#H5N8 and #H7N9 packaging signals constrain #HA #reassortment with a seasonal #H3N2 #influenza A virus (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.]

H5N8 and H7N9 packaging signals constrain HA reassortment with a seasonal H3N2 influenza A virus

Maria C. White, Hui Tao, John Steel, and Anice C. Lowen

PNAS published ahead of print February 13, 2019 / DOI: https://doi.org/10.1073/pnas.1818494116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 17, 2019 (received for review October 26, 2018)

 

Significance

Influenza A viruses (IAV) can exchange genetic material in coinfected cells in a process termed reassortment. The last three IAV pandemic strains arose from reassortment events involving human and nonhuman IAVs. Because introduction of the hemagglutinin (HA) gene from a nonhuman virus is required for a pandemic, we addressed the compatibility of human and avian IAV. We show that sequence differences between human and avian HA genes limit the potential for reassortment. However, human IAV still incorporated heterologous HA genes at a low level in coinfected animals. This observed low level of incorporation could become significant if reassortant viruses had a fitness advantage within the host, such as resistance to preexisting immunity, and highlights the continued need for IAV surveillance.

 

Abstract

Influenza A virus (IAV) has a segmented genome, which (i) allows for exchange of gene segments in coinfected cells, termed reassortment, and (ii) necessitates a selective packaging mechanism to ensure incorporation of a complete set of segments into virus particles. Packaging signals serve as segment identifiers and enable segment-specific packaging. We have previously shown that packaging signals limit reassortment between heterologous IAV strains in a segment-dependent manner. Here, we evaluated the extent to which packaging signals prevent reassortment events that would raise concern for pandemic emergence. Specifically, we tested the compatibility of hemagglutinin (HA) packaging signals from H5N8 and H7N9 avian IAVs with a human seasonal H3N2 IAV. By evaluating reassortment outcomes, we demonstrate that HA segments carrying H5 or H7 packaging signals are significantly disfavored for incorporation into a human H3N2 virus in both cell culture and a guinea pig model. However, incorporation of the heterologous HAs was not excluded fully, and variants with heterologous HA packaging signals were detected at low levels in vivo, including in naïve contact animals. This work indicates that the likelihood of reassortment between human seasonal IAV and avian IAV is reduced by divergence in the RNA packaging signals of the HA segment. These findings offer important insight into the molecular mechanisms governing IAV emergence and inform efforts to estimate the risks posed by H7N9 and H5N8 subtype avian IAVs.

influenza A virus – reassortment – packaging – zoonosis – antigenic shift

Keywords: Influenza A; Pandemic Influenza; Seasonal Influenza; Avian Influenza; Reassortant strain; H3N2; H5N8; H7N9; Animal models.

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#Influenza virus #polymerase #inhibitors in #clinical development (Curr Opin Infect Dis., abstract)

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

Curr Opin Infect Dis. 2019 Feb 4. doi: 10.1097/QCO.0000000000000532. [Epub ahead of print]

Influenza virus polymerase inhibitors in clinical development.

Hayden FG1, Shindo N2.

Author information: 1 Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA. 2 Health Emergencies Program, World Health Organization, Geneva, Switzerland.

 

Abstract

PURPOSE OF REVIEW:

We review antivirals inhibiting subunits of the influenza polymerase complex that are advancing in clinical development.

RECENT FINDINGS:

Favipiravir, pimodivir, and baloxavir are inhibitory in preclinical models for influenza A viruses, including pandemic threat viruses and those resistant to currently approved antivirals, and two (favipiravir and baloxavir) also inhibit influenza B viruses. All are orally administered, although the dosing regimens vary. The polymerase basic protein 1 transcriptase inhibitor favipiravir has shown inconsistent clinical effects in uncomplicated influenza, and is teratogenic effects in multiple species, contraindicating its use in pregnancy. The polymerase basic protein 2 cap-binding inhibitor pimodivir displays antiviral effects alone and in combination with oseltamivir in uncomplicated influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Single doses of the polymerase acidic protein cap-dependent endonuclease inhibitor baloxavir are effective in alleviating symptoms and rapidly inhibiting viral replication in otherwise healthy and higher risk patients with acute influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Combinations of newer polymerase inhibitors with neuraminidase inhibitors show synergy in preclinical models and are currently undergoing clinical testing in hospitalized patients.

