The Expanding host range of HPAI H5N1
#18,250
Influenza viruses evolve via two well established routes; Antigenic drift & Antigenic Shift (reassortment).
- Antigenic drift causes small, incremental changes in the virus over time. Drift is the standard evolutionary process of influenza viruses, and often come about due to replication errors that are common with single-strand RNA viruses (see NIAID Video: Antigenic Drift) or due to host adaptation.
- Shift occurs when one virus swap out chunks of their genetic code with gene segments from another virus. This is known as reassortment. While far less common than drift, shift can produce abrupt, dramatic, and sometimes pandemic inducing changes to the virus (see NIAID Video: How Influenza Pandemics Occur).
In either case, most mutations/reassortments are evolutionary failures.
They die out quickly because they are not as biologically `fit’ as the parental virus they must compete with. Only rarely does a mutation convey enough of an evolutionary advantage to allow it to become `fixed' in a host, and potentially transmitted onward.
While reassortment gets most of our attention due to its ability to change a virus radically overnight, antigenic drift - over years or decades - can eventually produce more `pandemic ready' viruses as well.
We've been following the evolution and spread of HPAI H5 viruses now for more than two decades. The H5N1 threat isn't from a single viral entity, however, but rather from a diverse and growing array of genetically similar viruses.As a result the H5N1 viruses circulating in the United States or Europe today are genetically distinct from the H5N1 viruses of the past, and even those currently circulating in Peru, Japan, or the Middle East.
Since 2020 a new clade 2.3.4.4b H5N1 virus became dominant, and it - and its variants - have shown an enhanced ability to spill over into mammals around the globe (see here, here, here, and here). One genotype (B3.13) has spilled over into American Dairy cows.
This clade has also greatly expanded its host range in birds (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK).
At the same time, we are seeing far fewer, and often less severe, human infections from HPAI H5N1. While the `right' reassortment could conceivably spark a pandemic, the $64 question remains; is HPAI H5 - in general - evolving towards becoming a bigger pandemic threat over time?
We've a preprint today that attempts to answer that question using large-scale computational modeling of H5 Influenza variants. This in silico analysis by researchers at the University of North Carolina at Charlotte, finds reasons to believe it is.
This is a lengthy, and technically complex study, much of which is admittedly above my pay grade. I've only posted some excerpts, so follow the link to read it in its entirety.
Large-Scale Computational Modeling of H5 Influenza Variants Against HA1-Neutralizing AntibodiesColby T Ford, Shirish Yasa, Khaled Obeid, Sayal Guirales-Medrano, Richard Allen White III, Daniel Janiesdoi: https://doi.org/10.1101/2024.07.14.603367
Abstract
In June 2024, the United States Department of Agriculture released a report that showed over 300 samples from 2022-2024 of highly pathogenic avian influenza have been detected in mammals. To date, the United States Centers for Disease Control reports that there have been 13 humans infected with H5N1 in 2024.
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 HA1-neutralizing antibodies. This study shows a trend of weakening of the 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 H5N1's spread.
These results indicate that the virus is well on its way to moving 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.
(SNIP)
Zoonosis Analysis.
In Figure 2a, a notable transition pattern is observed from avian species (class Aves) to mammals (class Mammalia), likely attributable to a mutagenic drift. Recent empirical studies have investigated the mutational dynamics of H5N1, revealing changes in the hemagglutinin (HA) protein.
While H5N1 influenza prefers binding to the α2-3 sialic receptors in birds, this study demonstrated a binding affinity of H5N1 to α2-6 sialic acid receptors, predominant in mammals, at almost equal proportion (64). These authors also show that mutations that decrease neutralization by sera from mice and ferrets immunized with the vaccine candidate reference strain A/American Wigeon/South Carolina/USDA000345-001/2021 exist in some of the most recently collected mammalian samples, the dairy cow outbreak starting in April 2024 (64).
Concurrently, we show here that mutations accumulated over time in the HA protein will confer reduced neutralization by antibodies more broadly than the current clade 2.3.4.4b H5N1 outbreak.
Our in silico study aligns with these findings, indicating a progressive decrease in H5N1’s binding affinity to antibodies in our isolates over time. As illustrated in Figure 3, while the binding affinity to antibodies remains relatively stable for avian isolates, there is a marked decline in affinity for primate isolates.
As the virus diversifies in the avian populations, the potential pool of variants with breakthrough potential into mammals increases. The phylogenetic analysis showing repeated transmission from avian populations to mammalian populations indicates that the evolution is occurring in birds rather than being driven by mammalian immune pressure.
This suggests a evolutionary trajectory in birds for H5N1 towards increased infection in primate hosts, facilitated by decreased susceptibility to neutralizing antibodies(Continue . . . )
Any one of them is potentially only a few mutations, or a single fortuitous reassortment, away from cracking the code to make it more transmissible in humans.
And if HPAI H5 ultimately fails, well . . . there are a plethora of avian, swine, and canine flu viruses with zoonotic potential in the wings (see CDC IRAT List).
