Immune responses against neuraminidase (NA) are of great interest for developing more robust influenza vaccines, but the role of anti-NA antibodies on influenza infectivity has not been established. We conducted household transmission studies in Managua, Nicaragua to examine the impact of anti-NA antibodies on influenza A/H3N2 susceptibility and infectivity. Analyzing these data with mathematical models capturing household transmission dynamics and their drivers, we estimated that having higher preexisting antibody levels against the hemagglutinin (HA) head, HA stalk, and NA was associated with reduced susceptibility to infection (relative susceptibility 0.67, 95% Credible Interval [CrI] 0.50-0.92 for HA head; 0.59, 95% CrI 0.42-0.82 for HA stalk; and 0.56, 95% CrI 0.40-0.77 for NA). Only anti-NA antibodies were associated with reduced infectivity (relative infectivity 0.36, 95% CrI 0.23-0.55). These benefits from anti-NA immunity were observed even among individuals with preexisting anti-HA immunity. These results suggest that influenza vaccines designed to elicit NA immunity in addition to hemagglutinin immunity may not only contribute to protection against infection but reduce infectivity of vaccinated individuals upon infection.

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 which list Florian Krammer as co-inventor. 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. Florian Krammer is a co-founder and scientific advisory board member of CastleVax. Florian Krammer has consulted for Merck, Curevac, Seqirus, GSK and Pfizer and is currently consulting for 3rd Rock Ventures, Gritstone and Avimex. The Krammer laboratory is collaborating with Dynavax on influenza vaccine development. Aubree Gordon has served on an RSV vaccine advisory board for Janssen.

This work was supported by the National Institutes of Allergy and Infectious Diseases through the Collaborative Influenza Vaccine Innovation Centers [75N93019C00051 to F.K. and A.G.]the St. Jude Center of Influenza Research and Surveillance [HHSN272201400006C to A.G.]; the St. Jude Center of Excellence for Influenza Research and Response [75N93021C00016 to A.G.]and grant R01 AI120997 to A.G. Aubree Gordon is supported by the Biosciences Initiative at the University of Michigan through a Mid‐career Biosciences Faculty Achievement Award (MBioFAR). S.C. acknowledges support by the European Commission under the EU4Health programme 2021-2027, Grant Agreement - Project: 101102733 - DURABLE, the Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases program (grant ANR-10-LABX-62-IBEID) the European Union's Horizon 2020 research and innovation programme under VEO grant agreement No. 874735, and the INCEPTION project (PIA/ANR16-CONV-0005). The funding agencies had no role in the design and conduct of the study, collection, management, analysis or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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This study was approved by the institutional review boards at the Nicaraguan Ministry of Health and the University of Michigan and is in accordance with the Helsinki Declaration of the World Medical Association. Written consent to participate or parental permission was obtained for all participants; in children older than 6 years, verbal assent was obtained.

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