Safety and Efficacy of Intravenous Zanamivir in Preventing Experimental Human Influenza A Virus Infection

1999 ◽  
Vol 43 (7) ◽  
pp. 1616-1620 ◽  
Author(s):  
David P. Calfee ◽  
Amy W. Peng ◽  
Lindsey M. Cass ◽  
Monica Lobo ◽  
Frederick G. Hayden
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Controlled Study ◽  
Nasal Discharge ◽  
Upper Respiratory Tract ◽  
Human Influenza ◽  
Safety And Efficacy ◽  
Viral Shedding ◽  
Respiratory Tract Illness ◽  
Double Blinded

ABSTRACT Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with ∼105 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50 · day/ml in placebo,P < 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo,P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.

scholarly journals Time dependent proinflammatory responses shape virus interference during coinfections of influenza A virus and influenza D virus

2021 ◽  
Author(s):  
Minhui Guan ◽  
Sherry Blackmon ◽  
Alicia K. Olivier ◽  
Xiaojian Zhang ◽  
Liyuan Liu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Upper Respiratory Tract ◽  
Proinflammatory Response ◽  
Tracheal Epithelial Cells ◽  
Viral Shedding ◽  
Proinflammatory Responses

Both influenza A virus (IAV) and influenza D virus (IDV) are enzootic in pigs. IAV causes approximately 100% morbidity with low mortality, whereas IDV leads to only mild respiratory diseases in pigs. In this study, we performed a series of coinfection experiments in vitro and in vivo to understand how IAV and IDV interact and cause pathogenesis during coinfection. Results showed that IAV inhibited IDV replication when infecting swine tracheal epithelial cells (STEC) with IAV 24- or 48- hours prior to IDV inoculation, and that IDV suppressed IAV replication when IDV preceded IAV inoculation by 48 hours. Virus interference was not identified during simultaneous IAV/IDV infections or with 6 hours between the two viral infections, regardless of their order. The interference pattern at 24- and 48-hours correlated with proinflammatory responses induced by the first infection, which was about 24-hours slower for IDV than IAV. The viruses did not interfere with each other if both infected the cells before proinflammatory responses were induced. Coinfection in pigs further demonstrated that IAV interfered both viral shedding and virus replication of IDV, especially in the upper respiratory tract. Clinically, coinfection of IDV and IAV did not show significant enhancement of disease pathogenesis, compared with the pigs infected with IAV alone. In summary, this study suggests that interference during coinfection of IAV and IDV is primarily due to the proinflammatory response and is therefore dependent on the time between infection, and the order of infection.

scholarly journals N-Glycolylneuraminic Acid in Animal Models for Human Influenza A Virus

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 815
Author(s):  
Cindy M. Spruit ◽  
Nikoloz Nemanichvili ◽  
Masatoshi Okamatsu ◽  
Hiromu Takematsu ◽  
Geert-Jan Boons ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Animal Models ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Sialic Acid Content ◽  
Acetylneuraminic Acid

The first step in influenza virus infection is the binding of hemagglutinin to sialic acid-containing glycans present on the cell surface. Over 50 different sialic acid modifications are known, of which N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two main species. Animal models with α2,6 linked Neu5Ac in the upper respiratory tract, similar to humans, are preferred to enable and mimic infection with unadapted human influenza A viruses. Animal models that are currently most often used to study human influenza are mice and ferrets. Additionally, guinea pigs, cotton rats, Syrian hamsters, tree shrews, domestic swine, and non-human primates (macaques and marmosets) are discussed. The presence of NeuGc and the distribution of sialic acid linkages in the most commonly used models is summarized and experimentally determined. We also evaluated the role of Neu5Gc in infection using Neu5Gc binding viruses and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)-/- knockout mice, which lack Neu5Gc and concluded that Neu5Gc is unlikely to be a decoy receptor. This article provides a base for choosing an appropriate animal model. Although mice are one of the most favored models, they are hardly naturally susceptible to infection with human influenza viruses, possibly because they express mainly α2,3 linked sialic acids with both Neu5Ac and Neu5Gc modifications. We suggest using ferrets, which resemble humans closely in the sialic acid content, both in the linkages and the lack of Neu5Gc, lung organization, susceptibility, and disease pathogenesis.

scholarly journals Pre-exposure with influenza A virus A/WSN/1933(H1N1) resulted in viral shedding reduction from pigs challenged with either swine H1N1 or H3N2 virus

