scholarly journals Infection of influenza virus neuraminidase-vaccinated mice with homologous influenza virus leads to strong protection against heterologous influenza viruses

2014 ◽  
Vol 95 (12) ◽  
pp. 2627-2637 ◽  
Author(s):  
Biao He ◽  
Haiyan Chang ◽  
Zhihua Liu ◽  
Chaoyang Huang ◽  
Xueying Liu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Infection ◽  
Lethal Dose ◽  
Influenza Viruses ◽  
Virus Challenge ◽  
Influenza Pandemics ◽  
Homologous Virus ◽  
Major Antigen ◽  
Influenza Virus Neuraminidase ◽  
Antibody Levels

Vaccination is the best measure to prevent influenza pandemics. Here, we studied the protective effect against heterologous influenza viruses, including A/reassortant/NYMC X-179A (pH1N1), A/Chicken/Henan/12/2004 (H5N1), A/Chicken/Jiangsu/7/2002 (H9N2) and A/Guizhou/54/89×A/PR/8/34 (A/Guizhou-X) (H3N2), in mice first vaccinated with a DNA vaccine of haemagglutinin (HA) or neuraminidase (NA) of A/PR/8/34 (PR8) and then infected with the homologous virus. We showed that PR8 HA or NA vaccination both protected mice against a lethal dose of the homologous virus; PR8 HA or NA DNA vaccination and then PR8 infection in mice offered poor or excellent protection, respectively, against a second, heterologous influenza virus challenge. In addition, before the second heterologous influenza infection, the highest antibody level against nucleoprotein (NP) and matrix (M1 and M2) proteins was found in the PR8 NA-vaccinated and PR8-infected group. The level of induced cellular immunity against NP and M1 showed a trend consistent with that seen in antibody levels. However, PR8 HA+NA vaccination and then PR8 infection resulted in limited protection against heterologous influenza virus challenge. Results of the present study demonstrated that infection of the homologous influenza virus in mice already immunized with a NA vaccine could provide excellent protection against subsequent infection of a heterologous influenza virus. These findings suggested that NA, a major antigen of influenza virus, could be an important candidate antigen for universal influenza vaccines.

scholarly journals Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 234
Author(s):  
Sarah Al-Beltagi ◽  
Cristian Alexandru Preda ◽  
Leah V. Goulding ◽  
Joe James ◽  
Juan Pu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Syncytial Virus ◽  
Influenza A Virus ◽  
Broad Spectrum ◽  
Influenza A ◽  
Respiratory Viruses ◽  
Influenza Viruses ◽  
Virus Challenge ◽  
2009 H1n1 ◽  
Syncytial Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

scholarly journals A Live-Attenuated Prime, Inactivated Boost Vaccination Strategy with Chimeric Hemagglutinin-Based Universal Influenza Virus Vaccines Provides Protection in Ferrets: A Confirmatory Study

Vaccines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 47 ◽  
Author(s):  
Raffael Nachbagauer ◽  
Florian Krammer ◽  
Randy Albrecht
Keyword(s):  
Influenza Virus ◽  
Respiratory Tract ◽  
Virus Vaccine ◽  
Influenza Viruses ◽  
Inactivated Vaccine ◽  
Upper Respiratory Tract ◽  
Live Attenuated Vaccine ◽  
Virus Surface ◽  
Virus Challenge ◽  
Attenuated Vaccine

