Ian F. Miller

Objectives Bevacizumab was approved for first-line treatment of metastatic colorectal cancer (mCRC) in 2004. However, adding bevacizumab to treatment consistently fails to be cost-effective owing to modest response rates. Recently, the European Commission (EC) funded ANGIOPREDICT consortium (www.angiopredict.com) identified a link between bevacizumab treatment response and intermediate-to-high chromosomal instability (CIN) in mCRC. Thus, the objective of the current study was to compare the cost-effectiveness of adding bevacizumab with first-line chemotherapy in the bevacizumab responsive CIN subtype across three European countries (Germany, Ireland and Spain) with varying costs of care and reimbursement policies. Methods We developed an open-source health economic model to estimate cost-effectiveness. The ANGIOPREDICT cohort informed progression risks and cause-specific mortality. Health utilities and adverse events probabilities were obtained from the literature. Costs were derived from surveys of collaborating consortium hospitals in Germany, Ireland, and Spain that participated in the recently completed EC funded COLOSSUS translational study (ANGIOPREDICT successor initiative) and the literature. Sensitivity analyses included individual and simultaneous variation of input parameters from a priori defined distributions. Results Bevacizumab was not cost effective even at willingness–to-pay (WTP) thresholds that are appreciably higher than those considered realistic. The highest incremental cost-effectiveness ratio (ICER) was in Germany at €241,188 per quality-adjusted life year (QALY), while the lowest was in Ireland at €180,477 per QALY. All deterministic and probabilistic sensitivity analyses demonstrated that these results were robust. Conclusions Even for patients with mCRC manifesting improved outcomes, adding bevacizumab to first-line chemotherapy is invariably not cost-effective in any of the countries examined. Variability in pricing, healthcare costs and WTP thresholds across countries did not commute this result.

The scale of influence of hydrological and thermal conditions on plant disease remains uncertain for most natural plant pathosystems, restricting our ability to predict the potential impacts of climate change. Analysis of the spatiotemporal spread of a fungal rust pathogen across four naturally occurring flax populations over the course of five growing seasons reveals both expected relationships with snow cover, relative humidity and temperature, and a novel footprint of severe drought. This indicates that climate change may have substantial drought-mediated impacts on the spread of plant disease, and points to a need for further research integrating population-level epidemiological studies with mechanistic environmental studies to explore the effects of drought on natural plant epidemics.

Climate change and shifting environmental conditions can allow pathogens to spread into previously unburdened areas. For plant pathogens, this dynamic has the potential to disrupt natural ecosystem equilibria and human agriculture, making predicting plant pathogen range shifts increasingly important. Although such predictions will hinge on an accurate understanding of the determinants of pathogen range—namely the environmental, geographical, and host range characteristics that modulate local pathogen habitation—few studies to date have probed these in natural plant populations. Here, we characterize range determinants for the model system of Lewis flax (Linum lewisii) and its pathogen, flax rust (Melampsora lini), in the Rocky Mountains. Transect surveys were performed to assess three relationships: (i) the effect of geographical features—elevation, slope aspect, slope grade, and land cover—on flax presence and density, (ii) the effect of geographical features on flax rust presence and prevalence, and (iii) the effects of flax's local population density and metapopulation structure on flax rust presence and prevalence. We found that flax population density, but not host metapopulation structure, influences the distribution of flax rust. Additionally, we showed that, while the distribution of flax was broadly constrained to a relatively narrow range of geographical and resulting environmental features, flax rust was evenly distributed across the full range of settings measured. These results indicate that a warming environment, which is expected to modulate such features, may restrict the optimal range of the plant more than that of its pathogen. Importantly, our results also suggest that even if flax shifts its spatial range to escape increasing climatic pressures, flax rust will not face any significant barriers to track this movement.

