Influenza has been overshadowed by the COVID-19 pandemic, but it remains a major threat to global health. Deploying innovative technologies to improve vaccines will be a welcome addition to the options for controlling influenza.
The PROTAC viruses target a selected viral protein to the ubiquitin-proteasome system, dramatically reducing their replication while retaining their capacity to elicit robust and broad cellular immunity. In an article published in Nature’s Biotechnology, the authors demonstrate protection against the viral challenges of the influenza A virus in mice and ferrets. The concept of using PROTACs to reduce the effectiveness of live viruses for use as vaccines — not only against influenza but also against other viral diseases for which effective vaccines are lacking — is promising and warrants further investigation.
Despite their effectiveness and widespread acceptance, influenza vaccines have well-known limitations. Influenza viruses undergo antigenic drift — a gradual accumulation of point mutations due to error-prone replication; mutations in certain cellular proteins can generate variants that evade immunity induced by prior infection or vaccination. Although influenza vaccines are re-formulated annually to account for antigenic drift, further antigenic drift during the 6- to 8-month period of vaccine manufacture can diminish their effectiveness. Influenza viruses can also undergo an antigenic shift. The antigenic shift usually occurs through the exchange of gene segments between animal and/or human influenza viruses and can generate variants that cause pandemics.
PROTAC technology may offer unique advantages for generating broad and robust immune responses. Implementing a seasonal influenza vaccine strategy using PROTAC viruses would require the design and co-administration of four vaccines to protect against both circulating Influenza A subtypes (H1N1 and H3N2) and B lineage viruses (Victoria and Yamagata). The authors believe it may be prudent to target the same viral protein in the four viruses to reduce the risk that replicative competence would be restored through genetic reassortment. PROTAC vaccines would not face the problems of egg-adaptive mutations and the introduction of glycosylation motifs that compromise the effectiveness of egg-based vaccines, making it possible to replicate faster. Choosing the best viral protein(s) to target and ensuring efficient split are among the details to be investigated as the authors’ approach is extended to additional viral pathogens.
Do you think this will change the general view of vaccines in society for the better or worse?