XBB.1.5 monovalent mRNA vaccine booster elicits robust neutralizing antibodies against XBB subvariants and JN.1

Abstract

COVID-19 vaccines have recently been updated to specifically encode or contain the spike protein of the SARS-CoV-2 XBB.1.5 subvariant, but their immunogenicity in humans has yet to be fully evaluated and reported, particularly against emergent viruses that are rapidly expanding. We now report that administration of an updated monovalent mRNA vaccine booster (XBB.1.5 MV) to previously uninfected individuals boosted serum virus-neutralizing antibodies significantly against not only XBB.1.5 (27.0-fold increase) and EG.5.1 (27.6-fold increase) but also key emerging viruses such as HV.1, HK.3, JD.1.1, and JN.1 (13.3- to 27.4-fold increase). Individuals previously infected by an Omicron subvariant had the highest overall serum neutralizing titers (ID₅₀ 1,504-22,978) against all viral variants tested. While immunological imprinting was still evident with the updated vaccines, it was not nearly as severe as observed with the previously authorized bivalent BA.5 vaccine. Our findings strongly support the official recommendation to widely apply the updated COVID-19 vaccines.

Keywords: COVID-19; HK.3; HV.1; JD.1.1; JN.1; Omicron subvariants; SARS-CoV-2; XBB.1.5 monovalent mRNA vaccine; immunological imprinting; serum neutralization.

Graphical abstract

Figure 1

Emergence of novel SARS-CoV-2 variants (A) Frequencies of SAR-CoV-2 Omicron subvariants in the denoted time period. Data were obtained from the Global Initiative on Sharing All Influenza Data (GISAID). The values in the upper left corner of each box denote the cumulative number of SAR-CoV-2 sequences deposited. (B) Phylogenetic tree based on spike proteins of SARS-CoV-2 variants. (C) Spike protein mutations in BA.2, BA.5, XBB.1.5, EG.5.1, HK.3, HV.1, and JD.1.1 relative to D614G. (D) Spike protein mutations in BA.2.86 and JN.1 relative to BA.2. See also Figure S1.

Figure 2

Neutralizing antibody titers before and after an XBB.1.5 mRNA booster, XBB infection, or both (A) Timeline representation of vaccine administration, SARS-CoV-2 infection, and serum collection intervals for each clinical cohort. Indicated time points represent the median in days for each cohort, with day 0 defined as the day of the initial SARS-CoV-2 vaccination. Numbers of participants for each group receiving a fourth wild-type (WT) monovalent vaccine (MV) is indicated. Other vaccine doses were received by all participants in each cohort. 15 participants from the Omicron infx + XBB.1.5 MV cohort had a pre-XBB Omicron infection (subgroup 1), while the other 10 had XBB infection (subgroup 2). N, sample size.(B–D) Serum virus-neutralizing titers (ID₅₀) of the cohorts against the indicated SARS-CoV-2 pseudoviruses. Geometric mean ID₅₀ titers (GMT) are shown along with the fold change between pre and post (MV or infx) serum samples. Horizontal bars show the fold change in GMT following XBB MV or infection between XBB.1.5 and all other viruses tested. The dotted line represents the assay limit of detection (LOD) of 25. Numbers under the dotted lines are non-responders to XBB MV or infection (<3-fold increase in ID₅₀ titers between pre- and post-XBB sera across all the viruses tested). In the Omicron infx + XBB.1.5 MV cohort, subgroups 1 and 2 are shown in rhombuses and circles, respectively. Statistical analyses were performed by Wilcoxon matched-pairs signed-rank tests. See also Tables S1 and S2 and Figures S2, S3, and S4.

Figure 3

Antigenic cartography of serum virus-neutralizing data Antigenic maps for all cohorts (A), the XBB.1.5 monovalent vaccine (XBB.1.5 MV) cohort (B), the XBB infection (XBB infx) cohort (C), the full infection + XBB.1.5 monovalent vaccine (Omicron infx + XBB.1.5 MV) cohort (D), and the pre-XBB and XBB subgroups of the Omicron infx + XBB.1.5 MV cohort (E and F). The top row shows antigenic maps generated with pre-XBB sera, and the bottom row shows maps generated with post-XBB sera. The length of each square in the antigenic maps corresponds to one antigenic unit and represents an approximately 2-fold change in ID₅₀ titer. Virus positions are shown in closed circles, while serum positions are shown by gray squares (pre-XBB sera) or pink squares (post-XBB sera). Antigenic distance from D614G is shown for each virus in parenthesis.

Figure 4

XBB.1.5 monovalent mRNA vaccines induced stronger boosts than a second BA.5 bivalent mRNA vaccine (A) Timeline representation of vaccine administration, SARS-CoV-2 infection, and serum collection intervals for each cohort. The cohort that received a second BA.5 bivalent vaccine (BA.5 BV × 2) was previously described. Indicated timepoints represent the median in days for each cohort, with day 0 defined as the day of the initial SARS-CoV-2 vaccination. Numbers of participants for each group receiving a fourth wild-type (WT) monovalent vaccine is indicated. n, sample size. (B–D) Fold changes in ID₅₀ titers of the indicated cohorts against D614G, BA.5, and XBB.1.5 between pre- and post-vaccination or infection. Geometric mean fold changes in ID₅₀ titer are shown as black bars and denoted above the dots. Statistical analyses were performed by employing Wilcoxon matched-pairs signed-rank tests. Data for the BA.5 BV × 2 cohort were extracted from a previously published study.