Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and ...extensive inflammatory infiltrate. Here, we quantified the cellular immune response to infection in the mouse lung by flow cytometry and demonstrate that mice infected with highly pathogenic (HP) H1N1 and H5N1 influenza viruses exhibit significantly high numbers of macrophages and neutrophils in the lungs compared to mice infected with low pathogenic (LP) viruses. Mice infected with the 1918 pandemic virus and a recent H5N1 human isolate show considerable similarities in overall lung cellularity, lung immune cell sub-population composition, and cellular immune temporal dynamics. Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections. Primary mouse and human macrophages and dendritic cells were also susceptible to 1918 and H5N1 influenza virus infection in vitro. These results together indicate that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection.
Abstract Background Recently, lower estimates of influenza vaccine effectiveness (VE) against A(H3N2) virus illness among those vaccinated during the previous season or multiple seasons have been ...reported; however, it is unclear whether these effects are due to differences in immunogenicity. Methods We performed hemagglutination inhibition antibody (HI) assays on serum collected at preseason, ∼30 days post-vaccination, and postseason from a prospective cohort of healthcare personnel (HCP). Eligible participants had medical and vaccination records for at least four years (since July, 2006), including 578 HCP who received 2010-11 trivalent inactivated influenza vaccine IIV3, containing A/Perth/16/2009-like A(H3N2) and 209 HCP who declined vaccination. Estimates of the percentage with high titers (≥40 and > 100) and geometric mean fold change ratios (GMRs) to A/Perth/16/2009-like virus by number of prior vaccinations were adjusted for age, sex, race, education, household size, hospital care responsibilities, and study site. Results Post-vaccination GMRs were inversely associated with the number of prior vaccinations, increasing from 2.3 among those with 4 prior vaccinations to 6.2 among HCP with zero prior vaccinations ( F 4,567 = 9.97, p < .0005). Thirty-two percent of HCP with 1 prior vaccination achieved titers >100 compared to only 11% of HCP with 4 prior vaccinations (adjusted odds ratio = 6.8, 95% CI = 3.1 – 15.3). Conclusion Our findings point to an exposure-response association between repeated IIV3 vaccination and HI for A(H3N2) and are consistent with recent VE observations. Ultimately, better vaccines and vaccine strategies may be needed in order to optimize immunogenicity and VE for HCP and other repeated vaccinees.
The seasonality of influenza virus infections in temperate climates and the role of environmental conditions like temperature and humidity in the transmission of influenza virus through the air are ...not well understood. Using ferrets housed at four different environmental conditions, we evaluated the respiratory droplet transmission of two influenza viruses (a seasonal H3N2 virus and an H3N2 variant virus, the etiologic virus of a swine to human summertime infection) and concurrently characterized the aerosol shedding profiles of infected animals. Comparisons were made among the different temperature and humidity conditions and between the two viruses to determine if the H3N2 variant virus exhibited enhanced capabilities that may have contributed to the infections occurring in the summer. We report here that although increased levels of H3N2 variant virus were found in ferret nasal wash and exhaled aerosol samples compared to the seasonal H3N2 virus, enhanced respiratory droplet transmission was not observed under any of the environmental settings. However, overall environmental conditions were shown to modulate the frequency of influenza virus transmission through the air. Transmission occurred most frequently at 23°C/30%RH, while the levels of infectious virus in aerosols exhaled by infected ferrets agree with these results. Improving our understanding of how environmental conditions affect influenza virus infectivity and transmission may reveal ways to better protect the public against influenza virus infections.
The etiology of community-acquired pneumonia requiring hospitalization in adults is evolving, in light of vaccine deployment and new diagnostic tests. This article defines pathogens potentially ...causing pneumonia. In a majority of cases, no pathogen was identified.
Pneumonia is a leading infectious cause of hospitalization and death among adults in the United States,
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with medical costs exceeding $10 billion in 2011.
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Routine administration of the pneumococcal conjugate vaccine in children has resulted in an overall reduction in the rate of invasive disease and pneumonia among adults, owing to herd immunity.
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The last U.S. population–based incidence estimates of hospitalization due to community-acquired pneumonia were made in the 1990s,
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before the availability of the pneumococcal conjugate vaccine and more sensitive molecular and antigen-based laboratory diagnostic tests. Thus, contemporary population-based etiologic studies involving U.S. adults with pneumonia are . . .
Influenza is a human pathogen that continues to pose a public health threat. The use of small mammalian models has become indispensable for understanding the virulence of influenza viruses. Among ...numerous species used in the laboratory setting, only the ferret model is equally well suited for studying both the pathogenicity and transmissibility of human and avian influenza viruses. Here, we compare the advantages and limitations of the mouse, ferret and guinea pig models for research with influenza A viruses, emphasizing the multifarious uses of the ferret in the assessment of influenza viruses with pandemic potential. Research performed in the ferret model has provided information, support and guidance for the public health response to influenza viruses in humans. We highlight the recent and emerging uses of this species in influenza virus research that are advancing our understanding of virus-host interactions.
