Doherty Institute - Research Publications
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ItemImpact of Emerging Antiviral Drug Resistance on Influenza Containment and Spread: Influence of Subclinical Infection and Strategic Use of a Stockpile Containing One or Two Drugs(PUBLIC LIBRARY SCIENCE, 2008-06-04)BACKGROUND: Wide-scale use of antiviral agents in the event of an influenza pandemic is likely to promote the emergence of drug resistance, with potentially deleterious effects for outbreak control. We explored factors promoting resistance within a dynamic infection model, and considered ways in which one or two drugs might be distributed to delay the spread of resistant strains or mitigate their impact. METHODS AND FINDINGS: We have previously developed a novel deterministic model of influenza transmission that simulates treatment and targeted contact prophylaxis, using a limited stockpile of antiviral agents. This model was extended to incorporate subclinical infections, and the emergence of resistant virus strains under the selective pressure imposed by various uses of one or two antiviral agents. For a fixed clinical attack rate, R(0) rises with the proportion of subclinical infections thus reducing the number of infections amenable to treatment or prophylaxis. In consequence, outbreak control is more difficult, but emergence of drug resistance is relatively uncommon. Where an epidemic may be constrained by use of a single antiviral agent, strategies that combine treatment and prophylaxis are most effective at controlling transmission, at the cost of facilitating the spread of resistant viruses. If two drugs are available, using one drug for treatment and the other for prophylaxis is more effective at preventing propagation of mutant strains than either random allocation or drug cycling strategies. Our model is relatively straightforward, and of necessity makes a number of simplifying assumptions. Our results are, however, consistent with the wider body of work in this area and are able to place related research in context while extending the analysis of resistance emergence and optimal drug use within the constraints of a finite drug stockpile. CONCLUSIONS: Combined treatment and prophylaxis represents optimal use of antiviral agents to control transmission, at the cost of drug resistance. Where two drugs are available, allocating different drugs to cases and contacts is likely to be most effective at constraining resistance emergence in a pandemic scenario.
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ItemDiagnosis and Antiviral Intervention Strategies for Mitigating an Influenza Epidemic(PUBLIC LIBRARY SCIENCE, 2011-02-04)BACKGROUND: Many countries have amassed antiviral stockpiles for pandemic preparedness. Despite extensive trial data and modelling studies, it remains unclear how to make optimal use of antiviral stockpiles within the constraints of healthcare infrastructure. Modelling studies informed recommendations for liberal antiviral distribution in the pandemic phase, primarily to prevent infection, but failed to account for logistical constraints clearly evident during the 2009 H1N1 outbreaks. Here we identify optimal delivery strategies for antiviral interventions accounting for logistical constraints, and so determine how to improve a strategy's impact. METHODS AND FINDINGS: We extend an existing SEIR model to incorporate finite diagnostic and antiviral distribution capacities. We evaluate the impact of using different diagnostic strategies to decide to whom antivirals are delivered. We then determine what additional capacity is required to achieve optimal impact. We identify the importance of sensitive and specific case ascertainment in the early phase of a pandemic response, when the proportion of false-positive presentations may be high. Once a substantial percentage of ILI presentations are caused by the pandemic strain, identification of cases for treatment on syndromic grounds alone results in a greater potential impact than a laboratory-dependent strategy. Our findings reinforce the need for a decentralised system capable of providing timely prophylaxis. CONCLUSIONS: We address specific real-world issues that must be considered in order to improve pandemic preparedness policy in a practical and methodologically sound way. Provision of antivirals on the scale proposed for an effective response is infeasible using traditional public health outbreak management and contact tracing approaches. The results indicate to change the transmission dynamics of an influenza epidemic with an antiviral intervention, a decentralised system is required for contact identification and prophylaxis delivery, utilising a range of existing services and infrastructure in a "whole of society" response.
