scholarly journals Live Attenuated Influenza H7N3 Vaccine is Safe, Immunogenic and Confers Protection in Animal Models

2014 ◽  
Vol 8 (1) ◽  
pp. 154-162 ◽  
Author(s):  
Andrey Rekstin ◽  
Yulia Desheva ◽  
Irina Kiseleva ◽  
Ted Ross ◽  
David Swayne ◽  
...  
Keyword(s):  
Animal Models ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Virus Infection ◽  
Vaccine Dose ◽  
Wild Type ◽  
Highly Pathogenic ◽  
Protection Against Infection ◽  
Homologous Challenge ◽  
H7n3 Virus

Background:In 2003 the outbreak of highly pathogenic H7 avian influenza occurred in the Netherlands. The avian H7 virus causing the outbreak was also detected in humans; one person died of pneumonia and acute respiratory distress syndrome. Our paper describes preclinical studies of a H7N3 live attenuated influenza A vaccine (LAIV) candidate in various animal models.Objectives:To study safety, immunogenicity and protection of H7N3 LAIV candidate in mice, ferrets and chickens.Methods:The vaccine was generated by a classical reassortment between low pathogenicity A/mallard/Netherlands/00 (H7N3) virus and A/Leningrad4/17/57 (H2N2) master donor virus (MDV).Results:Immunogenicity was found that H7N3 LAIV was similar to the MDV in terms of replication in the respiratory organs of mice and failed to replicate in mouse brains. One dose of a H7N3 LAIV elicited measurable antibody response and it was further boosted with a second vaccine dose. Immunization of mice with H7N3 LAIV provided protection against infection following a homologous challenge with wild type H7N3 virus. Attenuated phenotype of H7N3 LAIV has been confirmed in ferrets. Immunogenicity and protective efficacy of H7N3 LAIV in ferrets were also demonstrated. The vaccine protected animals from subsequent infection with wild type H7N3 virus. The results of histopathology study revealed that inoculation of H7N3 LAIV in ferrets did not cause any inflammation or destructive changes in lungs.Lack of H7N3 LAIV replication in chicken demonstrated complete safety of this preparation for poultry.Conclusion:Results of our study suggest that new H7N3 LAIV candidate is safe, immunogenic and protects from homologues influenza virus infection in mice and ferrets.

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 A Host-Restricted Self-Attenuated Influenza Virus Provides Broad Pan-Influenza A Protection in a Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Minjin Kim ◽  
Yucheol Cheong ◽  
Jinhee Lee ◽  
Jongkwan Lim ◽  
Sanguine Byun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Infection Model ◽  
Wild Type ◽  
Group 1

Influenza virus infections can cause a broad range of symptoms, form mild respiratory problems to severe and fatal complications. While influenza virus poses a global health threat, the frequent antigenic change often significantly compromises the protective efficacy of seasonal vaccines, further increasing the vulnerability to viral infection. Therefore, it is in great need to employ strategies for the development of universal influenza vaccines (UIVs) which can elicit broad protection against diverse influenza viruses. Using a mouse infection model, we examined the breadth of protection of the caspase-triggered live attenuated influenza vaccine (ctLAIV), which was self-attenuated by the host caspase-dependent cleavage of internal viral proteins. A single vaccination in mice induced a broad reactive antibody response against four different influenza viruses, H1 and rH5 (HA group 1) and H3 and rH7 subtypes (HA group 2). Notably, despite the lack of detectable neutralizing antibodies, the vaccination provided heterosubtypic protection against the lethal challenge with the viruses. Sterile protection was confirmed by the complete absence of viral titers in the lungs and nasal turbinates after the challenge. Antibody-dependent cellular cytotoxicity (ADCC) activities of non-neutralizing antibodies contributed to cross-protection. The cross-protection remained robust even after in vivo depletion of T cells or NK cells, reflecting the strength and breadth of the antibody-dependent effector function. The robust mucosal secretion of sIgA reflects an additional level of cross-protection. Our data show that the host-restricted designer vaccine serves an option for developing a UIV, providing pan-influenza A protection against both group 1 and 2 influenza viruses. The present results of potency and breadth of protection from wild type and reassortant viruses addressed in the mouse model by single immunization merits further confirmation and validation, preferably in clinically relevant ferret models with wild type challenges.

