Hybrid immunity from bivalent vaccination and prior infection enhances humoral and innate protection against Omicron XBB.1.16 and EG.5.1.1 variants in Japan.

INTRODUCTION

Emerging Omicron sublineages XBB.1.16 and EG.5.1.1 have caused breakthrough infections, challenging vaccine efficacy. Hybrid immunity-vaccination plus prior SARS-CoV-2 infection-augments neutralizing activity. We investigated whether innate immune responses also contribute to breakthrough prevention.

METHODS

We analyzed samples from a previous case-control study of 50 breakthrough infection cases and 50 controls, all adults with ≥3 mRNA vaccine doses, recruited in June 2023 during the XBB.1.5 wave in Japan. Participants were classified as hybrid immunity (prior PCR-confirmed infection or N-IgG positive), high-vaccine-induced immunity (N-IgG negative, S-IgG > 104 U/mL), or low-vaccine-induced immunity (N-IgG negative, S-IgG < 104 U/mL). Neutralization titers (NT50) were measured against ancestral SARS-CoV-2, XBB.1.16, and EG.5.1.1. Cytokines and innate markers were analyzed in serum and cell-based assays.

RESULTS

Breakthrough cases were enriched in the low-vaccine-induced immunity group, with fewer exhibiting hybrid immunity. Hybrid immunity yielded higher NT50 values than vaccine-only groups, but humoral immunity alone did not predict breakthrough infection. Cytokine analysis showed elevated IL-8 in hybrid non-breakthrough participants, with no differences in SARS-CoV-2-specific T-cell responses. Macrophages stimulated with the nucleocapsid protein induced IL-8, which promoted neutrophil chemotaxis. S100A8/A9, a neutrophil activation marker, correlated with IL-8 and was elevated in hybrid immunity.

DISCUSSION: Hybrid immunity may protect against Omicron XBB.1.16/EG.5.1.1 via IL-8-dependent macrophage-neutrophil interactions, highlighting a synergistic role of humoral and innate immunity.