Compositions and methods for dengue virus chimeric constructs in vaccines

Inventors

Stinchcomb, Dan T. • Kinney, Claire • Kinney, Richard M • Livengood, Jill A

Assignees

Takeda Vaccines Inc • US Department of Health and Human Services

Abstract

Embodiments herein report compositions, uses and manufacturing of dengue virus constructs and live attenuated dengue viruses. Some embodiments concern a composition that includes, but is not limited to, a tetravalent dengue virus composition. In certain embodiments, compositions can include constructs of one or more serotypes of dengue virus, such as dengue-1 (DEN-1) virus, dengue-2 (DEN-2) virus, dengue-3 (DEN-3) or dengue-4 (DEN-4) virus constructs. In other embodiments, constructs disclosed herein can be combined in a composition to generate a vaccine against more one or more dengue virus constructs that may or may not be subsequently passaged in mammalian cells.

Core Innovation

Embodiments herein report compositions, methods, uses and manufacturing procedures for dengue virus constructs and vaccine compositions thereof. Some embodiments concern compositions that include chimeric flavivirus virus constructs used in vaccine compositions, alone or combined with other constructs. These compositions can include constructs of one or more serotypes of dengue virus, including dengue-1 (DEN-1), dengue-2 (DEN-2), dengue-3 (DEN-3), and dengue-4 (DEN-4) viruses.

The invention addresses the problem of dengue virus infection, which causes dengue fever and, in severe cases, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), with no effective vaccine currently available. The four dengue virus serotypes cause significant morbidity and mortality worldwide, infecting 50-100 million people annually and threatening 3.5 billion individuals. Infection with one dengue serotype does not protect against others but increases risk of severe disease upon secondary infection with a different serotype. Mosquito control has been insufficient to prevent outbreaks, highlighting the need for an effective vaccine.

Embodiments include compositions comprising live, attenuated dengue viruses and chimeric dengue virus constructs with an attenuated dengue virus backbone incorporating structural genes from one or more dengue virus serotypes. Constructs can include modified DEN-2 backbones such as PDK-53 with varying passages in cell culture that maintain attenuation and safety while increasing production or enhancing immune response. Immunogenic compositions induce immune responses to one or more dengue virus serotypes. Embodiments also disclose manufacturing strategies enhancing safety and genetic stability of vaccine candidates through serial passages in cell cultures, use of specific mutations that maintain attenuation while improving vaccine characteristics, and combining multiple chimeric constructs for multivalent vaccines.

Claims Coverage

The patent claims focus on several inventive features related to dengue virus polypeptides, pharmaceutical compositions, kits, and methods for inducing immune responses using these dengue virus constructs.

The claims cover specific dengue virus polypeptides, compositions including pharmaceutical formulations and kits, compositions comprising mono- and multivalent dengue virus constructs, and methods for inducing immune responses to one or more dengue virus serotypes, emphasizing the use of attenuated dengue-2 virus backbones and chimeric constructs of dengue serotypes.

Stated Advantages

Documented Applications