scholarly journals Influenza Neuraminidase Characteristics and Potential as a Vaccine Target

2021 ◽  
Vol 12 ◽  
Author(s):  
Sarah Creytens ◽  
Mirte N. Pascha ◽  
Marlies Ballegeer ◽  
Xavier Saelens ◽  
Cornelis A. M. de Haan
Keyword(s):  
Influenza A ◽  
Critical Role ◽  
Influenza Vaccines ◽  
Host Immune System ◽  
Protective Potential ◽  
Virus Life Cycle ◽  
Technology Platforms ◽  
Near Future ◽  
Experimental Challenge ◽  
Experimental Influenza

Neuraminidase of influenza A and B viruses plays a critical role in the virus life cycle and is an important target of the host immune system. Here, we highlight the current understanding of influenza neuraminidase structure, function, antigenicity, immunogenicity, and immune protective potential. Neuraminidase inhibiting antibodies have been recognized as correlates of protection against disease caused by natural or experimental influenza A virus infection in humans. In the past years, we have witnessed an increasing interest in the use of influenza neuraminidase to improve the protective potential of currently used influenza vaccines. A number of well-characterized influenza neuraminidase-specific monoclonal antibodies have been described recently, most of which can protect in experimental challenge models by inhibiting the neuraminidase activity or by Fc receptor-dependent mechanisms. The relative instability of the neuraminidase poses a challenge for protein-based antigen design. We critically review the different solutions that have been proposed to solve this problem, ranging from the inclusion of stabilizing heterologous tetramerizing zippers to the introduction of inter-protomer stabilizing mutations. Computationally engineered neuraminidase antigens have been generated that offer broad, within subtype protection in animal challenge models. We also provide an overview of modern vaccine technology platforms that are compatible with the induction of robust neuraminidase-specific immune responses. In the near future, we will likely see the implementation of influenza vaccines that confront the influenza virus with a double punch: targeting both the hemagglutinin and the neuraminidase.

scholarly journals Matrix Protein 2 Extracellular Domain-Specific Monoclonal Antibodies Are an Effective and Potentially Universal Treatment for Influenza A

2020 ◽  
Author(s):  
Lynn Bimler ◽  
Sydney L. Ronzulli ◽  
Amber Y. Song ◽  
Scott K. Johnson ◽  
Cheryl A. Jones ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Human Health ◽  
Influenza A ◽  
Matrix Protein ◽  
Critical Role ◽  
Extracellular Domain ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Protective Potential

Influenza virus infection causes significant morbidity and mortality worldwide. Humans fail to make a universally protective memory immune response to influenza A. Hemagglutinin and Neuraminidase undergo antigenic drift and shift, resulting in new influenza A strains to which humans are naive. Seasonal vaccines are often ineffective and escape mutants have been reported to all treatments for influenza A. In the absence of a universal influenza A vaccine or treatment, influenza A will remain a significant threat to human health. The extracellular domain of the M2-ion channel (M2e) is an ideal antigenic target for a universal therapeutic agent, as it is highly conserved across influenza A serotypes, has a low mutation rate, and is essential for viral entry and replication. Previous M2e-specific monoclonal antibodies (M2e-MAbs) show protective potential against influenza A, however, they are either strain specific or have limited efficacy. We generated seven murine M2e-MAbs and utilized in vitro and in vivo assays to validate the specificity of our novel M2e-MAbs and to explore the universality of their protective potential. Our data shows our M2e-MAbs bind to M2e peptide, HEK cells expressing the M2 channel, as well as, influenza virions and MDCK-ATL cells infected with influenza viruses of multiple serotypes. Our antibodies significantly protect highly influenza A virus susceptible BALB/c mice from lethal challenge with H1N1 A/PR/8/34, pH1N1 A/CA/07/2009, H5N1 A/Vietnam/1203/2004, and H7N9 A/Anhui/1/2013 by improving survival rates and weight loss. Based on these results, at least four of our seven M2e-MAbs show strong potential as universal influenza A treatments. IMPORTANCE Despite a seasonal vaccine and multiple therapeutic treatments, Influenza A remains a significant threat to human health. The biggest obstacle is producing a vaccine or treatment for influenza A is their universality or efficacy against not only seasonal variances in the influenza virus, but also against all human, avian, and swine serotypes and, therefore, potential pandemic strains. M2e has huge potential as a target for a vaccine or treatment against influenza A. It is the most conserved external protein on the virus. Antibodies against M2e have made it to clinical trials, but not succeeded. Here, we describe novel M2e antibodies produced in mice that are not only protective at low doses, but that we extensively test to determine their universality and found to be cross protective against all strains tested. Additionally, our work begins to elucidate the critical role of isotype for an influenza A monoclonal antibody therapeutic.

