scholarly journals Prospects of HA-Based Universal Influenza Vaccine

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Anwar M. Hashem
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Globular Domain ◽  
Universal Vaccine ◽  
Viral Hemagglutinin ◽  
Heterosubtypic Immunity ◽  
Antibody Libraries ◽  
Universal Influenza Vaccine ◽  
Immunodominant Epitopes

Current influenza vaccines afford substantial protection in humans by inducing strain-specific neutralizing antibodies (Abs). Most of these Abs target highly variable immunodominant epitopes in the globular domain of the viral hemagglutinin (HA). Therefore, current vaccines may not be able to induce heterosubtypic immunity against the divergent influenza subtypes. The identification of broadly neutralizing Abs (BnAbs) against influenza HA using recent technological advancements in antibody libraries, hybridoma, and isolation of single Ab-secreting plasma cells has increased the interest in developing a universal influenza vaccine as it could provide life-long protection. While these BnAbs can serve as a source for passive immunotherapy, their identification represents an important step towards the design of such a universal vaccine. This review describes the recent advances and approaches used in the development of universal influenza vaccine based on highly conserved HA regions identified by BnAbs.

scholarly journals Influenza H3 and H1 hemagglutinins have different genetic barriers for resistance to broadly neutralizing stem antibodies

2019 ◽  
Author(s):  
Nicholas C. Wu ◽  
Andrew J. Thompson ◽  
Juhye M. Lee ◽  
Wen Su ◽  
Britni M. Arlian ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Viral Fitness ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Influenza Hemagglutinin ◽  
Genetic Barriers ◽  
Universal Influenza Vaccine

ABSTRACTIn the past decade, the discovery and characterization of broadly neutralizing antibodies (bnAbs) to the highly conserved stem region of influenza hemagglutinin (HA) have provided valuable insights for development of a universal influenza vaccine. However, the genetic barrier for resistance to stem bnAbs has not been thoroughly evaluated. Here, we performed a series of deep mutational scanning experiments to probe for resistance mutations. We found that the genetic barrier to resistance to stem bnAbs is generally very low for the H3 subtype but substantially higher for the H1 subtype. Several resistance mutations in H3 cannot be neutralized by stem bnAbs at the highest concentration tested, do not reduce in vitro viral fitness and in vivo pathogenicity, and are often present in circulating strains as minor variants. Thus, H3 HAs have a higher propensity than H1 HAs to escape major stem bnAbs and creates a potential challenge in the development of a bona fide universal influenza vaccine.ONE SENTENCE SUMMARYAcquisition of resistance by influenza virus to broadly neutralizing hemagglutinin stem antibodies varies tremendously depending on subtype.

scholarly journals Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247963 ◽  
Author(s):  
Alexander A. Cohen ◽  
Zhi Yang ◽  
Priyanthi N. P. Gnanapragasam ◽  
Susan Ou ◽  
Kim-Marie A. Dam ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Electron Tomography ◽  
Covalent Attachment ◽  
Humoral Immune ◽  
Group 2 ◽  
Multiple Strains ◽  
Universal Influenza Vaccine

Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

scholarly journals Development of Universal Influenza Vaccines Targeting Conserved Viral Proteins

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 169 ◽  
Author(s):  
Jazayeri ◽  
Poh
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza Viruses ◽  
Surface Proteins ◽  
Influenza Vaccines ◽  
Influenza Pandemics ◽  
Host Immune Responses ◽  
Production Platform ◽  
Universal Influenza Vaccine

Vaccination is still the most efficient way to prevent an infection with influenza viruses. Nevertheless, existing commercial vaccines face serious limitations such as availability during epidemic outbreaks and their efficacy. Existing seasonal influenza vaccines mostly induce antibody responses to the surface proteins of influenza viruses, which frequently change due to antigenic shift and or drift, thus allowing influenza viruses to avoid neutralizing antibodies. Hence, influenza vaccines need a yearly formulation to protect against new seasonal viruses. A broadly protective or universal influenza vaccine must induce effective humoral as well as cellular immunity against conserved influenza antigens, offer good protection against influenza pandemics, be safe, and have a fast production platform. Nanotechnology has great potential to improve vaccine delivery, immunogenicity, and host immune responses. As new strains of human epidemic influenza virus strains could originate from poultry and swine viruses, development of a new universal influenza vaccine will require the immune responses to be directed against viruses from different hosts. This review discusses how the new vaccine platforms and nanoparticles can be beneficial in the development of a broadly protective, universal influenza vaccine.

