Fig 1.
Influenza A virus diversity & host spillover.
(A) IAV transmission. IAV jumps from its natural reservoir to different animals, including farmed animals, undergoing adaptation to this new biological environment. The virus can infect humans sporadically or acquire human-to-human transmission traits and become endemic such as the currently circulating subtypes H1N1 and H3N2 that cause yearly epidemics. (B) H5 and H5N1 timeline. HPAI H5N1’s first outbreak was reported in 1959 and first detected in humans in 1997, leading to 6 deaths. Since then, H5N1 and other emergent subtypes (e.g., H5N6 and H5N8) have caused several outbreaks with many human fatalities. Recently, the new H5N1 clade 2.3.4.4b caused an outbreak in U.S. dairy cows, subsequently transmitted to humans (dairy farm workers), threatening human health. Created with Biorender.
Table 1.
Clinically approved antiviral drugs against influenza viruses.
Table 2.
Small molecules, peptides, and monoclonal antibodies against influenza viruses in clinical trials.
Fig 2.
(Blue): Rapid evolution of IAV. It relies on a vast viral repertoire widespread through many species, the ability to reassort, and a high mutation rate (the latter two allow adaptations to new biology). All these factors render vaccines and antivirals ineffective. (Yellow): Current IAV targeting strategies. Established global surveillance among animals and humans is key for selecting effective vaccines against circulating IAV strains, and preventing future outbreaks. Today, prevention and therapeutic solutions are limited. The emergence of drug-resistant variants demands the development of new therapeutic alternatives. (Green): Antiviral development needs improvements in several areas. Identification of new antiviral strategies targeting previously unknown viral-host biology (e.g., viral inclusions), better human-based platforms for screening, testing, and validating drugs (e.g., organs-on-a-chip), implementation of technological approaches that bypass one-on-one testing (e.g., AlphaFold) in drug discovery and drug resistance forecasting, and refined delivery systems (e.g., nanoparticles). Created with Biorender.