Compositions and methods for vaccination against respiratory syncytial virus infection

Inventors

EMPEY, Kerry McGarr • Petrovsky, Nikolai • Marshall, Christopher

Assignees

VAXINE Pty Ltd • University of Pittsburgh • Calder Biosciences Inc

Abstract

Disclosed herein are compositions for vaccination against respiratory syncytial virus (RSV) comprising a RSV F polypeptide stabilized in a prefusion conformation and an inulin adjuvant. Also disclosed herein are methods of vaccinating a subject against a respiratory syncytial virus (RSV) infection comprising administering to the subject an RSV F polypeptide stabilized in a prefusion conformation and an inulin adjuvant. In some embodiments, the subject is a female, and the method can reduce RSV infection in the subject and/or in the offspring of the subject. In some embodiments, the method decreases vaccine-enhanced respiratory disease (VERD) and/or eosinophilia in the subject or offspring of the subject.

Core Innovation

The disclosed invention concerns RSV vaccination compositions and vaccination methods that combine an RSV F polypeptide stabilized in a prefusion conformation with an inulin adjuvant. The RSV F polypeptide comprises SEQ ID NO: 6 or SEQ ID NO: 7 and is described in connection with engineered prefusion-stabilized forms, including trimeric prefusion forms such as DS-Cav1. The inulin adjuvant is described as an inulin material such as delta inulin, with optional CpG in the disclosed discussion of formulations and immune responses.

The problem addressed is vaccine-enhanced respiratory disease (VERD) and associated immunopathology such as eosinophilia. The disclosure attributes an immune-rationale contrast to prefusion RSV F as a neutralizing target and to adjuvant-associated immune skewing, including a description that alum association can be Th2-biased and can relate to VERD. The disclosed approach targets increasing Th1:Th2 immune response ratios following administration, thereby countering the Th2-associated features linked to VERD and eosinophilia.

In maternal vaccination, co-administration of the prefusion-stabilized RSV F polypeptide with the inulin adjuvant is described as increasing Th1:Th2 ratios in dams and offspring, and reducing RSV infection in dams and offspring. The disclosure further states that this strategy decreases VERD and eosinophilia, and is associated with reduced airway inflammation and mucus and reductions in Th2 cytokines such as IL-4 and IL-13 as well as eosinophil-associated cytokines, while increasing Th1-type responses such as IFN-gamma. Supporting results in a mouse maternal vaccination model and a cotton rat model are described, including effects on neutralizing antibodies, lung protection, and cellular immune phenotypes.

Claims Coverage

The document provides two independent claims, each directed to a method of vaccinating a subject against RSV infection with a prefusion-stabilized RSV F polypeptide comprising SEQ ID NO: 6 or SEQ ID NO: 7 together with an inulin adjuvant, where administration increases the Th1:Th2 cell response ratio versus a control. The independent claims differ mainly in how the inulin adjuvant is specified.

Across the independent claims, the core claim coverage centers on vaccinating against RSV by administering a prefusion-stabilized RSV F polypeptide (SEQ ID NO: 6 or SEQ ID NO: 7) together with an inulin adjuvant, where the adjuvant increases a Th1:Th2 cell response ratio versus a control. Dependent claims further cover refinements such as specific inulin selection, vaccine formulation context with a pharmaceutically acceptable carrier, and comparative outcomes including reduced RSV infection, decreased VERD in offspring, and decreased eosinophilia.

Stated Advantages

Documented Applications