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ItemA Biological Model for Influenza Transmission: Pandemic Planning Implications of Asymptomatic Infection and Immunity(PUBLIC LIBRARY SCIENCE, 2007-11-28)BACKGROUND: The clinical attack rate of influenza is influenced by prior immunity and mixing patterns in the host population, and also by the proportion of infections that are asymptomatic. This complexity makes it difficult to directly estimate R(0) from the attack rate, contributing to uncertainty in epidemiological models to guide pandemic planning. We have modelled multiple wave outbreaks of influenza from different populations to allow for changing immunity and asymptomatic infection and to make inferences about R(0). DATA AND METHODS: On the island of Tristan da Cunha (TdC), 96% of residents reported illness during an H3N2 outbreak in 1971, compared with only 25% of RAF personnel in military camps during the 1918 H1N1 pandemic. Monte Carlo Markov Chain (MCMC) methods were used to estimate model parameter distributions. FINDINGS: We estimated that most islanders on TdC were non-immune (susceptible) before the first wave, and that almost all exposures of susceptible persons caused symptoms. The median R(0) of 6.4 (95% credibility interval 3.7-10.7) implied that most islanders were exposed twice, although only a minority became ill in the second wave because of temporary protection following the first wave. In contrast, only 51% of RAF personnel were susceptible before the first wave, and only 38% of exposed susceptibles reported symptoms. R(0) in this population was also lower [2.9 (2.3-4.3)], suggesting reduced viral transmission in a partially immune population. INTERPRETATION: Our model implies that the RAF population was partially protected before the summer pandemic wave of 1918, arguably because of prior exposure to interpandemic influenza. Without such protection, each symptomatic case of influenza would transmit to between 2 and 10 new cases, with incidence initially doubling every 1-2 days. Containment of a novel virus could be more difficult than hitherto supposed.
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ItemUnderstanding influenza transmission, immunity and pandemic threats(WILEY, 2009-07)The current pandemic threat can be best understood within an ecological framework that takes account of the history of past pandemics caused by influenza A, the relationships between pandemic and seasonal spread of influenza viruses, and the importance of immunity and behavioural responses in human populations. Isolated populations without recent exposure to seasonal influenza seem more susceptible to new pandemic viruses, and much collateral evidence suggests that this is due to immunity directed against epitopes shared between pandemic and previously circulating strains of inter-pandemic influenza A virus. In the highly connected modern world, most populations are regularly exposed to non-pandemic viruses, which can even boost immunity without causing influenza symptoms. Such naturally-induced immunity helps to explain the low attack-rates of seasonal influenza, as well as the moderate attack-rates in many urbanized populations affected by 1918-1919 and later pandemics. The effectiveness of immunity, even against seasonal influenza, diminishes over time because of antigenic drift in circulating viruses and waning of post-exposure immune responses. Epidemiological evidence suggests that cross-protection against a new pandemic strain could fade even faster. Nevertheless, partial protection, even of short duration, induced by prior seasonal influenza or vaccination against it, could provide important protection in the early stages of a new pandemic.
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ItemUnderstanding mortality in the 1918-1919 influenza pandemic in England and Wales(WILEY-BLACKWELL, 2011-03)BACKGROUND: The causes of recurrent waves in the 1918-1919 influenza pandemic are not fully understood. OBJECTIVES: To identify the risk factors for influenza onset, spread and mortality in waves 1, 2 and 3 (summer, autumn and winter) in England and Wales in 1918-1919. METHODS: Influenza mortality rates for 333 population units and putative risk factors were analysed by correlation and by regressions weighted by population size and adjusted for spatial trends. RESULTS: For waves 1 and 3, influenza mortality was higher in younger, northerly and socially disadvantaged populations experiencing higher all-cause mortality in 1911-1914. Influenza mortality was greatest in wave 2, but less dependent on underlying population characteristics. Wave duration was shorter in areas with higher influenza mortality, typically associated with increasing population density. Regression analyses confirmed the importance of geographical factors and pre-pandemic mortality for all three waves. Age effects were complex, with the suggestion that younger populations with greater mortality in wave 1 had lesser mortality in wave 2. CONCLUSIONS: Our findings suggest that socially disadvantaged populations were more vulnerable, that older populations were partially protected by prior immunity in wave 1 and that exposure of (younger) populations in one wave could protect against mortality in the subsequent wave. An increase in viral virulence could explain the greater mortality in wave 2. Further modelling of causal processes will help to explain, in considerable detail, how social and geographical factors, season, pre-existing and acquired immunity and virulence affected viral transmission and pandemic mortality in 1918-1919.