scholarly journals Safety and Protective Efficacy of Intramuscular Vaccination with a Live aroA Derivative of Pasteurella multocida B:2 against Experimental Hemorrhagic Septicemia in Calves

2007 ◽  
Vol 75 (12) ◽  
pp. 5837-5844 ◽  
Author(s):  
Mark P. Dagleish ◽  
J. Christopher Hodgson ◽  
Saeed Ataei ◽  
Anna Finucane ◽  
Jeanie Finlayson ◽  
...  
Keyword(s):  
Pasteurella Multocida ◽  
Wild Type Strain ◽  
Protective Efficacy ◽  
Vaccine Dose ◽  
Immunoglobulin M ◽  
Wild Type ◽  
Amyloid A ◽  
Challenge Control ◽  
Temperature Responses ◽  
Dose Dependent

ABSTRACT Three groups of five calves, namely, V1, V2, and V3, were immunized intramuscularly at 4 and 8 weeks of age with ca. 109, 108, and 107 CFU, respectively, of a derivative of Pasteurella multocida B:2 wild-type strain 85020 containing a deletion in the aroA gene (strain JRMT12). The first and second vaccinations resulted in significantly (P < 0.01) higher rectal temperature responses in groups V1 and V2 than in group V3. Serum immunoglobulin M (IgM) and IgG titers did not increase in any group until after the second vaccination and were then significantly higher in groups V1 and V2 than in group V3 (P = 0.001 for both IgM and IgG). All vaccinated groups and three unvaccinated challenge control calves (group CC) were injected subcutaneously at 10 weeks of age with ca. 107 CFU of strain 85020. Vaccinated calves survived the challenge, but two CC animals developed clinical disease and were killed for humane reasons. After challenge, mean serum amyloid A concentrations were significantly higher (P < 0.001) in the CC group than in the vaccinated groups. Postmortem examination revealed that calves in the CC group showed the most extensive range of bacteriologically positive tissues and gross and histopathological lesions. Overall, a clear dose-dependent response was present, with those receiving a higher vaccine dose being less affected clinically, bacteriologically, and pathologically by the wild-type challenge. The V2 treatment appeared to give the best combination of high immune response, protection, and safety.

scholarly journals Highly Pathogenic Avian Influenza A(H7N3) Virus in Poultry Workers, Mexico, 2012

2013 ◽  
Vol 19 (9) ◽  
Author(s):  
Irma Lopez-Martinez ◽  
Amanda Balish ◽  
Gisela Barrera-Badillo ◽  
Joyce Jones ◽  
Tatiana E. Nuñez-García ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Highly Pathogenic Avian Influenza ◽  
Highly Pathogenic ◽  
Pathogenic Avian Influenza ◽  
Poultry Workers ◽  
H7n3 Virus

scholarly journals Reemerging H5N1 Influenza Viruses in Hong Kong in 2002 Are Highly Pathogenic to Ducks

2004 ◽  
Vol 78 (9) ◽  
pp. 4892-4901 ◽  
Author(s):  
Katharine M. Sturm-Ramirez ◽  
Trevor Ellis ◽  
Barry Bousfield ◽  
Lucy Bissett ◽  
Kitman Dyrting ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Hong Kong ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Neurological Dysfunction ◽  
Aquatic Birds ◽  
Antigenic Analysis ◽  
Highly Pathogenic ◽  
H5n1 Influenza

ABSTRACT Waterfowl are the natural reservoir of all influenza A viruses, which are usually nonpathogenic in wild aquatic birds. However, in late 2002, outbreaks of highly pathogenic H5N1 influenza virus caused deaths among wild migratory birds and resident waterfowl, including ducks, in two Hong Kong parks. In February 2003, an avian H5N1 virus closely related to one of these viruses was isolated from two humans with acute respiratory distress, one of whom died. Antigenic analysis of the new avian isolates showed a reactivity pattern different from that of H5N1 viruses isolated in 1997 and 2001. This finding suggests that significant antigenic variation has recently occurred among H5N1 viruses. We inoculated mallards with antigenically different H5N1 influenza viruses isolated between 1997 and 2003. The new 2002 avian isolates caused systemic infection in the ducks, with high virus titers and pathology in multiple organs, particularly the brain. Ducks developed acute disease, including severe neurological dysfunction and death. Virus was also isolated at high titers from the birds' drinking water and from contact birds, demonstrating efficient transmission. In contrast, H5N1 isolates from 1997 and 2001 were not consistently transmitted efficiently among ducks and did not cause significant disease. Despite a high level of genomic homology, the human isolate showed striking biological differences from its avian homologue in a duck model. This is the first reported case of lethal influenza virus infection in wild aquatic birds since 1961.