Prospects of using conservative linear B-cell epitopes of influenza virus A neuraminidase for induction of cross-protective immune response

2021 ◽  
Vol 21 (3) ◽  
pp. 147-151
Author(s):  
Ivan А. Sychev ◽  
Pavel M. Kopeikin ◽  
Elena V. Tsvetkova ◽  
Olga V. Shamova ◽  
Yulia A. Desheva ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
B Cell ◽  
Broad Spectrum ◽  
Influenza A ◽  
Influenza Vaccines ◽  
H3n2 Virus ◽  
B Cell Epitopes ◽  
Protective Potential ◽  
Linear B

BACKGROUND: Influenza is a dangerous, widespread infectious disease that takes thousands of lives during annual epidemics, and also causes significant damage to the countrys economy. The most effective means of fighting the influenza virus is vaccination of the population. Due to the variability of influenza viruses, the strain composition of influenza vaccines must be updated annually. In this regard, an urgent task is to improve the existing influenza vaccines in order to expand their spectrum of action. One of the promising approaches is the targeted induction of the humoral immune response to the conservative linear epitopes of influenza A virus neuraminidase. AIM: This project is aimed at assessing the immunogenicity and cross-protective activity of conserved neuraminidase epitopes in order to select promising targets for the targeted design of broad-spectrum influenza vaccines. MATERIALS AND METHODS: Peptides corresponding to linear B-cell epitopes of neuraminidase were chemically synthesized de novo. The peptides were conjugated with keyhole limpet hemocyanin. CBA mice were immunized and challenged with A/PR/8/34 (H1N1) and A/Philippines/2/1982 (H3N2) viruses at a dose of 3 LD50. The survival rate of the animals was assessed within 14 days after infection. The immunogenicity of the peptides was assessed in a standard enzyme-linked immunosorbent assay using the recombinant neuraminidase proteins of the viruses A/California/07/2009 (H1N1) and A/Hong Kong/4801/2014 (H3N2) as antigen. RESULTS: Immunization of neuraminidase with peptides MNPNQKIITIGS and ILRTQESEC, but not DNWKGSNRP, protected mice from lethality caused by the H1N1 and/or H3N2 virus. The protective potential of the peptides correlated with the levels of antineuraminidase antibodies after immunization. CONCLUSIONS: The presence of a cross-protective potential in two conserved linear B-cell epitopes of influenza A neuraminidase (MNPNQKIITIGS and ILRTQESEC) allows them to be recommended as a target for the development of a broad-spectrum influenza vaccine.

A Fungal Cu/Zn-Containing Superoxide Dismutase Enhances the Therapeutic Efficacy of a Plant Polyphenol Extract in Experimental Influenza Virus Infection

2010 ◽  
Vol 65 (5-6) ◽  
pp. 419-428 ◽  
Author(s):  
Julia Serkedjieva ◽  
Tsvetanka Stefanova ◽  
Ekaterina Krumova
Keyword(s):  
Superoxide Dismutase ◽  
Influenza Virus ◽  
Virus Infection ◽  
Protective Effect ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Protective Role ◽  
Combined Application ◽  
Combined Use ◽  
Experimental Influenza