SUMMARY:

These new polymerase inhibitors promise to add to the clinical management options and overall control strategies for influenza virus infections.

PMID: 30724789 DOI: 10.1097/QCO.0000000000000532

Keywords: Antivirals; Drugs Resistance; Influenza A; Pandemic Influenza; Favipiravir; Pimodivir; Baloxavir.

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Back to the Future for #Influenza #Preimmunity-Looking Back at Influenza Virus History to Infer the #Outcome of Future #Infections (Viruses, abstract)

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

Viruses. 2019 Jan 30;11(2). pii: E122. doi: 10.3390/v11020122.

Back to the Future for Influenza Preimmunity-Looking Back at Influenza Virus History to Infer the Outcome of Future Infections.

Francis ME1, King ML2, Kelvin AA3,4,5.

Author information: 1 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. M.Francis@dal.ca. 2 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. MorganKing@dal.ca.  3 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. akelvin@dal.ca. 4 Department of Pediatrics, Division of Infectious Disease, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. akelvin@dal.ca. 5 Canadian Centre for Vaccinology, IWK Health Centre, Halifax NS B3K 6R8, Canada. akelvin@dal.ca.

 

Abstract

The influenza virus-host interaction is a classic arms race. The recurrent and evolving nature of the influenza virus family allows a single host to be infected several times. Locked in co-evolution, recurrent influenza virus infection elicits continual refinement of the host immune system. Here we give historical context of circulating influenza viruses to understand how the individual immune history is mirrored by the history of influenza virus circulation. Original Antigenic Sin was first proposed as the negative influence of the host’s first influenza virus infection on the next and Imprinting modernizes Antigenic Sin incorporating both positive and negative outcomes. Building on imprinting, we refer to preimmunity as the continual refinement of the host immune system with each influenza virus infection. We discuss imprinting and the interplay of influenza virus homology, vaccination, and host age establishing preimmunity. We outline host signatures and outcomes of tandem infection according to the sequence of virus and classify these relationships as monosubtypic homologous, monosubtypic heterologous, heterosubtypic, or heterotypic sequential infections. Finally, the preimmunity knowledge gaps are highlighted for future investigation. Understanding the effects of antigenic variable recurrent influenza virus infection on immune refinement will advance vaccination strategies, as well as pandemic preparedness.

KEYWORDS: Spanish influenza; antigenic drift; antigenic shift; immune response; imprinting; influenza virus; original antigenic sin; orthomyxoviridae; pandemic; preimmunity

PMID: 30704019 DOI: 10.3390/v11020122

Keywords: Influenza A; Pandemic Influenza; Immunology.

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Dynamic #perspectives on the #search for a #universal #influenza #vaccine (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Dynamic perspectives on the search for a universal influenza vaccine

Chadi M Saad-Roy, Adrian B McDermott, Bryan T Grenfell

The Journal of Infectious Diseases, jiz044, https://doi.org/10.1093/infdis/jiz044

Published: 31 January 2019

 

Abstract

A universal influenza vaccine (UIV) could considerably alleviate the public health burden of both seasonal and pandemic influenza. While significant progress has been achieved in clarifying basic immunology and virology relating to UIV, a number of important questions relating to the dynamics of infection, immunity, and pathogen evolution remain unsolved. Here, we review these gaps, which span integrative levels, from cellular to global and timescales from molecular events to decades. We argue that they can be best addressed by a tight integration of empirical (laboratory, epidemiological) research and theory and suggest fruitful areas for this synthesis. In particular, quantifying natural and vaccinal limitations on viral transmission are central to this effort.

Topic:  influenza – immunity – influenza vaccines – infection – public health medicine – virology – pathogenic organism – pandemics – pathogenicity – immunology – use techniques of reflection and clarification in communication – transmission of virus

Issue Section:

Supplement Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Influenza A; Pandemic Influenza; Vaccines.

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#Influenza #Vaccines: Good, But We Can Do Better (J Infect Dis., summary)

[Source: Journal of Infectious Diseases, full page: (LINK). Summary, edited.]

Influenza Vaccines: Good, But We Can Do Better

Catharine I. Paules, M.D. and Anthony S. Fauci, M.D.

Corresponding author: Catharine I. Paules Assistant Professor, Infectious Diseases Penn State University College of Medicine, Milton S. Hershey Medical Center 500 university drive Hershey PA 17033 cpaules@pennstatehealth.psu.edu

Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.

