Uncertainties in the governance of animal disease: an interdisciplinary framework for analysis

Uncertainty is an inherent feature of strategies to contain animal disease. In this paper, an interdisciplinary framework for representing strategies of containment, and analysing how uncertainties are embedded and propagated through them, is developed and illustrated. Analysis centres on persistent, periodic and emerging disease threats, with a particular focus on cryptosporidiosis, foot and mouth disease and avian influenza. Uncertainty is shown to be produced at strategic, tactical and operational levels of containment, and across the different arenas of disease prevention, anticipation and alleviation. The paper argues for more critically reflexive assessments of uncertainty in containment policy and practice. An interdisciplinary approach has an important contribution to make, but is absent from current real-world containment policy.     

Antiviral resistance and the control of pandemic influenza: the roles of stochasticity, evolution and model details

Antiviral drugs, most notably the neuraminidase inhibitors, are an important component of control strategies aimed to prevent or limit any future influenza pandemic. The potential large-scale use of antiviral drugs brings with it the danger of drug resistance evolution. A number of recent studies have shown that the emergence of drug-resistant influenza could undermine the usefulness of antiviral drugs for the control of an epidemic or pandemic outbreak. While these studies have provided important insights, the inherently stochastic nature of resistance generation and spread, as well as the potential for ongoing evolution of the resistant strain have not been fully addressed. Here, we study a stochastic model of drug resistance emergence and consecutive evolution of the resistant strain in response to antiviral control during an influenza pandemic. We find that taking into consideration the ongoing evolution of the resistant strain does not increase the probability of resistance emergence; however, it increases the total number of infecteds if a resistant outbreak occurs. Our study further shows that taking stochasticity into account leads to results that can differ from deterministic models. Specifically, we find that rapid and strong control cannot only contain a drug sensitive outbreak, it can also prevent a resistant outbreak from occurring. We find that the best control strategy is early intervention heavily based on prophylaxis at a level that leads to outbreak containment. If containment is not possible, mitigation works best at intermediate levels of antiviral control. Finally, we show that the results are not very sensitive to the way resistance generation is modeled.     

Organization and evaluation of the effectiveness of emergency prophylaxis and early treatment of influenza with remantadine in Serevodvinsk

The complex system of influenza control was introduced into practice at the public health institutions of Severodvinsk in 1976-1980. The effectiveness of the urgent prophylaxis and early treatment of influenza with remantadin, one of the most important elements of this system, was evaluated. The use of remantadin for the early and preventive treatment (urgent prophylaxis) of influenza among the population of the city decreased influenza morbidity 1.7-1.85 times, reduced the duration of the main clinical symptoms of the disease and sick leaves, the frequency of post-influenza complications, as well as the number of visitations of the sick by physicians.     

Optimal isolation control strategies and cost-effectiveness analysis of a two-strain avian influenza model

The most important and effective measures against disease outbreaks in the absence of valid medicines or vaccine are quarantine and isolation strategies. In this paper optimal control theory is applied to a system of ordinary differential equation describing a two-strain avian influenza transmission via the Pontryagin's Maximum Principle. To this end, a pair of control variables representing the isolation strategies for individuals with avian and mutant strains were incorporated into the transmission model. The infection averted ratio (IAR) and the incremental cost-effectiveness ratio (ICER) were calculated to investigate the cost-effectiveness of all possible combinations of the control strategies. The simulation results show that the implementation of the combination strategy during the epidemic is the most cost-effective strategy for avian influenza transmission. This is followed by the control strategy involving isolation of individuals with the mutant strain. Also observed was the fact that low mutating and more virulent virus results in an increased control effort of isolating individuals with the avian strain; and high mutating with more virulent virus results in increased efforts in isolating individuals with the mutant strain.     

Effectiveness of realistic vaccination strategies for contact networks of various degree distributions

A "contact network" that models infection transmission comprises nodes (or individuals) that are linked when they are in contact and can potentially transmit an infection. Through analysis and simulation, we studied the influence of the distribution of the number of contacts per node, defined as degree, on infection spreading and its control by vaccination. Three random contact networks of various degree distributions were examined. In a scale-free network, the frequency of high-degree nodes decreases as the power of the degree (the case of the third power is studied here); the decrease is exponential in an exponential network, whereas all nodes have the same degree in a constant network. Aiming for containment at a very early stage of an epidemic, we measured the sustainability of a specific network under a vaccination strategy by employing the critical transmissibility larger than which the epidemic would occur. We examined three vaccination strategies: mass, ring, and acquaintance. Irrespective of the networks, mass preventive vaccination increased the critical transmissibility inversely proportional to the unvaccinated rate of the population. Ring post-outbreak vaccination increased the critical transmissibility inversely proportional to the unvaccinated rate, which is the rate confined to the targeted ring comprising the neighbors of an infected node; however, the total number of vaccinated nodes could mostly be fewer than 100 nodes at the critical transmissibility. In combination, mass and ring vaccinations decreased the pathogen's "effective" transmissibility each by the factor of the unvaccinated rate. The amount of vaccination used in acquaintance preventive vaccination was lesser than the mass vaccination, particularly under a highly heterogeneous degree distribution; however, it was not as less as that used in ring vaccination. Consequently, our results yielded a quantitative assessment of the amount of vaccination necessary for infection containment, which is universally applicable to contact networks of various degree distributions.     

