Explore the vast range of titles available.

The source, timing, and geographical origin of the 1918–1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ∼1907, acquired avian N1 neuraminidase and internal protein genes. We find that the resulting pandemic virus jumped directly to swine but was likely displaced in humans by ∼1922 by a reassortant with an antigenically distinct H1 HA. Hence, although the swine lineage was a direct descendent of the pandemic virus, the post-1918 seasonal H1N1 lineage evidently was not, at least for HA. These findings help resolve several seemingly disparate observations from 20th century influenza epidemiology, seroarcheology, and immunology. The phylogenetic results, combined with these other lines of evidence, suggest that the high mortality in 1918 among adults aged ∼20 to ∼40 y may have been due primarily to their childhood exposure to a doubly heterosubtypic putative H3N8 virus, which we estimate circulated from ∼1889–1900. All other age groups (except immunologically naive infants) were likely partially protected by childhood exposure to N1 and/or H1-related antigens. Similar processes may underlie age-specific mortality differences between seasonal H1N1 vs. H3N2 and human H5N1 vs. H7N9 infections.

\"Learn all about the flu, from what causes it and how it affects people to how it is diagnosed and treated\"-- Provided by publisher.

Only four mutations in H5N1 HA are required to enable ferret-to-ferret transmission of a reassortant virus containing the H5 HA and the remaining seven gene segments from a human pandemic H1N1 influenza virus. Elements involved in H5N1 transmission Whether avian H5N1 viruses can gain the ability to transmit between humans was uncertain. The viral haemagglutinin protein (HA) mediates virus binding to host-specific cellular receptors, but previous studies have shown that alterations in HA that enable binding to human-type receptors are not sufficient to enable respiratory droplet transmission of H5N1 viruses in ferrets, the best animal model for human-to-human transmission. Imai et al . show that only four mutations in H5N1 HA are required to enable ferret-to-ferret transmission of a reassortant virus containing H5 HA, with the remaining genes from human pandemic H1N1 influenza virus. It is probable that further adaptations in other avian virus genes would be required to mediate transmission of wholly avian H5N1 in mammals, but human H1N1 and H5N1 viruses are genetically compatible and the emergence of H5-HA-containing viruses might be expected to cause a pandemic because humans lack immunity to H5 viruses. Knowledge of the mutations involved in adapting H5 HA to mammalian transmission could help with surveillance and monitoring of H5N1 viruses adapting towards pandemic potential. Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors 1 , 2 , 3 . Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virus—comprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus—that was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian–human reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production and distribution of effective countermeasures.

Background. We estimate vaccine effectiveness (VE) against both influenza A/subtypes and B/lineages in Canada for the 2011-2012 trivalent inactivated influenza vaccine (TIV) with components entirely unchanged from the 2010-2011 TIV and in the context of phenotypic and genotypic characterization of circulating viruses. Methods. In a test-negative case-control study VE was estimated as [1-adjustedOddsRatio] × 100 for RT-PCRconfirmed influenza in vaccinated vs nonvaccinated participants. Viruses were characterized by hemagglutination inhibition (HI) and sequencing of antigenic sites of the hemagglutinin (HA) gene. Results. There were 1507 participants. VE against A(H1N1)pdm09 was 80% (95% confidence interval [CI], 52%-92%): circulating viruses were HI-characterized as vaccine-matched and bore just 2 aminoacid (AA) differences from vaccine. VE against A/H3N2 was 51% (95% CI, 10%-73%): circulating viruses were HI-characterized as vaccine-related but bore ≥11AA differences from vaccine. VE against influenza was 51% (95% CI, 26%-67%) in total: 71% (95% CI, 40%-86%) for lineage-matched B/Victoria and 27% (95% CI, -21% to 56%) for lineagemismatched B/Yamagata. For both influenza A and B types, VE was similar among recipients of either 2010-2011 or 2011-2012 TIV alone, higher when vaccinated both seasons. Conclusions. Phenotypic and genotypic characterization of circulating and vaccine viruses enhances understanding of TIV performance, shown in 2011-2012 to be substantial against well-conserved A(HINI) pdm09 and lineagematched influenza B, suboptimal against genetic-variants of A/H3N2, and further reduced against lineage-mismatched influenza B. With unchanged vaccine components, protection may extend beyond a single season.

Avian influenza viruses (AIVs) circulate globally, spilling over into domestic poultry and causing zoonotic infections in humans. Fortunately, AIVs are not yet capable of causing sustained human-to-human infection; however, AIVs are still a high risk as future pandemic strains, especially if they acquire further mutations that facilitate human infection and/or increase pathogenesis. Molecular characterization of sequencing data for known genetic markers associated with AIV adaptation, transmission, and antiviral resistance allows for fast, efficient assessment of AIV risk. Here we summarize and update the current knowledge on experimentally verified molecular markers involved in AIV pathogenicity, receptor binding, replicative capacity, and transmission in both poultry and mammals with a broad focus to include data available on other AIV subtypes outside of A/H5N1 and A/H7N9.

The history of influenza outbreaks.

Vaccination is one of the most cost-effective ways to prevent infection. Influenza vaccines propagated in cultured cells are approved for use in humans, but their yields are often suboptimal. Here, we screened A/Puerto Rico/8/34 (PR8) virus mutant libraries to develop vaccine backbones (defined here as the six viral RNA segments not encoding haemagglutinin and neuraminidase) that support high yield in cell culture. We also tested mutations in the coding and regulatory regions of the virus, and chimeric haemagglutinin and neuraminidase genes. A combination of high-yield mutations from these screens led to a PR8 backbone that improved the titres of H1N1, H3N2, H5N1 and H7N9 vaccine viruses in African green monkey kidney and Madin–Darby canine kidney cells. This PR8 backbone also improves titres in embryonated chicken eggs, a common propagation system for influenza viruses. This PR8 vaccine backbone thus represents an advance in seasonal and pandemic influenza vaccine development. The availability of high-yield virus strains remains an important bottleneck in the rapid production of influenza vaccines. Here, the authors report the development of influenza A vaccine backbone that improves the virus yield of various seasonal and pandemic influenza vaccine strains in cell culture.