XBB.1.5 monovalent vaccine induces lasting cross-reactive responses to SARS-CoV-2 variants such as HV.1 and JN.1, as well as SARS-CoV-1, but elicits limited XBB.1.5 specific antibodies

Abstract

The evolution of the antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacted by the nature and number of antigenic exposures. First-generation coronavirus disease 2019 (COVID-19) vaccines encoded an ancestral spike protein. Updated bivalent vaccines and breakthrough infections have shaped the intricate diversity of the polyclonal antibody response and specificity of individual antibody clones. We and others previously showed that bivalent vaccines containing the ancestral and Omicron (BA.5) spikes induce high levels of cross-reactive antibodies but undetectable BA.5-specific antibodies in serum. Here, we assessed sera collected before as well as 1 and 3 months following administration of an updated XBB.1.5 monovalent vaccine to individuals with diverse infection and vaccination histories. Vaccination increased neutralization against recent variants of concern, including HV.1, JN.1, and the vaccine-homologous XBB.1.5. Antibody binding and avidity against ancestral and XBB.1.5 antigens significantly increased after vaccination. However, antibody depletion experiments showed that most of the response was cross-reactive to the ancestral spike, and only low levels of XBB.1.5-specific antibodies to the spike or the receptor-binding domain were detected. Importantly, increased antibody levels were still detectable in circulation 3 months post-vaccination and cross-reacted with severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) as measured by pseudovirus neutralization and binding assays. Overall, our data suggest that the XBB.1.5 monovalent vaccine predominantly elicits a cross-reactive response imprinted by viral spike antigens encountered early during the pandemic.IMPORTANCEUpdated COVID-19 vaccine formulations and SARS-CoV-2 exposure history affect the antibody response to SARS-CoV-2. High titers of antibodies are induced in serum by XBB.1.5 monovalent vaccination. Antibody depletion experiments reveal that the majority of the antibody response is cross-reactive to the ancestral spike, despite vaccination increasing neutralization against recently circulating Omicron variants. Vaccine-induced SARS-CoV-2 antibodies cross-react with SARS-CoV-1 and remain in the bloodstream for at least 3 months after immunization.

Keywords: COVID-19 vaccine; SARS-CoV-2; XBB.1.5 monovalent vaccine; cross-reactive immune responses; imprinting.

Fig 1

Serum neutralization profile against ancestral WA.1, XBB.1.5, HV.1, and JN.1 in individuals with diverse exposure histories receiving an XBB.1.5 monovalent vaccine. Schematic representation of recent immune history and sample collection time points in study participants (A). Live virus neutralization titers expressed as 50% inhibitory dilution (ID₅₀) at baseline and 1 or 3 months post-vaccination against ancestral WA.1, XBB.1.5, HV.1, and JN.1 (B). Fold change (increase) in ID₅₀ values at 1 and 3 months post-vaccination with respect to baseline reactivity (C–F). Fold difference (decrease) in ID₅₀ values for XBB.1.5, HV.1, and JN.1 with respect to ancestral WA.1 (G–I). In panel A, individuals were stratified based on each vaccine type and presence/absence of a breakthrough infection prior to the 3 month serum collection time point. The sample size for each group is indicated on the left side. The timing (average number of days ± standard deviation) between each event is indicated above every dashed arrow. Further details are provided in Table S2; and Fig. S1. In panel B, Friedman’s test, followed by Dunn’s multiple comparison test, was used among different groups. Only statistically significant differences are shown. Bars = geometric means; error bars = geometric standard deviations. The assay limit of detection (LoD) is indicated by the horizontal dotted line. Values at the LoD are positive for neutralization at a 1:10 dilution, while values below the LoD are indicated as half of the LoD for graphing purposes. In panels B–I, individuals with a breakthrough infection between 1 and 3 months post-vaccination (n = 6) are highlighted in red. Each symbol represents a single participant. In panels C–I, the average fold change is indicated above the x axis.

