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.
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 (AIV) with good adaptation and various mutations have threatened both human and animals’ health. The H7 subtypes have the potential to cause pandemic threats to human health ...due to the highly pathogenic characteristics. Therefore, it is quite urgent to develop a novel biosensor for rapid and sensitive detection of H7 subtypes. In this work, a biosensor based on luminescence resonance energy transfer (LRET) from BaGdF5:Yb/Er upconversion nanoparticles (UCNPs) to gold nanoparticles (AuNPs) has been developed for rapid and sensitive H7 subtypes detection. The amino modified capture oligonucleotide probes are covalently linked to poly(ethylenimine) (PEI) modified BaGdF5:Yb/Er UCNPs. The thiol modified oligonucleotides with H7 hemagglutinin gene sequence are conjugated to surfaces of AuNPs. The hybridization process between complementary strands of H7 Hemagglutinin gene and its probe brings the energy donor and acceptor into close proximity, leading to the quenching of fluorescence of UCNPs. A linear response is obtained ranging from 10 pm to 10 nm and the limit of detection (LOD) is around 7 pm with detection time around 2 hours. This biosensor is expected to be a valuable diagnostic tool for rapid and sensitive detection of AIV.
An upconversion luminescence resonance energy transfer (LRET) biosensor based on BaGdF5:Yb/Er UCNPs and AuNPs is developed for rapid and ultrasensitive detection of avian influenza virus. Capture oligonucleotide probe and target oligonucleotide specific for H7 sequence are immoboilized on UCNPs and AuNPs, respectively. A low detection of limit (LOD) of 7 pm within 2 h is achieved based on capture‐target oligonucleotide hybridization.
The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new ...approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable receptor-binding domain (RBD) of viral hemagglutinin displayed on a nanoparticle (np) able to elicit antibody responses that neutralize H1N1 influenza viruses spanning over 90 years. Co-display of RBDs from multiple strains across time, so that the adjacent RBDs are heterotypic, provides an avidity advantage to cross-reactive B cells. Immunization with the mosaic RBD-np elicited broader antibody responses than those induced by an admixture of nanoparticles encompassing the same set of RBDs as separate homotypic arrays. Furthermore, we identified a broadly neutralizing monoclonal antibody in a mouse immunized with mosaic RBD-np. The mosaic antigen array signifies a unique approach that subverts monotypic immunodominance and allows otherwise subdominant cross-reactive B cell responses to emerge.
The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of ...the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins' in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
Background. We estimated the effectiveness of inactivated influenza vaccines for the prevention of laboratory-confirmed, medically attended influenza during 3 seasons with variable antigenic match ...between vaccine and patient strains. Methods. Patients were enrolled during or after a clinical encounter for acute respiratory illness. Influenza infection was confirmed by culture or reverse-transcriptase polymerase chain reaction. Case-control analyses were performed that used data from patients who were ill without influenza (hereafter, “test-negative control subjects”) and data from asymptomatic control subjects from the population (hereafter, “traditional control subjects”). Vaccine effectiveness (VE) was estimated as 100 × (1 − adjusted odds ratio). Influenza isolates were antigenically characterized. Results. Influenza was detected in 167 (20%) of 818 patients in 2004–2005, in 51 (14%) of 356 in 2005–2006, and in 102 (11%) of 932 in 2006–2007. Analyses that used data from test-negative control subjects showed that VE was 10% (95% confidence interval CI, −36% to 40%) in 2004–2005, 21% (95% CI,−52% to 59%) in 2005–2006, and 52% (95% CI, 22% to 70%) in 2006–2007. Using data from traditional control subjects, VE for those seasons was estimated to be 5% (95% CI, −52% to 40%), 11% (95% CI, −96% to 59%), and 37% (95% CI, −10% to 64%), respectively; confidence intervals included 0. The percentage of viruses that were antigenically matched to vaccine strains was 5% (3 of 62) in 2004–2005, 5% (2 of 42) in 2005–2006, and 91% (85 of 93) in 2006–2007. Conclusions. Influenza VE varied substantially across 3 seasons and was highest when antigenic match was optimal. VE estimates that used data from test-negative control subjects were consistently higher than those that used data from traditional control subjects.
Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise ...measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution. DOI: http://dx.doi.org/10.7554/eLife.01914.001.
Influenza vaccines that confer broad and durable protection against diverse viral strains would have a major effect on global health, as they would lessen the need for annual vaccine reformulation ...and immunization
. Here we show that computationally designed, two-component nanoparticle immunogens
induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens contain 20 haemagglutinin glycoprotein trimers in an ordered array, and their assembly in vitro enables the precisely controlled co-display of multiple distinct haemagglutinin proteins in defined ratios. Nanoparticle immunogens that co-display the four haemagglutinins of licensed quadrivalent influenza vaccines elicited antibody responses in several animal models against vaccine-matched strains that were equivalent to or better than commercial quadrivalent influenza vaccines, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved haemagglutinin stem. The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens makes them attractive candidates for a supraseasonal influenza vaccine candidate with the potential to replace conventional seasonal vaccines
.
Twenty-nine distinct epizootics of high-pathogenicity avian influenza (HPAI) have occurred since 1959. The H5N1 HPAI panzootic affecting Asia, Africa and Eastern Europe has been the largest among ...these, affecting poultry and/or wild birds in 63 countries. A stamping-out programme achieved eradication in 24 of these epizootics (and is close to achieving eradication in the current H5N2 epizootic in South African ostriches), but vaccination was added to the control programmes in four epizootics when stamping out alone was not effective. During the 2002 to 2010 period, more than 113 billion doses of avian influenza (AI) vaccine were used in at-risk national poultry populations of over 131 billion birds. At two to three doses per bird for the 15 vaccinating countries, the average national vaccination coverage rate was 41.9% and the global AI vaccine coverage rate was 10.9% for all poultry. The highest national coverage rate was nearly 100% for poultry in Hong Kong and the lowest national coverage was less than 0.01% for poultry in Israel and The Netherlands. Inactivated AI vaccines accounted for 95.5% and live recombinant virus vaccines for 4.5% of the vaccines used. Most of these vaccines were used in the H5N1 HPAI panzootic, with more than 99% employed in the People's Republic of China, Egypt, Indonesia and Vietnam. Implementation of vaccination in these four countries occurred after H5N1 HPAI became enzootic in domestic poultry and vaccination did not result in the enzootic infections. Vaccine usage prevented clinical disease and mortality in chickens, and maintained rural livelihoods and food security during HPAI outbreaks. Low-pathogenicity notifiable avian influenza (LPNAI) became reportable to the World Organisation for Animal Health in 2006 because some H5 and H7 low-pathogenicity avian influenza (LPAI) viruses have the potential to mutate to HPAI viruses. Fewer outbreaks of LPNAI have been reported than of HPAI and only six countries used vaccine in control programmes, accounting for 8.1% of the total H5/H7 AI vaccine usage, as compared to 91.9% of the vaccine used against HPAI. Of the six countries that have used vaccine to control LPNAI, Mexico, Guatemala, El Salvador and Italy have been the biggest users. In countries with enzootic HPAI and LPNAI, development and implementation of exit strategies has been difficult.
The emergence of human infection with a novel H7N9 influenza virus in China raises a pandemic concern. Chicken H9N2 viruses provided all six of the novel reassortant’s internal genes. However, it is ...not fully understood how the prevalence and evolution of these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that over more than 10 y of cocirculation of multiple H9N2 genotypes, a genotype (G57) emerged that had changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens in China, caused widespread outbreaks in 2010–2013 before the H7N9 viruses emerged in humans, and finally provided all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential.
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