scholarly journals MyD88 Signaling Is Indispensable for Primary Influenza A Virus Infection but Dispensable for Secondary Infection

2010 ◽  
Vol 84 (24) ◽  
pp. 12713-12722 ◽  
Author(s):  
Sang-Uk Seo ◽  
Hyung-Joon Kwon ◽  
Joo-Hye Song ◽  
Young-Ho Byun ◽  
Baik Lin Seong ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
Protective Efficacy ◽  
Secondary Infection ◽  
Influenza Virus Infection ◽  
Lethal Challenge ◽  
Influenza A Virus Infection ◽  
Myd88 Signaling ◽  
Deficient Mice

ABSTRACT Recent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenza A virus infection (A/PR/8/34 [PR8]; H1N1), we adapted several innate signal-deficient mice (e.g., TRIF−/−, MyD88−/−, MyD88−/− TRIF−/−, TLR3−/− TLR7−/−, and IPS-1−/−). In this study, we found that MyD88 signaling was required for recruitment of CD11b+ granulocytes, production of early inflammatory cytokines, optimal proliferation of CD4 T cells, and production of Th1 cytokines by T cells. However, PR8 virus-specific IgG and IgA antibody levels in both systemic and mucosal compartments were normal in TLR- and RLR-deficient mice. To further assess the susceptibility of these mice to influenza virus infection, protective efficacy was determined after primary or secondary lethal challenge. We found that MyD88−/− and MyD88−/− TRIF−/− mice were more susceptible to primary influenza virus infection than the B6 mice but were fully protected against homologous (H1N1) and heterosubtypic (H5N2) secondary infection when primed with a nonlethal dose of PR8 virus. Taken together, these results show that MyD88 signaling plays an important role for resisting primary influenza virus infection but is dispensable for protection against a secondary lethal challenge.

scholarly journals Functional Genomic and Serological Analysis of the Protective Immune Response Resulting from Vaccination of Macaques with an NS1-Truncated Influenza Virus

2007 ◽  
Vol 81 (21) ◽  
pp. 11817-11827 ◽  
Author(s):  
C. R. Baskin ◽  
H. Bielefeldt-Ohmann ◽  
A. García-Sastre ◽  
T. M. Tumpey ◽  
N. Van Hoeven ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Pandemic ◽  
Adaptive Immune Response ◽  
Live Vaccine ◽  
Innate Immune ◽  
Vaccine Group ◽  
Homologous Challenge

ABSTRACT We are still inadequately prepared for an influenza pandemic due to the lack of a vaccine effective for subtypes to which the majority of the human population has no prior immunity and which could be produced rapidly in sufficient quantities. There is therefore an urgent need to investigate novel vaccination approaches. Using a combination of genomic and traditional tools, this study compares the protective efficacy in macaques of an intrarespiratory live influenza virus vaccine produced by truncating NS1 in the human influenza A/Texas/36/91 (H1N1) virus with that of a conventional vaccine based on formalin-killed whole virus. After homologous challenge, animals in the live-vaccine group had greatly reduced viral replication and pathology in lungs and reduced upper respiratory inflammation. They also had lesser induction of innate immune pathways in lungs and of interferon-sensitive genes in bronchial epithelium. This postchallenge response contrasted with that shortly after vaccination, when more expression of interferon-sensitive genes was observed in bronchial cells from the live-vaccine group. This suggested induction of a strong innate immune response shortly after vaccination with the NS1-truncated virus, followed by greater maturity of the postchallenge immune response, as demonstrated with robust influenza virus-specific CD4+ T-cell proliferation, immunoglobulin G production, and transcriptional induction of T- and B-cell pathways in lung tissue. In conclusion, a single respiratory tract inoculation with an NS1-truncated influenza virus was effective in protecting nonhuman primates from homologous challenge. This protection was achieved in the absence of significant or long-lasting adverse effects and through induction of a robust adaptive immune response.

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