M2e-Based Universal Influenza A Vaccines.
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ABSTRACT:
SUBMITTER: Deng L
PROVIDER: S-EPMC4494237 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6800501 | biostudies-literature
Project description:We developed a new chimeric M2e and H3 hemagglutinin (HA) stalk protein vaccine (M2e-H3 stalk) by genetic engineering of modified H3 stalk domain conjugated with conserved M2e epitopes to overcome the drawbacks of low efficacy by monomeric domain-based universal vaccines. M2e-H3 stalk protein expressed and purified from Escherichia coli was thermostable, displaying native-like antigenic epitopes recognized by antisera of different HA subtype proteins and influenza A virus infections. Adjuvanted M2e-H3 stalk vaccination induced M2e and stalk-specific IgG antibodies recognizing viral antigens on virus particles and on the infected cell surface, CD4+ and CD8+ T-cell responses, and antibody-dependent cytotoxic cell surrogate activity in mice. M2e-H3 stalk was found to confer protection against heterologous and heterosubtypic cross-group subtype viruses (H1N1, H5N1, H9N2, H3N2, H7N9) at similar levels in adult and aged mice. These results provide evidence that M2e-H3 stalk chimeric proteins can be developed as a universal influenza A virus vaccine candidate for young and aged populations.
| S-EPMC9243060 | biostudies-literature
Project description:Influenza vaccines with broad cross-protection are urgently needed. The highly conserved ectodomain of the influenza matrix protein 2 (M2e) can be a promising candidate if its low immunogenicity was overcome. In this study, we generated protein nanoclusters self-assembled from conformation-stabilized M2e tetramers (tM2e) to improve its immunogenicity. The resulting nanoclusters showed an average hydrodynamic diameter of 227 nm. Vaccination with the nanoclusters by an intranasal route elicited high levels of serum antigen-specific IgG in mice (approximately 100-fold higher than that obtained with soluble tM2e), as well as antigen-specific T cell and mucosal antibody responses. The immunity conferred complete protection against lethal challenge with homo- as well as heterosubtypic viruses. These results demonstrate that nanoclusters assembled from conformation-stabilized M2e are promising as a potential universal influenza A vaccine. Self-assembly into nanoclusters represents a novel approach for increasing the immunogenicity of vaccine antigens.From the clinical editorIn order to develop more effective influenza vaccination, the highly conserved ectodomain of M2e could be a promising candidate. Unfortunately, it is a weak antigen for vaccination purposes. In this study, self-assembled protein nanoclusters of tM2e were generated and tested. The nanoclusters demonstrated superior vaccination properties, with complete protection against lethal challenge in the studied rodent model, raising hope for the introduction of similar vaccines to challenge human influenza outbreaks.
| S-EPMC3948190 | biostudies-literature
Project description:MotivationInfluenza A viral heterogeneity remains a significant threat due to unpredictable antigenic drift in seasonal influenza and antigenic shifts caused by the emergence of novel subtypes. Annual review of multivalent influenza vaccines targets strains of influenza A and B likely to be predominant in future influenza seasons. This does not induce broad, cross protective immunity against emergent subtypes. Better strategies are needed to prevent future pandemics. Cross-protection can be achieved by activating CD8+ and CD4+ T cells against highly conserved regions of the influenza genome. We combine available experimental data with informatics-based immunological predictions to help design vaccines potentially able to induce cross-protective T-cells against multiple influenza subtypes.ResultsTo exemplify our approach we designed two epitope ensemble vaccines comprising highly conserved and experimentally verified immunogenic influenza A epitopes as putative non-seasonal influenza vaccines; one specifically targets the US population and the other is a universal vaccine. The USA-specific vaccine comprised 6 CD8+ T cell epitopes (GILGFVFTL, FMYSDFHFI, GMDPRMCSL, SVKEKDMTK, FYIQMCTEL, DTVNRTHQY) and 3 CD4+ epitopes (KGILGFVFTLTVPSE, EYIMKGVYINTALLN, ILGFVFTLTVPSERG). The universal vaccine comprised 8 CD8+ epitopes: (FMYSDFHFI, GILGFVFTL, ILRGSVAHK, FYIQMCTEL, ILKGKFQTA, YYLEKANKI, VSDGGPNLY, YSHGTGTGY) and the same 3 CD4+ epitopes. Our USA-specific vaccine has a population protection coverage (portion of the population potentially responsive to one or more component epitopes of the vaccine, PPC) of over 96 and 95% coverage of observed influenza subtypes. The universal vaccine has a PPC value of over 97 and 88% coverage of observed subtypes.Availability and implementationhttp://imed.med.ucm.es/Tools/episopt.html CONTACT: d.r.flower@aston.ac.uk.
