While a universal influenza vaccine, providing life-long protective immunity against all current and future drifted and shifted subtypes of influenza virus after 2 or 3 doses, would be a game-changing solution to reducing the global burden of influenza and its associated morbidity and mortality, other approaches to solving this problem are urgently needed. There is still much to learn about immune responses to respiratory pathogens, such as influenza virus, and vaccine approaches that drive life-long immunity to respiratory viruses have yet to be demonstrated in humans. Therefore, we propose to develop a broadly protective influenza booster vaccine that can be administered, either seasonally or during pandemics, to individuals with prior exposures to either natural infection or seasonal vaccination. Given the non-uniform influenza immune history in a given population of individuals, it is likely that booster vaccines will need to be customized either at the individual or regional level, based on local influenza virus epidemiology or vaccine uptake. Nucleic acid vaccine platforms provide the ideal framework for such personalized-medicine approaches, due to the flexibility of development, as typified by the ongoing COVID-19 pandemic. As proof-of-concept, here we propose to apply our clinical-stage replicating RNA vaccine platform to develop a booster vaccine targeting the conserved hemagglutinin stem and nucleoprotein of group 1 influenza viruses and evaluating immunogenicity and efficacy against heterologous group 1 influenza virus infections in mouse and ferret models of pre-existing influenza virus immunity. These data will inform the feasibility of such an approach and characterize what types of pre-existing immunity, in terms of anti-hemagglutinin antibody specificity and magnitude, are required for booster vaccine efficacy. As these pre-existing antibody criteria are easily assessed in humans, it is likely that a personalized approach to influenza booster vaccination is achievable.
Public Health Relevance Statement: Project Narrative The evolutionary landscape of influenza virus is constantly in flux with immune-escape mutations accumulating in drifted variants and the occasional spillover of zoonotic subtypes leading to global pandemics like the current COVID-19 pandemic. This complicates vaccine development with the current solution requiring annual updates to inactivated virus vaccines. Here we propose to develop a fixed-design RNA vaccine that can be administered as a booster immunization in influenza virus pre-immune individuals and characterize the specificity and magnitude of the pre-existing anti-hemagglutinin antibody responses that contribute to vaccine efficacy. These data will inform the design of other versions of the vaccine to match the types of pre-existing immunity present at the population level.
Project Terms: Antibodies; Antibody Specificity; Epitopes; Antigenic Determinants; Binding Determinants; Antigens; immunogen; Automobile Driving; driving; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Birds; Aves; Avian; Cessation of life; Death; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Epidemiology; epidemiologic; epidemiological; Ferrets; Future; Hemagglutinin; Recording of previous events; History; Human; Modern Man; Immunity; Secondary Immunization; Booster Immunization; booster vaccination; Infection; Influenza; Grippe; influenza virus vaccine; Influenza Vaccines; flu vaccine; flu virus vaccine; vaccine against flu; vaccine against influenza; Lead; Pb element; heavy metal Pb; heavy metal lead; Learning; Lipids; Maintenance; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nucleoproteins; Problem Solving; Response RT; Response Time; psychomotor reaction time; Reaction Time; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; RNA; social role; Role; Safety; Specificity; Technology; Time; Vaccination; Influenza vaccination; Flu vaccination; Influenza immunization; Prophylactic vaccination against influenza; flu immunisation; influenza virus vaccination; vaccination against influenza; Vaccines; Inactivated Vaccines; Inactivated Virus Vaccine; Killed Vaccines; Virus; Population Heterogeneity; diverse populations; heterogeneous population; population diversity; Custom; Nonstructural Protein; Non-structural Protein; base; improved; Clinical; Phase; Variant; Variation; Individual; non-human primate; nonhuman primate; Immunological response; host response; immune