Climate change and shifting environmental conditions can allow pathogens to spread into previously unburdened areas. For plant pathogens, this dynamic has the potential to disrupt natural ecosystem equilibria and human agriculture, making predicting plant pathogen range shifts an increasingly important enterprise. Although such predictions will hinge on an accurate understanding of the determinants of pathogen range – namely the environmental, geographical, and host range characteristics that modulate local pathogen habitation – few studies to date have probed these in natural plant populations. Here, we characterize range determinants for the model system of Lewis flax (Linum Lewisii) and its pathogen, flax rust (Melamspora lini), in the Rocky Mountains. Transect surveys were performed to assess three relationships: i) the effect of geographical features – elevation, slope aspect, slope grade, and land-cover – on flax presence and density, ii) the effect of geographical features on flax rust presence and prevalence, and iii) the effects of flax’s local population density and metapopulation structure on flax rust presence and prevalence. We found that flax population density, but not host metapopulation structure, influences the distribution of flax rust. Additionally, we showed that, while the distribution of flax was broadly constrained to a relatively narrow range of geographical and resulting environmental features, flax rust was evenly distributed across the full range of settings measured. These results indicate that a warming environment, which is expected to modulate such features, may restrict the optimal range of the plant more so than that of its pathogen. Importantly, our results also suggest that even if flax shifts its spatial range to escape increasing climatic pressures, flax rust will not face any significant barriers to track this movement.

Evidence that climate change will impact the ecology and evolution of individual plant species is growing. However, little, as yet, is known about how climate change will affect interactions between plants and their pathogens. Climate drivers could affect the physiology, and thus demography, and ultimately evolutionary processes affecting both plant hosts and their pathogens. Because the impacts of climate drivers may operate in different directions at different scales of infection, and, furthermore, may be nonlinear, abstracting across these processes may mis-specify outcomes. Here, we use mechanistic models of plant–pathogen interactions to illustrate how counterintuitive outcomes are possible, and we introduce how such framing may contribute to understanding climate effects on plant–pathogen systems. We discuss the evidence-base derived from wild and agricultural plant–pathogen systems that could inform such models, specifically in the direction of estimates of physiological, demographic and evolutionary responses to climate change. We conclude by providing an overview of knowledge gaps and directions for future research in this important area. This article is part of the theme issue ‘Infectious disease ecology and evolution in a changing world’.

The potential for climate change to exacerbate the burden of human infectious diseases is increasingly recognized, but its effects on infectious diseases of plants have received less attention. Understanding the impacts of climate on the epidemiological dynamics of plant pathogens is imperative, as these organisms play central roles in natural ecosystems and also pose a serious threat to agricultural production and food security. We use the fungal ‘flax rust’ pathogen (Melampsora lini) and its subalpine wildflower host Lewis flax (Linum lewisii) to investigate how climate change might affect the dynamics of fungal plant pathogen epidemics using a combination of empirical and modeling approaches. Our results suggest that climate change will initially slow transmission at both the within- and between-host scales. However, moderate resurgences in disease spread are predicted as warming progresses, especially if the rate of greenhouse gas emissions continues to increase at its current pace. These findings represent an important step towards building a holistic understanding of climate effects on plant infectious disease that encompasses demographic, epidemiological, and evolutionary processes. A core result is that neglecting processes at any one scale of plant pathogen transmission may bias projections of climate effects, as climate drivers have variable and cascading impacts on processes underlying transmission that occur at different scales.

The evolution of SARS-CoV-2 virulence, or lethality, threatens to exacerbate the burden of COVID-19 on society. How might COVID-19 vaccines alter selection for increased SARS-CoV-2 virulence? Framing current evidence surrounding SARS-CoV-2 biology and COVID-19 vaccines in the context of evolutionary theory indicates that prospects for virulence evolution remain uncertain. However, differential effects of vaccinal immunity on transmission and disease severity between respiratory compartments could select for increased virulence. To bound expectations for this outcome, we analyse an evo-epidemiological model. Synthesizing model predictions with vaccine efficacy data, we conclude that while vaccine-driven virulence remains a theoretical possibility, the risk is low if vaccines provide sustained robust protection against infection. Furthermore, we found that any increases in transmission concomitant with increases in virulence would be unlikely to threaten prospects for herd immunity in a highly immunized population. Given that virulence evolution would nevertheless impact unvaccinated individuals and populations with low vaccination rates, it is important to achieve high vaccination rates worldwide and ensure that vaccinal immunity provides robust protection against both infection and disease, potentially through the use of booster doses.

