scholarly journals Universal Influenza Virus Vaccines That Target the Conserved Hemagglutinin Stalk and Conserved Sites in the Head Domain

2019 ◽  
Vol 219 (Supplement_1) ◽  
pp. S62-S67 ◽  
Author(s):  
Florian Krammer ◽  
Peter Palese
Keyword(s):  
Clinical Trials ◽  
Influenza Virus ◽  
Vaccination Strategy ◽  
Influenza Virus Vaccine ◽  
Target Antigen ◽  
Vaccine Candidates ◽  
Head Domain ◽  
Viral Hemagglutinin ◽  
Stalk Domain ◽  
New Generation

Abstract Due to limitations of current influenza virus vaccines, new vaccines that mediate broad protection and show high efficacy against seasonal and pandemic viruses are urgently needed. The conserved stalk of the viral hemagglutinin has been identified as potential target antigen for this new generation of vaccines. A vaccination strategy based on chimeric hemagglutinin (cHA), which refocuses the immune response toward the stalk domain and the conserved neuraminidase, is currently being tested in clinical trials. Here we discuss how to improve the cHA antigens to generate vaccine candidates that both induce a broad antistalk response and target conserved immunosubdominant epitopes in the head domain of the hemagglutinin. These novel constructs, termed mosaic hemagglutinins, should provide enhanced protection and should be tested in clinical trials to assess their improved potential as universal influenza virus vaccine candidates.

scholarly journals Chimeric Hemagglutinin-Based Live-Attenuated Vaccines Confer Durable Protective Immunity against Influenza A Viruses in a Preclinical Ferret Model

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 40
Author(s):  
Wen-Chun Liu ◽  
Raffael Nachbagauer ◽  
Daniel Stadlbauer ◽  
Shirin Strohmeier ◽  
Alicia Solórzano ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Antibody Responses ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Humoral And Cellular Immunity ◽  
Stalk Domain ◽  
One Year

Epidemic or pandemic influenza can annually cause significant morbidity and mortality in humans. We developed novel chimeric hemagglutinin (cHA)-based universal influenza virus vaccines, which contain a conserved HA stalk domain from a 2009 pandemic H1N1 (pH1N1) strain combined with globular head domains from avian influenza A viruses. Our previous reports demonstrated that prime-boost sequential immunizations induced robust antibody responses directed toward the conserved HA stalk domain in ferrets. Herein, we further followed vaccinated animals for one year to compare the efficacy and durability of these vaccines in the preclinical ferret model of influenza. Although all cHA-based immunization regimens induced durable HA stalk-specific and heterosubtypic antibody responses in ferrets, sequential immunization with live-attenuated influenza virus vaccines (LAIV-LAIV) conferred the best protection against upper respiratory tract infection by a pH1N1 influenza A virus. The findings from this study suggest that our sequential immunization strategy for a cHA-based universal influenza virus vaccine provides durable protective humoral and cellular immunity against influenza virus infection.

scholarly journals An R848 conjugated influenza virus vaccine elicits robust IgG to hemagglutinin stem in a newborn nonhuman primate model

2020 ◽  
Author(s):  
Elene A Clemens ◽  
Beth C Holbrook ◽  
Masaru Kanekiyo ◽  
Jonathan W Yewdell ◽  
Barney S Graham ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Severe Disease ◽  
Vaccination Strategy ◽  
Influenza Virus Vaccine ◽  
Antibody Responses ◽  
Primate Model ◽  
Rapid Induction ◽  
Neonatal Immune System ◽  
Protective Antibodies

Abstract Eliciting broadly protective antibodies is a critical goal for the development of more effective vaccines against influenza. Optimizing protection is of particular importance in newborns, who are highly vulnerable to severe disease following infection. An effective vaccination strategy for this population must surmount the challenges associated with the neonatal immune system as well as mitigate the inherent immune subdominance of conserved influenza virus epitopes, responses to which can provide broader protection. Here, we show that prime-boost vaccination with a TLR7/8 agonist (R848)-conjugated influenza A virus (IAV) vaccine elicits antibody responses to the highly conserved hemagglutinin stem and promotes rapid induction of virus neutralizing stem-specific antibodies following viral challenge. These findings support the efficacy of R848 as an effective adjuvant for newborns and demonstrate its ability to enhance antibody responses to subdominant antigenic sites in this at-risk population.

scholarly journals Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial

2020 ◽  
Vol 20 (1) ◽  
pp. 80-91 ◽  
Author(s):  
David I Bernstein ◽  
Jeffrey Guptill ◽  
Abdollah Naficy ◽  
Raffael Nachbagauer ◽  
Francesco Berlanda-Scorza ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Influenza Virus ◽  
Virus Vaccine ◽  
Phase 1 ◽  
Influenza Virus Vaccine ◽  
Vaccine Candidates ◽  
Phase 1 Clinical Trial

scholarly journals Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates

Vaccine ◽  
2015 ◽  
Vol 33 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Andrew J. Broadbent ◽  
Celia P. Santos ◽  
Myeisha Paskel ◽  
Yumiko Matsuoka ◽  
Janine Lu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza Virus Vaccine ◽  
Vaccine Candidates ◽  
Cold Adapted

scholarly journals An Inactivated Influenza Virus Vaccine Approach to Targeting the Conserved Hemagglutinin Stalk and M2e Domains

