What question did this study set out to answer?

The study aims to determine the cross-reactive capabilities of neuraminidase-inhibiting antibodies following infection with H1N1pdm.

April 19, 2026Open Access

Neuraminidase-inhibiting antibodies boosted by H1N1pdm infection cross-react differently with H5N1 of clades 2.3.4.4b and 2.3.2.1a

Key Points

The study aims to determine the cross-reactive capabilities of neuraminidase-inhibiting antibodies following infection with H1N1pdm.
Examined antibody responses in convalescent sera from H1N1pdm-infected individuals.
Compared NAI responses against different H5N1 clades.
Conducted longitudinal analysis to evaluate the durability of antibody responses.
Performed amino acid substitutions to assess effects on antigenic divergence.
Significantly higher NAI responses were noted against H5N1 clade 2.3.4.4b compared to non-flu controls.
Lower NAI responses were observed against clade 2.3.2.1a H5N1, indicating antigenic divergence.
NAI responses from H1N1pdm infection waned by day 90 post-infection.

Abstract

AbstractAntibodies against neuraminidase (NA) are an independent correlate of protection and the antigenic relatedness between H1N1pdm and H5N1 NAs suggests that seasonal influenza infection may provide cross-reactive immunity. In this study, recent H1N1pdm infection elicited modest NA-inhibiting (NAI) antibody responses against contemporary A/Victoria/4897/2022 (H1N1pdm) but strong responses against older A/California/7/2009 (H1N1pdm). Convalescent sera exhibited significantly higher cross-reactive NAI against clade 2.3.4.4b H5N1 (A/Texas/37/2024) than non-flu A patients, whereas H3N2 infection did not elicit such cross-reactivity. NAI titers were comparable between N1-California and N1-Texas but lower against N1-Victoria, indicating greater antigenic similarity between N1-California and N1-Texas. This was supported by stronger inhibition of N1-Texas by N1-California sheep antiserum compared with N1-Victoria sheep antiserum. Surprisingly, H1N1pdm-infected patients exhibited very low NAI against clade 2.3.2.1a H5N1 (N1-Bangladesh; GMT of 171 vs GMT 1159 for N1-Texas). Mouse antisera demonstrated reduced reciprocal inhibition between N1-Texas and N1-Bangladesh, consistent with their antigenic divergence. When four residues in N1-Bangladesh were substituted with their corresponding residues in N1-Texas, N1-Bangladesh antiserum showed reduced NAI, while N1-Texas antisera showed increased inhibition compared with wild-type N1-Bangladesh. This suggests that these amino acid differences are partially responsible for their antigenic divergence. Importantly, longitudinal analysis revealed that boosted cross-reactive NAI responses waned by day 90 post-infection, highlighting their limited durability. Together, these findings demonstrate that seasonal H1N1pdm infection can transiently boost cross-reactive NAI antibodies against clade 2.3.4.4b H5N1, but antigenic divergence in clade 2.3.2.1a limits cross-reactivity. As such, the impact of pre-existing antibody during an H5N1 outbreak is dependent on the infecting clade.

Neuraminidase-inhibiting antibodies boosted by H1N1pdm infection cross-react differently with H5N1 of clades 2.3.4.4b and 2.3.2.1a

Key Points

Abstract

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