Fig 2

Binding and cross-reactivity profiles of sera from XBB.1.5 vaccine recipients. Schematic representation of antibody depletion used to characterize XBB.1.5 binding-specific antibodies (A). Briefly, chemically activated magnetic beads are coupled with recombinant spike or receptor-binding domain (RBD) proteins, followed by incubation with the target serum sample and separation of non-bound antibodies after two rounds of depletion. Binding antibody levels expressed as area under the curve (AUC) at baseline, 1 or 3 months post-vaccination against recombinant ancestral Wuhan-1 or XBB.1.5 spike (B and C) and RBD (G and H). Confirmation of antibody depletion using ancestral Wuhan-1 spike or RBD (D and I). Wuhan-1 spike or RBD depleted sera assessed against XBB.1.5 spike or RBD (E and J). Proportion of XBB.1.5-specific or Wuhan-1 cross-reactive, spike, or RBD antibodies (F and K). Values exceeding 100% are shown as 100%. Pie charts show the proportion of individuals who have any XBB.1.5-specific responses. Cross-reactive binding antibodies against the spike of JN.1 (L), BA.2.87.1 (M), and SARS-CoV-1 (N), or against the S2 domain of SARS-CoV-2 (O). Cross-reactive neutralizing antibodies expressed as 50% inhibitory dilution (ID₅₀) measured in a single cycle pseudovirus neutralization assay against SARS-CoV-1 (pCoV1, right panel) (P). SARS-CoV-2 D614G pseudovirus was included as reference (pCoV2, left panel). Fold change (increase) in ID₅₀ values at 1 and 3 months post-vaccination with respect to baseline titers in SARS-CoV-2 (Q) and SARS-CoV-1 (R) pseudovirus neutralization assays. In panels B–O, Friedman’s test, followed by Dunn’s multiple comparison test, was used among different groups. Only statistically significant differences are shown. Bars = geometric means; error bars = geometric standard deviations. The assay limit of detection (LoD) is indicated by the horizontal dotted line. Values at the LoD are positive for binding or neutralization at a 1:10 dilution, while values below the LoD are indicated as half of the LoD for graphing purposes. In panels B–Q, individuals with a breakthrough infection between 1 and 3 months post-vaccination (n = 6) are highlighted in red. Each symbol represents a single participant. In panels P–Q, the average fold change is indicated above the x axis. The ID₅₀ values calculated for the pseudovirus-based neutralization assays represent the titer (dilution) at >50% inhibition. Reactive antibodies are antibodies directed to the spike/RBD of a particular strain. Specific antibodies are antibodies directed specifically to the spike/RBD of a particular strain with no reactivity to the antigens of the other strains tested.

Fig 3

Antibody avidity profile in sera from XBB.1.5 vaccine recipients. Correlation between binding antibody levels against WT, XBB.1.5, or JN.1, spike or against the receptor-binding domain (RBD) of ancestral and XBB.1.5 viruses, and neutralization against ancestral WA.1, XBB.1.5, or JN.1 viruses (A–E). Antibody avidity was measured by ELISA using 8 M urea. Reactivity against the indicated antigens of plates treated with urea (red bars) or not treated (blue bars) is shown. Ancestral spike (F), XBB.1.5 spike (H), WT RBD (J), and XBB.1.5 RBD (L). Avidity index [(urea-treated sample AUC/non-treated sample AUC) × 100] of samples against ancestral spike (G), XBB.1.5 spike (I), ancestral RBD (K), and XBB.1.5 RBD (M) are shown. Friedman’s test, followed by Dunn’s multiple comparison test, was used among different groups. Only statistically significant differences are shown. Bars represent the geometric means, with error bars depicting the geometric standard deviations. Correlation coefficient (R) and significance value (P) are indicated above the x axis. AUC, area under the curve; ID₅₀, 50% inhibitory dilution.

Fig 4

IgM measurement in sera from XBB.1.5 vaccine recipients. IgM antibody levels measured at baseline and 1 or 3 months post-vaccination against recombinant ancestral Wuhan-1 or XBB.1.5 spike (A and B). Confirmation of antibody depletion using ancestral Wuhan-1 spike (C). Wuhan-1 spike depleted sera assessed against XBB.1.5 spike (D). Proportion of XBB.1.5 spike-specific or Wuhan-1 spike cross-reactive antibodies (E). Pie charts show the proportion of individuals with any specific responses to XBB.1.5 spike. An analysis of variance test was used for statistical comparisons among different groups. Only statistically significant differences are shown. Bars = geometric means; error bars = geometric standard deviations. The assay limit of detection (LoD) is indicated by the horizontal dotted line. Values at the LoD indicate positive binding at a 1:10 dilution, while values below the LoD are shown as half of the LoD for graphing purposes.