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. 2024 Feb 23;10(8):eadj9945.
doi: 10.1126/sciadv.adj9945. Epub 2024 Feb 23.

Waning immunity and IgG4 responses following bivalent mRNA boosting

Ninaad Lasrado  1 , Ai-Ris Y Collier  1 , Jessica Miller  1 , Nicole P Hachmann  1 , Jinyan Liu  1 , Trisha Anand  1 , Esther A Bondzie  1 , Jana L Fisher  1 , Camille R Mazurek  1 , Robert C Patio  1 , Stefanie L Rodrigues  1 , Marjorie Rowe  1 , Nehalee Surve  1 , Darren M Ty  1 , Cindy Wu  1 , Taras M Chicz  2 , Xin Tong  2 , Bette Korber  3 , Ryan P McNamara  2 , Dan H Barouch  1   2
Affiliations

Waning immunity and IgG4 responses following bivalent mRNA boosting

Ninaad Lasrado et al. Sci Adv. .

Abstract

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

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Figures

Fig. 1.
Fig. 1.. Key spike mutations found in SARS-CoV-2 Omicron and XBB subvariants.
Spike amino acid substitutions in baseline sequences for BA.2, BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.16 are depicted. XBB variants are recombinants between parental sequences BJ.1 (BA.2.10.1) and a sublineage of BA.2.75 (BM.1.1.1). BA.2 mutations compared with the ancestral WA1/2020 Spike are shown in black, and additional mutations relative to BA.2 are highlighted in colors corresponding to individual variants. Light gray shading indicates differences in prominent XBB lineages relative to the original recombinant founder. NTD, N-terminal domain; RBD, receptor binding domain.
Fig. 2.
Fig. 2.. NAb responses to SARS-CoV-2 Omicron and XBB subvariants.
NAb titers against the WA1/2020, BA.2, BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.16 variants by luciferase-based pseudovirus neutralization assays at baseline before boosting, at week 3 following boosting, and at month 3 following boosting in nucleocapsid seronegative participants are shown. Median NAb titers (red bars) are depicted and shown numerically. LOD indicated by dotted lines represents the starting dilution used for the NAb assay, 1:20.
Fig. 3.
Fig. 3.. Cellular immune responses to SARS-CoV-2 Omicron and XBB variants.
IFN-γ+ CD4+ and IFN-γ+ CD8+ T cell responses in PBMCs from vaccinees to WA1/2020, BQ.1.1, and XBB.1.5 spike-specific peptide pools by intracellular cytokine staining assays at baseline before boosting, and at month 3 following boosting are shown. Medians (red bars) are depicted and shown numerically.
Fig. 4.
Fig. 4.. Antibody and Fc effector function profiling by systems serology following bivalent mRNA immunization.
(A) Spike-specific IgG1, IgG2, IgG3, and IgG4 responses against WA1/2020, BA.1, BA.2, BQ.1.1, and XBB.1.5 spike antigens by Luminex-based assay at baseline before boosting, week 3 following boosting, and at month 3 following boosting in nucleocapsid seronegative participants. (B) Spike-specific ADCP, ADNP, and ADCD activity against WA1/2020, BA.1, BQ.1.1, and XBB.1.5 at baseline before boosting, week 3 after boost, and at month 3 after boost is shown. Medians of the mean fluorescence intensities (MFI) in red bars are depicted, and fold changes are shown numerically. Phagocytosis score for ADCP and ADNP activity is calculated as follows: phagocytosis score = % THP-1 bead-positive cells × median fluorescent intensity of bead-positive cells/10,000. LOD indicated by dotted lines represent the median MFI of an Ebolavirus glycoprotein negative control.
Fig. 5.
Fig. 5.. Antibody and Fc effector function profiling by systems serology following third monovalent mRNA immunization.
(A) Spike-specific IgG1, IgG2, IgG3, and IgG4 responses against spikes of WA1/2020, Gamma, and Delta variants by Luminex-based assay at baseline before boosting, at week 3 following boosting, and at month 6 following boosting in vaccinees who received third monovalent mRNA vaccines. (B) Spike-specific ADCP, ADNP, and ADCD activity against WA1/2020, Delta, and BA.1 at baseline before boosting, week 3 after boost, and month 6 after boost is shown. Medians of the MFI in red bars are depicted, and fold changes are shown numerically. Phagocytosis score for ADCP and ADNP activity is calculated as follows: phagocytosis score = % THP-1 bead-positive cells × median fluorescent intensity of bead-positive cells/10,000. LOD indicated by dotted lines represent the median MFI of an Ebolavirus glycoprotein negative control.
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