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Principal Investigator: BRUCE Steven KLEIN
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $285,674
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT: Pre-existing T cell responses have been correlated with decreased disease severity and positive
clinical outcomes during the influenza pandemic of 2009 and the recent COVID-19 pandemic. Therefore,
diversifying T cell responses, particularly targeting conserved internal viral proteins such as the influenza virus
nucleoprotein (NP), could confer protection against both epidemic and pandemic strains of influenza A virus
(IAV). We have designed a mosaic nucleoprotein (MNP) composed of 9-mer epitopes derived from the complete
set of 7,422 NP sequences from human, swine, and avian IAVs. We have strong evidence that a vaccine
formulation consisting of MNP and a combination adjuvant (Adjuplex + TLR-4 agonist glucopyranosyl lipid A
[GLA]) elicits T cell responses that protect against epidemic and pandemic strains of influenza A virus in mice.
Avian influenza viruses have decimated poultry in the US and many parts of the world, and most concerningly,
these viruses have spilled over to infect multiple mammalian species, including cats and cows. Most notably, the
H5N1 avian influenza virus in cows is rapidly spreading to multiple states in the US. Currently, there is serious
concern about the possibility of the rapidly spreading avian influenza virus in cows mutating to gain the potential
to infect humans, cause severe disease, and efficiently spread by airborne transmission. Therefore, it is critical
to develop vaccine strategies to protect humans, and contain avian influenza virus infection and transmission in
cows. Significantly, the MNP we generated exhibits close homology to the NP of the H5N1 virus affecting dairy
cows in the ongoing outbreak. We hypothesize that the MNP will be immunogenic and that T cell responses
elicited by the MNP-based vaccine will provide effective protection against the currently circulating strains of
avian influenza virus isolated from cows.
The aims of this administrative supplement are: (1) Test the hypothesis that mosaic nucleoprotein (MNP)
formulated in the combination adjuvants (Adjuplex+GLA or Adjuplex+CdN) will elicit diverse antibody and T cell
responses in circulation and mammary gland of ferrets and cows; (2) Test the hypothesis that mosaic
nucleoprotein (MNP) formulated in the combination adjuvants (Adjuplex+GLA or Adjuplex+CdN) will protect
ferrets against H5N1 in lungs, upper respiratory tract, and the mammary gland. The proposed studies will have
implications in the development of effective vaccines to protect humans against avian influenza, break the
transmission cycle in cows and mitigate spillover into humans.
Terms: <Adjuvant><Administrative Supplement><Affect><Agonist><Animals><Antibodies><Antigenic Determinants><Avian Influenza><Avian Influenza A Virus><Avian Influenza Virus><Avian Orthomyxovirus Type A><Binding Determinants><Bird Flu><Bird Flu vaccine><Bovine Species><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cats><Cats Mammals><Cattle><Circulation><Clinical><Dairying><Development><Disease><Disease Outbreaks><Disorder><Domestic Cats><Domestic Fowls><Epidemic><Epitopes><Exhibits><Feline Species><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><Ferrets><Fowl Pest><Fowl Plague><Fowl Plague Virus><H5N1><H5N1 virus><Human><Immunity><Influenza A><Influenza A H5N1><Influenza A Virus, H5N1 Subtype><Influenza A virus><Influenza Vaccines><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Lipid A><Lung><Lung Respiratory System><Mammary gland><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutate><Myxovirus pestis galli><Nucleoproteins><Orthomyxovirus Type A><Outbreaks><Outcome><Poultry><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 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><Severity of illness><T cell response><Testing><Transmission><Type A Influenza><Upper respiratory tract><Vaccine Antigen><Vaccines><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><avian flu><avian flu vaccine><avian flu virus><avian influenza H5N1><avian influenza H5N1 virus><avian influenza vaccine><avian strains of influenza><bird flu virus><bovid><bovine><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><cow><cross reactivity><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease severity><flu infection><flu vaccine><flu virus infection><flu virus pandemic><flu virus vaccine><fungal pathogen><fungi pathogen><immunogenic><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza in birds><influenza infection><influenza virus infection><influenza virus pandemic><influenza virus vaccine><influenzavirus><mosaic><novel><pandemic flu><pandemic influenza><pandemic strain of influenza><pathogenic fungus><pathogenic virus><porcine influenza><programs><pulmonary><respiratory><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><swine influenza><transmission process><upper airway tract><vaccine against avian influenza><vaccine against flu><vaccine against influenza><vaccine development><vaccine formulation><vaccine strategy><viral pathogen><viral transmission><virus pathogen><virus protein><virus transmission>