On 29 March 2013, the Chinese Center for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A(H7N9) virus. The recent human infections with ...H7N9 virus, totalling over 130 cases with 39 fatalities to date, have been characterized by severe pulmonary disease and acute respiratory distress syndrome (ARDS). This is concerning because H7 viruses have typically been associated with ocular disease in humans, rather than severe respiratory disease. This recent outbreak underscores the need to better understand the pathogenesis and transmission of these viruses in mammals. Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides. Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus.
Using stored serum samples from blood donors and subjects in previous influenza vaccine trials, CDC investigators found that vaccination with the routine trivalent seasonal influenza vaccine induced ...little immunity against the current pandemic H1N1 virus and that 34% of subjects born before 1950 had some immunity to this pandemic virus.
CDC investigators found that vaccination with the routine trivalent seasonal influenza vaccine induced little immunity against the current pandemic H1N1 virus and that 34% of subjects born before 1950 had some immunity to this pandemic virus.
On June 11, 2009, the World Health Organization declared that an influenza pandemic was under way. The 2009 pandemic H1N1 virus (2009 H1N1) has a unique combination of genes from both North American and Eurasian swine lineages that has not been identified previously in either swine or human populations.
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The hemagglutinin gene of 2009 H1N1 belongs to the classical swine lineage, which was first introduced into swine populations around 1918 and shares antigenic similarity with triple reassortant swine influenza viruses that have circulated in pigs in the United States for more than a decade; these strains have been associated . . .
Serological techniques play a critical role in various aspects of influenza surveillance, vaccine development and evaluation, and sometimes in diagnosis, particularly for novel influenza virus ...infections of humans. Because individuals are repeatedly exposed to antigenically and genetically diverse influenza viruses over a lifetime, the gold standard for detection of a recent influenza virus infection or response to current vaccination is the demonstration of a seroconversion, a fourfold or greater rise in antibody titer relative to a baseline sample, to a circulating influenza strain or vaccine component. The hemagglutination-inhibition assay remains the most widely used assay to detect strain-specific serum antibodies to influenza. The hemagglutination-inhibition assay is also used to monitor antigenic changes among influenza viruses which are constantly evolving; such antigenic data is essential for consideration of changes in influenza vaccine composition. The use of the hemagglutinin-specific microneutralization assay has increased, in part, owing to its sensitivity for detection of human antibodies to novel influenza viruses of animal origin. Neutralization assays using replication-incompetent pseudotyped particles may be advantageous in some laboratory settings for detection of antibodies to influenza viruses with heightened biocontainment requirements. The use of standardized protocols and antibody standards are important steps to improve reproducibility and interlaboratory comparability of results of serologic assays for influenza viruses.
Background. Laboratory correlates of influenza vaccine protection can best be identified by examining people who are infected despite vaccination. While the importance of antibody to viral ...hemagglutinin (HA) has long been recognized, the level of protection contributed independently by antibody to viral neuraminidase (NA) has not been determined. Methods. Sera from a controlled trial of the efficacies of inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) were tested by hemagglutination inhibition (HAI) assay, microneutralization (MN) assay, and a newly standardized lectin-based neuraminidase inhibition (NAI) assay. Results. The NAI assay detected a vaccine response in 37% of IIV recipients, compared with 77% and 67% of participants in whom responses were detected by the HAI and MN assays, respectively. For LAIV recipients, the NAI, HAI, and MN assays detected responses in 6%, 21%, and 17%, respectively. In IIV recipients, as NAI assay titers rose, the frequency of infection fell, similar to patterns seen with HAI and MN assays. HAI and MN assay titers were highly correlated, but NAI assay titers exhibited less of a correlation. Analyses suggested an independent role for NAI antibody in protection, which was similar in the IIV, LAIV, and placebo groups. Conclusions. While NAI antibody is not produced to a large extent in response to current IIV, it appears to have an independent role in protection. As new influenza vaccines are developed, NA content should be considered. Clinical Trials Registration. NCT00538512.
Recent reports of mild to severe influenza-like illness in humans caused by a novel swine-origin 2009 A(H1N1) influenza virus underscore the need to better understand the pathogenesis and ...transmission of these viruses in mammals. In this study, selected 2009 A(H1N1) influenza isolates were assessed for their ability to cause disease in mice and ferrets and compared with a contemporary seasonal H1N1 virus for their ability to transmit to naïve ferrets through respiratory droplets. In contrast to seasonal influenza H1N1 virus, 2009 A(H1N1) influenza viruses caused increased morbidity, replicated to higher titers in lung tissue, and were recovered from the intestinal tract of intranasally inoculated ferrets. The 2009 A(H1N1) influenza viruses exhibited less efficient respiratory droplet transmission in ferrets in comparison with the highly transmissible phenotype of a seasonal H1N1 virus. Transmission of the 2009 A(H1N1) influenza viruses was further corroborated by characterizing the binding specificity of the viral hemagglutinin to the sialylated glycan receptors (in the human host) by use of dose-dependent direct receptor-binding and human lung tissue-binding assays.
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