The twenty-first century has witnessed a wave of severe infectious disease outbreaks, not least the COVID-19 pandemic, which has had a devastating impact on lives and livelihoods around the globe. The 2003 severe acute respiratory syndrome coronavirus outbreak, the 2009 swine flu pandemic, the 2012 Middle East respiratory syndrome coronavirus outbreak, the 2013–2016 Ebola virus disease epidemic in West Africa and the 2015 Zika virus disease epidemic all resulted in substantial morbidity and mortality while spreading across borders to infect people in multiple countries. At the same time, the past few decades have ushered in an unprecedented era of technological, demographic and climatic change: airline flights have doubled since 2000, since 2007 more people live in urban areas than rural areas, population numbers continue to climb and climate change presents an escalating threat to society. In this Review, we consider the extent to which these recent global changes have increased the risk of infectious disease outbreaks, even as improved sanitation and access to health care have resulted in considerable progress worldwide.

A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (for example, warmer environments¹, younger populations^2,3,4) have yet to be framed within a comprehensive analysis. We synthesized factors hypothesized to drive the pace and burden of this pandemic in SSA during the period from 25 February to 20 December 2020, encompassing demographic, comorbidity, climatic, healthcare capacity, intervention efforts and human mobility dimensions. Large diversity in the probable drivers indicates a need for caution in interpreting analyses that aggregate data across low- and middle-income settings. Our simulation shows that climatic variation between SSA population centers has little effect on early outbreak trajectories; however, heterogeneity in connectivity, although rarely considered, is likely an important contributor to variance in the pace of viral spread across SSA. Our synthesis points to the potential benefits of context-specific adaptation of surveillance systems during the ongoing pandemic. In particular, characterizing patterns of severity over age will be a priority in settings with high comorbidity burdens and poor access to care. Understanding the spatial extent of outbreaks warrants emphasis in settings where low connectivity could drive prolonged, asynchronous outbreaks resulting in extended stress to health systems.

How might COVID-19 vaccines alter selection for increased SARS-CoV-2 virulence, or lethality? Framing current evidence surrounding SARS-CoV-2 biology and COVID-19 vaccines in the context of evolutionary theory indicates that prospects for virulence evolution remain uncertain. However, differential effects of vaccinal immunity on transmission and disease severity between respiratory compartments could select for increased virulence. To bound expectations for this outcome, we analyze an evo-epidemiological model. Synthesizing model predictions with vaccine efficacy data, we conclude that while vaccine driven virulence evolution remains a theoretical risk, it is unlikely to threaten prospects for herd immunity in immunized populations. Given that this event would nevertheless impact unvaccinated populations, virulence should be monitored to facilitate swift mitigation efforts. Significance statement: Vaccines can provide personal and population level protection against infectious disease, but these benefits can exert strong selective pressures on pathogens. Virulence, or lethality, is one pathogen trait that can evolve in response to vaccination. We investigated whether COVID-19 vaccines could select for increased SARS-CoV-2 virulence by reviewing current evidence about vaccine efficacy and SARS-CoV-2 biology in the context of evolutionary theory, and subsequently analyzing a mathematical model. Our findings indicate that while vaccine-driven virulence evolution in SARS-CoV-2 is a theoretical risk, the consequences of this event would be limited for vaccinated populations. However, virulence evolution should be monitored, as the ramifications of a more virulent strain spreading into an under-vaccinated population would be more severe.