Large-Scale Computational Modeling of H5 Influenza Variants Against HA1-Neutralizing Antibodies

Abstract

The United States Department of Agriculture has recently released reports that show samples from 2022-2024 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds (1). To date, the United States Centers for Disease Control reports that there have been 27 humans infected with H5N1 in 2024 (2). The broader potential impact on human health remains unclear. In this study, we computationally model 1,804 protein complexes consisting of various H5 isolates from 1959 to 2024 against 11 hemagglutinin domain 1 (HA1)-neutralizing antibodies. This study shows a trend of weakening binding affinity of existing antibodies against H5 isolates over time, indicating that the H5N1 virus is evolving immune escape of our medical defenses. We also found that based on the wide variety of host species and geographic locations in which H5N1 was observed to have been transmitted from birds to mammals, there is not a single central reservoir host species or location associated with H5N1s spread. These results indicate that the virus has potential to move from epidemic to pandemic status in the near future. This study illustrates the value of high-performance computing to rapidly model protein-protein interactions and viral genomic sequence data at-scale for functional insights into medical preparedness. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have shown cases of avian influenza transmissions to mammals that are increasing in frequency, which is of concern to human health. Since 1997, nearly a thousand H5N1 cases have been reported in humans with a 52% fatality rate. Previous analyses have indicated specific mutations on the hemagglutinin protein that allow for this "host jumping" between birds and mammals (3). There are also existing evidence of recent viral strains with reduced neutralization to sera (4). Added value of this studyThis study provides a comprehensive look at the mutational space of hemagglutinin of H5N1 influenza and presents computational predictions of the binding between various HA1-neutralizing antibodies derived from infected vaccinated patients and humanized mice and 1,804 representative H5 HA1 proteins. These analyses show a weakening trend of existing antibodies. We also confirm that the mutations found in other studies that enable zoonosis also affect binding affinities of the antibodies tested. Furthermore, through phylogenetic analyses, we quantify the avian-to-mammalian transmissions from 1959 to 2024 and show a persistent circulation of isolates between North America and Europe. Taken together, the continuous transmission of H5N1 from birds to mammals and the increase in immuno-evasive HA strains in mammals sampled over time suggest that antigenic drift is a source of spillover risk. Implications of all the available evidenceOur findings indicate that the worsening in antibody binding, along with the increase in of avian-to-mammalian H5N1 influenza transmissions are risks to public health. Through the findings of previous studies along with the predictions reported in this study, we can now monitor specific mutations of interest, quantified by their potential impact on antibody evasion, and inform public health monitoring of circulating isolates in 2024 and beyond. In addition, these findings may help to guide future vaccine and therapeutic development in the fight against H5N1 influenza infections in humans.