1.3). HK.3 was initially discovered in East Asia and is rapidly spreading worldwide. Notably, the XBB subvariants bearing both S:L455F and S:F456L substitutions, including HK.3, are called the "FLip" variants. These FLip variants, such as JG.3 (XBB.1.9.2.5.1.3.3), JF.1 (XBB.1.16.6.1) and GK.3 (XBB.1.5.70.3), have emerged convergently, suggesting that the acquisition of these two substitutions confers a growth advantage to XBB in the human population. Here, we investigated the virological properties of HK.3 as a representative of the FLip variants.

microbiology↗

bioRxiv2023

Antiviral efficacy of the SARS-CoV-2 XBB breakthrough infection sera against Omicron subvariants including EG.5

As of July 2023, EG.5.1 (a.k.a. XBB.1.9.2.5.1), a XBB subvariant bearing the S:Q52H and S:F456L substitutions, alongside the S:F486P substitution (Figure S1A), has rapidly spread in some countries. On July 19, 2023, the WHO classified EG.5 as a variant under monitoring. First, we showed that EG.5.1 exhibits a higher effective reproduction number compared with XBB.1.5, XBB.1.16, and its parental lineage (XBB.1.9.2), suggesting that EG.5.1 will spread globally and outcompete these XBB subvariants in the near future. We then addressed whether EG.5.1 evades from the antiviral effect of the humoral immunity induced by breakthrough infection (BTI) of XBB subvariants and performed a neutralization assay using XBB BTI sera. However, the 50% neutralization titer (NT50) of XBB BTI sera against EG.5.1 was comparable to those against XBB.1.5/1.9.2 and XBB.1.16. Moreover, the sensitivity of EG.5.1 to convalescent sera of XBB.1- and XBB.1.5-infected hamsters was similar to those of XBB.1.5/1.9 and XBB.1.16. These results suggest that the increased Re of EG.5.1 is attributed to neither increased infectivity nor immune evasion from XBB BTI, and the emergence and spread of EG.5 is driven by the other pressures. We previously demonstrated that Omicron BTI cannot efficiently induce antiviral humoral immunity against the variant infected. In fact, the NT50s of the BTI sera of Omicron BA.1, BA.2, and BA.5 against the variant infected were 3.0-, 2.2-, and 3.4-fold lower than that against the ancestral B.1.1 variant, respectively. However, strikingly, we found that the NT50 of the BTI sera of XBB1.5/1.9 and XBB.1.16 against the variant infected were 8.7- and 8.3-fold lower than that against the B.1.1 variant. These results suggest that XBB BTI cannot efficiently induce antiviral humoral immunity against XBB subvariants. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/552415v1_figs1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@f95376org.highwire.dtl.DTLVardef@d66fa8org.highwire.dtl.DTLVardef@3c8841org.highwire.dtl.DTLVardef@15824c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure S1.C_FLOATNO Virological features of EG.5.1 and XBB BTI (A) Frequency of mutations of interest in the representative XBB sublineages. Only mutations with a frequency >0.5 in at least one but not all the representative sublineages are shown. Note that the S proteins of XBB.1.5 and XBB.1.9.2 are identical. (B) Estimated epidemic dynamics of the representative XBB sublineages in countries where >50 sequences of EG.5.1, XBB.1.5, XBB.1.9.2, and XBB.1.16 were detected from April 1, 2023 to July 13, 2023. Countries are ordered according to the number of detected sequences of EG.5.1. Line, posterior mean; ribbon, 95% Bayesian confidence interval. The dynamics for EG.5.1 is highlighted by a red arrowhead. (C) Estimated relative Re of the representative XBB sublineages in the six countries. The relative Re of XBB.1.5 is set to 1 (horizontal dashed line). Violin, posterior distribution; dot, posterior mean; line, 95% Bayesian confidence interval. (D) Lentivirus-based pseudovirus assay. HOS-ACE2-TMPRSS2 