Reply to Editorial Correspondence on the Immunogenicity of Advanced Influenza Vaccines and Their Role in Neuraminidase Inhibition Antibody Production

By
Pavithra Daulagala
Benjamin J Cowling
Hui-Ling Yen
January 24, 2026

The Journal Of Infectious Diseases

Overview

This correspondence addresses the immunogenicity of neuraminidase (NA) antibodies induced by advanced influenza vaccines in older adults. It highlights that NA content alone does not predict antibody response and discusses the limitations of using ≥4-fold rise in neuraminidase inhibition (NAI) titers as a sole endpoint in highly primed populations.

Background

Neuraminidase inhibition antibodies are increasingly recognized as correlates of protection against severe influenza. However, influenza vaccine formulations vary in NA antigen content, which is not standardized, and factors such as NA protein stability and conformation influence immunogenicity. The antibody response in older adults, who often have preexisting immunity, may be affected by high baseline antibody titers, complicating interpretation of vaccine efficacy endpoints.

Data Highlights

Vaccine Type	N1 Protein Content	N2 Protein Content	NAI Antibody GMFR (D0 to D30)
Standard-dose quadrivalent (SD-IIV4)	Reference	Reference	No significant difference
High-dose trivalent (HD-IIV3)	1.4-fold higher than SD-IIV4	5.1-fold higher than SD-IIV4	No significant difference compared to SD-IIV4
Recombinant quadrivalent (RIV4)	Measured but specific values not provided	Measured but specific values not provided	Not specified
MF59-adjuvanted trivalent (aIIV3)	NA content not quantified due to adjuvant presence	NA content not quantified due to adjuvant presence	Not specified

Key Findings

NA antigen content varies across influenza vaccine formulations and is not standardized.
Higher NA protein content in HD-IIV3 compared to SD-IIV4 did not translate into significantly higher NAI antibody responses.
NA protein stability and structural conformation influence immunogenicity beyond antigen quantity.
High baseline NAI and hemagglutination inhibition (HAI) antibody titers can reduce fold-rise in antibody response postvaccination (antibody ceiling effect).
Using ≥4-fold rise in NAI antibody titers alone may misclassify protection status in highly primed older adults.
Comprehensive assessment including baseline titers and geometric mean titers is necessary to evaluate NA immunogenicity accurately.

Clinical Implications

Clinicians and researchers should recognize that NA content alone is insufficient to predict vaccine-induced immunity, especially in older adults with preexisting antibodies. Evaluations of influenza vaccine efficacy should incorporate multiple immunological endpoints beyond seroconversion rates to better assess protection. Future vaccine development and immunogenicity studies need to address the determinants of NA antibody responses to optimize protective effects.

Conclusion

The correspondence underscores the complexity of assessing neuraminidase immunogenicity in influenza vaccines and the limitations of current endpoints in older adults. A multifaceted approach is essential for understanding and improving vaccine-mediated protection against influenza.

References

Authors of original article (2023) -- Antineuraminidase antibody responses in older adults following enhanced influenza vaccines
Gao et al. -- NA enzyme activity and immunogenicity studies
Zhang -- Editorial correspondence on NA immunogenicity