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Front Immunol
. 2026 Jul 2:17:1807238.
doi: 10.3389/fimmu.2026.1807238. eCollection 2026.
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
Kouki Matsuda 1 , Shohei Yamamoto 2 , Chihiro Motozono 3 , Yoshiki Aritsu 3 , Yuki Furukawa 1 , Airi Noborio 1 , Daisuke Takada 1 , Hiyori Sasagawa 1 , Yuichi Akahori 1 , Kiyoto Tsuchiya 4 , Hiroyuki Gatanaga 4 , Takamasa Ueno 3 , Norio Ohmagari 5 , Tetsuya Mizoue 2 , Kenji Maeda 1
Affiliations
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.
Keywords: COVID-19; bivalent vaccine; breakthrough infection; hybrid immunity; innate immunity.
. 2026 Jul 2:17:1807238.
doi: 10.3389/fimmu.2026.1807238. eCollection 2026.
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
Kouki Matsuda 1 , Shohei Yamamoto 2 , Chihiro Motozono 3 , Yoshiki Aritsu 3 , Yuki Furukawa 1 , Airi Noborio 1 , Daisuke Takada 1 , Hiyori Sasagawa 1 , Yuichi Akahori 1 , Kiyoto Tsuchiya 4 , Hiroyuki Gatanaga 4 , Takamasa Ueno 3 , Norio Ohmagari 5 , Tetsuya Mizoue 2 , Kenji Maeda 1
Affiliations
- PMID: 42465771
- PMCID: PMC13374799
- DOI: 10.3389/fimmu.2026.1807238
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.
Keywords: COVID-19; bivalent vaccine; breakthrough infection; hybrid immunity; innate immunity.