Heterogeneity of Circulating Influenza Viruses and Their Impact on Influenza Virus Vaccine Effectiveness During the Influenza Seasons 2016/17 to 2018/19 in Austria

ABSTRACT The highly sensitive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 107 fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.

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Immunity to influenza in ferrets: VII. Effect of previous infection with heterotypic and heterologous influenza viruses on the response of ferrets to inactivated influenza virus vaccines

Journal of Hygiene ◽

10.1017/s0022172400023251 ◽

1974 ◽

Vol 72 (1) ◽

pp. 91-100 ◽

Cited By ~ 20

Author(s):

C. McLaren ◽

C. W. Potter

Keyword(s):

Influenza Virus ◽

Hong Kong ◽

Virus Vaccine ◽

Serum Antibody ◽

Influenza Virus Vaccine ◽

Challenge Infection ◽

Influenza Viruses ◽

Subsequent Challenge ◽

Ann Arbor ◽

Previous Infection

SUMMARYNormal ferrets did not produce serum antibody following immunization with 200 i.u. of inactivated A/Hong Kong/68 influenza virus vaccine and were found to be susceptible to subsequent challenge infection with A/Hong Kong/68 virus. High titres of virus were recovered from nasal washings collected 3 days after infection, serum antibody was produced, increased nasal protein was detected and HI antibody was detected in nasal washings. Ferrets infected with influenza virus A/PR/8/34 7 weeks before immunization with inactivated A/HK/68 virus did, however, produce serum HI antibody to A/HK/68 virus. This antibody conferred partial immunity to challenge infection with A/HK/68 virus, as shown by decreased titres of virus in nasal washings and reduced levels of nasal protein. Previous infection of ferrets with influenza virus B/Ann Arbor/66 did not result in the production of serum antibody to A/HK/68 virus following immunization with A/HK/68 vaccine and the animals were completely susceptible to subsequent challenge infection with A/HK/68 virus. Differences in the amount of nasal protein and nasal antibody produced after A/HK/68 infection were also found in ferrets previously infected with either A/PR/8/34 or B/AA/66 virus, compared with normal ferrets.

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Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

Journal of Virology ◽

10.1128/jvi.03099-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3610-3618 ◽

Cited By ~ 50

Author(s):

Wenqian He ◽

Caitlin E. Mullarkey ◽

J. Andrew Duty ◽

Thomas M. Moran ◽

Peter Palese ◽

...

Keyword(s):

Influenza Virus ◽

Monoclonal Antibodies ◽

Virus Vaccine ◽

Neutralizing Antibodies ◽

Influenza A ◽

Human Peripheral Blood ◽

Influenza Virus Vaccine ◽

Influenza Viruses ◽

Broadly Neutralizing Antibodies ◽

Variable Regions

ABSTRACTCurrent influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of “universal” influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferiorin vitrobut was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during “universal” influenza virus vaccine design.IMPORTANCEInfluenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a “universal” influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of “universal” influenza virus vaccines and therapeutics.

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

Scientific Reports ◽

10.1038/s41598-021-01780-8 ◽

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.

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MDCK cell-cultured influenza virus vaccine protects mice from lethal challenge with different influenza viruses

Applied Microbiology and Biotechnology ◽

10.1007/s00253-011-3860-8 ◽

2012 ◽

Vol 94 (5) ◽

pp. 1173-1179 ◽

Cited By ~ 11

Author(s):

Kun Liu ◽

Zhidong Yao ◽

Liangyan Zhang ◽

Junli Li ◽

Li Xing ◽

...

Keyword(s):

Influenza Virus ◽

Virus Vaccine ◽

Mdck Cell ◽

Influenza Virus Vaccine ◽

Influenza Viruses ◽

Lethal Challenge

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Is a Universal Influenza Virus Vaccine Possible?

Annual Review of Medicine ◽

10.1146/annurev-med-120617-041310 ◽

2020 ◽

Vol 71 (1) ◽

pp. 315-327 ◽

Cited By ~ 10

Author(s):

Raffael Nachbagauer ◽

Peter Palese

Keyword(s):

Immune Response ◽

Influenza Virus ◽

Virus Vaccine ◽

Pandemic Influenza ◽

Seasonal Influenza ◽

Influenza Virus Vaccine ◽

Lessons Learned ◽

Influenza Viruses ◽

Immunization Strategies ◽

Rapid Changes

Influenza viruses remain a severe burden to human health because of their contribution to overall morbidity and mortality. Current seasonal influenza virus vaccines do not provide sufficient protection to alleviate the annual impact of influenza and cannot confer protection against potentially pandemic influenza viruses. The lack of protection is due to rapid changes of the viral epitopes targeted by the vaccine and the often suboptimal immunogenicity of current immunization strategies. Major efforts to improve vaccination approaches are under way. The development of a universal influenza virus vaccine may be possible by combining the lessons learned from redirecting the immune response toward conserved viral epitopes, as well as the use of adjuvants and novel vaccination platforms.

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

10.1101/2021.04.28.441797 ◽

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.