Democratic Pedagogy and the Discourse of Containment

This article points to the application of a discourse of containment in pedagogical practice. Growing out of a containment culture that has its beginnings in Cold War domestic strategies, the discourse of containment limits democratic possibilities in our classrooms, producing and legitimating a culture that governs what can be said and who can speak. Drawing on the mythologized version of the Rosa Parks story and the current agenda of conservative cultural managers and news media to contain the story around September 11,1 analyze the stakes in the political struggle over the control of the production of meaning in our classrooms.     

Control of snakebite envenoming: A mathematical modeling study

A mathematical model is designed to assess the impact of some interventional strategies for curtailing the burden of snakebite envenoming in a community. The model is fitted with real data set. Numerical simulations have shown that public health awareness of the susceptible individuals on snakebite preventive measures could reduce the number of envenoming and prevent deaths and disabilities in the population. The simulations further revealed that if at least fifty percent of snakebite envenoming patients receive early treatment with antivenom a substantial number of deaths will be averted. Furthermore, it is shown using optimal control that combining public health awareness and antivenom treatment averts the highest number of snakebite induced deaths and disability adjusted life years in the study area. To choose the best strategy amidst limited resources in the study area, cost effectiveness analysis in terms of incremental cost effectiveness ratio is performed. It has been established that the control efforts of combining public health awareness of the susceptible individuals and antivenom treatment for victims of snakebite envenoming is the most cost effective strategy. Approximately the sum of US$72,548 is needed to avert 117 deaths or 2,739 disability adjusted life years that are recorded within 21 months in the study area. Thus, the combination of these two control strategies is recommended.     

Optimizing Treatment Regimes to Hinder Antiviral Resistance in Influenza across Time Scales

The large-scale use of antivirals during influenza pandemics poses a significant selection pressure for drug-resistant pathogens to emerge and spread in a population. This requires treatment strategies to minimize total infections as well as the emergence of resistance. Here we propose a mathematical model in which individuals infected with wild-type influenza, if treated, can develop de novo resistance and further spread the resistant pathogen. Our main purpose is to explore the impact of two important factors influencing treatment effectiveness: i) the relative transmissibility of the drug-resistant strain to wild-type, and ii) the frequency of de novo resistance. For the endemic scenario, we find a condition between these two parameters that indicates whether treatment regimes will be most beneficial at intermediate or more extreme values (e.g., the fraction of infected that are treated). Moreover, we present analytical expressions for effective treatment regimes and provide evidence of its applicability across a range of modeling scenarios: endemic behavior with deterministic homogeneous mixing, and single-epidemic behavior with deterministic homogeneous mixing and stochastic heterogeneous mixing. Therefore, our results provide insights for the control of drug-resistance in influenza across time scales.     

Can influenza epidemics be prevented by voluntary vaccination?

Previous modeling studies have identified the vaccination coverage level necessary for preventing influenza epidemics, but have not shown whether this critical coverage can be reached. Here we use computational modeling to determine, for the first time, whether the critical coverage for influenza can be achieved by voluntary vaccination. We construct a novel individual-level model of human cognition and behavior; individuals are characterized by two biological attributes (memory and adaptability) that they use when making vaccination decisions. We couple this model with a population-level model of influenza that includes vaccination dynamics. The coupled models allow individual-level decisions to influence influenza epidemiology and, conversely, influenza epidemiology to influence individual-level decisions. By including the effects of adaptive decision-making within an epidemic model, we can reproduce two essential characteristics of influenza epidemiology: annual variation in epidemic severity and sporadic occurrence of severe epidemics. We suggest that individual-level adaptive decision-making may be an important (previously overlooked) causal factor in driving influenza epidemiology. We find that severe epidemics cannot be prevented unless vaccination programs offer incentives. Frequency of severe epidemics could be reduced if programs provide, as an incentive to be vaccinated, several years of free vaccines to individuals who pay for one year of vaccination. Magnitude of epidemic amelioration will be determined by the number of years of free vaccination, an individuals' adaptability in decision-making, and their memory. This type of incentive program could control epidemics if individuals are very adaptable and have long-term memories. However, incentive-based programs that provide free vaccination for families could increase the frequency of severe epidemics. We conclude that incentive-based vaccination programs are necessary to control influenza, but some may be detrimental. Surprisingly, we find that individuals' memories and flexibility in adaptive decision-making can be extremely important factors in determining the success of influenza vaccination programs. Finally, we discuss the implication of our results for controlling pandemics.     

