London School of Hygiene & Tropical Medicine

Viral sequencing has become an important tool for understanding and monitoring an outbreak in real time. By analysing a virus’s genetic code, we can investigate where the outbreak may have originated, how the virus is evolving and whether there are any important genetic changes that could affect the public health response.

Within days of the first widely reported case of hantavirus infection from a traveler onboard the Atlantic expedition ship, the genome of the Andes hantavirus strain identified through testing was publicly shared. The speed at which this current genome has been shared should be applauded, as it provides a valuable early signal to help with managing the outbreak. But it should also be viewed as preliminary evidence, rather than a definitive picture of the outbreak’s evolutionary history.

What can we learn from viral sequencing during outbreaks?

Sequencing can help identify the likely source and reservoir of the virus and estimate how long the virus may have been circulating before detection. Sequences can offer an early clue about the likely reservoir and geographic origin of the virus by showing which previously known strains it most closely resembles. That can help narrow down which host species or ecological source may be involved in any spillover event.

Comparing genomes from different patients also allows researchers to reconstruct how the outbreak is spreading and determine whether cases are linked through human-to-human transmission or represent separate spillover events from the natural reservoir.

It is also valuable for diagnostics. Sequencing enables scientists to check whether mutations have occurred in regions targeted by PCR-based tests, helping confirm that existing diagnostic assays remain accurate and reliable.

What have we learned so far about the strain in this current Andes hantavirus outbreak?

From the single complete genome sequence, we can already infer several important things about the current outbreak. The sequence is broadly consistent with what we would expect from a hantavirus spillover from its natural reservoir (rats), rather than the emergence of a dramatically altered virus. 

Reassuringly, the closest related sequences are from the 2018–2019 outbreak in Argentina, suggesting the virus remains part of a known viral lineage rather than representing a highly divergent new strain. Viruses naturally accumulate mutations over time as they replicate, so some genetic differences compared with earlier outbreak sequences are expected. Preliminary analyses indicate only a relatively small degree of change from the most closely related Argentine sequences.

The virus’s three individual segments also have close relatives to one another, which suggests it has not undergone reassortment – a process where segmented viruses can exchange segments with another strain, potentially creating a novel variant. The absence of evidence for reassortment implies the outbreak virus likely emerged from a single, relatively stable viral lineage rather than from a recent mixing event between different hantaviruses.

What are the challenges with viral sequencing?

In the early stages of the COVID-19 pandemic, we saw people over-interpret early genomic data. That ultimately led us to write a commentary in Nature Microbiology on why phylogenetic interpretation during outbreaks requires caution - a message that is still very relevant today.

Epidemiology (who, when and where) and phylogenetics (evolutionary history) are often much better at ruling out transmission than definitely proving it, particularly where there isn’t already strong evidence. If a genome is clearly different, that argues strongly against direct transmission between the two sources. However, if the genomes are highly similar, that could be compatible with direct transmission between the two, a shared exposure source or a repeated spillover event from the same reservoir. 

The initial findings from the hantavirus strain are compatible with another spillover event from the natural reservoir host, rather than a virus that has substantially changed biologically. However, caution is still needed because conclusions are currently based on limited data. Given the relatively short timescale involved, you would also not necessarily expect many mutations to accumulate between linked cases.

At this point we still do not know how genetically diverse the outbreak is and whether there are multiple introductions into humans or whether cases came from a single spillover event from rodents to humans, followed by human-to-human transmission. Single sequences cannot reliably establish how quickly a virus is evolving during the outbreak.

Additional sequencing from more patients and potential animal reservoirs of hantavirus will be essential for reconstructing transmission chains and assessing whether the virus is undergoing any functional change.