Most pandemic viruses show little adaptation before infecting humans

A new University of California San Diego study published in Cell challenges a long-standing assumption about how animal viruses become capable of sparking human epidemics and pandemics. Using a phylogenetic, genome-wide analysis across multiple viral families, researchers report that most zoonotic viruses - infectious pathogens that spread from animals to humans, including the cause of COVID-19 - do not show evidence of special evolutionary adaptation before spilling over into humans.

This work has direct relevance to the ongoing controversy around COVID-19 origins. 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 - and it represents another nail in the coffin for theories invoking laboratory manipulation."

Joel Wertheim, PhD, senior author and professor of medicine, Division of Infectious Diseases and Global Public Health, UC San Diego School of Medicine

The prevailing model of zoonotic emergence has often assumed that viruses must first acquire adaptive mutations before they can sustain human-to-human spread. To test that assumption, the research team analyzed viral genomes from outbreaks caused by influenza A virus, Ebola virus, Marburg virus, mpox virus, SARS-CoV and SARS-CoV-2. They focused on the evolutionary period immediately preceding human outbreaks, where any substantial pre-spillover adaptation should leave a detectable imprint.

Across these diverse viruses, the investigators found a strikingly consistent pattern: selection pressures before zoonotic emergence were indistinguishable from those acting during routine circulation in animal reservoirs. In other words, there was no evolutionary signal suggesting that these viruses were being "pre-adapted" for humans prior to their outbreaks. Instead, measurable changes in selection typically appeared only after sustained transmission began in people.

"From a broad epidemiological standpoint, our findings challenge the idea that pandemic viruses are evolutionarily special before they reach humans," Wertheim said. "Rather than requiring rare, finely tuned adaptations in animals, many viruses may already possess the basic capacity to infect and transmit between humans. What matters most is human exposure to a diverse array of animal viruses."

The study relies on a sophisticated phylogenetic framework that measures changes in the intensity of natural selection across entire viral genomes. By comparing rates of different types of mutations, the researchers were able to detect whether natural selection was intensified, relaxed or unchanged across key evolutionary transitions. Importantly, the team validated their approach using known examples of and artificially selected viruses propagated in cell culture or in laboratory animals, which produced clear and reproducible evolutionary signatures distinct from natural transmission.

Those controls proved critical when examining one historical outlier: the reemergence of H1N1 influenza A virus in 1977. Unlike other zoonotic events analyzed, the 1977 H1N1 strain showed both unusually limited genetic divergence from 1950s viruses and a clear shift in selection consistent with viruses that propagated in cell culture or in laboratory animals.

"The 1977 influenza story is, in many ways, even more compelling than what we found for COVID-19," Wertheim said. "Our results provide new molecular evidence supporting the long-suspected idea that the H1N1 pandemic was sparked by a laboratory strain - possibly in the context of a failed vaccine trial."

Historical records and prior genetic analyses have suggested that the 1977 H1N1 virus appeared almost unchanged after a 20-year absence, a pattern difficult to reconcile with natural evolution. The new findings add another layer, showing that the virus also experienced selection similar to that seen in laboratory-adapted influenza strains and live-attenuated vaccines.

Beyond settling historical debates, the authors argue that their work has important implications for how scientists interpret future outbreaks. By establishing what "normal" zoonotic emergence looks like at the genomic level, the framework provides a benchmark for distinguishing natural spillovers from scenarios involving laboratory handling or prolonged artificial selection.

"This doesn't mean lab accidents don't happen," Wertheim emphasized. "But it does mean that if a virus had been extensively passaged in a lab before an outbreak, we would expect to see it in the evolutionary record. In nearly all pandemics we've studied, that signal simply isn't there."

Looking ahead, the researchers see potential applications in outbreak forensics, viral surveillance and pandemic preparedness.

"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."