Influenza Outbreak during Sydney World Youth Day 2008: The Utility of Laboratory Testing and Case Definitions on Mass Gathering Outbreak Containment

Background

Influenza causes annual epidemics and often results in extensive outbreaks in closed communities. To minimize transmission, a range of interventions have been suggested. For these to be effective, an accurate and timely diagnosis of influenza is required. This is confirmed by a positive laboratory test result in an individual whose symptoms are consistent with a predefined clinical case definition. However, the utility of these clinical case definitions and laboratory testing in mass gathering outbreaks remains unknown.

Methods and Results

An influenza outbreak was identified during World Youth Day 2008 in Sydney. From the data collected on pilgrims presenting to a single clinic, a Markov model was developed and validated against the actual epidemic curve. Simulations were performed to examine the utility of different clinical case definitions and laboratory testing strategies for containment of influenza outbreaks. Clinical case definitions were found to have the greatest impact on averting further cases with no added benefit when combined with any laboratory test. Although nucleic acid testing (NAT) demonstrated higher utility than indirect immunofluorescence antigen or on-site point-of-care testing, this effect was lost when laboratory NAT turnaround times was included. The main benefit of laboratory confirmation was limited to identification of true influenza cases amenable to interventions such as antiviral therapy.

Conclusions

Continuous re-evaluation of case definitions and laboratory testing strategies are essential for effective management of influenza outbreaks during mass gatherings.     

Assessment of border control measures and community containment measures used in Japan during the early stages of Pandemic (H1N1) 2009

Background

In the early stages of Pandemic (H1N1) 2009, border control measures were taken by quarantine stations to block the entry of infected individuals into Japan and community containment measures were implemented to prevent the spreading. The objectives of this study were to describe these measures and the characteristics of infected individuals, and to assess the measures'' effectiveness.

Methodology/Principal Findings

Border control and community containment measures implemented from April to June (Period I: April 28–May 21, Period II: May 22–June 18) 2009 were described. Number of individuals identified and disease characteristics were analyzed. For entry screening, a health declaration form and an infrared thermoscanner were used to detect symptomatic passengers. Passengers indicated for the rapid influenza test underwent the test followed by RT-PCR. Patients positive for H1N1 were isolated, and close contacts were quarantined. Entry cards were handed out to all asymptomatic passengers informing them about how to contact a health center in case they developed symptoms. Nine individuals were identified by entry screening and 1 during quarantine to have Pandemic (H1N1) 2009. Health monitoring by health centers was performed in period I for passengers arriving from affected countries and in period II for those who had come into contact with the individuals identified by entry screening. Health monitoring identified 3 infected individuals among 129,546 in Period I and 5 among 746 in Period II. Enhanced surveillance, which included mandatory reporting of details of the infected individuals, identified 812 individuals, 141 (18%) of whom had a history of international travel. Twenty-four of these 141 passengers picked up by enhanced surveillance had been developing symptoms on entry and were missed at screening.

Conclusion/Significance

Symptomatic passengers were detected by the various entry screening measures put in place. Enhanced surveillance provided data for the improvement of public health measures in future pandemics.     

Baculovirus Displaying Hemagglutinin Elicits Broad Cross-Protection against Influenza in Mice

The widespread influenza virus infection further emphasizes the need for novel vaccine strategies that effectively reduce the impact of epidemic as well as pandemic influenza. Conventional influenza vaccines generally induce virus neutralizing antibody responses which are specific for a few antigenically related strains within the same subtype. However, antibodies directed against the conserved stalk domain of HA could neutralize multiple subtypes of influenza virus and thus provide broad-spectrum protection. In this study, we designed and constructed a recombinant baculovirus-based vaccine, rBac-HA virus, that expresses full-length HA of pandemic H1N1 influenza virus (A/California/04/09) on the viral envelope. We demonstrated that repeated intranasal immunizations with rBac-HA virus induced HA stalk-specific antibody responses and protective immunity against homologous as well as heterosubtypic virus challenge. The adoptive transfer experiment shows that the cross-protection is conferred by the immune sera which contain HA stalk-specific antibodies. These results warrant further development of rBac-HA virus as a broad-protective vaccine against influenza. The vaccine induced protection against infection with the same subtype as well as different subtype, promising a potential universal vaccine for broad protection against different subtypes to control influenza outbreaks including pandemic.     

