Generation of a live attenuated influenza A vaccine by proteolysis targeting

Abstract

Live attenuated virus vaccines have been generated by several strategies, including cold-adapted live attenuated influenza vaccines (CAIVs), codon-deoptimized virus, premature termination codon-harboring virus, hyper-interferon-sensitive virus and viral-protein-altered virus 1-12 . However, current attenuation strategies are often accompanied by decrease or loss of safety, efficacy or productivity 1,[13][14][15][16] . In addition, immune escape due to rapid viral evolution poses a further challenge for traditional influenza vaccines 1,13 . Thus, there is an urgent need for new vaccine approaches that could enable the generation of safer and more effective live vaccines in a simpler way 2 .

PROTAC vaccine: A new way to live attenuated vaccines

“…Despite the use of existing vaccines, influenza still causes 3–5 million severe cases and .3–.65 million deaths worldwide each year, 1 highlighting the need for new vaccine strategies that can generate improved vaccines and thus expand our antiviral arsenal. In a proof‐of‐concept study, 2 Si et al. describe the development of a proteolysis‐targeting chimeric (PROTAC) vaccine technology by using the host cellular ubiquitin‐proteasome system to conditionally degrade influenza viral proteins (Figure 1 ).…”

“… 4 Recent studies have demonstrated several strategies to design live attenuated vaccines that are in development. 2 , 4 , 5 , 6 , 7 Compared to these approaches, the PROTAC vaccine uses a distinct design principle—targeting viral protein to the host's ubiquitin‐proteasome system for degradation and thus attenuating viral replication.…”

“…However, potential loss or dysfunction of VHL in some patients with VHL diseases 10 raise potential safety concerns for this PROTAC vaccine strain in these patients. Fortunately, more than 600 E3 ubiquitin ligases have been found 2 , 11 in human, and numerous PTDs recognized by other E3 ubiquitin ligases can be designed and used to generate diverse PROTAC vaccine strains, which could enable personalized selection for populations with different genetic backgrounds, such as those with defective expression of a specific E3 ubiquitin ligase. In addition, PROTAC vaccines may not suit those patients who are receiving therapy with proteasome inhibitors, such as Bortezomib.…”

“…The authors further show that the PROTAC vaccine strain was able to elicit robust and broad immunity, including humoural, mucosal and cellular immune responses, and provided cross‐reactive protection against homologous and heterologous influenza viral challenges in mice and ferrets. Furthermore, the authors demonstrate that PTD‐mediated viral protein degradation by the proteasome enhanced presentation of viral antigens, 2 which is critical for inducing strong T cell responses 9 …”

“…4 Recent studies have demonstrated several strategies to design live attenuated vaccines that are in development. 2,[4][5][6][7] Compared to these approaches, the PROTAC vaccine uses a distinct design principle-targeting viral protein to the The PROTACs typically refer to chemical small molecules or peptide-based molecules that contain two covalently linked functional moieties, one specifically binding to a protein of interest (POI) and the other to E3 ubiquitin ligase, and are able to induce ubiquitylation of the POI for its subsequent degradation by proteasome. 8 By generating PROTAC vaccines, Si et al expand the application of this targeted protein degradation technology to organisms.…”