| Autor: |
Helty Adisetiyo, Justin Taft, Lennie Sender, Marta Martín-Fernández, Sofija Buta, Kayvan Niazi, Elizabeth Gabitzsch, Peter A. Sieling, Philip T. Liu, Roosheel S. Patel, Adrian Rice, Lise Zakin, Patricia Spilman, Annie Shin, Shahrooz Rabizadeh, Hermes Garban, Jeffrey T. Safrit, Brett Morimoto, Dusan Bogunovic, Patrick Soon-Shiong |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.11.04.20225417 |
| Popis: |
To address the need for a safe, efficacious vaccine against SARS-CoV-2 infection with the critical properties of enabling both blocking viral entry into cells and clearing virus from cells already infected, we have developed a bivalent, human adenovirus serotype 5 (hAd5) SARS-CoV- 2 S-Fusion + N-ETSD vaccine that is currently in clinical testing. This vaccine uses the next- generation hAd5 [E1-, E2b-, E3-] platform previously used successfully in cancer patients with pre-existing adenovirus immunity, engineered to express both SARS-CoV-2 spike (S) protein modified to improve the generation of neutralizing antibodies to block entry of the virus, and nucleocapsid (N) protein with an Enhanced T cell Stimulation Domain (ETSD) to activate CD4+ and CD8+ T cells to clear the virus and block replication by killing infected cells. The targeting of N to endosomes and lysosomes to enhance CD4+ and CD8+ T-cell responses distinguishes our vaccine. In our previously reported pre-clinical studies we showed that in mice, the hAd5 S-Fusion + N-ETSD vaccine elicits both humoral and T-cell responses that are robust and T helper cell 1 (Th1) dominant. Here we report that the hAd5 S-Fusion + N-ETSD vaccine is recognized by anti-sera and T cells from previously SARS-CoV-2 infected patients, and that the presence of N is vital for T-cell recall. The findings presented herein: (i) demonstrate specific recognition of hAd5 S-Fusion + N-ETSD infected cells by plasma antibodies from previously SARS-CoV-2 infected patients, but not antibodies from virus-naïve subjects; (ii) show enhanced binding of plasma SARS-CoV-2 antibodies from previously infected patients to monocyte-derived dendritic cells (MoDCs) expressing the hAd5 S-Fusion + N-ETSD vaccine as compared to hAd5 S-Fusion alone; (iii) reveal N-ETSD localizes to vesicles associated with MHC class II antigen presentation, including endosomes, lysosomes and autophagosomes in MoDCs; (iv) demonstrate endosome/lysosome-targeted N-ETSD elicits higher interferon-γ T-cell responses than cytoplasm-localized N; and (v) N-ETSD alone or in the hAd5 S-Fusion + N-ETSD construct induces both CD4+ and CD8+ T cell memory recall. This recognition of hAd5 S-Fusion + N-ETSD vaccine antigens by T cells from previously SARS-CoV-2 infected patients, together with the ability of this vaccine candidate to elicit de novo immune responses in naïve mice suggests that it re-capitulates the natural immune response to SARS-CoV-2 to activate both B and T cells towards viral neutralization and recognition of infected cells, critical for prevention of COVID-19 disease. Intriguingly, our hAd5 S-Fusion + N-ETSD T-cell biased vaccine has the potential to not only provide protection for uninfected individuals, but also to be utilized as a therapeutic for already infected patients to induce rapid clearance of the virus by activating T cells to kill the virus-infected cells, thereby reducing viral replication and lateral transmission. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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