M2e-based universal influenza vaccines: a historical overview and new approaches to development

Abstract The influenza A virus was isolated for the first time in 1931, and the first attempts to develop a vaccine against the virus began soon afterwards. In addition to causing seasonal epidemics, influenza viruses can cause pandemics at random intervals, which are very hard to predict. Vaccination is the most effective way of preventing the spread of influenza infection. However, seasonal vaccination is ineffective against pandemic influenza viruses because of antigenic differences, and it takes approximately six months from isolation of a new virus to develop an effective vaccine. One of the possible ways to fight the emergence of pandemics may be by using a new type of vaccine, with a long and broad spectrum of action. The extracellular domain of the M2 protein (M2e) of influenza A virus is a conservative region, and an attractive target for a universal influenza vaccine. This review gives a historical overview of the study of M2 protein, and summarizes the latest developments in the preparation of M2e-based universal influenza vaccines.

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RNA-Sequencing-Based Transcriptomic Analysis Reveals a Role for Annexin-A1 in Classical and Influenza A Virus-Induced Autophagy

Cells ◽

10.3390/cells9061399 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1399 ◽

Cited By ~ 1

Author(s):

Jianzhou Cui ◽

Dhakshayini Morgan ◽

Dao Han Cheng ◽

Sok Lin Foo ◽

Gracemary L. R. Yap ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Infection ◽

Critical Role ◽

Mtor Inhibitors ◽

Influenza Viruses ◽

Annexin A1 ◽

Underlying Mechanisms

Influenza viruses have been shown to use autophagy for their survival. However, the proteins and mechanisms involved in the autophagic process triggered by the influenza virus are unclear. Annexin-A1 (ANXA1) is an immunomodulatory protein involved in the regulation of the immune response and Influenza A virus (IAV) replication. In this study, using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) deletion of ANXA1, combined with the next-generation sequencing, we systematically analyzed the critical role of ANXA1 in IAV infection as well as the detailed processes governing IAV infection, such as macroautophagy. A number of differentially expressed genes were uniquely expressed in influenza A virus-infected A549 parental cells and A549 ∆ANXA1 cells, which were enriched in the immune system and infection-related pathways. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the role of ANXA1 in autophagy. To validate this, the effect of mechanistic target of rapamycin (mTOR) inhibitors, starvation and influenza infection on autophagy was determined, and our results demonstrate that ANXA1 enhances autophagy induced by conventional autophagy inducers and influenza virus. These results will help us to understand the underlying mechanisms of IAV infection and provide a potential therapeutic target for restricting influenza viral replication and infection.

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Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

Molecules ◽

10.3390/molecules25122903 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2903

Author(s):

Maggie C. Duncan ◽

Pascal Amoa Onguéné ◽

Ibuki Kihara ◽

Derrick N. Nebangwa ◽

Maya E. Naidu ◽

...

Keyword(s):

Ion Channel ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Viruses ◽

Drug Resistant ◽

M2 Protein ◽

Virtual Screen ◽

Chebulagic Acid ◽

Virus Strains

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development.

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Design, synthesis and primary immunologic evaluation of M2e-CRM197 conjugate as a universal influenza vaccine candidate

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666201104145006 ◽

2020 ◽

Vol 21 ◽

Author(s):

