A novel #reassortant #influenza A (#H1N1) virus #infection in #swine in #Shandong Province, eastern #China (Transbound Emerg Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Transbound Emerg Dis. 2019 Sep 19. doi: 10.1111/tbed.13360. [Epub ahead of print]

A novel reassortant influenza A (H1N1) virus infection in swine in Shandong Province, eastern China.

Yu Z1,2,3, Cheng K4, He H5, Wu J1,2,3.

Author information: 1 Poultry Institute, Shandong Academy of Agricultural Sciences, Jinan, 250023, China. 2 Shandong Provincial Key Laboratory of Poultry Diseases Diagnosis and Immunology. 3 Poultry Breeding Engineering Technology Center of Shandong Province. 4 Dairy Cattle Research Center, Shandong Academy of Agricultural Sciences, Jinan, 250132, China. 5 College of Life Sciences, Shandong Normal University, Jinan, 250014, China.



Influenza A (H1N1) viruses are distributed worldwide and pose a threat to public health. Swine, as a natural host and mixing vessel of influenza A (H1N1) virus, play a critical role in the transmission of this virus to humans. Furthermore, swine influenza A (H1N1) viruses have provided all eight genes or some genes to the genomes of influenza strains that historically have caused human pandemics. Hence, persistent surveillance of influenza A (H1N1) virus in swine herds could contribute to the prevention and control of this virus. Here, we report a novel reassortant influenza A (H1N1) virus generated by reassortment between 2009 pandemic H1N1 viruses and swine viruses. We also found that this virus is prevalent in swine herds in Shandong Province, eastern China. Our findings suggest that surveillance of the emergence of the novel reassortant influenza A (H1N1) virus in swine is imperative.

© 2019 Blackwell Verlag GmbH.

KEYWORDS: H1N1; human; influenza; reassortant; swine

PMID: 31535780 DOI: 10.1111/tbed.13360

Keywords: Seasonal Influenza; Swine Influenza; H1N1; H1N1pdm09; Pigs; Reassortant strain; Shandong; China.



#Mucosal #CD8+ T cell responses induced by an MCMV based #vaccine #vector confer protection against #influenza challenge (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]


Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

Xiaoyan Zheng, Jennifer D. Oduro, Julia D. Boehme, Lisa Borkner, Thomas Ebensen, Ulrike Heise, Marcus Gereke, Marina C. Pils, Astrid Krmpotic, Carlos A. Guzmán, Dunja Bruder, Luka Čičin-Šain

Published: September 16, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008036 / This is an uncorrected proof.



Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections.


Author summary

Vaccines against influenza typically induce immune responses based on antibodies, small molecules that recognize the virus particles outside of cells and neutralize them before they infect a cell. However, influenza rapidly evolves, escaping immune recognition, and the fastest evolution is seen in the part of the virus that is recognized by antibodies. Therefore, every year we are confronted with new flu strains that are not recognized by our antibodies against the strains from previous years. The other branch of the immune system is made of killer T cells, which recognize infected cells and target them for killing. Influenza does not rapidly evolve to escape T cell killing; thus, vaccines inducing T-cell responses to influenza might provide long-term protection. We introduced an antigen from influenza into the murine cytomegalovirus (MCMV) and used it as a vaccine vector inducing killer T-cell responses of unparalleled strength. Our vector controls influenza replication and provides relief to infected mice, but only if we administered it through the nose, to activate killer T cells that will persist in the lungs close to the airways. Therefore, our data show that the subset of lung-resident killer T cells is sufficient to protect against influenza.


Citation: Zheng X, Oduro JD, Boehme JD, Borkner L, Ebensen T, Heise U, et al. (2019) Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge. PLoS Pathog 15(9): e1008036. https://doi.org/10.1371/journal.ppat.1008036

Editor: Christopher M. Snyder, Thomas Jefferson University, UNITED STATES

Received: July 17, 2019; Accepted: August 21, 2019; Published: September 16, 2019

Copyright: © 2019 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was supported by the European Research Council through the ERC Starting Grant 260934 to LCS and the Helmholtz Association through the Helmholtz EU Partnering Grant PIE-008 to LCS. XZ was supported by a scholarship from the Chinese Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Influenza A; CMV; Vaccines; Animal models.


#Growth activation of #influenza virus by #trypsin and effect of T-705 (#favipiravir) on trypsin-optimized growth condition (Acta Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Acta Virol. 2019;63(3):309-315. doi: 10.4149/av_2019_311.

Growth activation of influenza virus by trypsin and effect of T-705 (favipiravir) on trypsin-optimized growth condition.

Daikoku T, Okuda T, Kawai M, Morita N, Tanaka T, Takemoto M, Fukuda Y, Takahashi K, Nomura N, Shiraki K.



Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071 was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia.

Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.

PMID: 31507197 DOI: 10.4149/av_2019_311

Keywords: Influenza A; H1N1; H3N2; Antivirals; Favipiravir; Oseltamivir.


