dsRNAs as influenza virus vaccine adjuvants or immuno-stimulants
Inventors
Carter, William A. • Strayer, David
Assignees
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Publication Number
US-7943147-B2
Publication Date
2011-05-17
Expiration Date
Abstract
Vaccine protection against acute or chronic viral infection is facilitated by using as an adjuvant or immuno-stimulant, a dsRNA together with an anti-influenza vaccine.
Core Innovation
The document describes synthetic configured double-stranded RNA (dsRNA) adjuvants used with anti-influenza vaccines to enhance protection against acute and chronic viral infection. In particular, it describes AMPLIGEN® and mismatched dsRNA analogs such as rI·r(C12,U)n, where rI is polyriboinosinic acid and r(C12,U) is a polyribocytidylic acid sequence containing unpaired uracils (U).
The core approach is coordinated administration of a seasonal influenza vaccine with a mismatched dsRNA, including co-administration and administration of a composition comprising the seasonal influenza vaccine and mismatched dsRNA. The document links the mismatched dsRNA to immune stimulation through innate antiviral pathways, including 2′,5′-oligoadenylate synthetase/RNase L and protein kinase, with activation of dendritic cells and interferon secretion, resulting in enhanced mucosal and systemic immune responses.
The document reports immune and protection outcomes including increased mucosal IgA, reduced nasal virus titers following challenge, and cross-protection across H5N1 variants. It also describes antigen-sparing effects, including that dsRNA such as poly(I:C) or dsRNA enables reduced vaccine dose with similar survival outcomes, and an extension to a primate model showing tolerability and protection from H5N1 disease following vaccination plus AMPLIGEN®.
Claims Coverage
The independent claim covers a method that enhances the immune response against a H5N1 avian influenza infection by using a specific mismatched dsRNA, rI·r(C12,U)n, as an adjuvant/immuno-stimulant together with a seasonal influenza vaccine. The coverage comprises 1 independent inventive method feature with refinements in dependent claims.
Seasonal influenza vaccine plus mismatched dsRNA adjuvant for enhanced H5N1 immune response
A method of enhancing the immune response against a H5N1 avian influenza infection, comprising co-administration of a seasonal influenza vaccine and a mismatched dsRNA, or administration of a composition comprising a seasonal influenza vaccine and a mismatched dsRNA; wherein the mismatched dsRNA is rI·r(C12,U)n with rI being polyriboinosinic acid and r(C12,U) being a polyribocytidylic acid sequence containing unpaired uracils; wherein the mismatched dsRNA acts as an adjuvant or immuno-stimulant; and wherein the method results in an enhanced immune response against an H5N1 avian influenza infection compared to administration of the seasonal influenza vaccine without the mismatched dsRNA.
Complexing mismatched dsRNA with an RNA-stabilizing polymer
The method further comprises complexing the mismatched dsRNA with an RNA-stabilizing polymer.
Using lysine or cellulose as the stabilizing polymer
The method includes using a stabilizing polymer selected from lysine or cellulose.
Intranasal administration of both vaccine and mismatched dsRNA
The seasonal influenza vaccine is administered intranasally and the mismatched dsRNA is administered intranasally.
Overall, the claims coverage centers on enhancing H5N1 immune responses by administering a seasonal influenza vaccine together with a defined mismatched dsRNA adjuvant rI·r(C12,U)n, with dependent refinements directed to dsRNA complexing with an RNA-stabilizing polymer (lysine or cellulose) and to intranasal administration of both components.
Stated Advantages
Enhanced immune response against an H5N1 avian influenza infection compared to administration of the seasonal influenza vaccine without the mismatched dsRNA.
Increased mucosal IgA and reduced nasal virus titers after challenge, including cross-protection across H5N1 variants.
Antigen-sparing effects, including reduced vaccine dose with similar survival outcomes.
Tolerability and protection from H5N1 disease in a primate model following vaccination plus AMPLIGEN®.
Documented Applications
Use of AMPLIGEN® and mismatched dsRNA such as rI·r(C12,U)n as adjuvants/immuno-stimulants with anti-influenza (seasonal) vaccines to enhance protection against H5N1 avian influenza infection, including challenge studies.
Application to protection across H5N1 variants involving antigenic drift and antigenic shift.
Use in a primate (macaque) model to show tolerability and protection from H5N1 disease following vaccination plus AMPLIGEN®.
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