Lu Xu ◽

Chun Zhang ◽

Jing Zhang ◽

Rong Yu ◽

Zhiguo Su

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Influenza A Virus ◽

Influenza A ◽

Vaccine Development ◽

Acute Infection ◽

Acid Hydrazide ◽

Influenza Viruses ◽

Carrier Protein ◽

Universal Influenza Vaccine

Background: Influenza is a contagious respiratory illness caused by acute infection of influenza viruses, among which influenza A virus causes epidemic seasonal infection nearly every year. Along with unpredictability of evolving influenza A virus and time-consuming vaccine development cycles, novel universal influenza vaccine designed to induce broadly cross-reactive immune responses against frequently mutant influenza A virus strains are greatly urgent. Objective: The aim of this study was to synthesize a novel vaccine through the dual-site specific conjugation of the constant epitope of 23 amino acids (M2e) of influenza A virus with highly immunogenic carrier protein of cross-reacting material (CRM197) under denaturation, and evaluate its primary immunogenicity in mice. Methods: The antigen (M2e) and the carrier protein (CRM197) were linked with different type of hetero-functionalized linkers, α-maleimide-ε-hydrazide polyethylene glycol 2k (MAL-PEG-HZ) and N-β-maleimidopropionic acid hydrazide (BMPH) separately. The immunogenicity of the M2e-CRM197 conjugates with different type of linkers was evaluated in mice, and the M2e-specific total IgG and IgG-isotypes were determined by ELSIA. Results: Immunogenicity study revealed that anti-M2e antibody could be induced by the conjugate products, M2e-PEGCRM197 and M2e-BMPH-CRM197, were approximately 30 and 90-fold higher than that of M2e group. In addition, the antiM2e antibody level induced by M2e-PEG-CRM197 conjugate was three times higher than that of M2e-BMPH-CRM197 conjugate, and the former could simultaneously activate both cellar and humoral immune responses. Conclusions: The M2e-CRM197 conjugated vaccines we synthesized in this study are highly immunogenic compared with M2e alone. Besides, evidences were presented here indicated that the hydrophilic, non-immunogenic and biocompatible chain of the cross-linker might be a better choice for development of conjugate vaccine.

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An Intranasal Virus-Like Particle Vaccine Broadly Protects Mice from Multiple Subtypes of Influenza A Virus

mBio ◽

10.1128/mbio.01044-15 ◽

2015 ◽

Vol 6 (4) ◽

Cited By ~ 49

Author(s):

Louis M. Schwartzman ◽

Andrea L. Cathcart ◽

Lindsey M. Pujanauski ◽

Li Qi ◽

John C. Kash ◽

...

Keyword(s):

Public Health ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Viruses ◽

Significant Protection ◽

Virus Infections ◽

Influenza A Viruses ◽

Virus Like Particle ◽

Practical Strategy ◽

Universal Influenza Vaccine

ABSTRACTInfluenza virus infections are a global public health problem, with a significant impact of morbidity and mortality from both annual epidemics and pandemics. The current strategy for preventing annual influenza is to develop a new vaccine each year against specific circulating virus strains. Because these vaccines are unlikely to protect against an antigenically divergent strain or a new pandemic virus with a novel hemagglutinin (HA) subtype, there is a critical need for vaccines that protect against all influenza A viruses, a so-called “universal” vaccine. Here we show that mice were broadly protected against challenge with a wide variety of lethal influenza A virus infections (94% aggregate survival following vaccination) with a virus-like particle (VLP) vaccine cocktail. The vaccine consisted of a mixture of VLPs individually displaying H1, H3, H5, or H7 HAs, and vaccinated mice showed significant protection following challenge with influenza viruses expressing 1918 H1, 1957 H2, and avian H5, H6, H7, H10, and H11 hemagglutinin subtypes. These experiments suggest a promising and practical strategy for developing a broadly protective “universal” influenza vaccine.IMPORTANCEThe rapid and unpredictable nature of influenza A virus evolution requires new vaccines to be produced annually to match circulating strains. Human infections with influenza viruses derived from animals can cause outbreaks that may be associated with high mortality, and such strains may also adapt to humans to cause a future pandemic. Thus, there is a large public health need to create broadly protective, or “universal,” influenza vaccines that could prevent disease from a wide variety of human and animal influenza A viruses. In this study, a noninfectious virus-like particle (VLP) vaccine was shown to offer significant protection against a variety of influenza A viruses in mice, suggesting a practical strategy to develop a universal influenza vaccine.

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A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus

Journal of Virology ◽

10.1128/jvi.01065-19 ◽

2019 ◽

Vol 94 (4) ◽

Cited By ~ 3

Author(s):

Andrew Smith ◽

Laura Rodriguez ◽

Maya El Ghouayel ◽

Aitor Nogales ◽

Jeffrey M. Chamberlain ◽

...