Influenza viruses cause severe diseases and mortality in humans on an annual basis. The current influenza virus vaccines can confer protection when they are well-matched with the circulating strains. However, due to constant changes of the virus surface glycoproteins, the vaccine efficacy can drop substantially in some seasons. In addition, the current seasonal influenza virus vaccines do not protect from avian influenza viruses of human pandemic potential. Novel influenza virus vaccines that aim to elicit antibodies against conserved epitopes like the hemagglutinin stalk could not only reduce the burden of drifted seasonal viruses but potentially also protect humans from infection with zoonotic and emerging pandemic influenza viruses. In this paper, we generated influenza virus vaccine constructs that express chimeric hemagglutinins consisting of exotic, avian head domains and a consistent stalk domain of a seasonal virus. Using such viruses in a sequential immunization regimen can redirect the immune response towards conserved epitopes. In this study, male ferrets received a live-attenuated vaccine virus based on the A/Ann Arbor/6/60 strain expressing a chimeric H8/1 (cH8/1) hemagglutinin, which was followed by a heterologous booster vaccination with a cH5/1N1 formalin inactivated non-adjuvanted whole virus. This group was compared to a second group that received a cH8/1N1 inactivated vaccine followed by a cH5/1N1 inactivated vaccine. Both groups showed a reduction in viral titers in the upper respiratory tract after the A(H1N1)pdm09 virus challenge. Animals that received the live-attenuated vaccine had low or undetectable titers in the lower respiratory tract. The results support the further development of chimeric hemagglutinin-based vaccination strategies. The outcome of this study confirms and corroborates findings from female ferrets primed with a A/Leningrad/134/17/57-based live attenuated cH8/1N1 vaccine followed by vaccination with an AS03-adjuvanted cH5/1N1 split virus vaccine 10.

scholarly journals Construction and Immunogenicity of a Novel Multivalent Vaccine Prototype Based on Conserved Influenza Virus Antigens

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 197 ◽  
Author(s):  
Anna Kirsteina ◽  
Inara Akopjana ◽  
Janis Bogans ◽  
Ilva Lieknina ◽  
Juris Jansons ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Matrix Protein ◽  
Influenza Infection ◽  
Alpha Helix ◽  
H1n1 Influenza ◽  
Dimensional Structure ◽  
Effective Vaccine ◽  
High Dose ◽  
Virus Challenge ◽  
Practical Applications

Influenza, an acute, highly contagious respiratory disease, remains a significant threat to public health. More effective vaccination strategies aimed at inducing broad cross-protection not only against seasonal influenza variants, but also zoonotic and emerging pandemic influenza strains are urgently needed. A number of conserved protein targets to elicit such cross-protective immunity have been under investigation, with long alpha-helix (LAH) from hemagglutinin stalk and ectodomain of matrix protein 2 ion channel (M2e) being the most studied ones. Recently, we have reported the three-dimensional structure and some practical applications of LAH expressed in Escherichia coli system (referred to as tri-stalk protein). In the present study, we investigated the immunogenicity and efficacy of a panel of broadly protective influenza vaccine prototypes based on both influenza tri-stalk and triple M2e (3M2e) antigens integrated into phage AP205 virus-like particles (VLPs). While VLPs containing the 3M2e alone induced protection against standard homologous and heterologous virus challenge in mice, only the combination of both conserved influenza antigens into a single VLP fully protected mice from a high-dose homologous H1N1 influenza infection. We propose that a combination of genetic fusion and chemical coupling techniques to expose two different foreign influenza antigens on a single particle is a perspective approach for generation of a broadly-effective vaccine candidate that could protect against the constantly emerging influenza virus strains.

scholarly journals RNA-Sequencing-Based Transcriptomic Analysis Reveals a Role for Annexin-A1 in Classical and Influenza A Virus-Induced Autophagy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1399 ◽  
Author(s):  
Jianzhou Cui ◽  
Dhakshayini Morgan ◽  
Dao Han Cheng ◽  
Sok Lin Foo ◽  
Gracemary L. R. Yap ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Critical Role ◽  
Mtor Inhibitors ◽  
Influenza Viruses ◽  
Annexin A1 ◽  
Underlying Mechanisms

Influenza viruses have been shown to use autophagy for their survival. However, the proteins and mechanisms involved in the autophagic process triggered by the influenza virus are unclear. Annexin-A1 (ANXA1) is an immunomodulatory protein involved in the regulation of the immune response and Influenza A virus (IAV) replication. In this study, using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) deletion of ANXA1, combined with the next-generation sequencing, we systematically analyzed the critical role of ANXA1 in IAV infection as well as the detailed processes governing IAV infection, such as macroautophagy. A number of differentially expressed genes were uniquely expressed in influenza A virus-infected A549 parental cells and A549 ∆ANXA1 cells, which were enriched in the immune system and infection-related pathways. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the role of ANXA1 in autophagy. To validate this, the effect of mechanistic target of rapamycin (mTOR) inhibitors, starvation and influenza infection on autophagy was determined, and our results demonstrate that ANXA1 enhances autophagy induced by conventional autophagy inducers and influenza virus. These results will help us to understand the underlying mechanisms of IAV infection and provide a potential therapeutic target for restricting influenza viral replication and infection.

