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Generation of a Live Attenuated Influenza A Vaccine Using Chemical-Triggered Intein

Noticeable morbidity and mortality can be caused by influenza A virus in humans. Conventional live attenuated influenza vaccine (LAIV) is one of the main strategies to control the spread of influenza, but its protective efficacy is often limited by its suboptimal immunogenicity and safety. Therefore, a new type of LAIV that can overcome the shortage of existing vaccines is urgently needed. Here, we report a novel method to construct the recombinant influenza A virus (IAV) regulated by small molecules. By inserting 4-hydroxytamoxifen (4-HT)-dependent intein into the polymerase acidic (PA) protein of IAV, a series of 4-HT-dependent recombinant viruses were generated and screened. Among them, the S218 recombinant virus strain showed excellent 4-HT dependent replication characteristics both in vitro and in vivo. Further immunological evaluation indicated that the 4-HT-dependent viruses were highly attenuated in the host and could elicit robust humoral, mucosal, and cellular immunity against the challenge of homologous viruses. The attenuated strategies presented here could also be broadly applied to the development of vaccines against other pathogens.

 

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The passage describes a study that introduces a novel method for constructing a recombinant influenza A virus (IAV) regulated by small molecules, with the aim of developing a more effective live attenuated influenza vaccine (LAIV). The researchers inserted a 4-hydroxytamoxifen (4-HT)-dependent intein into the polymerase acidic (PA) protein of IAV, resulting in the generation of a series of 4-HT-dependent recombinant viruses. Among these, the S218 recombinant virus strain demonstrated excellent 4-HT-dependent replication characteristics both in laboratory settings (in vitro) and in animal models (in vivo).

The 4-HT-dependent viruses exhibited high attenuation in the host, meaning they were less virulent, and could induce strong immune responses. The immune evaluation demonstrated that these viruses elicited robust humoral (antibody-mediated), mucosal (related to the mucous membranes), and cellular (involving immune cells) immunity when challenged with similar viruses. This indicates that the 4-HT-dependent viruses have the potential to provide effective protection against homologous (similar) viral challenges.

Moreover, the study suggests that the strategies employed in this research can be applied more broadly to the development of vaccines against other pathogens, beyond influenza. This implies that the methodology used to construct the 4-HT-dependent recombinant viruses may have broader implications for developing vaccines against various infectious diseases caused by different pathogens.

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S7827 4-Hydroxytamoxifen (Afimoxifene) 4-Hydroxytamoxifen (Afimoxifene) is the active metabolite of tamoxifen and a selective estrogen receptor (ER) modulator that is widely used in the therapeutic and chemopreventive treatment of breast cancer. It activates on-target modification frequency for intein-Cas9 variants.

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Estrogen/progestogen Receptor CRISPR/Cas9