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Principal Investigator: Ralph S Baric
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2020
Award: $1,088,512
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Vaccination represents one of the most effective public health measures for protecting at risk populations from
emerging pathogens. However, FDA approved vaccines are lacking for the vast majority of emerging
pathogens, and therefore new vaccines and vaccination strategies are needed to protect susceptible
populations from viruses such as MERS-CoV, Ebola virus (EBOV), chikungunya virus (CHIKV) and Zika virus
(ZIKV). Adjuvants represent an essential component of modern vaccinology, since recombinant protein or virus
like particle (VLP) based vaccines are poorly immunogenic in the absence of adjuvant-mediated innate
immune stimulation. In fact, a growing body of evidence suggests that combinations of adjuvants that stimulate
multiple innate immune pathways are capable of eliciting broadly protective, long-lived immune responses
similar to those stimulated by natural infections. However, to date, only a small number of adjuvants have been
approved for human use, and we have a poor understanding of their mechanisms of action or the host
susceptibility alleles that regulate their performance. This lack of knowledge impedes our ability to develop new
adjuvants, while also limiting our capacity to rationally combine different adjuvants to develop broadly
protective vaccine formulations. Furthermore, since the innate immune pathways targeted by both FDA
approved and experimental adjuvants are highly polymorphic, it is likely that host genetic variation will
significantly impact both the efficacy and safety of individual adjuvants across diverse populations. Therefore,
the development of safe and effective adjuvants and vaccine formulations requires an understanding of how
specific adjuvants/vaccines perform in diverse populations. Importantly, we can also take advantage of this
diversity in responses to identify the polymorphic genes and genetic networks that regulate the response to
specific adjuvants, and then use that information to rationally select adjuvant combinations designed to safely
elicit durably protective immunity in at risk populations. Therefore, our Program, which takes advantage of our
research team's expertise in adjuvant development, vaccinology, and complex trait genetics, proposes to use
advanced Systems Vaccinology and Genetics approaches to define the polymorphic genes/gene networks that
regulate the response to specific adjuvants. We will then use this information to identify specific adjuvants or
adjuvant combinations that will elicit protective immunity in populations who are at increased risk of vaccine
failure. This program will results in several high impact deliverables, including: 1) broadly efficacious pre-IND
vaccines for several high consequence emerging pathogens, including EBOV, influenza, MERS-CoV, and
ZIKV, 2) novel adjuvant formulations that are designed to safely elicit durable protective immunity in genetically
diverse populations, including individuals who are at risk of vaccine failure 3) improved animal models for
testing vaccine safety and efficacy, and 4) general knowledge of adjuvant immune regulatory genes that will
inform the development of new adjuvants with novel mechanisms of action and improved efficacy/safety
profiles.
Terms: <2019 novel coronavirus><2019-nCoV><21+ years old><Adjuvant><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Antibody Response><Assay><BSL-3 facility><BSL3 facility><Bioassay><Biologic Assays><Biological Assay><Blood Serum><CHIKV><Chikungunya virus><Communicable Diseases><Complex Genetic Trait><Consultations><Data Set><Dataset><Development><EBOV><Ebola virus><Equipment><Evaluation><FDA approved><Failure><Formulation><Future><Genes><Genetic><Genetic Diversity><Genetic Variation><Glycoproteins><Goals><Human><Human Volunteers><Immune response><Immunity><Immunization><Immunoactivators><Immunoadjuvants><Immunologic Adjuvants><Immunologic Sensitization><Immunologic Stimulation><Immunological Adjuvant><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunopotentiators><Immunostimulants><Immunostimulation><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza Virus><Knowledge><Laboratories><Lentivirinae><Lentivirus><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Measures><Mediating><Messenger RNA><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modern Man><Modernization><Performance><Phase><Population><Population Heterogeneity><Populations at Risk><Predisposition gene><Public Health><Recombinant Proteins><Regulator Genes><Research><Risk><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Safety><Sampling><Serum><Severe acute respiratory syndrome coronavirus 2><Subfamily lentivirinae><Susceptibility Gene><Transcriptional Regulatory Elements><Universities><Vaccinated><Vaccination><Vaccines><Virus><Virus-Lenti><Virus-like particle><Wuhan coronavirus><ZIKV><Zika Virus><adulthood><advanced system><base><biosafety level 3 facility><design><designing><develop a vaccine><development of a vaccine><developmental><diverse populations><ebolavirus><genetic approach><genetic strategy><heterogeneous population><host response><immune adjuvant><immunogenic><immunoresponse><improved><influenzavirus><innate immune pathways><mRNA><model of animal><model organism><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><pathogen><population diversity><predisposing gene><programs><recombinant virus><regulatory gene><respiratory virus><response><susceptibility allele><susceptibility locus><susceptibility variant><trans acting element><vaccination strategy><vaccination study><vaccination trial><vaccine development><vaccine efficacy><vaccine evaluation><vaccine formulation><vaccine safety><vaccine screening><vaccine study><vaccine testing><vaccine trial><vaccinology><virus-like nanoparticles><viruslike particle><zikav>