Document text
Principal Investigator: Barney Graham
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $3,038,369
Funding agency: National Institute of Allergy and Infectious Diseases
Improvements in vaccines against influenza that increase potency, breadth and durability of protection would improve worldwide ability to combat seasonal changes in influenza viruses (drift) and emergence of new pandemic strains (shift). This study aims to develop new platforms and vaccination strategies against ever-changing influenza viruses. Nanoparticle-, and nucleic acid-based vaccines have been developed against multiple seasonal and pandemic strains of influenza viruses, including H7N9, and H5N1 avian influenza viruses. In addition, studies are ongoing to design and optimize vaccine antigens to present conserved regions of the influenza virus hemagglutinin (HA) in order to develop a vaccine that provides broader universal protection. These include nanoparticle display of the stabilized HA stem trimers of both group 1 and group 2 influenza HA, multiple HAs from different subtypes, as well as a collection of less-conserved HA globular head domains. Testing has been conducted to evaluate candidates, as well as adjuvants to boost immune response, and determine the optimal strategies for immunization. Several candidates showed promising results that lead to further evaluations in animal infection models of influenza viruses. Multiple cycles of iterative structure-based design yielded a structurally stabilized trimer of the HA stem derived from both group 1 and group 2 HA subtypes of influenza A viruses. Several versions of these immunogens were generated and tested its immunogenicity in animal models. Immunization with these nanoparticles induces homologous and heterologous binding antibodies in mice and ferrets with low levels of neutralizing antibodies. Despite this relatively weak neutralizing activity, immunization confers significant protective immunity in animals against heterosubtypic lethal influenza virus challenges. Passive transfer of immunoglobulins from immunized mice provides complete protection against lethal influenza virus challenges in recipient mice, indicating the protection is antibody-mediated. Further studies to determine the immunological basis of protection are underway. A phase 1 clinical trial of a lead candidate of group 1 HA stem nanoparticle vaccine has been initiated. A lead candidate of group 2 HA stem nanoparticle has been manufactured for intended phase 1 clinical trial that is expected to start late 2020. In addition, collaborations to develop gene-based vaccine platforms such as mRNA platform are underway. The first-in-human clinical trial of ferritin nanoparticle vaccine displaying influenza HA has recently been finished. Collaborations to utilize designed nanoparticle to display influenza antigens yield promising immunogenicity and protective efficacy results in animal models. Exploring alternative vaccine antigens such as viral neuraminidase (NA) has made progress in the past year and continues to discover and design desired universal influenza vaccine antigens.
Terms: <Acylneuraminyl hydrolase><Adjuvant><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigens><Assay><Binding><Bioassay><Biologic Assays><Biological Assay><Bird Flu vaccine><Clinical Trials><Collaborations><Collection><Early-Stage Clinical Trials><Evaluation><Ferrets><Ferritin><Genes><Goals><Grippe><H5N1><H5N1 virus><H7N9><Head><Hemagglutinin><Immune Globulins><Immune response><Immunity><Immunization><Immunize><Immunochemical Immunologic><Immunoglobulins><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunostimulation><Infection><Influenza><Influenza A><Influenza A Virus, H5N1 Subtype><Influenza A Virus, H7N9 Subtype><Influenza A virus><Influenza HA><Influenza Hemagglutinin><Influenza Vaccines><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Lead><Mediating><Messenger RNA><Methodology><Mice><Mice Mammals><Modeling><Molecular Interaction><Murine><Mus><N-Acylneuraminate Glycohydrolases><Neuraminidase><Nucleic Acids><Oligosaccharide Sialidase><Orthomyxovirus Type A><Pb element><Phase 1 Clinical Trials><Phase I Clinical Trials><Production><Public Health><Sialidase><Structure><Testing><Time><Type A Influenza><Vaccine Antigen><Vaccines><Viral><avian flu vaccine><avian influenza H5N1><avian influenza H5N1 virus><avian influenza vaccine><base><combat><design><designing><develop a vaccine><development of a vaccine><exo alpha sialidase><first in man><first-in-human><flu HA><flu hemagglutinin><flu infection><flu vaccine><flu virus strain><flu virus vaccine><heavy metal Pb><heavy metal lead><host response><human subject><immunogen><immunogenicity><immunoresponse><improved><influenza infection><influenza virus HA><influenza virus hemagglutinin><influenza virus strain><influenza virus vaccine><influenzavirus><lead candidate><mRNA><model of animal><model organism><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><pandemic><pandemic disease><pandemic flu><pandemic influenza><pandemic strain of influenza><phase I protocol><protective efficacy><seasonal flu><seasonal influenza><stem><tool><universal flu vaccine><universal influenza vaccine><vaccination strategy><vaccine against flu><vaccine against influenza><vaccine candidate><vaccine development><vaccine formulation>