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. 2025 Jun 2;222(6):e20241930.
doi: 10.1084/jem.20241930. Epub 2025 Apr 3.

Identification of a seasonal influenza vaccine-induced broadly protective neuraminidase antibody

Anders Madsen #  1   2   3 , Nisreen M A Okba #  4   5 , Tossapol Pholcharee #  6 , Hanover C Matz  3 , Huibin Lv  6   7 , Maria Ibanez Trullen  4   5 , Julian Q Zhou  3 , Jackson S Turner  3 , Aaron J Schmitz  3 , Fangjie Han  3 , Stephen C Horvath  3 , Sameer Kumar Malladi  3 , Florian Krammer  4   5   8   9 , Nicholas C Wu  6   7   10   11 , Ali H Ellebedy  3   12   13
Affiliations

Identification of a seasonal influenza vaccine-induced broadly protective neuraminidase antibody

Anders Madsen et al. J Exp Med. .

Abstract

Seasonal influenza viruses cause significant global illness and death annually, and the potential spillover of avian H5N1 poses a serious pandemic threat. Traditional influenza vaccines target the variable hemagglutinin (HA) protein, necessitating annual vaccine updates, while the slower-evolving neuraminidase (NA) presents a promising target for broader protection. We investigated the breadth of anti-NA B cell responses to seasonal influenza vaccination in humans. We screened plasmablast-derived monoclonal antibodies (mAbs) from three donors, identifying 11 clonally distinct NA mAbs from 268 vaccine-specific mAbs. Among these, mAb-297 showed exceptionally broad NA inhibition, effectively protecting mice against lethal doses of influenza A and B viruses, including H5N1. We show that mAb-297 targets a common binding motif in the conserved NA active site. Our findings show that while B cell responses against NA following conventional, egg-derived influenza vaccines are rare, inducing broadly protective NA antibodies through such vaccination remains feasible, highlighting the importance of improving NA immunogens to develop a more broadly protective influenza vaccine.

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Conflict of interest statement

Disclosures: J.S. Turner reported "other" from Abbvie outside the submitted work. F. Krammer reported that The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines influenza virus vaccines and influenza virus therapeutics that list F. Krammer as co-inventor. F. Krammer has received royalty payments from some of these patents. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. F. Krammer is the cofounder and scientific advisory board member of Castlevax. F. Krammer has consulted for Merck, GSK, Sanofi, Curevac, Seqirus, and Pfizer, and is currently consulting for Third Rock Ventures, Gritstone, and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics. N.C. Wu reported personal fees from Helixon outside the submitted work. A.H. Ellebedy reported grants from Moderna during the conduct of the study; and the Ellebedy laboratory received funding from Emergent BioSolutions, and AbbVie, which is unrelated to the data presented in the current study. A.H. Ellebedy has received consulting and speaking fees from InBios International, Fimbrion Therapeutics, RGAX, Mubadala Investment Company, Moderna, Pfizer, GSK, Danaher, Third Rock Ventures, Goldman Sachs, and Morgan Stanley and is the founder of ImmuneBio Consulting. No other disclosures were reported.

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