| S-EPMC5079473 | biostudies-literature
Project description:SignificanceAlthough the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24-amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.
| S-EPMC9060463 | biostudies-literature
Project description:Annually recurring seasonal influenza causes massive economic loss and poses severe threats to public health worldwide. The current seasonal influenza vaccines are the most effective means of preventing influenza infections but possess major weaknesses. Seasonal influenza vaccines require annual updating of the vaccine strains. However, it is an unreachable task to accurately predict the future circulating strains. Vaccines with mismatched strains dramatically compromise the vaccine efficacy. In addition, the seasonal influenza vaccines are ineffective against an unpredictable pandemic. A universal influenza vaccine would overcome these weaknesses of the seasonal vaccines and abolish the threat of influenza pandemics. One approach under investigation is to design influenza vaccine immunogens based on conserved, type-specific amino acid sequences and conformational epitopes, rather than strain-specific. Such vaccines can elicit broadly reactive humoral and cellular immunity. Universal influenza vaccine development has intensively employed nanotechnology because the structural and morphological properties of nanoparticles dramatically improve vaccine immunogenicity and the induced immunity duration. Layered protein nanoparticles can decrease off-target immune responses, fine-tune antigen recognition and processing, and facilitate comprehensive immune response induction. Herein, we review the designs of effective nanoparticle universal influenza vaccines, the recent discoveries of specific nanoparticle features that contribute to immunogenicity enhancement, and recent progress in clinical trials.
| S-EPMC8650199 | biostudies-literature
Project description:Influenza affects millions of people worldwide and can result in severe sickness and even death. The best method of prevention is vaccination; however, the seasonal influenza vaccine often suffers from low efficacy and requires yearly vaccination due to changes in strain and viral mutations. More conserved universal influenza antigens like M2 ectodomain (M2e) and the stalk region of hemagglutinin (HA stalk) have been used clinically but often suffer from low antigenicity. To increase antigenicity, universal antigens have been formulated using nano/microparticles as vaccine carriers against influenza. Utilizing polymers, liposomes, metal, and protein-based particles, indicators of immunity and protection in mouse, pig, ferrets, and chicken models of influenza have been shown. In this review, seasonal and universal influenza vaccine formulations comprised of these materials including their physiochemical properties, fabrication, characterization, and biologic responses in vivo are highlighted. The review is concluded with future perspectives for nano/microparticles as carrier systems and other considerations within the universal influenza vaccine delivery landscape. Graphical Abstract.
