Recombinant modified vaccinia virus ankara (MVA) respiratory syncytial virus (RSV) vaccine
Inventors
Cheminay, Cédric • Steigerwald, Robin • Chaplin, Paul
Assignees
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Publication Number
US-10532094-B2
Publication Date
2020-01-14
Expiration Date
Abstract
Provided herein are recombinant modified vaccinia virus Ankara (MVA) strains as improved vaccines against infection with Respiratory Syncytial Virus (RSV virus) and to related products, methods and uses. Specifically, provided herein are genetically engineered recombinant MVA vectors comprising at least one nucleotide sequence encoding an antigenic determinant of an RSV membrane glycoprotein and at least one nucleotide sequence encoding an antigenic determinant of an RSV nucleocapsid protein. Also provided herein are products, methods and uses thereof, e.g., suitable to affect an immune response in a subject, or suitable to diagnose an RSV infection, as well as to determine whether a subject is at risk of recurrent RSV infection.
Core Innovation
The invention relates to recombinant modified vaccinia virus Ankara (MVA) vaccines for RSV, where the recombinant MVA comprises at least one nucleotide sequence encoding an antigenic determinant of an RSV membrane glycoprotein F, including a nucleotide sequence encoding SEQ ID NO:6. The recombinant MVA is administered to a subject to treat or prevent an RSV infection, and is provided in a single dose in the stated method.
The disclosed constructs further include RSV nucleocapsid antigenic determinants, including at least one of N and/or M2, with constructs that include nucleocapsid antigens reported to elicit stronger RSV-specific CD8+ T-cell responses. The summary states that these nucleocapsid-containing constructs improve lung viral-load reduction and provide near-sterilizing immunity, and it highlights an improvement particularly after intranasal administration with IgA secretion.
The document also contrasts the disclosed MVA RSV approach with FI-RSV and reports improved safety characteristics. It states reduced or undetected Th2-associated IL-4/IL-5 and enhanced disease markers are observed relative to FI-RSV, while the MVA platform is characterized by background/attenuation properties and definitions for antigenic determinants and sterile immunity.
Claims Coverage
The independent claim provides a single-dose treatment/prevention method for RSV using a recombinant MVA that encodes a specified RSV F antigenic determinant (SEQ ID NO:6). Dependent claims add inventive features by introducing additional RSV nucleocapsid antigenic determinants (M2 and/or N), constraining the encoding architecture (single open reading frame separated by a self-cleaving protease domain), and specifying a self-cleaving protease source (2A fragment from Foot-and-Mouth Disease Virus).
Single-dose recombinant MVA encoding RSV F SEQ ID NO:6
Administering in a single dose a recombinant modified vaccinia virus Ankara (MVA) comprising at least one nucleotide sequence encoding an antigenic determinant of an RSV membrane glycoprotein F comprising a nucleotide sequence encoding SEQ ID NO:6 to treat or prevent RSV in a subject.
Added RSV nucleocapsid determinant M2 matrix protein
Providing a recombinant MVA that additionally contains a nucleotide sequence encoding the RSV nucleocapsid antigenic determinant M2 matrix protein.
Single open reading frame with self-cleavage separation for N and M2
Encoding both the antigenic determinant of the RSV N nucleocapsid and the antigenic determinant of the RSV M2 matrix protein within a single open reading frame separated by a self-cleavage protease domain.
2A self-cleaving protease domain from Foot and Mouth Disease Virus
Using, for the self-cleaving protease domain, the 2A protease fragment sequence derived from Foot and Mouth Disease Virus.
Overall, the claim set centers on a single-dose recombinant MVA encoding the RSV F antigenic determinant SEQ ID NO:6, with further inventive coverage achieved by adding RSV nucleocapsid determinants (M2 and/or N) and by defining an encoding architecture that links N and M2 in a single open reading frame via a self-cleaving protease domain, including a Foot-and-Mouth Disease Virus 2A protease fragment.
Stated Advantages
Stronger RSV-specific CD8+ T-cell responses are elicited by nucleocapsid-containing constructs.
Improved lung viral-load reduction is reported.
Near-sterilizing immunity is reported, particularly after intranasal administration with IgA secretion.
Improved safety versus FI-RSV is reported, including reduced or undetected Th2-associated IL-4/IL-5 and enhanced disease markers relative to FI-RSV.
Documented Applications
Treating or preventing an RSV in a subject using a recombinant MVA administered as a single dose.
Diagnosing RSV infection and determining risk of recurrent infection or lack of sterile immunity using RT-qPCR-based detection concepts as described in the document summary.
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