scholarly journals Vaccination with Vesicular Stomatitis Virus-Vectored Chimeric Hemagglutinins Protects Mice against Divergent Influenza Virus Challenge Strains

2015 ◽  
Vol 90 (5) ◽  
pp. 2544-2550 ◽  
Author(s):  
Alex B. Ryder ◽  
Raffael Nachbagauer ◽  
Linda Buonocore ◽  
Peter Palese ◽  
Florian Krammer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Vesicular Stomatitis Virus ◽  
Humoral Immunity ◽  
Influenza Viruses ◽  
Full Length ◽  
Influenza Vaccines ◽  
Serum Antibodies ◽  
Virus Challenge ◽  
Vaccination Strategies ◽  
Vesicular Stomatitis

ABSTRACTSeasonal influenza virus infections continue to cause significant disease each year, and there is a constant threat of the emergence of reassortant influenza strains causing a new pandemic. Available influenza vaccines are variably effective each season, are of limited scope at protecting against viruses that have undergone significant antigenic drift, and offer low protection against newly emergent pandemic strains. “Universal” influenza vaccine strategies that focus on the development of humoral immunity directed against the stalk domains of the viral hemagglutinin (HA) show promise for protecting against diverse influenza viruses. Here, we describe such a strategy that utilizes vesicular stomatitis virus (VSV) as a vector for chimeric hemagglutinin (cHA) antigens. This vaccination strategy is effective at generating HA stalk-specific, broadly cross-reactive serum antibodies by both intramuscular and intranasal routes of vaccination. We show that prime-boost vaccination strategies provide protection against both lethal homologous and heterosubtypic influenza challenge and that protection is significantly improved with intranasal vaccine administration. Additionally, we show that vaccination with VSV-cHAs generates greater stalk-specific and cross-reactive serum antibodies than does vaccination with VSV-vectored full-length HAs, confirming that cHA-based vaccination strategies are superior at generating stalk-specific humoral immunity. VSV-vectored influenza vaccines that express chimeric hemagglutinin antigens offer a novel means for protecting against widely diverging influenza viruses.IMPORTANCEUniversal influenza vaccination strategies should be capable of protecting against a wide array of influenza viruses, and we have developed such an approach utilizing a single viral vector system. The potent antibody responses that these vaccines generate are shown to protect mice against lethal influenza challenges with highly divergent viruses. Notably, intranasal vaccination offers significantly better protection than intramuscular vaccination in a lethal virus challenge model. The results described in this study offer insights into the mechanisms by which chimeric hemagglutinin (HA)-based vaccines confer immunity, namely, that the invariant stalk of cHA antigens is superior to full-length HA antigens at inducing cross-reactive humoral immune responses and that VSV-cHA vaccine-induced protection varies by site of inoculation, and contribute to the further development of universal influenza virus vaccines.

scholarly journals Intranasal Vaccination with 1918 Influenza Virus-Like Particles Protects Mice and Ferrets from Lethal 1918 and H5N1 Influenza Virus Challenge

2009 ◽  
Vol 83 (11) ◽  
pp. 5726-5734 ◽  
Author(s):  
Lucy A. Perrone ◽  
Attiya Ahmad ◽  
Vic Veguilla ◽  
Xiuhua Lu ◽  
Gale Smith ◽  
...  
Keyword(s):  
Influenza Virus ◽  
H5n1 Virus ◽  
Influenza Pandemic ◽  
Human Case ◽  
Lethal Challenge ◽  
Virus Like Particles ◽  
Virus Challenge ◽  
H5n1 Influenza ◽  
Pandemic Virus ◽  
Homologous Virus

