On State-Space Reduction in Multi-Strain Pathogen Models, with an Application to Antigenic Drift in Influenza A

Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi-strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state-space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status-based models. The cornerstone of our method is the introduction of immunity variables, which describe multi-strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one-dimensional manifold in a two-dimensional trait space. Our framework broadens the class of multi-strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi-strain pathogens.: Many important human pathogens, including HIV and influenza viruses, consist of many different “strains,” which elicit distinct immune responses in their hosts. Infection by one variant usually triggers partial cross-immunity against several other variants. This process leads to a complicated and dynamic immunity structure in the host population. Most existing models of a population with a multi-strain pathogen are either very complex, or rely on specific simplifying assumptions. Here, we suggest a new way of simplifying such models that allows for greater flexibility in underlying assumptions. This approach could lead to deeper understanding of the ecology and evolution of multi-strain pathogens. We apply our approach to a simple model of evolution of influenza A that illustrates one hypothesis about how influenza A evolution may be structured.