scholarly journals Enhancing Neuraminidase Immunogenicity of Influenza A Viruses by Rewiring RNA Packaging Signals

2020 ◽  
Vol 94 (16) ◽  
Author(s):  
Allen Zheng ◽  
Weina Sun ◽  
Xiaoli Xiong ◽  
Alec W. Freyn ◽  
Julia Peukes ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Virus Surface ◽  
Virus Challenge ◽  
Packaging Signals

ABSTRACT Humoral immune protection against influenza virus infection is mediated largely by antibodies against hemagglutinin (HA) and neuraminidase (NA), the two major glycoproteins on the virus surface. While influenza virus vaccination efforts have focused mainly on HA, NA-based immunity has been shown to reduce disease severity and provide heterologous protection. Current seasonal vaccines do not elicit strong anti-NA responses—in part due to the immunodominance of the HA protein. Here, we demonstrate that by swapping the 5′ and 3′ terminal packaging signals of the HA and NA genomic segments, which contain the RNA promoters, we are able to rescue influenza viruses that express more NA and less HA. Vaccination with formalin-inactivated “rewired” viruses significantly enhances the anti-NA antibody response compared to vaccination with unmodified viruses. Passive transfer of sera from mice immunized with rewired virus vaccines shows better protection against influenza virus challenge. Our results provide evidence that the immunodominance of HA stems in part from its abundance on the viral surface, and that rewiring viral packaging signals—thereby increasing the NA content on viral particles—is a viable strategy for improving the immunogenicity of NA in an influenza virus vaccine. IMPORTANCE Influenza virus infections are a major source of morbidity and mortality worldwide. Increasing evidence highlights neuraminidase as a potential vaccination target. This report demonstrates the efficacy of rewiring influenza virus packaging signals for creating vaccines with more neuraminidase content which provide better neuraminidase (NA)-based protection.

scholarly journals Chimeric Hemagglutinin-Based Live-Attenuated Vaccines Confer Durable Protective Immunity against Influenza A Viruses in a Preclinical Ferret Model

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 40
Author(s):  
Wen-Chun Liu ◽  
Raffael Nachbagauer ◽  
Daniel Stadlbauer ◽  
Shirin Strohmeier ◽  
Alicia Solórzano ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Antibody Responses ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Humoral And Cellular Immunity ◽  
Stalk Domain ◽  
One Year

Epidemic or pandemic influenza can annually cause significant morbidity and mortality in humans. We developed novel chimeric hemagglutinin (cHA)-based universal influenza virus vaccines, which contain a conserved HA stalk domain from a 2009 pandemic H1N1 (pH1N1) strain combined with globular head domains from avian influenza A viruses. Our previous reports demonstrated that prime-boost sequential immunizations induced robust antibody responses directed toward the conserved HA stalk domain in ferrets. Herein, we further followed vaccinated animals for one year to compare the efficacy and durability of these vaccines in the preclinical ferret model of influenza. Although all cHA-based immunization regimens induced durable HA stalk-specific and heterosubtypic antibody responses in ferrets, sequential immunization with live-attenuated influenza virus vaccines (LAIV-LAIV) conferred the best protection against upper respiratory tract infection by a pH1N1 influenza A virus. The findings from this study suggest that our sequential immunization strategy for a cHA-based universal influenza virus vaccine provides durable protective humoral and cellular immunity against influenza virus infection.

scholarly journals Interferon mediated prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine lacking non-structural protein 1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raveen Rathnasinghe ◽  
Mirella Salvatore ◽  
Hongyong Zheng ◽  
Sonia Jangra ◽  
Thomas Kehrer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Type I ◽  
Respiratory Pathogens ◽  
Structural Protein ◽  
Human Influenza Virus

AbstractThe influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

scholarly journals Influenza A Virus Vaccination: Immunity, Protection, and Recent Advances Toward A Universal Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 434 ◽  
Author(s):  
Christopher E. Lopez ◽  
Kevin L. Legge
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
Virus Infections ◽  
Universal Vaccine

Influenza virus infections represent a serious public health threat and account for significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. Despite being an important countermeasure to combat influenza virus and being highly efficacious when matched to circulating influenza viruses, current preventative strategies of vaccination against influenza virus often provide incomplete protection due the continuous antigenic drift/shift of circulating strains of influenza virus. Prevention and control of influenza virus infection with vaccines is dependent on the host immune response induced by vaccination and the various vaccine platforms induce different components of the local and systemic immune response. This review focuses on the immune basis of current (inactivated influenza vaccines (IIV) and live attenuated influenza vaccines (LAIV)) as well as novel vaccine platforms against influenza virus. Particular emphasis will be placed on how each platform induces cross-protection against heterologous influenza viruses, as well as how this immunity compares to and contrasts from the “gold standard” of immunity generated by natural influenza virus infection.

scholarly journals Ethanol Extract of Caesalpinia decapetala Inhibits Influenza Virus Infection In Vitro and In Vivo

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 557 ◽  
Author(s):  
Li Zhang ◽  
Jungang Chen ◽  
Chang Ke ◽  
Haiwei Zhang ◽  
Shoujun Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Antiviral Agents ◽  
Influenza Virus Infection ◽  
Virus Titer ◽  
Ethanol Extract ◽  
Influenza Viruses ◽  
Virus Infections

