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Pandemic influenza viruses cause significant mortality in humans. In the 20th century, 3 influenza viruses caused major pandemics: the 1918 H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. These pandemics were initiated by the introduction and successful adaptation of a novel hemagglutinin subtype to humans from an animal source, resulting in antigenic shift. Despite global concern regarding a new pandemic influenza, the emergence pathway of pandemic strains remains unknown. Here we estimated the evolutionary history and inferred date of introduction to humans of each of the genes for all 20th century pandemic influenza strains. Our results indicate that genetic components of the 1918 H1N1 pandemic virus circulated in mammalian hosts, i.e., swine and humans, as early as 1911 and was not likely to be a recently introduced avian virus. Phylogenetic relationships suggest that the A/Brevig Mission/1/1918 virus (BM/1918) was generated by reassortment between mammalian viruses and a previously circulating human strain, either in swine or, possibly, in humans. Furthermore, seasonal and classic swine H1N1 viruses were not derived directly from BM/1918, but their precursors co-circulated during the pandemic. Mean estimates of the time of most recent common ancestor also suggest that the H2N2 and H3N2 pandemic strains may have been generated through reassortment events in unknown mammalian hosts and involved multiple avian viruses preceding pandemic recognition. The possible generation of pandemic strains through a series of reassortment events in mammals over a period of years before pandemic recognition suggests that appropriate surveillance strategies for detection of precursor viruses may abort future pandemics.

Several Avian paramyxoviruses 1 (synonymous with Newcastle disease virus or NDV, used hereafter) classification systems have been proposed for strain identification and differentiation. These systems pioneered classification efforts; however, they were based on different approaches and lacked objective criteria for the differentiation of isolates. These differences have created discrepancies among systems, rendering discussions and comparisons across studies difficult. Although a system that used objective classification criteria was proposed by Diel and co-workers in 2012, the ample worldwide circulation and constant evolution of NDV, and utilization of only some of the criteria, led to identical naming and/or incorrect assigning of new sub/genotypes. To address these issues, an international consortium of experts was convened to undertake in-depth analyses of NDV genetic diversity. This consortium generated curated, up-to-date, complete fusion gene class I and class II datasets of all known NDV for public use, performed comprehensive phylogenetic neighbor-Joining, maximum-likelihood, Bayesian and nucleotide distance analyses, and compared these inference methods. An updated NDV classification and nomenclature system that incorporates phylogenetic topology, genetic distances, branch support, and epidemiological independence was developed. This new consensus system maintains two NDV classes and existing genotypes, identifies three new class II genotypes, and reduces the number of sub-genotypes. In order to track the ancestry of viruses, a dichotomous naming system for designating sub-genotypes was introduced. In addition, a pilot dataset and sub-trees rooting guidelines for rapid preliminary genotype identification of new isolates are provided. Guidelines for sequence dataset curation and phylogenetic inference, and a detailed comparison between the updated and previous systems are included. To increase the speed of phylogenetic inference and ensure consistency between laboratories, detailed guidelines for the use of a supercomputer are also provided. The proposed unified classification system will facilitate future studies of NDV evolution and epidemiology, and comparison of results obtained across the world.

The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.