cells were infected with pseudoviruses bearing each S protein. The amount of input virus was normalized to the amount of HIV-1 p24 capsid protein. The percentage infectivity of XBB.1.5/1.9.2, XBB.1.5/1.9.2+Q52H, XBB.1.5/1.9.2+F456L, and EG.5.1 compared to that of XBB.1.5/1.9.2 are shown. The horizontal dash line indicates the mean value of the percentage infectivity of the XBB.1.5/1.9.2. Assays were performed in quadruplicate. The presented data are expressed as the average {+/-} SD. Each dot indicates the result of an individual replicate. (E-G) Neutralization assay. Assays were performed with pseudoviruses harboring the S proteins of B.1.1, BA.1, BA.2, BA.5, BQ.1.1, XBB.1, XBB.1.5/1.9.2, XBB.1.16, EG.5.1, XBB.1.5/1.9.2+Q52H, and XBB.1.5/1.9.2+F456L. The following sera were used: convalescent sera from fully vaccinated individuals who had been infected with XBB.1.5 (one 3-dose vaccinated. 1 donor in total), XBB.1.9 (one 3-dose vaccinated donor, one 4-dose vaccinated donor and one 5-dose vaccinated donor. 3 donors in total), and XBB.1.16 (one 2-dose vaccinated donor, two 3-dose vaccinated donors, and one 4-dose vaccinated donor. 4 donors in total) (E); sera from hamster infected with XBB.1 (left) or XBB.1.5 (right) (F); and convalescent sera from fully vaccinated individuals who had been infected with BA.1 (thirteen 2-dose vaccinated, 13 donors in total) (left)1, BA.2 (nine 2-dose vaccinated and four 3-dose vaccinated donors. 13 donors in total) (middle)19, and BA.5 (one 2-dose vaccinated, thirteen 3-dose vaccinated donors, and one 4-dose vaccinated. 15 donors in total) (right)19 (G). Each dot indicates the result of an individual replicate. Assays for each serum sample were performed in triplicate to determine the 50% neutralization titer (NT50). Each dot represents one NT50 value, and the geometric mean and 95% confidence interval are shown. The number in parenthesis indicates the mean of NT50 values. The horizontal dash line indicates the detection limit (120-fold). In D, statistically significant differences (**, P < 0.001, ***, P < 0.0001) versus XBB.1.5/1.9.2 were determined by two-sided Students t tests. Blue asterisks indicate decreased percentage of infectivity. In E and G, statistically significant differences versus B.1.1 were determined by two-sided Wilcoxon signed-rank tests. The fold change between B.1.1 and the variant indicated is shown in red. Background information on the convalescent donors is summarized in Table S1. In F, statistically significant differences (*, P < 0.01, **, P < 0.001) between B.1.1 and XBB.1 (left) or XBB.1.5/1.9.2 (right) were determined by two-sided Wilcoxon signed-rank tests and indicated with asterisks. Red asterisks indicate decreased NT50s. C_FIG

microbiology↗

bioRxiv2023

Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility

Broadly neutralizing antibodies (bnAbs) against HIV-1 target conserved epitopes, thereby inhibiting viral entry. Yet surprisingly, those recognizing linear epitopes in the HIV-1 gp41 membrane proximal external region (MPER) are elicited neither by peptide nor protein scaffold vaccines. Here, we observe that while Abs generated by MPER/liposome vaccines may exhibit human bnAb-like paratopes, B-cell programming without constraints imposed by the gp160 ectodomain selects Abs unable to access the MPER within its native "crawlspace". During natural infection, the flexible hinge of IgG3 partially mitigates steric occlusion of less pliable IgG1 subclass Abs with identical MPER specificity, until affinity maturation refines entry mechanisms. The IgG3 subclass maintains B-cell competitiveness, exploiting bivalent ligation resulting from greater intramolecular Fab arm length, offsetting weak antibody affinity. These findings suggest future immunization strategies.

immunology↗