Keyword(s):

Influenza Vaccine ◽

Influenza A ◽

H1n1 Virus ◽

Influenza Infection ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Temperature Sensitive ◽

Live Attenuated Influenza Vaccine ◽

Cell Immunity

ABSTRACT Influenza A virus (IAV) causes significant morbidity and mortality, despite the availability of viral vaccines. The efficacy of live attenuated influenza vaccines (LAIVs) has been especially poor in recent years. One potential reason is that the master donor virus (MDV), on which all LAIVs are based, contains either the internal genes of the 1960 A/Ann Arbor/6/60 or the 1957 A/Leningrad/17/57 H2N2 viruses (i.e., they diverge considerably from currently circulating strains). We previously showed that introduction of the temperature-sensitive (ts) residue signature of the AA/60 MDV into a 2009 pandemic A/California/04/09 H1N1 virus (Cal/09) results in only 10-fold in vivo attenuation in mice. We have previously shown that the ts residue signature of the Russian A/Leningrad/17/57 H2N2 LAIV (Len LAIV) more robustly attenuates the prototypical A/Puerto Rico/8/1934 (PR8) H1N1 virus. In this work, we therefore introduced the ts signature from Len LAIV into Cal/09. This new Cal/09 LAIV is ts in vitro, highly attenuated (att) in mice, and protects from a lethal homologous challenge. In addition, when our Cal/09 LAIV with PR8 hemagglutinin and neuraminidase was used to vaccinate mice, it provided enhanced protection against a wild-type Cal/09 challenge relative to a PR8 LAIV with the same attenuating mutations. These findings suggest it may be possible to improve the efficacy of LAIVs by better matching the sequence of the MDV to currently circulating strains. IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.

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Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/939860 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 58

Author(s):

Marine L. B. Hillaire ◽

Albert D. M. E. Osterhaus ◽

Guus F. Rimmelzwaan

Keyword(s):

T Lymphocytes ◽

Influenza A Virus ◽

Cytotoxic T Lymphocytes ◽

Influenza A ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza Vaccines ◽

Virus Infections ◽

Influenza A Viruses ◽

Heterosubtypic Immunity

There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8+T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8+T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses.

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The PB2-E627K Mutation Attenuates Viruses Containing the 2009 H1N1 Influenza Pandemic Polymerase

mBio ◽

10.1128/mbio.00067-10 ◽

2010 ◽

Vol 1 (1) ◽

Cited By ~ 47

Author(s):

Brett W. Jagger ◽

Matthew J. Memoli ◽

Zong-Mei Sheng ◽

Li Qi ◽

Rachel J. Hrabal ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

H1n1 Virus ◽

Influenza Pandemic ◽

Influenza Infection ◽

H1n1 Influenza ◽

Influenza Viruses ◽

Pandemic Virus ◽

2009 H1n1 ◽

Animal Reservoirs

ABSTRACTThe swine-origin H1N1 influenza A virus emerged in early 2009 and caused the first influenza pandemic in 41 years. The virus has spread efficiently to both the Northern and the Southern Hemispheres and has been associated with over 16,000 deaths. Given the virus’s recent zoonotic origin, there is concern that the virus could acquire signature mutations associated with the enhanced pathogenicity of previous pandemic viruses or H5N1 viruses with pandemic potential. We tested the hypothesis that mutations in the polymerase PB2 gene at residues 627 and 701 would enhance virulence but found that influenza viruses containing these mutations in the context of the pandemic virus polymerase complex are attenuated in cell culture and mice.IMPORTANCEInfluenza A virus (IAV) evolution is characterized by host-specific lineages, and IAVs derived in whole or in part from animal reservoirs have caused pandemics in humans. Because IAVs are known to acquire host-adaptive genome mutations, and since the PB2 gene of the 2009 H1N1 virus is of recent avian derivation, there exists concern that the pathogenicity of the 2009 H1N1 influenza A pandemic virus could be potentiated by acquisition of the host-adaptive PB2-E627K or -D701N mutations, which have been shown to enhance the virulence of other influenza viruses. We present data from a mouse model of influenza infection showing that such mutations do not increase the virulence of viruses containing the 2009 H1N1 viral polymerase.

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ANALYSIS OF MIGRATION OF AQUATIC AND SEMIAQUATIC BIRDS ON THE TERRITORY OF THE REPUBLIC OF DAGESTAN AND JUSTIFICATION OF THE CHOICE OF KEY POINTS OF MONITORING OF INFLUENZA A VIRUS

South of Russia ecology development ◽

10.18470/1992-1098-2019-1-137-149 ◽

2019 ◽

Vol 14 (1) ◽

pp. 137-149

Author(s):

A. Yu. Alekseev ◽

T. A. Murashkina ◽

J. M. Jamalutdinov ◽

S. S. Abdullaev ◽

K. A. Akhmedrabadanov ◽

...