Erratic flu vaccination emerges from short-sighted behavior in contact networks

The effectiveness of seasonal influenza vaccination programs depends on individual-level compliance. Perceptions about risks associated with infection and vaccination can strongly influence vaccination decisions and thus the ultimate course of an epidemic. Here we investigate the interplay between contact patterns, influenza-related behavior, and disease dynamics by incorporating game theory into network models. When individuals make decisions based on past epidemics, we find that individuals with many contacts vaccinate, whereas individuals with few contacts do not. However, the threshold number of contacts above which to vaccinate is highly dependent on the overall network structure of the population and has the potential to oscillate more wildly than has been observed empirically. When we increase the number of prior seasons that individuals recall when making vaccination decisions, behavior and thus disease dynamics become less variable. For some networks, we also find that higher flu transmission rates may, counterintuitively, lead to lower (vaccine-mediated) disease prevalence. Our work demonstrates that rich and complex dynamics can result from the interaction between infectious diseases, human contact patterns, and behavior.     

Combination Effects of Peramivir and Favipiravir against Oseltamivir-Resistant 2009 Pandemic Influenza A(H1N1) Infection in Mice

Antiviral drugs are being used for therapeutic purposes against influenza illness in humans. However, antiviral-resistant variants often nullify the effectiveness of antivirals. Combined medications, as seen in the treatment of cancers and other infectious diseases, have been suggested as an option for the control of antiviral-resistant influenza viruses. Here, we evaluated the therapeutic value of combination therapy against oseltamivir-resistant 2009 pandemic influenza H1N1 virus infection in DBA/2 mice. Mice were treated for five days with favipiravir and peramivir starting 4 hours after lethal challenge. Compared with either monotherapy, combination therapy saved more mice from viral lethality and resulted in increased antiviral efficacy in the lungs of infected mice. Furthermore, the synergism between the two antivirals, which was consistent with the survival outcomes of combination therapy, indicated that favipiravir could serve as a critical agent of combination therapy for the control of oseltamivir-resistant strains. Our results provide new insight into the feasibility of favipiravir in combination therapy against oseltamivir-resistant influenza virus infection.     

Antibody Persistence in Adults Two Years after Vaccination with an H1N1 2009 Pandemic Influenza Virus-Like Particle Vaccine

The influenza virus is a human pathogen that causes epidemics every year, as well as potential pandemic outbreaks, as occurred in 2009. Vaccination has proven to be sufficient in the prevention and containment of viral spreading. In addition to the current egg-based vaccines, new and promising vaccine platforms, such as cell culture-derived vaccines that include virus-like particles (VLPs), have been developed. VLPs have been shown to be both safe and immunogenic against influenza infections. Although antibody persistence has been studied in traditional egg-based influenza vaccines, studies on antibody response durations induced by VLP influenza vaccines in humans are scarce. Here, we show that subjects vaccinated with an insect cell-derived VLP vaccine, in the midst of the 2009 H1N1 influenza pandemic outbreak in Mexico City, showed antibody persistence up to 24 months post-vaccination. Additionally, we found that subjects that reported being revaccinated with a subsequent inactivated influenza virus vaccine showed higher antibody titres to the pandemic influenza virus than those who were not revaccinated. These findings provide insights into the duration of the antibody responses elicited by an insect cell-derived pandemic influenza VLP vaccine and the possible effects of subsequent influenza vaccination on antibody persistence induced by this VLP vaccine in humans.     

Seasonal influenza activity in Japan and epidemiological investigation for avian influenza

We analyzed the seasonal influenza activity in 2004/05 and 2005/06 seasons. In 2004/05 season, the prevalence of influenza started lately. The arrival of a peak of influenzal prevalence was the ninth week, and was late in comparison with an average year. The prevalence scale was very large, and the estimation number of patients was 17,700,000. Since the start of the 2004/05 season, influenza activity has mainly been associated with influenza B viruses. The start of prevalence of 2005/06 season was 50th week and was comparatively early. The peak of the prevalence was the 4th week, same as an average year. Since the start of the 2005/06 season, influenza activity has mainly been associated with influenza A/H3 viruses.H5N1 highly pathogenic avian influenza virus have spread through Africa and Europe from Asia. For purpose such as inhibition of the outbreak of new variant influenza, the prevention of human to human infection and expansion, early containment, the public health organization has to do unified epidemiological investigation immediately nationwide. By doing epidemiological investigation, the prevention of infection expansion, specification of the source of infection, assessment of the risk of infection, and early detection of new variant influenza virus and containment, are expected.     