The combined protective effect of a polyphenol-rich extract, isolated from Geranium sanguineum L. (PC), and a novel naturally glycosylated Cu/Zn-containing superoxide dismutase, produced from the fungal strain Humicula lutea 103 (HL-SOD), in the experimental influenza A virus infection (EIVI) in mice, induced with the virus A/Aichi/2/68 (H3N2), was investigated. The combined application of HL-SOD and PC in doses, which by themselves do not defend significantly mice in EIVI, resulted in a synergistically increased protection, determined on the basis of protective indices and amelioration of lung injury. Lung weights and consolidation as well as infectious lung virus titers were all decreased significantly parallel to the reduction of the mortality rates; lung indices were raised. The excessive production of reactive oxygen species (ROS) by alveolar macrophages (aMØ) as well as the elevated levels of the lung antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), induced by EIVI, were brought to normal. For comparative reasons the combined protective effect of PC and vitamin C was investigated. The obtained results support the combined use of antioxidants for the treatment of influenza virus infection and in general indicate the beneficial protective role of combinations of viral inhibitors of natural origin with diverse modes of action.

scholarly journals Intersection of Sex and Frailty in Humoral Immune Responses to Influenza Vaccine in Community-Dwelling Older Adults

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 271-272
Author(s):  
Janna Shapiro ◽  
Helen Kuo ◽  
Rosemary Morgan ◽  
Huifen Li ◽  
Sabra Klein ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Responses ◽  
Influenza A ◽  
Community Dwelling ◽  
Influenza Vaccines ◽  
Health Study ◽  
Cardiovascular Health Study ◽  
High Dose ◽  
Humoral Immune ◽  
Humoral Immune Responses

Abstract Older adults bear the highest burden of severe disease and complications associated with seasonal influenza, with annual vaccination serving as the best option for protection. Variability in vaccine efficacy exists, yet the host factors that affect immune responses to inactivated influenza vaccines (IIV) are incompletely understood. We hypothesized that sex and frailty interact to affect vaccine-induced humoral responses among older adults. To test this hypothesis, community-dwelling adults above 75 years of age were recruited yearly, assessed for frailty (as defined by the Cardiovascular Health Study criteria), and vaccinated with the high-dose trivalent IIV. Humoral immune responses were evaluated via hemagglutination inhibition titers. The study began during the 2014-2015 influenza season, with yearly cohorts ranging from 76-163 individuals. A total of 617 vaccinations were delivered from 2014-2019. In preliminary analyses, the outcome of interest was seroconversion, defined as ≥ 4-fold rise in titers. Crude odds ratios suggest that females are more likely to seroconvert to influenza A strains (H1N1: OR = 1.39, (0.98-1.96) ; H3N2: 1.17 (0.85 – 1.62)), while males are more likely to seroconvert to the B strain (OR = 0.85 (0.60 – 1.22)). Furthermore, this sex difference was modified by frailty – for example, the odds of seroconversion to H1N1 were 65% higher for females than males among those who were nonfrail, and only 30% higher among females who were frail. Together, these results suggest that sex and frailty interact to impact immune responses to influenza vaccines. These findings may be leveraged to better protect vulnerable populations.

scholarly journals Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wayne D. Harshbarger ◽  
Derrick Deming ◽  
Gordon J. Lockbaum ◽  
Nattapol Attatippaholkun ◽  
Maliwan Kamkaew ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Critical Role ◽  
Binding Activity ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Structural Details ◽  
Structural Solution

AbstractBroadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of VH3-30 antibodies and reveals that 3I14 represents a novel structural solution within the VH3-30 repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.

scholarly journals Protection of Mice and Poultry from Lethal H5N1 Avian Influenza Virus through Adenovirus-Based Immunization

2006 ◽  
Vol 80 (4) ◽  
pp. 1959-1964 ◽  
Author(s):  
Wentao Gao ◽  
Adam C. Soloff ◽  
Xiuhua Lu ◽  
Angela Montecalvo ◽  
Doan C. Nguyen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Influenza A ◽  
Recombinant Adenovirus ◽  
Critical Role ◽  
H5n1 Avian Influenza Virus ◽  
Recent Emergence ◽  
Boost Vaccine ◽  
Subcutaneous Immunization