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 117 ◽  
Author(s):  
Weina Sun ◽  
Allen Zheng ◽  
Robert Miller ◽  
Florian Krammer ◽  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Matrix Protein ◽  
Antigenic Site ◽  
Influenza Virus Vaccine ◽  
Antibody Responses ◽  
The Matrix ◽  
Stalk Domain ◽  
Vaccine Approach ◽  
Multiple Strains

Universal influenza virus vaccine candidates that focus on the conserved hemagglutinin (HA) stalk domain and the extracellular domain of the matrix protein 2 (M2e) have been developed to increase the breadth of protection against multiple strains. In this study, we report a novel inactivated influenza virus vaccine approach that combines these two strategies. We inserted a human consensus M2e epitope into the immunodominant antigenic site (Ca2 site) of three different chimeric HAs (cHAs). Sequential immunization with inactivated viruses containing these modified cHAs substantially enhanced M2e antibody responses while simultaneously boosting stalk antibody responses. The combination of additional M2e antibodies with HA stalk antibodies resulted in superior antibody-mediated protection in mice against challenge viruses expressing homologous or heterosubtypic hemagglutinin and neuraminidase compared to vaccination strategies that targeted the HA stalk or M2e epitopes in isolation.

scholarly journals The Long Road to a Universal Influenza Virus Vaccine

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 125
Author(s):  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Vaccine ◽  
Antigenic Drift ◽  
Surface Glycoprotein ◽  
Influenza B ◽  
Virus Infections ◽  
Stalk Domain

Seasonal and pandemic influenza virus infections can cause significant disease worldwide. Current vaccines only provide limited, short-lived protection, and antigenic drift/shift in the hemagglutinin (HA) surface glycoprotein necessitates their annual reformulation and re-administration. To overcome these limitations, universal influenza virus vaccine strategies aim at eliciting broadly protective antibodies to conserved epitopes of the HA. We have developed two approaches. (1) The first is based on “chimeric” HA constructs that retain the conserved stalk domain of the HA and have exotic HA heads. Vaccination and boosting with such constructs successfully redirects the immune system in animals and in humans towards the conserved immune sub-dominant domains of the HA stalks; this results in an antigenic silencing of the HA heads and a protective immune response facilitated by the conserved HA stalks. In mice and ferrets, such a strategy protects the animals against homo-subtypic and hetero-subtypic challenge with influenza A strains as well as against influenza B variants. It is hoped that vaccine constructs expressing three components (i.e., conserved group 1 HA stalks, conserved group 2 HA stalks, and conserved influenza B HA stalks) will be protective against all future seasonal and pandemic strains. (2) The “mosaic” HA approach is based on antigenic silencing of the major immunodominant antigenic sites of the HA heads by only replacing those epitopes with corresponding sequences of exotic avian HAs, yielding “mosaic” HAs. In mice, a prime-boost vaccination regime with inactivated viruses expressing “mosaic” HAs elicited highly cross-reactive antibodies against the stalk domain of the HAs that were capable of eliciting Fc-mediated effector functions in vitro. Extensive trials will be necessary in the future in order to identify the optimal vaccination regime (“chimeric” HA-based versus “mosaic” HA-based) in humans.

scholarly journals Pandemic influenza virus vaccines boost hemagglutinin stalk-specific antibody responses in primed adult and pediatric cohorts

npj Vaccines ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Raffael Nachbagauer ◽  
Bruno Salaun ◽  
Daniel Stadlbauer ◽  
Mohammad A. Behzadi ◽  
Damien Friel ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Pandemic Influenza ◽  
Influenza Virus Vaccine ◽  
Cross Reactivity ◽  
Antigenic Drift ◽  
Lethal Challenge ◽  
Cell Responses ◽  
Adults And Children ◽  
Stalk Domain

AbstractLicensed influenza virus vaccines target the head domain of the hemagglutinin (HA) glycoprotein which undergoes constant antigenic drift. The highly conserved HA stalk domain is an attractive target to increase immunologic breadth required for universal influenza virus vaccines. We tested the hypothesis that immunization with a pandemic influenza virus vaccine boosts pre-existing anti-stalk antibodies. We used chimeric cH6/1, full length H2 and H18 HA antigens in an ELISA to measure anti-stalk antibodies in recipients participating in clinical trials of A/H1N1, A/H5N1 and A/H9N2 vaccines. The vaccines induced high titers of anti-H1 stalk antibodies in adults and children, with higher titers elicited by AS03-adjuvanted vaccines. We also observed cross-reactivity to H2 and H18 HAs. The A/H9N2 vaccine elicited plasmablast and memory B-cell responses. Post-vaccination serum from vaccinees protected mice against lethal challenge with cH6/1N5 and cH5/3N4 viruses. These findings support the concept of a chimeric HA stalk-based universal influenza virus vaccine. clinicaltrials.gov: NCT02415842.

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