scholarly journals Targeting Antigens for Universal Influenza Vaccine Development

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 973
Author(s):  
Quyen-Thi Nguyen ◽  
Young-Ki Choi
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Influenza Viruses ◽  
Target Antigen ◽  
Cell Responses ◽  
Universal Influenza Vaccine ◽  
Virus Strains

Traditional influenza vaccines generate strain-specific antibodies which cannot provide protection against divergent influenza virus strains. Further, due to frequent antigenic shifts and drift of influenza viruses, annual reformulation and revaccination are required in order to match circulating strains. Thus, the development of a universal influenza vaccine (UIV) is critical for long-term protection against all seasonal influenza virus strains, as well as to provide protection against a potential pandemic virus. One of the most important strategies in the development of UIVs is the selection of optimal targeting antigens to generate broadly cross-reactive neutralizing antibodies or cross-reactive T cell responses against divergent influenza virus strains. However, each type of target antigen for UIVs has advantages and limitations for the generation of sufficient immune responses against divergent influenza viruses. Herein, we review current strategies and perspectives regarding the use of antigens, including hemagglutinin, neuraminidase, matrix proteins, and internal proteins, for universal influenza vaccine development.

scholarly journals Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

2020 ◽  
Author(s):  
Alexander A. Cohen ◽  
Zhi Yang ◽  
Priyanthi NP Gnanapragasam ◽  
Susan Ou ◽  
Kim-Marie A. Dam ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Electron Tomography ◽  
Covalent Attachment ◽  
Humoral Immune ◽  
Group 2 ◽  
Multiple Strains ◽  
Universal Influenza Vaccine

AbstractCurrent influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

scholarly journals Evaluation of Influenza Vaccination Efficacy: A Universal Epidemic Model

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Lily Ph. Nizolenko ◽  
Alexander G. Bachinsky ◽  
Sergei I. Bazhan
Keyword(s):  
Influenza Vaccine ◽  
Vaccination Coverage ◽  
Pandemic Influenza ◽  
Epidemic Model ◽  
Seasonal Influenza ◽  
Influenza Epidemic ◽  
Universal Vaccine ◽  
Seasonal Influenza Vaccine ◽  
Pandemic Strains ◽  
Universal Influenza Vaccine

By means of a designed epidemic model, we evaluated the influence of seasonal vaccination coverage as well as a potential universal vaccine with differing efficacy on the aftermath of seasonal and pandemic influenza. The results of the modeling enabled us to conclude that, to control a seasonal influenza epidemic with a reproduction coefficientR0≤1.5, a 35% vaccination coverage with the current seasonal influenza vaccine formulation is sufficient, provided that other epidemiology measures are regularly implemented. IncreasingR0level of pandemic strains will obviously require stronger intervention. In addition, seasonal influenza vaccines fail to confer protection against antigenically distinct pandemic influenza strains. Therefore, the necessity of a universal influenza vaccine is clear. The model predicts that a potential universal vaccine will be able to provide sufficient reliable (90%) protection against pandemic influenza only if its efficacy is comparable with the effectiveness of modern vaccines against seasonal influenza strains (70%–80%); given that at least 40% of the population has been vaccinated in advance, ill individuals have been isolated (observed), and a quarantine has been introduced. If other antiepidemic measures are absent, a vaccination coverage of at least 80% is required.

scholarly journals Influenza vaccine–induced human bone marrow plasma cells decline within a year after vaccination

Science ◽  
2020 ◽  
Vol 370 (6513) ◽  
pp. 237-241 ◽  
Author(s):  
Carl W. Davis ◽  
Katherine J. L. Jackson ◽  
Megan M. McCausland ◽  
Jaime Darce ◽  
Cathy Chang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Influenza Vaccine ◽  
Influenza Vaccination ◽  
Plasma Cells ◽  
Serum Antibody ◽  
Universal Vaccine ◽  
Bone Marrow Plasma ◽  
Antibody Levels

A universal vaccine against influenza would ideally generate protective immune responses that are not only broadly reactive against multiple influenza strains but also long-lasting. Because long-term serum antibody levels are maintained by bone marrow plasma cells (BMPCs), we investigated the production and maintenance of these cells after influenza vaccination. We found increased numbers of influenza-specific BMPCs 4 weeks after immunization with the seasonal inactivated influenza vaccine, but numbers returned to near their prevaccination levels after 1 year. This decline was driven by the loss of BMPCs induced by the vaccine, whereas preexisting BMPCs were maintained. Our results suggest that most BMPCs generated by influenza vaccination in adults are short-lived. Designing strategies to enhance their persistence will be a key challenge for the next generation of influenza vaccines.

