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Volume 13
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10.3390/vaccines13020140
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Cross-Reactive Fc-Mediated Antibody Responses to Influenza HA Stem Region in Human Sera Following Seasonal Vaccination

by
Ayae Nishiyama
1,
Takuto Nogimori
1,
Yuji Masuta
1,
Tomoka Matsuura
2,3,
Tetsuo Kase
2,3,
Kyoko Kondo
4,
Satoko Ohfuji
2,3,
Yu Nakagama
3,5,
Natsuko Kaku
3,5,
Sachie Nakagama
3,5,
Yuko Nitahara
3,5,
Yoshimasa Takahashi
6,
Hiroshi Kakeya
3,7,8,
Yasutoshi Kido
3,5,8,
Wakaba Fukushima
2,3,8 and
Takuya Yamamoto
1,9,10,*
1
Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan
2
Department of Public Health, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
3
Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
4
Management Bureau, Osaka Metropolitan University Hospital, Osaka 545-8585, Japan
5
Department of Virology and Parasitology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
6
Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
7
Department of Infection Control Science, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
8
Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka 545-0051, Japan
9
Laboratory of Aging and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
10
Department of Virology and Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
*
Author to whom correspondence should be addressed.
Vaccines 2025, 13(2), 140; https://doi.org/10.3390/vaccines13020140
Submission received: 26 December 2024 / Revised: 21 January 2025 / Accepted: 27 January 2025 / Published: 28 January 2025
(This article belongs to the Special Issue Immunity to Influenza Viruses and Vaccines)
Review Reports Versions Notes

Abstract

Background: Current influenza A vaccines primarily induce neutralizing antibodies targeting the variable hemagglutinin (HA) head domain, limiting their effectiveness against diverse or emerging influenza A virus (IAV) subtypes. The conserved HA stem domain, particularly the long α-helix (LAH) epitope, is a focus of universal vaccine research due to its cross-protective potential. Additionally, Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are recognized as important protective immune mechanisms. This study evaluated IgG responses to the HA head, stem, and LAH regions and assessed cross-reactive potential through neutralization, ADCC, and ADCP assays. Methods: IgG responses to the HA head, stem, and LAH regions were measured in vaccinated individuals. Functional assays were conducted for neutralization, ADCC, and ADCP to evaluate the association between antibody levels and immune function. Results: The results showed that HA head-specific IgG increased significantly after vaccination in 50 individuals, whereas stem-specific IgG increased by 72% and LAH-specific IgG by 12–14%. Among the induced antibody subclasses, IgG1 was predominantly increased. Neutralization titers were detected in viruses of the same strain as the vaccine strain, but not in classical or pandemic strains (H5N1, H7N9). HA stem-specific IgG1 antibody titers showed a significant correlation with ADCC/ADCP activity breadth, but no correlation was observed with neutralization breadth. Conclusion: These findings suggest that although current influenza vaccines can induce HA stem-targeted cross-reactive antibodies, their quantity may be insufficient for broad cross-protection, underscoring the need for improved vaccine strategies.
Keywords: influenza virus; vaccine; antibody-dependent cellular cytotoxicity; antibody-dependent cellular phagocytosis influenza virus; vaccine; antibody-dependent cellular cytotoxicity; antibody-dependent cellular phagocytosis

Share and Cite

MDPI and ACS Style

Nishiyama, A.; Nogimori, T.; Masuta, Y.; Matsuura, T.; Kase, T.; Kondo, K.; Ohfuji, S.; Nakagama, Y.; Kaku, N.; Nakagama, S.; et al. Cross-Reactive Fc-Mediated Antibody Responses to Influenza HA Stem Region in Human Sera Following Seasonal Vaccination. Vaccines 2025, 13, 140. https://doi.org/10.3390/vaccines13020140

AMA Style

Nishiyama A, Nogimori T, Masuta Y, Matsuura T, Kase T, Kondo K, Ohfuji S, Nakagama Y, Kaku N, Nakagama S, et al. Cross-Reactive Fc-Mediated Antibody Responses to Influenza HA Stem Region in Human Sera Following Seasonal Vaccination. Vaccines. 2025; 13(2):140. https://doi.org/10.3390/vaccines13020140

Chicago/Turabian Style

Nishiyama, Ayae, Takuto Nogimori, Yuji Masuta, Tomoka Matsuura, Tetsuo Kase, Kyoko Kondo, Satoko Ohfuji, Yu Nakagama, Natsuko Kaku, Sachie Nakagama, and et al. 2025. "Cross-Reactive Fc-Mediated Antibody Responses to Influenza HA Stem Region in Human Sera Following Seasonal Vaccination" Vaccines 13, no. 2: 140. https://doi.org/10.3390/vaccines13020140

APA Style

Nishiyama, A., Nogimori, T., Masuta, Y., Matsuura, T., Kase, T., Kondo, K., Ohfuji, S., Nakagama, Y., Kaku, N., Nakagama, S., Nitahara, Y., Takahashi, Y., Kakeya, H., Kido, Y., Fukushima, W., & Yamamoto, T. (2025). Cross-Reactive Fc-Mediated Antibody Responses to Influenza HA Stem Region in Human Sera Following Seasonal Vaccination. Vaccines, 13(2), 140. https://doi.org/10.3390/vaccines13020140

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