A unified theory for predicting pathogen competition

The COVID-19 pandemic showed that predicting the invasion of a novel pathogen into the human population and its evolutionary potential to generate new variants is crucial for preventing future outbreaks. New research conducted at Princeton University and the University of Chicago published today in the journal Science presents a unified theory for predicting such invasion and its consequences for competing pathogens.

“Many different pathogens infect the human population, so explaining the differences in strain circulation patterns has been a major challenge,” said lead author Sang Woo Park, a recent PhD graduate from Princeton’s Department of Ecology and Evolutionary Biology and a Life Science Research Foundation fellow at the University of Chicago. “For example, influenza and SARS-CoV-2 exhibit strain replacement, meaning that the emergence of a new strain causes the extinction of previous strains. This adds major challenges to vaccine development. But this is not necessarily the case for other pathogens. For example, RSV, a common respiratory pathogen for cold especially among children, has two strains that circulate together.”

“Other researchers provided key insights into understanding pathogen competition for influenza, SARS-CoV-2, and RSV” Park said. “Instead, we wanted to develop a single, unified theory that can explain why we see strain replacement in some pathogens but not in others.”

“Developing a unified theory is important because it allows us to compare different pathogens and identify mechanisms that drive the differences in strain circulation patterns across pathogens, ” said co-author C. Jessica Metcalf, Princeton Professor of Ecology and Evolutionary Biology and Public Affairs and an associated faculty member in Princeton’s High Meadows Environmental Institute.

In this paper, the authors extended classical theory from community ecology for predicting the outcome of species competition. They showed that the same ideas could be applied to compare competing pathogen strains and predict if a new strain will replace its competitor.

“In ecological terms, the ability of one strain to spread in a population already containing another is a key predictor for strain co-circulation,” said co-author Jonathan Levine, Princeton’s J.N. Allison Professor of Environmental Studies, the chair of Ecology and Evolutionary Biology, and an associated faculty member in the High Meadows Environmental Institute.

“What’s surprising is that our model predicts that most competing strains can spread in the presence of its competitors across common human pathogens, including influenza and SARS-CoV-2,” said Bryan Grenfell, who is the senior author on the paper and serves as Princeton’s Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs and an associated faculty member in the High Meadows Environmental Institute. “This result initially seemed to contradict observations of strain replacement in influenza and SARS-CoV-2. Instead, this study revealed that there is another layer of complexity to predicting strain co-circulation.”

The research found that strain coexistence further requires both competing strains to persist in a population following their initial invasion. The authors then showed that population-level immunity can predict whether new and old strains will stay in the population, and eventually co-circulate.

“When a new strain enters the population for the first time, it infects a lot of people, making them immune, ” said Park. “This build-up of immunity prevents the strain from entering the population again until there is a sufficient amount of susceptible individuals in the population through either births or waning of immunity.”

“How quickly the susceptible population grows after an outbreak is a key factor that determines the potential for another outbreak, and thus the ability of strains to co-circulate ” said co-author Sarah Cobey, a professor in the Department of Ecology and Evolution at the University of Chicago.

“Overall, this work implies that there is a high diversity of pathogens that have the potential to invade the population,” added Park. “This work underlines the importance of understanding the interactions between different pathogens for predicting future outbreaks and preventing them.”

UC Berkeley’s Trevor J. McMinn Endowed Professor Mike Boots (who was not involved in this work) commented on the findings, “This framework will be useful for understanding mechanisms that determine the invasion of new variants as we prepare for the next pandemic.”

The paper, “Predicting pathogen mutual invasibility and co-circulation” was published online Oct. 10 by Science. The work was supported by funds from Princeton Catalysis Initiative, Princeton Precision Health, Princeton High Meadows Environmental Institute, Charlotte Elizabeth Procter Fellowship of Princeton University, Peter and Carmen Lucia Buck Foundation Award of the Life Sciences Research Foundation, National Science Foundation, and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services CEIRR contract.