| S-EPMC8741137 | biostudies-literature
Project description:BackgroundCurrent influenza virus vaccines are effective when well matched to the circulating strains. Unfortunately, antigenic drift and the high diversity of potential emerging zoonotic and pandemic viruses make it difficult to select the right strains for vaccine production. This problem causes vaccine mismatches, which lead to sharp drops in vaccine effectiveness and long response times to manufacture matched vaccines in case of novel pandemic viruses.AimsTo provide an overview of universal influenza virus vaccines and therapeutic antibodies in preclinical and clinical development.SourcesPubMed and clinicaltrials.gov were used as sources for this review.ContentUniversal influenza virus vaccines that target conserved regions of the influenza virus including the haemagglutinin stalk domain, the ectodomain of the M2 ion channel or the internal matrix and nucleoproteins are in late preclinical and clinical development. These vaccines could confer broad protection against all influenza A and B viruses including drift variants and thereby abolish the need for annual re-formulation and re-administration of influenza virus vaccines. In addition, these novel vaccines would enhance preparedness against emerging influenza virus pandemics. Finally, novel therapeutic antibodies against the same conserved targets are in clinical development and could become valuable tools in the fight against influenza virus infection.ImplicationsBoth universal influenza virus vaccines and therapeutic antibodies are potential future options for the control of human influenza infections.
| S-EPMC5389886 | biostudies-literature
Project description:BackgroundIntranasal delivery of vaccines directed against respiratory pathogens is an attractive alternative to parenteral administration. However, using this delivery route for inactivated vaccines usually requires the use of potent mucosal adjuvants, and no such adjuvant has yet been approved for human use.Methodology/principal findingsWe have developed a live attenuated Bordetella pertussis vaccine, called BPZE1, and show here that it can be used to present the universal influenza virus epitope M2e to the mouse respiratory tract to prime for protective immunity against viral challenge. Three copies of M2e were genetically fused to the N-terminal domain of filamentous hemagglutinin (FHA) and produced in recombinant BPZE1 derivatives in the presence or absence of endogenous full-length FHA. Only in the absence of FHA intranasal administration of the recombinant BPZE1 derivative induced antibody responses to M2e and effectively primed BALB/c mice for protection against influenza virus-induced mortality and reduced the viral load after challenge. Strong M2e-specific antibody responses and protection were observed after a single nasal administration with the recombinant BPZE1 derivative, followed by a single administration of M2e linked to a virus-like particle without adjuvant, whereas priming alone with the vaccine strain did not protect.Conclusions/significanceUsing recombinant FHA-3M2e-producing BPZE1 derivatives for priming and the universal influenza M2e peptide linked to virus-like particles for boosting may constitute a promising approach for needle-free and adjuvant-free nasal vaccination against influenza.
| S-EPMC3602086 | biostudies-literature
Project description:Despite the availability of vaccines, influenza remains a major public health challenge. A key reason is the virus capacity for immune escape: ongoing evolution allows the continual circulation of seasonal influenza, while novel influenza viruses invade the human population to cause a pandemic every few decades. Current vaccines have to be updated continually to keep up to date with this antigenic change, but emerging 'universal' vaccines-targeting more conserved components of the influenza virus-offer the potential to act across all influenza A strains and subtypes. Influenza vaccination programmes around the world are steadily increasing in their population coverage. In future, how might intensive, routine immunization with novel vaccines compare against similar mass programmes utilizing conventional vaccines? Specifically, how might novel and conventional vaccines compare, in terms of cumulative incidence and rates of antigenic evolution of seasonal influenza? What are their potential implications for the impact of pandemic emergence? Here we present a new mathematical model, capturing both transmission dynamics and antigenic evolution of influenza in a simple framework, to explore these questions. We find that, even when matched by per-dose efficacy, universal vaccines could dampen population-level transmission over several seasons to a greater extent than conventional vaccines. Moreover, by lowering opportunities for cross-protective immunity in the population, conventional vaccines could allow the increased spread of a novel pandemic strain. Conversely, universal vaccines could mitigate both seasonal and pandemic spread. However, where it is not possible to maintain annual, intensive vaccination coverage, the duration and breadth of immunity raised by universal vaccines are critical determinants of their performance relative to conventional vaccines. In future, conventional and novel vaccines are likely to play complementary roles in vaccination strategies against influenza: in this context, our results suggest important characteristics to monitor during the clinical development of emerging vaccine technologies.
| S-EPMC5157952 | biostudies-literature