Development of Mutations Useful for Attenuating Dengue Viruses and Chimeric Dengue Viruses


Although flaviviruses cause a great deal of human suffering and economic loss, there is a shortage of effective vaccines. This invention relates to dengue virus mutations that may contribute to the development of improved dengue vaccines. Site directed and random mutagenesis techniques were used to introduce mutations into the dengue virus genome and to assemble a collection of useful mutations for incorporation in recombinant live attenuated dengue virus vaccines. The resulting mutant viruses were screened for several valuable phenotypes, including temperature sensitivity in Vero cells or human liver cells, host cell restriction in mosquito cells or human liver cells, host cell adaptation for improved replication in Vero cells, and attenuation in mice or in mosquitoes. The genetic basis for each observed phenotype was determined by direct sequence analysis of the genome of the mutant virus. Mutations identified through these sequencing efforts have been further evaluated by re-introduction of the identified mutations, singly, or in combination, into recombinant dengue virus and characterization of the resulting recombinant virus for phenotypes. In this manner, a menu of attenuating and growth promoting mutations was developed that is useful in fine-tuning the attenuation and growth characteristics of dengue virus vaccine candidates. The mutations promoting growth in Vero cells have usefulness for the production of live or inactivated dengue virus vaccines.

Inventors:

Stephen Whitehead (NIAID)  ➽ more inventions...

Brian Murphy (NIAID)  ➽ more inventions...

Kathryn Hanley (NIAID)  ➽ more inventions...

Joseph Blaney (NIAID)  ➽ more inventions...


Intellectual Property:
US Pat: 8,039,003 issued 2011-10-18
US Pat: 7,560,118 issued 2009-07-14
PCT Pat: 7,226,602 issued 2007-06-05
US Pat: 8,632,782 issued 2014-01-21
US Pat: RE045053 issued 2014-07-29
US Pat: RE45016 issued 2014-07-15
US Pat: RE45,123 issued 2014-09-09
US Pat: 9,707,287 issued 2017-07-18
US Pat: 10,500,264 issued 2019-12-10
US Application No. 14/096,424 filed on 2013-12-04
US Application No. 15/650,482 filed on 2017-07-14

Collaboration Opportunity:

The National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or bm25f@nih.gov for more information.


Licensing Contact:
Peter Soukas, J.D.
Email: peter.soukas@nih.gov
Phone: 301-496-2644

OTT Reference No: E-120-2001-0
Updated: Feb 28, 2011