ABSTRACT Influenza vaccines capable of inducing cross-reactive or heterotypic immunity could be an important first line of prevention against a novel subtype virus. Influenza virus-like particles (VLPs) displaying functional viral proteins are effective vaccines against replication-competent homologous virus, but their ability to induce heterotypic immunity has not been adequately tested. To measure VLP vaccine efficacy against a known influenza pandemic virus, recombinant VLPs were generated from structural proteins of the 1918 H1N1 virus. Mucosal and traditional parenteral administrations of H1N1 VLPs were compared for the ability to protect against the reconstructed 1918 virus and a highly pathogenic avian H5N1 virus isolated from a fatal human case. Mice that received two intranasal immunizations of H1N1 VLPs were largely protected against a lethal challenge with both the 1918 virus and the H5N1 virus. In contrast, mice that received two intramuscular immunizations of 1918 VLPs were only protected against a homologous virus challenge. Mucosal vaccination of mice with 1918 VLPs induced higher levels of cross-reactive immunoglobulin G (IgG) and IgA antibodies than did parenteral vaccination. Similarly, ferrets mucosally vaccinated with 1918 VLPs completely survived a lethal challenge with the H5N1 virus, while only a 50% survival rate was observed in parenterally vaccinated animals. These results suggest a strategy of VLP vaccination against a pandemic virus and one that stimulates heterotypic immunity against an influenza virus strain with threatening pandemic potential.

scholarly journals Influenza virus inhibits respiratory syncytial virus (RSV) infection via a two-wave expression of interferon-induced protein with tetratricopeptide (IFIT) proteins

2020 ◽  
Author(s):  
Yaron Drori ◽  
Jasmine Jacob-Hirsch ◽  
Rakefet Pando ◽  
Aharona Glatman-Freedman ◽  
Nehemya Friedman ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Influenza Virus ◽  
Respiratory Syncytial Virus ◽  
Influenza Infection ◽  
Treatment Strategies ◽  
Respiratory Viruses ◽  
Influenza Viruses ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Mouse Lungs

AbstractInfluenza viruses and respiratory syncytial virus (RSV) are respiratory viruses that primarily circulate worldwide during the autumn and winter seasons. Seasonal surveillance shows that RSV infection generally precedes influenza. However, in the last four winter seasons (2016-2020) an overlap of the morbidity peaks of both viruses was observed in Israel, and was paralleled by significantly lower RSV infection rates. To investigate whether the influenza virus inhibits RSV we performed coinfection of Human cervical carcinoma (HEp2) cells or mice with influenza and RSV and we observed that the influenza inhibited RSV growth, both in vitro and in vivo. Mass spectrometry analysis of mouse lungs infected with influenza identified a two-wave pattern of protein expression upregulation, which included members of the interferon-induced protein with tetratricopeptide (IFITs) family. Interestingly, in the second peak of upregulation, influenza viruses were no longer detectable in mouse lungs. We also observed that knockdown and overexpression of IFITs in HEp2 cells affected RSV multiplicity. In conclusion, influenza infection inhibits RSV infectivity via upregulation of IFIT proteins in a two-wave modality. Understanding of the interaction between influenza and RSV viruses and immune system involvement will contribute to the development and optimization of future treatment strategies against these viruses.Author SummaryRespiratory syncytial virus (RSV) and influenza viruses are both respiratory viruses associated with morbidity and mortality worldwide. RSV is usually detected in October, with a clear peak in December, whereas influenza virus arrives in November and peaks in January. In the last four seasons, influenza infection overlapped with that of RSV in Israel, which resulted in decreased morbidity of RSV suggesting that influenza virus inhibits RSV infection. To identify the mechanism responsible for the influenza inhibition of RSV we performed experiments in culture and in mice. We observed that influenza infection results in two wave modality of inhibition of RSV infection. Using mass spectrometry perfornmed on lungs from infected mice we show that influenza infection induces the expression of (IFIT) family of proteins which also showed a two-wave modality. Using knockdown and overexpression experiments we showed that indeed the IFTIs inhibits RSV infection. Our study provides new insights on the interaction between influenza and RSV viruses and immune system involvement and contribute to the development of future treatment strategies against these viruses.

