Project 1: Development of an HTLV-1 mRNA vaccine

Washington University, Saint Louis MO

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT - PROJECT 1: Development of an HTLV-1 mRNA vaccine The study of retroviruses has led to important discoveries in basic cell biology including cell signaling, regulation of gene expression, cellular transformation, and cancer development. Our collaborative work within this P01 focuses on human T-cell leukemia virus type 1 (HTLV-1), which is the infectious cause of adult T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disease HAM/TSP. Disease progression by HTLV-1 has been attributed to the viral gene Tax. However, we and others have provided strong evidence that another viral gene, termed Hbz, plays a critical role throughout infection, establishment of latency, and finally in the malignant process. In the past funding cycle, we identified the importance of Hbz in HTLV-1 pathobiology through gene editing (Viral Vector Core). These results support the utility of future Hbz-targeted therapeutic mechanisms for the treatment of HTLV-1-associated diseases. We also expanded our proposed work through P01 collaborations to develop an envelope (Env) mRNA lipid nanoparticle (LNP) vaccine (Project 3, Animal Core). mRNA vaccine technology has recently emerged as a safe, effective, and scalable approach to combat infectious diseases and cancer, offering several advantages over traditional vaccine design and production. The HTLV-1 Env glycoprotein is immunogenic and required for entry of target cells – making it a favorable target for vaccine development. Our initial Env mRNA-LNP vaccine candidate is immunogenic and protective in our rabbit model of infection. However, a majority of ATLL patients do not express Env (or Tax), whereas Hbz is the only viral gene consistently expressed throughout infection and disease development. Taken together, this suggests that an effective vaccine against HTLV-1 and subsequent disease development should target both Hbz and Env. Our overall hypothesis is that an HTLV-1 mRNA-LNP vaccine (Hbz, Env) can be developed to elicit neutralizing antibody (nAb) and T-cell responses that prevent infection and/or HTLV-1-mediated disease. This highly integrated proposal has three Aims and several Project and Core collaborations. Aim 1 will identify the optimal immunogenic Hbz and Env mRNA vaccine using different vaccine candidates. We will utilize in vitro approaches to examine relative efficacy (expression, localization, conformation, effects on cell signaling) of each vaccine candidate. We will also use in vivo approaches to assess and compare vaccine immunogenicity (Ab, nAb, T-cell responses) in HLA-transgenic mice (Project 3, Animal Core B). Aim 2 will measure the effectiveness of Hbz and/or Env mRNA vaccine protection. Studies in rabbits will measure vaccine-induced Ab, nAb, T-cell responses, protection against viral challenge, and treatment of viral infection (Project 3, Animal Core B, Genomics Core C). Studies in HLA-transgenic humanized mice will be used to measure vaccine protection against and treatment of disease (Project 2, Animal Core B, Genomics Core C). We will also characterize genomic phenotype of cells that escape vaccine protection (Genomics Core C). Aim 3 will assess the importance of nAb and/or CD8 T cells on protection and vaccine response in animals (Animal Core B, Genomics Core C).