ABSTRACT The recent emergence of highly pathogenic avian influenza virus (HPAI) strains in poultry and their subsequent transmission to humans in Southeast Asia have raised concerns about the potential pandemic spread of lethal disease. In this paper we describe the development and testing of an adenovirus-based influenza A virus vaccine directed against the hemagglutinin (HA) protein of the A/Vietnam/1203/2004 (H5N1) (VN/1203/04) strain isolated during the lethal human outbreak in Vietnam from 2003 to 2005. We expressed different portions of HA from a recombinant replication-incompetent adenoviral vector, achieving vaccine production within 36 days of acquiring the virus sequence. BALB/c mice were immunized with a prime-boost vaccine and exposed to a lethal intranasal dose of VN/1203/04 H5N1 virus 70 days later. Vaccination induced both HA-specific antibodies and cellular immunity likely to provide heterotypic immunity. Mice vaccinated with full-length HA were fully protected from challenge with VN/1203/04. We next evaluated the efficacy of adenovirus-based vaccination in domestic chickens, given the critical role of fowl species in the spread of HPAI worldwide. A single subcutaneous immunization completely protected chickens from an intranasal challenge 21 days later with VN/1203/04, which proved lethal to all control-vaccinated chickens within 2 days. These data indicate that the rapid production and subsequent administration of recombinant adenovirus-based vaccines to both birds and high-risk individuals in the face of an outbreak may serve to control the pandemic spread of lethal avian influenza.

Role of the chaperone protein 14-3-3ε in the regulation of influenza A virus-activated beta interferon

2021 ◽  
Author(s):  
Ee-Hong Tam ◽  
Yen-Chin Liu ◽  
Chian-Huey Woung ◽  
Helene Minyi Liu ◽  
Guan-Hong Wu ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Ns1 Protein ◽  
Chaperone Protein ◽  
Influenza A Virus Infection

The NS1 protein of the influenza A virus plays a critical role in regulating several biological processes in cells, including the type I interferon (IFN) response. We previously profiled the cellular factors that interact with the NS1 protein of influenza A virus and found that the NS1 protein interacts with proteins involved in RNA splicing/processing, cell cycle regulation, and protein targeting processes, including 14-3-3ε. Since 14-3-3ε plays an important role in RIG-I translocation to MAVS to activate type I IFN expression, the interaction of the NS1 and 14-3-3ε proteins may prevent the RIG-I-mediated IFN response. In this study, we confirmed that the 14-3-3ε protein interacts with the N-terminal domain of the NS1 protein and that the NS1 protein inhibits RIG-I-mediated IFN-β promoter activation in 14-3-3ε-overexpressing cells. In addition, our results showed that knocking down 14-3-3ε can reduce IFN-β expression elicited by influenza A virus and enhance viral replication. Furthermore, we found that threonine in the 49 th amino acid position of the NS1 protein plays a role in the interaction with 14-3-3ε. Influenza A virus expressing C-terminus-truncated NS1 with T49A mutation dramatically increases IFN-β mRNA in infected cells and causes slower replication than that of virus without the T-to-A mutation. Collectively, this study demonstrates that 14-3-3ε is involved in influenza A virus-initiated IFN-β expression and that the interaction of the NS1 protein and 14-3-3ε may be one of the mechanisms for inhibiting type I IFN activation during influenza A virus infection. IMPORTANCE Influenza A virus is an important human pathogen causing severe respiratory disease. The virus has evolved several strategies to dysregulate the innate immune response and facilitate its replication. We demonstrate that the NS1 protein of influenza A virus interacts with the cellular chaperone protein 14-3-3ε, which plays a critical role in RIG-I translocation that induces type I IFN expression, and that NS1 protein prevents RIG-I translocation to mitochondrial membrane. The interaction site for 14-3-3ε is the RNA-binding domain (RBD) of the NS1 protein. Therefore, this research elucidates a novel mechanism by which the NS1 RBD mediates IFN-β suppression to facilitate influenza A viral replication. Additionally, the findings reveal the antiviral role of 14-3-3ε during influenza A virus infection.