2019 ◽  
Vol 228 ◽  
pp. 26-31 ◽  
Author(s):  
Zhao Wang ◽  
Jieshi Yu ◽  
Milton Thomas ◽  
Chithra C. Sreenivasan ◽  
Ben M. Hause ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
H3n2 Virus ◽  
Viral Shedding

scholarly journals The human H5N1 influenza A virus polymerase complex is active in vitro over a broad range of temperatures, in contrast to the WSN complex, and this property can be attributed to the PB2 subunit

2008 ◽  
Vol 89 (12) ◽  
pp. 2923-2932 ◽  
Author(s):  
Birgit G. Bradel-Tretheway ◽  
Z. Kelley ◽  
Shikha Chakraborty-Sett ◽  
Toru Takimoto ◽  
Baek Kim ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Elevated Temperatures ◽  
Expression System ◽  
Lung Epithelial Cells ◽  
Upper Respiratory Tract ◽  
Polymerase Complex ◽  
H5n1 Influenza

Influenza A virus (IAV) replicates in the upper respiratory tract of humans at 33 °C and in the intestinal tract of birds at close to 41 °C. The viral RNA polymerase complex comprises three subunits (PA, PB1 and PB2) and plays an important role in host adaptation. We therefore developed an in vitro system to examine the temperature sensitivity of IAV RNA polymerase complexes from different origins. Complexes were prepared from human lung epithelial cells (A549) using a novel adenoviral expression system. Affinity-purified complexes were generated that contained either all three subunits (PA/PB1/PB2) from the A/Viet/1203/04 H5N1 virus (H/H/H) or the A/WSN/33 H1N1 strain (W/W/W). We also prepared chimeric complexes in which the PB2 subunit was exchanged (H/H/W, W/W/H) or substituted with an avian PB2 from the A/chicken/Nanchang/3-120/01 H3N2 strain (W/W/N). All complexes were functional in transcription, cap-binding and endonucleolytic activity. Complexes containing the H5N1 or Nanchang PB2 protein retained transcriptional activity over a broad temperature range (30–42 °C). In contrast, complexes containing the WSN PB2 protein lost activity at elevated temperatures (39 °C or higher). The E627K mutation in the avian PB2 was not required for this effect. Finally, the avian PB2 subunit was shown to confer enhanced stability to the WSN 3P complex. These results show that PB2 plays an important role in regulating the temperature optimum for IAV RNA polymerase activity, possibly due to effects on the functional stability of the 3P complex.

scholarly journals Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, placebo-controlled study

EBioMedicine ◽  
2019 ◽  
Vol 40 ◽  
pp. 574-582 ◽  
Author(s):  
Ellie Hershberger ◽  
Susan Sloan ◽  
Kristin Narayan ◽  
Catherine A. Hay ◽  
Patrick Smith ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Influenza A ◽  
Controlled Study ◽  
Phase 2 ◽  
Double Blind ◽  
Safety And Efficacy

scholarly journals Respiratory Bacteria Stabilize and Promote Airborne Transmission of Influenza A Virus

mSystems ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Hannah M. Rowe ◽  
Brandi Livingston ◽  
Elisa Margolis ◽  
Amy Davis ◽  
Victoria A. Meliopoulos ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Bacterial Species ◽  
Bacterial Flora ◽  
Transmission Dynamics ◽  
Environmental Stability ◽  
Upper Respiratory Tract ◽  
Airborne Transmission ◽  
Content Type ◽  
Mortality And Morbidity

Infection with influenza A virus (IAV), especially when complicated with a secondary bacterial infection, is a leading cause of global mortality and morbidity. Gaining a greater understanding of the transmission dynamics of IAV is important during seasonal IAV epidemics and in the event of a pandemic. Direct bacterium-virus interactions are a recently appreciated aspect of infectious disease biology. Direct interactions between IAV and specific bacterial species of the human upper respiratory tract were found to promote the stability and infectivity of IAV during desiccation stress. Viral environmental stability is an important aspect during transmission, suggesting a potential role for bacterial respiratory communities in IAV transmission. Airborne transmission of IAV was abrogated upon depletion of nasal bacterial flora with topical antibiotics. This defect could be functionally complemented by S. pneumoniae coinfection. These data suggest that bacterial coinfection may be an underappreciated aspect of IAV transmission dynamics.

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