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Viral adaptation is not a necessary precursor to outbreaks of novel zoonotic viruses, says a new study published in Cell on March 6, 2026.
Using a phylogenetic framework to characterise natural selection, researchers led by Jennifer L Havens of the University of California investigated the hypothesis that zoonotic viruses require adaptation before zoonosis to sustain human-to-human transmission.
The researchers analyzed the evolutionary histories of several major viral outbreaks, including COVID-19, the 2009 H1N1 influenza pandemic, the 2013-2016 West African Ebola virus disease (Ebola) epidemic, the 2004-2005 Angolan Marburg epidemic, and the 2022-2023 mpox epidemic.
No evidence was found of a change in selection intensity immediately prior to outbreaks in humans compared with typical selection within reservoir hosts. Selection signatures on SARS-CoV-2 were unchanged until its emergence in humans, the study said.
There were suggestions that SARS-CoV-2 was passaged or modified in a laboratory context, prior to emergence. The study said that if there was extensive evolution in an intermediate host or passage in a laboratory context prior to emergence, there would be a detectable change in selection on the stem preceding SARS-CoV-2.
However, the analysis of “selection on the stem preceding SARS-CoV-2 emergence across 15 putatively non-recombinant regions found no evidence of intensification or relaxation of selection compared with selection of the bat host reservoir”.
The study found no evidence to suggest SARS-CoV-2 experienced prolonged selective pressure in an environment different from related bat viruses prior to its emergence in humans. Instead, measurable changes in selection typically appeared only after sustained transmission began in people, with mutations that improve transmission in the new host.
“This work has direct relevance to the ongoing controversy around COVID-19 origins,” said Joel Wertheim, University of California and one of the authors in a press statement.
“From an evolutionary perspective, we find no evidence that SARS-CoV-2 was shaped by selection in a laboratory or prolonged evolution in an intermediate host prior to its emergence. That absence of evidence is exactly what we would expect from a natural zoonotic event."
In contrast, the reemergence of H1N1 influenza A virus in 1977 was preceded by a shift in selection intensity, consistent with the hypothesis of passage in a laboratory setting.
In 1977, the H1N1 influenza A virus reemerged in humans after going extinct 20 years prior. The re-emergent virus was closely related to a strain that had been circulating in the 1950s. Unlike other analysed zoonotic events, the 1977 H1N1 strain showed both unusually limited genetic divergence from 1950s viruses and a clear shift in selection consistent with viruses propagated in cell culture or laboratory animals.
It has been proposed that H1N1 reemerged in 1977 without expected evolution because it was frozen in a laboratory before it was accidentally allowed to re-establish “wild” human-to-human transmission, perhaps involving a live-attenuated viral vaccine or a laboratory-adapted virus used as a challenge virus during an influenza vaccine trial.
Holistic phylogenetic analysis of selection regimes can be used to detect evolutionary signals of host switching or laboratory passage, providing insight into the circumstances of past and future viral emergence, the study suggested.
“Our goal is not just to understand the past, but to be better prepared for the future,” Wertheim said. “By clarifying how pandemics actually begin, we can focus attention where it belongs — on surveillance, prevention and reducing the opportunities for the constant barrage of viral spillover.”
