A key priority for infectious disease research is to clarify how pathogen genetic variation, modulated by host immunity, transmission bottlenecks, and epidemic dynamics, determines the wide variety of pathogen phylogenies observed at scales that range from individual host to population. We call the melding of immunodynamics, epidemiology, and evolutionary biology required to achieve this synthesis pathogen "phylodynamics." We introduce a phylodynamic framework for the dissection of dynamic forces that determine the diversity of epidemiological and phylogenetic patterns observed in RNA viruses of vertebrates. A central pillar of this model is the Evolutionary Infectivity Profile, which captures the relationship between immune selection and pathogen transmission.

Summary Background The isolation of symptomatic cases and tracing of contacts has been used as an early COVID-19 containment measure in many countries, with additional physical distancing measures also introduced as outbreaks have grown. To maintain control of infection while also reducing disruption to populations, there is a need to understand what combination of measures—including novel digital tracing approaches and less intensive physical distancing—might be required to reduce transmission. We aimed to estimate the reduction in transmission under different control measures across settings and how many contacts would be quarantined per day in different strategies for a given level of symptomatic case incidence. Methods For this mathematical modelling study, we used a model of individual-level transmission stratified by setting (household, work, school, or other) based on BBC Pandemic data from 40 162 UK participants. We simulated the effect of a range of different testing, isolation, tracing, and physical distancing scenarios. Under optimistic but plausible assumptions, we estimated reduction in the effective reproduction number and the number of contacts that would be newly quarantined each day under different strategies. Results We estimated that combined isolation and tracing strategies would reduce transmission more than mass testing or self-isolation alone: mean transmission reduction of 2% for mass random testing of 5% of the population each week, 29% for self-isolation alone of symptomatic cases within the household, 35% for self-isolation alone outside the household, 37% for self-isolation plus household quarantine, 64% for self-isolation and household quarantine with the addition of manual contact tracing of all contacts, 57% with the addition of manual tracing of acquaintances only, and 47% with the addition of app-based tracing only. If limits were placed on gatherings outside of home, school, or work, then manual contact tracing of acquaintances alone could have an effect on transmission reduction similar to that of detailed contact tracing. In a scenario where 1000 new symptomatic cases that met the definition to trigger contact tracing occurred per day, we estimated that, in most contact tracing strategies, 15 000–41 000 contacts would be newly quarantined each day. Interpretation Consistent with previous modelling studies and country-specific COVID-19 responses to date, our analysis estimated that a high proportion of cases would need to self-isolate and a high proportion of their contacts to be successfully traced to ensure an effective reproduction number lower than 1 in the absence of other measures. If combined with moderate physical distancing measures, self-isolation and contact tracing would be more likely to achieve control of severe acute respiratory syndrome coronavirus 2 transmission. Funding Wellcome Trust, UK Engineering and Physical Scienc...

Strain structure is of fundamental importance in the underlying dynamics of a number of pathogens. However, previous models have been too complex to accommodate many strains. This paper offers a solution to this problem, in the form of a simple model that is capable of capturing the dynamics of a large number of antigenic types that interact via host cross-immunity. We derive the structure of the model, which can manage the complexity of many strains by using a status-based formulation, assuming polarized immunity and cross-immunity act to reduced transmission probability. We then apply the model to address basic questions in strain dynamics, focusing particularly on the interpandemic dynamics of influenza. This model shows that strains have a tendency to ''cluster.'' For a long infectious period, relative to host lifetime, clusters may coexist. By contrast, a short infectious period leads to a single dominant cluster at any given time. We show how the speed of cluster replacement depends on the specificity of cross-immunity and on the underlying pathogen mutation rate.

Influenza epidemics vary in intensity from year to year, driven by climatic conditions and by viral antigenic evolution. However, important spatial variation remains unexplained. Here we show predictable differences in influenza incidence among cities, driven by population size and structure. Weekly incidence data from 603 cities in the United States reveal that epidemics in smaller cities are focused on shorter periods of the influenza season, whereas in larger cities, incidence is more diffuse. Base transmission potential estimated from city-level incidence data is positively correlated with population size and with spatiotemporal organization in population density, indicating a milder response to climate forcing in metropolises. This suggests that urban centers incubate critical chains of transmission outside of peak climatic conditions, altering the spatiotemporal geometry of herd immunity.

A key question in pandemic influenza is the relative roles of innate immunity and target cell depletion in limiting primary infection and modulating pathology. Here, we model these interactions using detailed data from equine influenza virus infection, combining viral and immune (type I interferon) kinetics with estimates of cell depletion. The resulting dynamics indicate a powerful role for innate immunity in controlling the rapid peak in virus shedding. As a corollary, cells are much less depleted than suggested by a model of human influenza based only on virus-shedding data. We then explore how differences in the influence of viral proteins on interferon kinetics can account for the observed spectrum of virus shedding, immune response, and influenza pathology. In particular, induction of high levels of interferon ("cytokine storms"), coupled with evasion of its effects, could lead to severe pathology, as hypothesized for some fatal cases of influenza.

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Genome segmentation facilitates reassortment and rapid evolution of influenza A virus. However, segmentation complicates particle assembly as virions must contain all eight vRNA species to be infectious. Specific packaging signals exist that extend into the coding regions of most if not all segments, but these RNA motifs are poorly defined. We measured codon variability in a large dataset of sequences to identify areas of low nucleotide sequence variation independent of amino acid conservation in each segment. Most clusters of codons showing very little synonymous variation were located at segment termini, consistent with previous experimental data mapping packaging signals. Certain internal regions of conservation, most notably in the PA gene, may however signify previously unidentified functions in the virus genome. To experimentally test the bioinformatics analysis, we introduced synonymous mutations into conserved codons within known packaging signals and measured incorporation of the mutant segment into virus particles. Surprisingly, in most cases, single nucleotide changes dramatically reduced segment packaging. Thus our analysis identifies cis-acting sequences in the influenza virus genome at the nucleotide level. Furthermore, we propose that strain-specific differences exist in certain packaging signals, most notably the haemagglutinin gene; this finding has major implications for the evolution of pandemic viruses.

Social mixing patterns are crucial in driving transmission of infectious diseases and informing public health interventions to contain their spread. Age-specific social mixing is often inferred from surveys of self-recorded contacts which by design often have a very limited number of participants. In addition, such surveys are rare, so public health interventions are often evaluated by considering only one such study. Here we report detailed population contact patterns for