#IFITM3 protects the #heart during #influenza virus #infection (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

IFITM3 protects the heart during influenza virus infection

Adam D. Kenney, Temet M. McMichael, Alexander Imas, Nicholas M. Chesarino, Lizhi Zhang, Lisa E. Dorn, Qian Wu, Omar Alfaour, Foued Amari, Min Chen, Ashley Zani, Mahesh Chemudupati, Federica Accornero, Vincenzo Coppola, Murugesan V. S. Rajaram, and Jacob S. Yount

PNAS first published August 26, 2019 / DOI: https://doi.org/10.1073/pnas.1900784116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved August 1, 2019 (received for review January 15, 2019)



We discovered that IFITM3 prevents efficient dissemination and replication of influenza virus in heart tissue, thereby limiting cardiac fibrosis and electrical dysfunction during infection. Since IFITM3 polymorphisms are among the only human genetic factors that have been reproducibly associated with hospitalization and mortality during influenza virus infection, our findings are relevant to the serious threat of influenza virus infection to human health. Furthermore, IFITM3 KO mice provide one of the first models for studying cardiac complications of influenza.



Influenza virus can disseminate from the lungs to the heart in severe infections and can induce cardiac pathology, but this has been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding the antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to cardiac dysfunction during infection is unclear. We show that IFITM3 deficiency in a new knockout (KO) mouse model increases weight loss and mortality following influenza virus infections. We investigated this enhanced pathogenesis with the A/PR/8/34 (H1N1) (PR8) influenza virus strain, which is lethal in KO mice even at low doses, and observed increased replication of virus in the lungs, spleens, and hearts of KO mice compared with wild-type (WT) mice. Infected IFITM3 KO mice developed aberrant cardiac electrical activity, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals, whereas WT mice exhibited a mild decrease in heart rate without irregular RR intervals. Cardiac electrical dysfunction in PR8-infected KO mice was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Infection with a sublethal dose of a less virulent influenza virus strain (A/WSN/33 [H1N1]) resulted in a milder cardiac electrical dysfunction in KO mice that subsided as the mice recovered. Our findings reveal an essential role for IFITM3 in limiting influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model for studying mild and severe influenza virus-induced cardiac dysfunction.

influenza – interferon – IFITM3 – heart



1 To whom correspondence may be addressed. Email: murugesan.rajaram@osumc.edu or Jacob.Yount@osumc.edu.

Author contributions: A.D.K., M.V.S.R., and J.S.Y. designed research; A.D.K., T.M.M., A.I., N.M.C., L.Z., L.E.D., Q.W., O.A., A.Z., M. Chemudupati, F. Accornero, M.V.S.R., and J.S.Y. performed research; F. Amari, M. Chen, and V.C. contributed new reagents/analytic tools; A.D.K., T.M.M., N.M.C., M.V.S.R., and J.S.Y. analyzed data; and A.D.K. and J.S.Y. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1900784116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Influenza A; Interferons.


#Mammalian #pathogenicity and transmissibility of a #reassortant Eurasian #avian-like A(#H1N1v) #influenza virus associated with #human #infection in #China (2015) (Virology, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virology. 2019 Aug 10;537:31-35. doi: 10.1016/j.virol.2019.08.008. [Epub ahead of print]

Mammalian pathogenicity and transmissibility of a reassortant Eurasian avian-like A(H1N1v) influenza virus associated with human infection in China (2015).

Pulit-Penaloza JA1, Belser JA1, Tumpey TM1, Maines TR2.

Author information: 1 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, 30329, USA. 2 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, 30329, USA. Electronic address: tmaines@cdc.gov.



Swine-origin (variant) H1 influenza A viruses associated with numerous human infections in North America in recent years have been extensively studied in vitro and in mammalian models to determine their pandemic potential. However, limited information is available on Eurasian avian-like lineage variant H1 influenza viruses. In 2015, A/Hunan/42443/2015 virus was isolated from a child in China with a severe infection. Molecular analysis revealed that this virus possessed several key virulence and human adaptation markers. Similar to what was previously observed in C57BL/6J mice, we report here that in the BALB/c mouse model, A/Hunan/42443/2015 virus caused more severe morbidity and higher mortality than did North American variant H1 virus isolates. Furthermore, the virus efficiently replicated throughout the respiratory tract of ferrets and exhibited a capacity for transmission in this model, underscoring the need to monitor zoonotic viruses that cross the species barrier as they continue to pose a pandemic threat.

Copyright © 2019. Published by Elsevier Inc.

KEYWORDS: Ferret; H1N1; Influenza; Pathogenesis; Variant virus

PMID: 31430632 DOI: 10.1016/j.virol.2019.08.008

Keywords: Avian Influenza; Swine Influenza; H1N1; Reassortant strain; Human; China.


#Influenza #Vaccine With Consensus Internal #Antigens as #Immunogens Provides Cross-Group Protection Against Influenza A Viruses (Front Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Microbiol. 2019 Jul 16;10:1630. doi: 10.3389/fmicb.2019.01630. eCollection 2019.

Influenza Vaccine With Consensus Internal Antigens as Immunogens Provides Cross-Group Protection Against Influenza A Viruses.

