Oregon Health & Science University

Triad National Security, LLC

Vir Biotechnology, Inc.

Klaus Frueh

Louis Picker

Scott G Hansen

Jay A Nelson

Daniel Malouli

Bette T M Korber

Jonah Sacha

Patrizia Caposio

Meaghan Hancock

Eric Bruening

James Theiler

Emily Marshall

Michael A Jarvis

David A Stein

Colin Powers

Jay Nelson

Collin Powers

Bette TM Korber

Human cytomegalovirus vectors comprising heterologous antigens are disclosed. The vectors derived from the TR strain, are ganciclovir sensitive, include active US2, US3, US6, US7 and UL131A genes, and have a deleterious or inactivating mutation in the UL82 gene preventing the expression of pp71.

Human cytomegalovirus comprising exogenous antigens

Provided herein are HIV-1 vaccines comprising a carrier and a population episensus antigen determined using the EpiGraph approach. Also provided are HIV-1 vaccines comprising a carrier, a population episensus antigen, and a tailored antigen. Also provided are methods of designing and producing an HIV-1 vaccine for a subject comprising designing vaccine antigens to optimally cover the diversity within a geographic area using an antigen amino acid sequence generated using the EpiGraph approach, and producing said designed vaccine antigen. Also provided are methods of inducing an effector memory T cell response comprising designing the one or more EpiGraph amino acid sequences, producing a vaccine comprising the one or more EpiGraph amino acid sequences and a vector, and administering the vaccine to a subject. Further provided are methods of treating HIV-1 in a subject comprising administering an effective amount of the described HIV-1 vaccines to the subject in need thereof.

HIV vaccines comprising one or more population episensus antigens

CMV vectors that lack active UL128, UL130, UL146 and UL147 proteins that may also comprise one or more microRNA regulatory elements (MRE) that restrict expression of the CMV are provided. Immunization with CMV vectors having the described features allows selection of different CD8+ T cell responses&#x2014;CD8+ T cells restricted by MHC-Ia, MHC-II, or by MHC-E.

Cytomegalovirus vectors eliciting T cells restricted by major histocompatibility complex E molecules

The present disclosure relates to recombinant rhesus cytomegalovirus (RhCMV) and human cytomegalovirus (HCMV) vectors encoding heterologous antigens, such as pathogen-specific antigens or tumor antigens, which may be used, for example, for the treatment or prevention of infectious disease or cancer. The recombinant RhCMV or HCMV vectors elicit and maintain high level cellular immune responses specific for the heterologous antigen while including deletions in one or more genes essential or augmenting for CMV replication, dissemination or spread.

Recombinant HCMV and RHCMV vectors and uses thereof

Methods of inducing a CD8+ T cell response to a heterologons antigen in which at least 10% of the CD8+ T cells are MHC-E restricted are disclosed. The method involves immunizing with a CMV vector that does not express UL128 and UL130 proteins. Also disclosed are recombinant CMV vectors comprising nucleic acids encoding a heterologous protein antigen, a UL40 protein, and a US28 protein but that do not express an active UL128 and UL130 protein. Also, disclosed are recombinant CMV vectors comprising nucleic acids encoding a heterologous protein antigen, but that do not express an active UL40 protein, UL128 protein, UL130 protein, and optionally a US28 protein. Also disclosed are recombinant CMV vectors comprising nucleic acids encoding a heterologous protein antigen, but that do not express an active US28 protein, UL128 protein, UL130 protein, and optionally a UL40 protein.

Methods and compositions useful in generating non canonical CD8+ T cell responses

Human cytomegalovirus vectors comprising heterologous antigens are disclosed. The vectors derived from the TR strain, are ganciclovir-sensitive, include active US2, US3, US6, US7 and UL131A genes, and have a deleterious or inactivating mutation in the UL82 gene preventing the expression of pp71.

Disclosed herein are recombinant CMV vectors comprising heterologous antigens and microRNA recognition elements to silence expression of CMV genes in the presence of microRNA derived from myeloid cells, an active UL128 protein and an active UL130 protein. Also disclosed are recombinant CMV vectors comprising heterologous antigens and microRNA recognition elements to silence expression of CMV genes in the presence of microRNA derived from myeloid cells, an inactive UL128 protein and an inactive UL130 protein. Also disclosed are methods of generating an unconventional immune response using these vectors. Such an immune response is characterized by generation of a CD8+ T cell response that is predominantly restricted by MHC-II.

CMV vectors comprising microRNA recognition elements

Disclosed are CMV vectors that lack active UL128, UL130, UL146 and UL147 proteins that may also comprise one or more microRNA regulatory elements (MRE) that restrict expression of the CMV. Immunization with the disclosed CMV vectors allow selection of different CD8+ T cell responses&#x2014;CD8+ T cells restricted by MHC-Ia, MHC-II, or by MHC-E.

CMV vectors comprising a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), and an active UL128 protein (or an ortholog thereof) but lacking an active UL130 protein (or an ortholog thereof) are provided. CMV vectors comprising a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), and an active UL130 protein (or an ortholog thereof) but lacking an active UL128 protein are also provided. In addition, methods of using CMV vectors to generate an immune response characterized as having at least 10% of the CD8+ T cells directed against epitopes presented by MHC Class II are provided.

Cytomegalovirus vectors enabling control of T cell targeting

This invention also relates to recombinant vectors expressing one or more of the human CMV (HCMV) glycoproteins US2, US3, US6 and US11 or corresponding functional rhesus CMV (RhCMV) homologues Rh182, Rh184, Rh185 or Rh189, methods of making them, uses for them, expression products from them, and uses for the expression products. This invention also relates to recombinant cytomegalovirus vectors vectors lacking one or more of the glycoproteins, methods of making them, uses for them, expression products from them, and uses for the expression products.

CMV glycoproteins and recombinant vectors

The recombinant rhesus cytomegalovirus (RhCMV) and human cytomegalovirus (HCMV) vectors of this invention encode heterologous antigens, such as pathogen-specific antigens or tumor antigens, which may be used, for example, for the treatment or prevention of infectious disease or cancer. The recombinant RhCMV or HCMV vectors elicit and maintain high level cellular immune responses specific for the heterologous antigen while including deletions in one or more genes essential or augmenting for CMV replication, dissemination or spread.

Growing community of inventors

Portland, OR, United States of America

Klaus Frueh