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Detailed Report on 2014/15 Influenza Virus Characteristics, and Estimates on Influenza Virus Vaccine Effectiveness from Austria’s Sentinel Physician Surveillance Network

PLoS ONE ◽

10.1371/journal.pone.0149916 ◽

2016 ◽

Vol 11 (3) ◽

pp. e0149916 ◽

Cited By ~ 12

Author(s):

Monika Redlberger-Fritz ◽

Michael Kundi ◽

Theresia Popow-Kraupp

Keyword(s):

Influenza Virus ◽

Virus Vaccine ◽

Influenza Virus Vaccine ◽

Vaccine Effectiveness ◽

Detailed Report ◽

Surveillance Network

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Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses

Journal of Virology ◽

10.1128/jvi.03337-14 ◽

2015 ◽

Vol 89 (6) ◽

pp. 3221-3235 ◽

Cited By ~ 60

Author(s):

Peter H. Goff ◽

Tomoko Hayashi ◽

Luis Martínez-Gil ◽

Maripat Corr ◽

Brian Crain ◽

...

Keyword(s):

Influenza Virus ◽

Humoral Immunity ◽

Virus Vaccine ◽

Safety Profile ◽

Influenza Virus Vaccine ◽

Influenza Viruses ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Viral Hemagglutinin ◽

Th1 And Th2

ABSTRACTCurrent vaccines against influenza virus infection rely on the induction of neutralizing antibodies targeting the globular head of the viral hemagglutinin (HA). Protection against seasonal antigenic drift or sporadic pandemic outbreaks requires further vaccine development to induce cross-protective humoral responses, potentially to the more conserved HA stalk region. Here, we present a novel viral vaccine adjuvant comprised of two synthetic ligands for Toll-like receptor 4 (TLR4) and TLR7. 1Z105 is a substituted pyrimido[5,4-b]indole specific for the TLR4-MD2 complex, and 1V270 is a phospholipid-conjugated TLR7 agonist. Separately, 1Z105 induces rapid Th2-associated IgG1 responses, and 1V270 potently generates Th1 cellular immunity. 1Z105 and 1V270 in combination with recombinant HA from the A/Puerto Rico/8/1934 strain (rPR/8 HA) effectively induces rapid and sustained humoral immunity that is protective against lethal challenge with a homologous virus. More importantly, immunization with the combined adjuvant and rPR/8 HA, a commercially available split vaccine, or chimeric rHA antigens significantly improves protection against both heterologous and heterosubtypic challenge viruses. Heterosubtypic protection is associated with broadly reactive antibodies to HA stalk epitopes. Histological examination and cytokine profiling reveal that intramuscular (i.m.) administration of 1Z105 and 1V270 is less reactogenic than a squalene-based adjuvant, AddaVax. In summary, the combination of 1Z105 and 1V270 with a recombinant HA induces rapid, long-lasting, and balanced Th1- and Th2-type immunity; demonstrates efficacy in a variety of murine influenza virus vaccine models assaying homologous, heterologous, and heterosubtypic challenge viruses; and has an excellent safety profile.IMPORTANCENovel adjuvants are needed to enhance immunogenicity and increase the protective breadth of influenza virus vaccines to reduce the seasonal disease burden and ensure pandemic preparedness. We show here that the combination of synthetic Toll-like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous, and heterosubtypic challenge models. Combining TLR4 and TLR7 ligands balances Th1- and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. The combined adjuvant has an attractive safety profile and the potential to augment seasonal-vaccine breadth, contribute to a broadly neutralizing universal vaccine formulation, and improve response time in an emerging pandemic.

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Cross-Reactive Immunity to Clade 2 Strains of Influenza Virus A Subtype H5N1 Induced in Adults and Elderly Patients by Fluval, a Prototype Pandemic Influenza Virus Vaccine Derived by Reverse Genetics, Formulated with a Phosphate Adjuvant, and Directed to Clade 1 Strains

Clinical and Vaccine Immunology ◽

10.1128/cvi.00327-08 ◽

2008 ◽

Vol 16 (4) ◽

pp. 437-443 ◽

Cited By ~ 14

Author(s):

György Fazekas ◽

Rita Martosne-Mendi ◽

Istvan Jankovics ◽

Istvan Szilvasy ◽

Zoltan Vajo

Keyword(s):

Influenza Virus ◽

Virus Vaccine ◽

Reverse Genetics ◽

Evolutionary Relationship ◽

Influenza Virus Vaccine ◽

Influenza Viruses ◽

Antigenic Structure ◽

Elderly Subjects ◽

H5n1 Influenza ◽

Clade 1

ABSTRACT High fatality rates and multiple cases of transmission of avian H5N1 influenza viruses to humans illustrate the urgent need for an efficacious, cross-protective vaccine against H5N1 strains. Extensive genetic characterization of H5N1 strains has elucidated the natural evolutionary relationship of these strains, linking groups known as clades to a common ancestor. Although the clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines, there is some evidence that cross-reactive immunity can be afforded. We aimed to assess the immunogenicity of a clade 1 H5N1 (NIBRG-14) whole-virus vaccine with an aluminum phosphate adjuvant and to determine whether it can induce cross-reactive immunity against antigenically drifted clade 2 H5N1 strains, both those derived by reverse genetics and wild-type isolates. A total of 88 (44 adult and 44 elderly) subjects, who received one dose (6 μg) of the vaccine, were studied. As judged by U.S. and European licensing criteria based on hemagglutination inhibition, the subjects developed cross-reactive immunity against all studied H5N1 strains belonging to a clade different from that of the strain utilized to produce the vaccine. Our findings highlight the importance of stockpiling, since cross-immune reactions induced by prepandemic vaccines will likely reduce morbidity and mortality in case of a pandemic.

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