Xie X1, Zhao C1, He Q1, Qiu T1, Yuan S1, Ding L1, Liu L1, Jiang L1, Wang J1, Zhang L1, Zhang C2, Wang X2, Zhou D2, Zhang X1, Xu J1.

Author information: 1 Shanghai Public Health Clinical Center and Institutes of Biomedical Science, Shanghai Medical College, Fudan University, Shanghai, China. 2 Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.



Given that continuing antigenic shift and drift of influenza A viruses result in the escape from previous vaccine-induced immune protection, a universal influenza vaccine has been actively sought. However, there were very few vaccines capable of eliciting cross-group ant-influenza immunity. Here, we designed two novel composite immunogens containing highly conserved T-cell epitopes of six influenza A virus internal antigens, and expressed them in DNA, recombinant adenovirus-based (AdC68) and recombinant vaccinia vectors, respectively, to formulate three vaccine forms. The introduction of the two immunogens via a DNA priming and viral vectored vaccine boosting modality afforded cross-group protection from both PR8 and H7N9 influenza virus challenges in mice. Both respiratory residential and systemic T cells contributed to the protective efficacy. Intranasal but not intramuscular administration of AdC68 based vaccine was capable of raising both T cell subpopulations to confer a full protection from lethal PR8 and H7N9 challenges, and blocking the lymphatic egress of T cells during challenges attenuated the protection. Thus, by targeting highly conserved internal viral epitopes to efficiently generate both respiratory and systemic memory T cells, the sequential vaccination strategy reported here represented a new promising candidate for the development of T-cell based universal influenza vaccines.

KEYWORDS: CD8+ T cell epitope; consensus sequence; cross-protection; lung residential T cells; universal influenza vaccine

PMID: 31379782 PMCID: PMC6647892 DOI: 10.3389/fmicb.2019.01630

Keywords: Influenza A; H1N1; H7N9; Vaccines; Animal models.


Improving Cross- #Protection against #Influenza Virus Using Recombinant #Vaccinia #Vaccine Expressing NP and M2 Ectodomain Tandem Repeats (Virol Sin., abstract)

[Source: Virologica Sinica, full page: (LINK). Abstract, edited.]

Improving Cross-Protection against Influenza Virus Using Recombinant Vaccinia Vaccine Expressing NP and M2 Ectodomain Tandem Repeats

Authors: Wenling Wang, Baoying Huang, Xiuping Wang, Wenjie Tan, Li Ruan

Research Article / First Online: 25 June 2019



Conventional influenza vaccines need to be designed and manufactured yearly. However, they occasionally provide poor protection owing to antigenic mismatch. Hence, there is an urgent need to develop universal vaccines against influenza virus. Using nucleoprotein (NP) and extracellular domain of matrix protein 2 (M2e) genes from the influenza A virus A/Beijing/30/95 (H3N2), we constructed four recombinant vaccinia virus-based influenza vaccines carrying NP fused with one or four copies of M2e genes in different orders. The recombinant vaccinia viruses were used to immunize BALB/C mice. Humoral and cellular responses were measured, and then the immunized mice were challenged with the influenza A virus A/Puerto Rico/8/34 (PR8). NP-specific humoral response was elicited in mice immunized with recombinant vaccinia viruses carrying full-length NP, while robust M2e-specific humoral response was elicited only in the mice immunized with recombinant vaccinia viruses carrying multiple copies of M2e. All recombinant viruses elicited NP- and M2e-specific cellular immune responses in mice. Only immunization with RVJ-4M2eNP induced remarkably higher levels of IL-2 and IL-10 cytokines specific to M2e. Furthermore, RVJ-4M2eNP immunization provided the highest cross-protection in mice challenged with 20 MLD50 of PR8. Therefore, the cross-protection potentially correlates with both NP and M2e-specific humoral and cellular immune responses induced by RVJ-4M2eNP, which expresses a fusion antigen of full-length NP preceded by four M2e repeats. These results suggest that the rational fusion of NP and multiple M2e antigens is critical toward inducing protective immune responses, and the 4M2eNP fusion antigen may be employed to develop a universal influenza vaccine.

Keywords: Influenza A virus (IAV) – Cross-protection – Recombinant vaccinia virus – Conserved antigen


Electronic supplementary material

The online version of this article ( https://doi.org/10.1007/s12250-019-00138-9) contains supplementary material, which is available to authorized users.




This work was supported by grant from the National Key Plan for Scientific Research and Development of China (2016YFC1200200). The authors gratefully acknowledge Professor Xiangmin Zhang (Wayne State University, Detroit, MI USA) for the revision of the manuscript in English.

Author Contributions

RL and WW designed the experiments. WW, HB, and WX carried out the experiments. RL and WW analyzed the data. WW and TW wrote the paper. WW, TW checked and finalized the manuscript. All authors read and approved the final manuscript.


Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Animal and Human Rights Statement

The whole study was approved by the Administrative Committee on Animal Welfare of the National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (Laboratory Animal Care and Use Committee Authorization, permit number 2016022910). All institutional and national guidelines for the care and use of laboratory animals were followed.

Keywords: Seasonal Influenza; H1N1; H3N2; Vaccines.