Keyword(s):

Avian Influenza ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Infection ◽

Influenza Viruses ◽

Migration Routes ◽

Scientific Publications ◽

Bird Populations ◽

Large Populations ◽

The Republic

Aim. The aim of the work is to carry out an analysis of the wetlands of the Republic of Dagestan in order to justify the selection of the collecting sites for material from migratory aquatic and semi aquatic birds in order to monitor the influenza A virus.Material and methods. Studying scientific publications of different years and available information on the wetlands of the Caspian Dagestan allowed establishing the areas of concentration of aquatic and semiaquatic birds where effective sampling for avian influenza is possible.Results. The spread of avian influenza viruses in nature is inextricably linked with migration of birds. Due to the presence of a large number of reservoirs, the western part of the Caspian region brings together large populations of wild waterbirds from various places within their migration routes. Mass accumulation encourages the interaction of birds of different species and populations, which in turn creates favorable conditions for the spread of various viral diseases.Conclusion. For an integrated assessment of the state of aquatic and semiaquatic bird populations, as well as monitoring the avian influenza infection rates, it is proposed to consider as model areas the wetlands of the Lake Aji (Papas), Lake Yuzhny Agrakhan, Agrakhansky Gulf, the Terek River delta and the Achikolsky systems of lake.

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Regulation of Host Immune Responses against Influenza A Virus Infection by Mitogen-Activated Protein Kinases (MAPKs)

Microorganisms ◽

10.3390/microorganisms8071067 ◽

2020 ◽

Vol 8 (7) ◽

pp. 1067

Author(s):

Jiabo Yu ◽

Xiang Sun ◽

Jian Yi Gerald Goie ◽

Yongliang Zhang

Keyword(s):

Immune Response ◽

Immune Responses ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Infection ◽

Influenza Viruses ◽

Mitogen Activated Protein Kinase ◽

Viral Diseases ◽

Cytokine Storm ◽

Mitogen Activated Protein

Influenza is a major respiratory viral disease caused by infections from the influenza A virus (IAV) that persists across various seasonal outbreaks globally each year. Host immune response is a key factor determining disease severity of influenza infection, presenting an attractive target for the development of novel therapies for treatments. Among the multiple signal transduction pathways regulating the host immune activation and function in response to IAV infections, the mitogen-activated protein kinase (MAPK) pathways are important signalling axes, downstream of various pattern recognition receptors (PRRs), activated by IAVs that regulate various cellular processes in immune cells of both innate and adaptive immunity. Moreover, aberrant MAPK activation underpins overexuberant production of inflammatory mediators, promoting the development of the “cytokine storm”, a characteristic of severe respiratory viral diseases. Therefore, elucidation of the regulatory roles of MAPK in immune responses against IAVs is not only essential for understanding the pathogenesis of severe influenza, but also critical for developing MAPK-dependent therapies for treatment of respiratory viral diseases. In this review, we will summarise the current understanding of MAPK functions in both innate and adaptive immune response against IAVs and discuss their contributions towards the cytokine storm caused by highly pathogenic influenza viruses.

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Prospects and Challenges in the Development of Universal Influenza Vaccines

Vaccines ◽

10.3390/vaccines8030361 ◽

2020 ◽

Vol 8 (3) ◽

pp. 361 ◽

Cited By ~ 4

Author(s):

Anders Madsen ◽

Rebecca Jane Cox

Keyword(s):

Influenza Vaccine ◽

Influenza A ◽

Vaccine Design ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Next Generation ◽

Universal Influenza Vaccine

Current influenza vaccines offer suboptimal protection and depend on annual reformulation and yearly administration. Vaccine technology has rapidly advanced during the last decade, facilitating development of next-generation influenza vaccines that can target a broader range of influenza viruses. The development and licensure of a universal influenza vaccine could provide a game changing option for the control of influenza by protecting against all influenza A and B viruses. Here we review important findings and considerations regarding the development of universal influenza vaccines and what we can learn from this moving forward with a SARS-CoV-2 vaccine design.

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