Return of inactivated whole-virus vaccine for superior efficacy

The swine, influenza, H1N1 outbreak in 2009 highlighted the inadequacy of the currently used antibody-based vaccine strategies as a preventive measure for combating influenza pandemics. The ultimate goal for successful control of newly arising influenza outbreaks is to design a single-shot vaccine that will provide long-lasting immunity against all strains of influenza A virus. A large amount of data from animal studies has indicated that the cross-reactive cytotoxic T (Tc) cell response against conserved influenza virus epitopes may be the key immune response needed for a universal influenza vaccine. However, decades of research have shown that the development of safe T-cell-based vaccines for influenza is not an easy task. Here, I discuss the overlooked but potentially highly advantageous inactivation method, namely, γ-ray irradiation, as a mean to reach the Holy Grail of influenza vaccinology.     

Impact of Travel Between Patches for Spatial Spread of Disease

A multipatch model is proposed to study the impact of travel on the spatial spread of disease between patches with different level of disease prevalence. The basic reproduction number for the ith patch in isolation is obtained along with the basic reproduction number of the system of patches, ℜ₀. Inequalities describing the relationship between these numbers are also given. For a two-patch model with one high prevalence patch and one low prevalence patch, results pertaining to the dependence of ℜ₀ on the travel rates between the two patches are obtained. For parameter values relevant for influenza, these results show that, while banning travel of infectives from the low to the high prevalence patch always contributes to disease control, banning travel of symptomatic travelers only from the high to the low prevalence patch could adversely affect the containment of the outbreak under certain ranges of parameter values. Moreover, banning all travel of infected individuals from the high to the low prevalence patch could result in the low prevalence patch becoming diseasefree, while the high prevalence patch becomes even more disease-prevalent, with the resulting number of infectives in this patch alone exceeding the combined number of infectives in both patches without border control. Under the set of parameter values used, our results demonstrate that if border control is properly implemented, then it could contribute to stopping the spatial spread of disease between patches.     

The Hospital's Perspective on Cost Containment

Cost containment has long been a concern of hospitals and the American Hospital Association (AHA). In recent years, however, cost containment has assumed a special prominence in hospitals, becoming both a political and social necessity. The hospitals'' and AHA''s activities in cost containment fall into four major categories: first, the Voluntary Effort to Contain Health Care Costs, of which AHA is a founding partner; second, administrative effectiveness; third, capital effectiveness, and, finally, medical effectiveness. Some programs to promote administrative effectiveness are shared administrative services, energy conservation, careful attention to staffing patterns and management effectiveness review. Capital effectiveness involves technology assessment and other means of deciding how to make the most of the hospital''s dollar. Medical effectiveness can be accomplished by such methods as medical audits, utilization reviews and shared clinical services.     

Transmission of a 2009 H1N1 Pandemic Influenza Virus Occurs before Fever Is Detected, in the Ferret Model

During the early phase of the 2009 influenza pandemic, attempts were made to contain the spread of the virus. Success of reactive control measures may be compromised if the proportion of transmission that occurs before overt clinical symptoms develop is high. In this study we investigated the timing of transmission of an early prototypic strain of pandemic H1N1 2009 influenza virus in the ferret model. Ferrets are the only animal model in which this can be assessed because they display typical influenza-like clinical signs including fever and sneezing after infection. We assessed transmission from infected animals to sentinels that were placed either in direct contact or in adjacent cages, the latter reflecting the respiratory droplet (RD) transmission route. We found that pre-symptomatic influenza transmission occurred via both contact and respiratory droplet exposure before the earliest clinical sign, fever, developed. Three of 3 animals exposed in direct contact between day 1 and 2 after infection of the donor animals became infected, and 2/3 of the animals exposed at this time period by the RD route acquired the infection, with the third animal becoming seropositive indicating either a low level infection or significant exposure. Moreover, this efficient transmission did not temporally correlate with respiratory symptoms, such as coughs and sneezes, but rather with the peak viral titre in the nose. Indeed respiratory droplet transmission did not occur late in infection, even though this was when sneezing and coughing were most apparent. None of the 3 animals exposed at this time by the RD route became infected and these animals remained seronegative at the end of the experiment. These data have important implications for pandemic planning strategies and suggest that successful containment is highly unlikely for a human-adapted influenza virus that transmits efficiently within a population.