Implications of broadly neutralizing antibodies in the development of a universal influenza vaccine

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.

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

10.1101/2019.12.30.891135 ◽

2019 ◽

Cited By ~ 1

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.

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

PLoS ONE ◽

10.1371/journal.pone.0247963 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0247963 ◽

Cited By ~ 1

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.

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Structure of the apo anti-influenza CH65 Fab

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x14027599 ◽

2015 ◽

Vol 71 (2) ◽

pp. 145-148 ◽

Cited By ~ 2

Author(s):

Peter S. Lee ◽

Ashley J. Arnell ◽

Ian A. Wilson

Keyword(s):

Neutralizing Antibodies ◽

Affinity Maturation ◽

Influenza Viruses ◽

Antigenic Drift ◽

Human Antibody ◽

Broadly Neutralizing Antibodies ◽

High Affinity ◽

Influenza Hemagglutinin ◽

Universal Influenza Vaccine ◽

Complementarity Determining Region

Influenza viruses remain a persistent challenge to human health owing to their inherent ability to evade the immune response by antigenic drift. However, the discovery of broadly neutralizing antibodies (bnAbs) against divergent viruses has sparked renewed interest in a universal influenza vaccine and novel therapeutic opportunities. Here, a crystal structure at 1.70 Å resolution is presented of the Fab of the human antibody CH65, which has broad neutralizing activity against a range of seasonal H1 isolates. Previous studies proposed that affinity maturation of this antibody lineage pre-organizes the complementarity-determining region (CDR) loops into an energetically favorable HA-bound conformation. Indeed, from the structural comparisons of free and HA-bound CH65 presented here, the CDR loops, and in particular the heavy-chain CDR3, adopt the same conformations in the free and bound forms. Thus, these findings support the notion that affinity maturation of the CH65 lineage favorably preconfigures the CDR loops for high-affinity binding to influenza hemagglutinin.

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Development of Universal Influenza Vaccines Targeting Conserved Viral Proteins

Vaccines ◽

10.3390/vaccines7040169 ◽

2019 ◽

Vol 7 (4) ◽

pp. 169 ◽

Cited By ~ 8

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.

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Targeting Antigens for Universal Influenza Vaccine Development

Viruses ◽

10.3390/v13060973 ◽

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.

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

10.1101/2020.01.18.911388 ◽

2020 ◽

Cited By ~ 1

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.

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Influenza vaccine to induce broadly neutralizing antibodies

Science-Business eXchange ◽

10.1038/scibx.2012.942 ◽

2012 ◽

Vol 5 (35) ◽

pp. 942-942

Keyword(s):

Influenza Vaccine ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies

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A Computationally Optimized Broadly Reactive Antigen Subtype–Specific Influenza Vaccine Strategy Elicits Unique Potent Broadly Neutralizing Antibodies against Hemagglutinin

The Journal of Immunology ◽

10.4049/jimmunol.1900379 ◽

2019 ◽

Vol 204 (2) ◽

pp. 375-385 ◽

Cited By ~ 6

Author(s):

Giuseppe A. Sautto ◽

Greg A. Kirchenbaum ◽

Rodrigo B. Abreu ◽

Jeffrey W. Ecker ◽

Spencer R. Pierce ◽

...

Keyword(s):

Influenza Vaccine ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Vaccine Strategy

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Conserved Influenza Hemagglutinin, Neuraminidase and Matrix Peptides Adjuvanted with ALFQ Induce Broadly Neutralizing Antibodies

Vaccines ◽

10.3390/vaccines9070698 ◽

2021 ◽

Vol 9 (7) ◽

pp. 698

Author(s):

Clara J. Sei ◽

Mangala Rao ◽

Richard F. Schuman ◽

Luke T. Daum ◽

Gary R. Matyas ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Influenza Viruses ◽

Igg Antibodies ◽

Broadly Neutralizing Antibodies ◽

Cellular Immune Responses ◽

Influenza Hemagglutinin ◽

Igg Isotypes ◽

Novel Strategy ◽

Cellular Immune ◽

Universal Influenza Vaccine

A universal influenza candidate vaccine that targets multiple conserved influenza virus epitopes from hemagglutinin (HA), neuraminidase (NA) and matrix (M2e) proteins was combined with the potent Army liposomal adjuvant (ALFQ) to promote induction of broad immunity to seasonal and pandemic influenza strains. The unconjugated and CRM-conjugated composite peptides formulated with ALFQ were highly immunogenic and induced both humoral and cellular immune responses in mice. Broadly reactive serum antibodies were induced across various IgG isotypes. Mice immunized with the unconjugated composite peptide developed antibody responses earlier than mice immunized with conjugated peptides, and the IgG antibodies were broadly reactive and neutralizing across Groups 1 and 2 influenza viruses. Multi-epitope unconjugated influenza composite peptides formulated with ALFQ provide a novel strategy for the development of a universal influenza vaccine. These synthetic peptide vaccines avoid the pitfalls of egg-produced influenza vaccines and production can be scaled up rapidly and economically.

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