Influenza virus infections can lead to viral pneumonia and acute respiratory distress syndrome in severe cases, causing significant morbidity and mortality and posing a great threat to human health. Because of the diversity of influenza virus strains and drug resistance to the current direct antiviral agents, there have been no effective drugs as yet to cure all patients infected by influenza viruses. Natural products from plants contain compounds with diverse structures that have the potential to interact with multiple host and virus factors. In this study, we identified the ethanol extract of Caesalpinia decapetala (Roth) Alston (EEC) as an inhibitor against the replication of a panel of influenza A and B viruses both on human pulmonary epithelial A549 and human monocytic U937 cells. The animal study revealed that EEC administration reduces the weight loss and improves the survival rate of mice infected with lethal influenza virus. Also, EEC treatment attenuated lung injury and reduced virus titer significantly. In conclusion, we showed that EEC has antiviral activity both in vitro and in vivo, suggesting that the plant C. decapetala has the potential to be further developed as a resource of new anti-influenza drugs.

scholarly journals Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Lukasz Kedzierski ◽  
Michelle D Tate ◽  
Alan C Hsu ◽  
Tatiana B Kolesnik ◽  
Edmond M Linossi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Growth Factor Receptor ◽  
Influenza Viruses ◽  
Cytokine Signaling ◽  
Virus Infections ◽  
Suppressor Of Cytokine Signaling ◽  
Inflammatory Conditions

Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.

scholarly journals Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine

2021 ◽  
Author(s):  
Raveen Rathnasinghe ◽  
Mirella Salvatore ◽  
Hongyong Zheng ◽  
Sonia Jangra ◽  
Thomas Kehrer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Type I ◽  
Respiratory Pathogens ◽  
Structural Protein ◽  
Human Influenza Virus

AbstractThe influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

scholarly journals Interpretation of responses and protective levels of antibody against attenuated influenza A viruses using single radial haemolysis

1984 ◽  
Vol 93 (2) ◽  
pp. 301-312 ◽  
Author(s):  
R. Al-Khayatt ◽  
R. Jennings ◽  
C. W. Potter
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Haemagglutination Inhibition ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
H1n1 Vaccine ◽  
Antibody Titres ◽  
Attenuated Viruses ◽  
Virus Strains

SummaryAntibody determinations against H3N2 and H1N1 type A influenza viruses were carried out on paired sera obtained from volunteers taking part in influenza virus vaccine studies, using both the haemagglutination-inhibition (HI) and single radial haemolysis (SRH) test. Good correlation between the HI and SRH test was found for both H3N2 and H1N1 antibody and the zone area increases corresponding to significant SRH antibody rises determined for both virus strains. In both H3N2 and H1N1 vaccine studies, intranasal infection of the volunteers with live attenuated viruses was involved and by the measurement of HI and SRH antibodies prior to and following infection, levels of antibody equating with protection against the infecting viruses could be estimated. For the HI test the antibody titres associated with 50% protection were 42 for H1N1, and 44 for H3N2 viruses; for the SRH test, 50% protection was associated with zone areas of 20·0–25·0 mm2for both H1N1 and H3N2 viruses.

scholarly journals The Next Generation of Influenza Vaccines: Towards a Universal Solution

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 26
Author(s):  
Christopher L.D. McMillan ◽  
Paul R. Young ◽  
Daniel Watterson ◽  
Keith J. Chappell
Keyword(s):  
Influenza Virus ◽  
Vaccine Development ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Effective Vaccine ◽  
Next Generation ◽  
Virus Infections ◽  
Virus Surface ◽  
Variable Head ◽  
Hemagglutinin Protein

Influenza viruses remain a constant burden in humans, causing millions of infections and hundreds of thousands of deaths each year. Current influenza virus vaccine modalities primarily induce antibodies directed towards the highly variable head domain of the hemagglutinin protein on the virus surface. Such antibodies are often strain-specific, meaning limited cross-protection against divergent influenza viruses is induced, resulting in poor vaccine efficacy. To attempt to counteract this, yearly influenza vaccination with updated formulations containing antigens from more recently circulating viruses is required. This is an expensive and time-consuming exercise, and the constant arms race between host immunity and virus evolution presents an ongoing challenge for effective vaccine development. Furthermore, there exists the constant pandemic threat of highly pathogenic avian influenza viruses with high fatality rates (~30–50%) or the emergence of new, pathogenic reassortants. Current vaccines would likely offer little to no protection from such viruses in the event of an epidemic or pandemic. This highlights the urgent need for improved influenza virus vaccines capable of providing long-lasting, robust protection from both seasonal influenza virus infections as well as potential pandemic threats. In this narrative review, we examine the next generation of influenza virus vaccines for human use and the steps being taken to achieve universal protection.

scholarly journals Prophylactic Protection Against Respiratory Viruses Conferred by a Prototype Live Attenuated Influenza Virus Vaccine

2021 ◽  
Author(s):  
Raveen Rathnasinghe ◽  
Mirella Salvatore ◽  
Hongyong Zheng ◽  
Sonia Jangra ◽  
Thomas Kehrer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Type I ◽  
Respiratory Pathogens ◽  
Structural Protein ◽  
Human Influenza Virus

Abstract The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

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