ArticleProceedings of the National Academy of Sciences of the United States of America2016
Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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101 citing papers in PubMed, 130 citations in OpenAlex.
- In silico analysis of pH stabilising mutations of hemagglutinin of influenza A virus H5N1 clade 2.3.4.4b.Npj viruses · 2026Review
- N-linked glycosylation sites with low occupancy support sustained circulation of the A(H3N2) influenza A virus in the human population.Journal of virology · 2026Article
- An In Vitro Screen Identifies H1 Influenza Hemagglutinin Substitutions That Alter mRNA-LNP Vaccine Responses Against the Stalk Domain.Vaccines · 2026Article
- A lethal human H5N5 influenza virus isolate exhibits low pandemic risk traits.bioRxiv : the preprint server for biology · 2026Article
- Standing HA phenotypic breadth shapes H5N1 cross-host potential.Research square · 2026Article
- New determinant of influenza hemagglutinin cleavability identified through random mutagenesis for acid-stabilizing mutations.Microbiology spectrum · 2026Article
- Identification of thermostability-enhancing mutations in H9N2 avian influenza virus hemagglutinin.Journal of virology · 2026Article
- Article
- Review
- Fatal human H3N8 influenza virus has a moderate pandemic risk.PLoS pathogens · 2026Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin.Nature ecology & evolution · 2026Article
- Resistance Mutations to Broadly Neutralizing Antibodies Destabilize Hemagglutinin and Attenuate H1N1 Influenza Virus.Viruses · 2025Article
- Host switching mutations in H5N1 influenza hemagglutinin suppress site-specific activation dynamics.Nature communications · 2025Article
- Eurasian 1C swine influenza A virus exhibits high pandemic risk traits.Emerging microbes & infections · 2025Article
- Isoleucine at position 137 of haemagglutinin acts as a mammalian adaptation marker of H9N2 avian influenza virus.Emerging microbes & infections · 2025Article
- Host Switching Mutations in H5N1 Influenza Hemagglutinin Suppress Site-specific Activation Dynamics.bioRxiv : the preprint server for biology · 2025Article
- Fatal Human H3N8 Influenza Virus has a Moderate Pandemic Risk.bioRxiv : the preprint server for biology · 2025Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza hemagglutinin.bioRxiv : the preprint server for biology · 2025Article
- Genetic Evolution of the Hemagglutinin Genes of Seasonal Influenza A Viruses in Türkiye Between 2017 and 2023.Influenza and other respiratory viruses · 2025Article
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41 more citing papers are in PubMed but not listed here.
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11 authors at 1 institution in 1 country.
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Abstract
Influenza pandemics require that a virus containing a hemagglutinin (HA) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. Although the HA protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. During virus entry, the HA protein binds receptors and is triggered by low pH in the endosome to cause membrane fusion; during egress, HA contributes to virus assembly and morphology. In 2009, a swine influenza virus (pH1N1) jumped to humans and spread globally. Here we link the pandemic potential of pH1N1 to its HA acid stability, or the pH at which this one-time-use nanomachine is either triggered to cause fusion or becomes inactivated in the absence of a target membrane. In surveillance isolates, our data show HA activation pH values decreased during the evolution of H1N1 from precursors in swine (pH 5.5-6.0), to early 2009 human cases (pH 5.5), and then to later human isolates (pH 5.2-5.4). A loss-of-function pH1N1 virus with a destabilizing HA1-Y17H mutation (pH 6.0) was less pathogenic in mice and ferrets, less transmissible by contact, and no longer airborne-transmissible. A ferret-adapted revertant (HA1-H17Y/HA2-R106K) regained airborne transmissibility by stabilizing HA to an activation pH of 5.3, similar to that of human-adapted isolates from late 2009-2014. Overall, these studies reveal that a stable HA (activation pH ≤ 5.5) is necessary for pH1N1 influenza virus pathogenicity and airborne transmissibility in ferrets and is associated with pandemic potential in humans.
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