 

Summary

Influenza viruses, particularly influenza A viruses, cause a substantial degree of morbidity and mortality worldwide, and are a persistent threat to global health. Influenza viruses have two distinct mechanisms of antigenic diversity, termed antigenic “drift” and antigenic “shift” that manifest in differing epidemiological forms, referred to as seasonal and pandemic influenza, respectively.1 Antigenic drift is a continuous process that results from the accumulation of point mutations in the viral hemagglutinin (HA) and neuraminidase (NA) genes. This process occurs in both influenza A and B viruses and is responsible for seasonal influenza epidemics, as these mutations allow the virus to escape immune protection induced by prior natural exposures and/or vaccinations. Seasonal influenza outbreaks consistently occur each year, yet they typically garner less public attention than an influenza pandemic.

(…)

Keywords: Influenza A; Pandemic Influenza; Vaccines.

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The way #forward: Potentiating protective #immunity to novel and #pandemic #influenza through engagement of memory CD4 T cells (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

The way forward: Potentiating protective immunity to novel and pandemic influenza through engagement of memory CD4 T cells

Andrea J Sant

The Journal of Infectious Diseases, jiy666, https://doi.org/10.1093/infdis/jiy666

Published: 31 January 2019

 

Abstract

Events in recent years have made it clear that potentially pandemic strains of influenza regularly pose a threat to human populations. Therefore, it is essential that we develop better strategies to enhance vaccine design and to predict those strains that will be most likely to spread from human-to-human.  CD4 T cells are a central component of protective immunity to influenza virus infection, acting both by potentiating responses of other lymphoid cells and by direct mediation of protective immunity. Animal models have revealed many discrete functions of CD4 T cell immunity to influenza viruses. However, because humans have a complex immunological history with influenza, they have a highly diverse influenza-specific CD4 T cell repertoire with regard to their stimulation history, specificity and functionality. These complexities in the influenza-specific CD4 T cell repertoire in humans constitute a formidable obstacle to predicting protective immune responses to potentially pandemic strains of influenza, and in devising optimal vaccine strategies to potentiate these responses. We suggest that more precise efforts to identify and enumerate both the positive and negative contributors of immunity in the CD4 T cell compartment will aid significantly in achievement of these goals and consider vaccination strategies that will poise humans to be more effectively positioned to respond to pandemic influenza threats.

Topic: influenza – immune response – immunity – animal model – orthomyxoviridae – t- lymphocyte – helper-inducer t-lymphocytes – vaccination – vaccines – infection – memory – pandemics – lymphoid cells

Issue Section: Supplement Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Influenza A; Pandemic Influenza; Immunology.

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Preparing for the Next #Influenza #Pandemic: The #Development of a #Universal Influenza #Vaccine (J Infect Dis., summary)

[Source: The Journal of Infectious Diseases, full page: (LINK). Summary, edited.]

Preparing for the Next Influenza Pandemic: The Development of a Universal Influenza Vaccine

Michelle C. Crank, John R. Mascola, Barney S. Graham*

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

*Correspondence: Barney S. Graham, MD, PhD; 40 Convent Dr. Bethesda, MD, 20892, Phone: 301 594-8468, Fax: 301-480-2771, Email: bgraham@nih.gov

Funding Statement: This work was supported by intramural funding from the National Institute of Allergy and Infectious Diseases.

Conflict of Interest Statement: JRM and BSG are listed as inventors on patents related to influenza vaccines including E-094-2014 & E-060-2015 (BSG), E-061-2016 (JRM), and E-066-2014 & E-228-2016 (both).

Keywords: Influenza, Vaccine, Pandemic

Word count: 1723 (including references) / Accepted Manuscript

Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.

___

 

Summary

At the centenary of the 1918 influenza pandemic that took upwards of 100 million lives within one year[1], the world remains unprepared to prevent a similar catastrophic event from occurring. In addition, seasonal epidemic influenza continues to cause worldwide morbidity and mortality on a yearly basis, and current vaccines offer suboptimal protective immunity. In this collection of articlesb, we review the scientific opportunities for developing influenza vaccines with broad coverage, commonly referred to as “universal” influenza vaccines, that would better protect us against the global burden of seasonal epidemics and offer the potential to protect us from a 1918-like pandemic event.

(…)

Keywords: Influenza A; Pandemic Influenza; Spanish Flu; Vaccines.

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