Development of a human T-cell leukemia virus type 1 mRNA vaccine
2023
Hochschulschrift
Zugriff:
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus which causes a lifelong infection. An estimated 5-10 million persons are infected worldwide. However, the true amount of global HTLV-1 carriers is likely much higher given recent reports from newly endemic areas. HTLV-1 is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy. The projected lifetime risk of developing ATL is ~5% in HTLV-1-infected individuals and 25% in perinatal HTLV-1 carriers. Despite the exceptional oncogenicity of this virus, no preventative vaccine has been tested in clinical trials to date. However, several vaccine studies have shown protection against HTLV-1 challenge in animals, demonstrating that developing vaccine is feasible.The COVID-19 pandemic and the success of SARS-Cov-2 spike protein mRNA vaccines spurred the popularity of the mRNA vaccine platform. Immunization with encapsulated mRNA offers numerous benefits over conventional vaccines, including improved safety through the delivery of a non-infectious agent and ability to regulate in vivo half-life, as well as enhanced efficacy through modulation of stability and translation. The use for mRNA vaccines in HTLV-1 research warrants investigation. In this study, we developed an mRNA lipid nanoparticle (mRNA-LNP) vaccine encoding for a codon optimized HTLV-1 envelope (Env) and evaluated its efficacy as a vaccine candidate in New Zealand white rabbits. Rabbits (n=6) were vaccinated with two doses of either Env mRNA-LNP or control GFP mRNA-LNP, then challenged with lethally irradiated HTLV-1-infected cells. All rabbits were rechallenged fifteen weeks later to evaluate the durability of vaccine-induced immune responses in protected rabbits. Anti-Env antibody responses were detected by western blot and quantitatively measured using infected cell binding assays in all Env mRNA-LNP vaccinated rabbits after two doses. Three (out of six) Env mRNA-LNP vaccinated rabbits had no detectable proviral load after first virus challenge, and two protected rabbits had no detectable proviral load after virus rechallenge. Proviral loads were significantly lower in Env mRNA-LNP vaccinated rabbits compared to GFP mRNA-LNP control rabbits. HTLV-1 tax and hbz expression was significantly lower for Env mRNA-LNP vaccinated rabbits compared to GFP mRNA-LNP rabbits. Cell-associated syncytia inhibition assays and cell-free viral infectivity assays detected significantly more neutralizing antibody activity in Env mRNA-LNP vaccinated rabbits compared to GFP mRNA-LNP control animals. Syncytia inhibition and neutralizing antibody activity were negatively correlated with proviral load at week six post infection, indicating at least an antibody correlate of protection. Using a flow-based intracellular interferon-γ assay, we found Env mRNA-LNP vaccinated rabbits had larger CD4+IFN-γ+ cell populations compared to GFP mRNA-LNP control rabbits two weeks after viral challenge. In conclusion, our Env mRNA-LNP vaccine was immunogenic and provided protection against HTLV-1 challenge in rabbits.
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Development of a human T-cell leukemia virus type 1 mRNA vaccine
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Autor/in / Beteiligte Person: | Tu, Joshua James |
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Veröffentlichung: | 2023 |
Medientyp: | Hochschulschrift |
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