scholarly journals Increased Interleukin-6 Levels in Nasal Lavage Samples following Experimental Influenza A Virus Infection

1998 ◽  
Vol 5 (5) ◽  
pp. 604-608 ◽  
Author(s):  
Deborah Gentile ◽  
William Doyle ◽  
Theresa Whiteside ◽  
Philip Fireman ◽  
Frederick G. Hayden ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A Virus ◽  
Interleukin 6 ◽  
Influenza A ◽  
Respiratory Infections ◽  
Nasal Lavage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Influenza A Virus Infection ◽  
Systemic Symptoms ◽  
Experimental Influenza

ABSTRACT Interleukin-6 (IL-6) is a pleotropic cytokine implicated in the pathogenesis of local inflammation during viral upper respiratory infections. This study determined if experimental influenza A virus infection causes local IL-6 production. Seventeen healthy, adult subjects were intranasally inoculated, by course drops, with a safety-tested strain of influenza A/Kawasaki/86 (H1N1) virus. Nasal lavage samples were collected, symptoms were recorded, and expelled nasal secretions were weighed once before and then daily for 8 days after the virus inoculation. Lavage samples were submitted for virus culture and were examined for IL-6 and IL-4 by enzyme-linked immunosorbent assay. The IL-6, but not IL-4, levels were significantly increased in the nasal lavage samples of the 12 subjects who shed virus but not in those of the 5 subjects who did not shed virus. Moreover, the elevations in IL-6 levels were related temporally to the development of nasal symptoms and secretions but not to systemic symptoms. These results suggest a role for locally produced IL-6 in the pathogenesis and expressed symptomatology of influenza A virus infection.

scholarly journals Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?

2018 ◽  
Author(s):  
Zheng-Rong Tiger Li ◽  
Veronika I. Zarnitsyna ◽  
Anice C. Lowen ◽  
Daniel Weissman ◽  
Katia Koelle ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cd8 T Cell ◽  
Influenza Vaccines ◽  
T Cell Epitopes ◽  
Word Count ◽  
Mhc I ◽  
Escape Variant ◽  
Replicative Fitness

AbstractThe high-degree conservation of CD8 T cell epitopes of influenza A virus (IAV) may allow T cell-inducing vaccines effective across different strains and subtypes. This conservation is not fully explained by functional constraint, since additional mutation(s) can compensate the replicative fitness loss of IAV escape-variant. Here, we propose three additional mechanisms that contribute to the conservation of CD8 T cell epitopes of IAV. First, influenza-specific CD8 T cells may protect predominantly against severe pathology rather than infection and may only have a modest effect on transmission. Second, polymorphism of human MHC-I gene restricts the advantage of an escape-variant to only a small fraction of human population, who carry the relevant MHC-I alleles. Finally, infection with CD8 T cell-escapevariants may result in compensatory increase in the responses to other epitopes of IAV. A combination of population genetics and epidemiological models is used to examine how the interplay between these mechanisms affects the rate of invasion of IAV escape-variants. We conclude that the invasion of an escape-variant will be very slow with a timescale of decades or longer, even if the escape-variant does not have a replicative fitness loss. Our results suggest T cell-inducing vaccines may not engender the rapid evolution of IAV and serve as a foundation for future modeling works on the long-term effectiveness and impacts of T cell-inducing influenza vaccines. (Word count: 221)ImportanceUniversal influenza vaccines against the conserved epitopes of influenza A virus have been proposed to minimize the burden of seasonal outbreaks and prepare for the pandemics. However, it is not clear to which extent the T cell-inducing vaccines will select for viruses that escape the T cell responses. Our mathematical models suggest how the nature of CD8 T cell protection contributes to the conservation of the CD8 T cell epitopes of influenza A virus. Also, it points out the essential biological parameters and questions that need addressing by future experimental works. (Word count: 91)

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