system response; immunoresponse; Immune response; Exposure to; Life; Adopted; Immunes; Immune; Event; Clinic; antibody titering; Antibody titer measurement; neutralizing antibody; interest; respiratory virus; develop a vaccine; develop vaccines; development of a vaccine; vaccine development; nucleic acid-based vaccine; Nucleic Acid Vaccines; Speed; respiratory infection virus; Modeling; response; RNA amplification; Influenza A virus; Influenza A; Influenza Viruses Type A; Influenzavirus A; Orthomyxovirus Type A; Type A Influenza; Influenza B Virus; Influenza B; Influenza Viruses Type B; Orthomyxoviruses Type B; Influenza Virus; influenzavirus; Dose; Data; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Update; Process; Development; developmental; Influenza A Virus, H5N1 Subtype; H5N1; H5N1 virus; avian influenza H5N1; avian influenza H5N1 virus; Influenza A Virus, H1N1 Subtype; H1N1; H1N1 Virus; pandemic disease; pandemic; pandemic influenza; flu virus pandemic; influenza virus pandemic; pandemic flu; pandemic strain of influenza; vaccine efficacy; immunogenicity; influenza virus strain; flu serotype; flu strain; flu subtype; flu viral strain; flu virus strain; influenza serotype; influenza strain; influenza subtype; influenza viral strain; design; designing; nanoparticle; nano particle; nano-sized particle; nanosized particle; manufacturing process; Population; Coupled; booster vaccine; booster dose; booster shot; stem; protective efficacy; public trust; pandemic preparedness; flexibility; flexible; T cell response; personalized medicine; personalization of treatment; personalized therapy; personalized treatment; Antibody Response; personalized approach; Personalized medical approach; individualized approach; precision approach; tailored approach; Formulation; universal influenza vaccine; universal flu vaccine; universal influenza virus vaccine; universal vaccine against flu; universal vaccine against influenza; antigen-specific T cells; RNA vaccine; RNA-based vaccine; mRNA vaccine; mRNA-based vaccine; COVID-19; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19; COVID-19 pandemic; COVID crisis; COVID epidemic; COVID pandemic; COVID-19 crisis; COVID-19 epidemic; COVID-19 global health crisis; COVID-19 global pandemic; COVID-19 health crisis; COVID-19 public health crisis; COVID19 crisis; COVID19 epidemic; COVID19 global health crisis; COVID19 global pandemic; COVID19 health crisis; COVID19 pandemic; COVID19 public health crisis; SARS-CoV-2 epidemic; SARS-CoV-2 global health crisis; SARS-CoV-2 global pandemic; SARS-CoV-2 pandemic; SARS-CoV2 epidemic; SARS-CoV2 pandemic; SARS-coronavirus-2 epidemic; SARS-coronavirus-2 pandemic; Severe Acute Respiratory Syndrome CoV 2 epidemic; Severe Acute Respiratory Syndrome CoV 2 pandemic; Severe acute respiratory syndrome coronavirus 2 epidemic; Severe acute respiratory syndrome coronavirus 2 pandemic; corona virus disease 2019 epidemic; corona virus disease 2019 pandemic; coronavirus disease 2019 crisis; coronavirus disease 2019 epidemic; coronavirus disease 2019 global health crisis; coronavirus disease 2019 global pandemic; coronavirus disease 2019 health crisis; coronavirus disease 2019 pandemic; coronavirus disease 2019 public health crisis; coronavirus disease crisis; coronavirus disease epidemic; coronavirus disease pandemic; coronavirus disease-19 global pandemic; coronavirus disease-19 pandemic; severe acute respiratory syndrome coronavirus 2 global health crisis; severe acute respiratory syndrome coronavirus 2 global pandemic; influenza infection; flu infection; flu virus infection; infected with flu; infected with flu virus; infected with influenza; infected with influenza virus; influenza virus infection; vaccine distribution; deploy vaccines; distribute vaccines; vaccine deployment; vaccine roll-out; vaccine rollout; vaccine acceptance; accept vaccination; accept vaccine; vaccination acceptability; vaccination acceptance; vaccination confidence; vaccination uptake; vaccination willingness; vaccine acceptability; vaccine confidence; vaccine uptake; vaccine willingness; respiratory pathogen; vaccination outcome; outcome following vaccination; outcome following vaccine; result following vaccination; result following vaccine; vaccination result; vaccine outcome; vaccine result; zoonotic spillover; Vaccinee; vaccinated individual; vaccinated participant; vaccinated patient; vaccinated person; vaccinated subject; vaccine platform