scholarly journals Development of live vaccine based on the Enterococcus faecium L3 vector for prevention influenza infections

2021 ◽  
Author(s):  
Yulia Desheva ◽  
Galina Leontieva ◽  
Tatiana Kramskaya ◽  
Tatiana Gupalova ◽  
Olga Kopteva ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Enterococcus Faecium ◽  
Influenza Infection ◽  
Probiotic Strain ◽  
Recombinant Vaccines ◽  
Local Immunity ◽  
Epidemic Season ◽  
The Third ◽  
Genes Encoding ◽  
Influenza Virus Neuraminidase

Abstract Probiotic microorganisms are currently considered as a promising platform for the development of recombinant vaccines expressing foreign antigens. In this study we generated and evaluated the live mucosal recombinant vaccine by integrating genes encoding influenza virus neuraminidase (NA) of N2 subtype into the DNA of the probiotic strain Enterococcus faecium L3 (L3). We confirmed NA expression in the pili of L3 using immune electron microscopy. Mice were fed with a probiotic vaccine containing the NA gene (L3-NA) or pure L3. Oral administration of L3-NA caused detectable increase of virus-specific serum IgG and local IgA after the third feeding. A the same time, single spleen cell suspensions were stimulated with whole A(H1N1)pdm09 virus followed by flow cytometry. In mice received L3-NA, the content of cytotoxic T-lymphocytes was more pronounced compared to mice receiving pure L3. Immunization with L3-NA increased the survival rate by 34% when the mice were infected using A(H1N1)pdm09 influenza virus after the third feeding. After S. pneumonia post-influenza infection, the L3-NA immunized mice were 50% more protected from lethality in comparison with L3 fed mice. Thus, a live probiotic vaccine candidate based on L3 induced the formation of systemic and local immunity and provide protection against complicated influenza. The approach based on a probiotic vaccine expressing viral epitopes can allow repeated immunization during epidemic season.

scholarly journals Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Christopher L. D. McMillan ◽  
Stacey T. M. Cheung ◽  
Naphak Modhiran ◽  
James Barnes ◽  
Alberto A. Amarilla ◽  
...  
Keyword(s):  
Influenza A ◽  
Vaccine Development ◽  
Influenza Viruses ◽  
Rapid Response ◽  
Efficient Production ◽  
Influenza A Viruses ◽  
Large Reservoir ◽  
Diverse Range ◽  
Virus Challenge ◽  
Homologous Virus

AbstractInfluenza viruses cause a significant number of infections and deaths annually. In addition to seasonal infections, the risk of an influenza virus pandemic emerging is extremely high owing to the large reservoir of diverse influenza viruses found in animals and the co-circulation of many influenza subtypes which can reassort into novel strains. Development of a universal influenza vaccine has proven extremely challenging. In the absence of such a vaccine, rapid response technologies provide the best potential to counter a novel influenza outbreak. Here, we demonstrate that a modular trimerization domain known as the molecular clamp allows the efficient production and purification of conformationally stabilised prefusion hemagglutinin (HA) from a diverse range of influenza A subtypes. These clamp-stabilised HA proteins provided robust protection from homologous virus challenge in mouse and ferret models and some cross protection against heterologous virus challenge. This work provides a proof-of-concept for clamp-stabilised HA vaccines as a tool for rapid response vaccine development against future influenza A virus pandemics.

scholarly journals Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection

2020 ◽  
Vol 76 (1) ◽  
pp. 189-198
Author(s):  
Yoshinori Ando ◽  
Takeshi Noshi ◽  
Kenji Sato ◽  
Toru Ishibashi ◽  
Yuki Yoshida ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Plasma Concentration ◽  
Influenza A ◽  
Lethal Dose ◽  
Influenza Viruses ◽  
Virus Titre ◽  
Dependent Endonuclease ◽  
Influenza A H1n1 ◽  
B Virus ◽  
Oseltamivir Phosphate

Abstract Background Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. Objectives We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. Methods BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5–50 mg/kg q12h), subcutaneous baloxavir acid (0.25–8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. Results Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. Conclusions PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

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