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Principal Investigator: Fredrick Heath Damron
Organization: WEST VIRGINIA UNIVERSITY
Fiscal Year: 2023
Award: $841,516
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Pertussis is a respiratory disease caused by the obligate human pathogen Bordetella pertussis. Two generations
of pertussis vaccines have been developed and licensed: whole cell pertussis (DTP) and acellular pertussis
(DTaP/Tdap). Pertussis was thought to be a disease of the past but has recently re-emerged. The number of
cases of pertussis in 2012 was 48-fold over the lowest year on record (1976), which was also a 50-year high.
While the increase of pertussis has multiple potential reasons, epidemiological studies clearly suggest that the
duration of immunity of both DTaP and Tdap wanes quickly each year after a booster, and regresses to non-
protective levels in humans. Each dose of whole cell vaccine contains hundreds of antigens, of which numerous
are immunodominant. Whole cell vaccines also induce T helper 1 and 17 (Th1/Th17) cellular immune responses.
On the other hand, acellular vaccines focus Th2-mediated humoral responses exclusively to pertussis toxin,
filamentous hemagglutinin, pertactin, and fimbriae. We aim to develop a vaccine that would induce Th1
responses and include a greater number of antigens than acellular vaccines. mRNA vaccines provide a platform
that can be easily modified for the targeted antigen/pathogen and they induce Th1 responses. mRNA vaccines
encode the antigen, which once expressed, results in immunity mediated by Tfh responses. We used an mRNA
platform to screen antigens of B. pertussis and identified a protective multivalent formulation (mRNA-DTP10; 8
pertussis antigens with diphtheria and tetanus antigens) in a murine challenge model. In this project, we will
further extend our studies and investigate the correlates of protection of the mRNA-pertussis vaccine in the
murine model with longevity studies and examine DTaP prime / mRNA-boost effects (SA1). Next, we will utilize
the coughing rat model of pertussis with whole body plethysmography to compare mRNA, whole cell, and
acellular immunity for protection against cough (SA2). We will study the mRNA pertussis vaccine in
immunogenicity and challenge experiments using the baboon model of pertussis (SA3). Lastly, we will aim to
develop a suite of assays to phenotype antibodies produced by mRNA pertussis vaccines and bridge each of
the pertussis models, which will facilitate clinical development. Through these studies, we aim to characterize
the mRNA-pertussis immunity and develop a clearer understanding of how this vaccine platform can be used to
overcome “complex or difficult” pathogens that employ numerous virulence factors. We expect the data acquired
in each aim will result in a deeper understanding of pertussis immunity as well as illuminate the mRNA platform
for bacterial vaccines.
Terms: <0-11 years old><11 year old><11 years of age><21+ years old><Ab response><Ab-mediated immunity><Ab-mediated protection><Acellular Vaccines><Adjuvant><Adolescent><Adolescent Youth><Adult><Adult Human><Airway infections><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigen Targeting><Antigens><Assay><Avidity><B pertussis><B pertussis infection><B. pertussis><B. pertussis infection><B. pertussis toxin><Baboons><Bacterial Vaccines><Bacterin><Belgium><Bioassay><Biologic Assays><Biological Assay><Bordetella><Bordetella pertussis><Bordetella pertussis infection><Bordetella pertussis toxin><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 pandemic><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><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Child><Child Youth><Children (0-21)><Clinical Trials><Collaborations><Common Rat Strains><Complex><Coughing><DTaP Vaccines><Data><Development><Diphtheria><Diphtheria-Tetanus-acellular Pertussis Vaccines><Disease><Disorder><Dose><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Evaluation><Formulation><Generations><Goals><H Pertussis><H. Pertussis><Haemophilus pertussis><Health><Hemagglutinin><Histamine-Sensitizing Factor><Human><IAP Pertussis Toxin><Immune memory><Immune response><Immunity><Immunize><Immunochemical Immunologic><Immunologic><Immunologic Memory><Immunological><Immunological Memory><Immunological response><Immunologically><Immunologics><Incidence><Infant><Inflammation><International><Intramuscular><Islet-Activating Protein><Laboratories><Lead><Length of Life><Leukocytosis><Licensing><Life><Longevity><Lymphocytosis-Promoting Factor><Manufacturer><Mediating><Membrane><Messenger RNA><Mice><Mice Mammals><Mission><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Murine><Mus><NIH><National Institutes of Health><Papio><Papios><Pathogenicity Factors><Pb element><Pertussigen><Pertussis><Pertussis Toxin><Pertussis Vaccine><Phenotype><Population><Pre-Clinical Model><Preclinical Models><Production><Protein Subunits><Proteins><Public Health><Pulmonary Body System><Pulmonary Organ System><RNA vaccine><RNA-based vaccine><Rat><Rats Mammals><Rattus><Research><Respiratory Disease><Respiratory Infections><Respiratory System><Respiratory System Disease><Respiratory System Disorder><Respiratory Tract Infections><Respiratory Tracts><Respiratory physiology><Respiratory tract structure><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><Savanna Baboons><Schedule><Scientist><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><Speed><Subunit Vaccines><Surrogate End Points><Surrogate Endpoint><Technology><Tetanus><Toxin><United States National Institutes of Health><Vaccine Production><Vaccines><Virulence Factors><Whole Body Plethysmography><Whole Cell Vaccine><Whooping Cough><adulthood><age 11 years><age group><anamnestic reaction><antibody biosynthesis><antibody-mediated immunity><antigen binding><antigen bound><booster dose><booster shot><booster vaccine><clinical development><clinical efficacy><clinical predictors><clostridial tetanus><conference><conformation><conformational><conformational state><conformationally><conformations><convention><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><develop a vaccine><develop vaccines><development of a vaccine><developmental><efficacy study><eleven year old><eleven years of age><epidemiologic investigation><epidemiology study><experiment><experimental research><experimental study><experiments><flexibility><flexible><heavy metal Pb><heavy metal lead><host response><human pathogen><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><in vivo><infected with B pertussis><infected with B. pertussis><infected with Burkholderia pertussis><interest><juvenile><juvenile human><kids><life span><lifespan><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-based vaccine><membrane structure><mouse model><murine model><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><pathogen><pertactin><pressure><produce vaccines><protein expression><protein purification><respiratory function><response><screening><screenings><secondary immune response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><study population><summit><symposia><symposium><technology platform><technology system><vaccine candidate><vaccine development><vaccine platform><vaccine strategy><youngster>