scholarly journals Broadly reactive influenza antibodies are not limited by germinal center competition with high affinity antibodies

2020 ◽  
Author(s):  
Rachael Keating ◽  
Jenny L. Johnson ◽  
David C. Brice ◽  
Jocelyn G. Labombarde ◽  
Alexander L. Dent ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Germinal Center ◽  
Variable Region ◽  
Germinal Centers ◽  
Protective Capacity ◽  
Universal Vaccine ◽  
High Affinity ◽  
Igm Antibodies ◽  
Global Pandemic ◽  
Universal Influenza Vaccine

ABSTRACTEnhancing the generation of broadly reactive influenza antibodies is a pertinent goal towards developing a universal influenza vaccine. While antibodies that bind conserved influenza epitopes have been identified in humans, the frequency of these antibodies is typically very low. The predominant theory is that antibodies specific for conserved influenza epitopes are limited in germinal centers by competition with high affinity antibodies specific for the variable region of the virus. Here, we show that reducing germinal center formation and removing competition with high affinity antibodies was not sufficient to increase broadly reactive influenza antibodies or enhance protection against distinct influenza subtypes. These data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to competition in germinal centers. Additionally, levels of IgM antibodies specific for the variable region of HA persisted in mice in the absence of germinal centers, further demonstrating that immunodominance can be established independent of germinal centers. Our data also highlight the protective capacity of germinal center-independent IgM antibodies, which are not typically considered when testing correlates of protection, and offer an alternate target for delivering a universal influenza vaccine.IMPORTANCEIt is estimated that 250,000 – 650,000 individuals worldwide die each year from seasonal influenza infections. Current vaccines provide little protection against newly emerging strains. Thus, considerable effort is focused on enhancing the generation of broadly reactive influenza antibodies in order to develop a universal influenza vaccine. However, broadly reactive antibodies are rare and the factors that limit their generation are not completely understood. Our data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to completion in the germinal centers with antibodies to the variable HA head. Understanding the factors limiting antibodies specific for conserved regions of the influenza virus is imperative for developing a universal vaccine, which could potentially circumvent a global pandemic

scholarly journals Broad and Protective Influenza B Virus Neuraminidase Antibodies in Humans after Vaccination and their Clonal Persistence as Plasma Cells

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Michael S. Piepenbrink ◽  
Aitor Nogales ◽  
Madhubanti Basu ◽  
Christopher F. Fucile ◽  
Jane L. Liesveld ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Influenza Virus ◽  
Influenza Vaccine ◽  
B Cell ◽  
Plasma Cells ◽  
Influenza B Virus ◽  
Influenza B ◽  
Specific Antibodies ◽  
B Virus ◽  
Universal Influenza Vaccine

ABSTRACTAlthough most seasonal inactivated influenza vaccines (IIV) contain neuraminidase (NA), the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Due to the propensity of influenza virus for antigenic drift and shift and its tendency to elicit predominantly strain-specific antibodies, humanity remains susceptible to waves of new strains of seasonal viruses and is at risk from viruses with pandemic potential for which limited or no immunity may exist. Here we demonstrate that the use of IIV results in increased levels of influenza B virus (IBV) NA-specific serum antibodies. Detailed analysis of the IBV NA B cell response indicates concurrent expansion of IBV NA-specific peripheral blood plasmablasts 7 days after IIV immunization which express monoclonal antibodies with broad and potent antiviral activity against both IBV Victoria and Yamagata lineages and prophylactic and therapeutic activity in mice. These IBV NA-specific B cell clonal lineages persisted in CD138+long-lived bone marrow plasma cells. These results represent the first demonstration that IIV-induced NA human antibodies can protect and treat influenza virus infectionin vivoand suggest that IIV can induce a subset of IBV NA-specific B cells with broad protective potential, a feature that warrants further study for universal influenza vaccine development.IMPORTANCEInfluenza virus infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets such as regions within the influenza neuraminidase protein. We have demonstrated that seasonal immunization stimulates neuraminidase-specific antibodies in humans that are broad and potent in their protection from influenza B virus when tested in mice. These antibodies further persist in the bone marrow, where they are expressed by long-lived antibody-producing cells, referred to here as plasma cells. The significance in our research is the demonstration that seasonal influenza immunization can induce a subset of neuraminidase-specific B cells with broad protective potential, a process that if further studied and enhanced could aid in the development of a universal influenza vaccine.

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