Antibodies mediate formation of neutrophil extracellular traps in the middle ear and facilitate secondary pneumococcal otitis media

Otitis media (OM) (a middle ear infection) is a common childhood illness that can leave some children with permanent hearing loss. OM can arise following infection with a variety of different pathogens, including a coinfection with influenza A virus (IAV) and Streptococcus pneumoniae (the pneumococcus). We and others have demonstrated that coinfection with IAV facilitates the replication of pneumococci in the middle ear. Specifically, we used a mouse model of OM to show that IAV facilitates the outgrowth of S. pneumoniae in the middle ear by inducing middle ear inflammation. Here, we seek to understand how the host inflammatory response facilitates bacterial outgrowth in the middle ear. Using B cell-deficient infant mice, we show that antibodies play a crucial role in facilitating pneumococcal replication. We subsequently show that this is due to antibody-dependent neutrophil extracellular trap (NET) formation in the middle ear, which, instead of clearing the infection, allows the bacteria to replicate. We further demonstrate the importance of these NETs as a potential therapeutic target through the transtympanic administration of a DNase, which effectively reduces the bacterial load in the middle ear. Taken together, these data provide novel insight into how pneumococci are able to replicate in the middle ear cavity and induce disease.

Swine flu, doctors and pandemics : Is there a duty to treat during a pandemic?

The swine influenza (H1N1) outbreak in 2009 highlighted the ethical and legal pressures facing general practitioners and health workers in emergency departments in determining the nature and limits of their obligations to their patients and the public. Health workers require guidance on the multiple, overlapping, and at times conflicting legal and ethical duties owed to patients and prospective patients, employers and fellow health workers, and their families. Existing sources of advice on these issues in Australia, by way of statements of medical ethics and other sources of advice, are shown to be in need of further amplification if health workers are to be provided with the certainty and guidance required. Given the complexity of the issues, Australia would therefore benefit from more extensive consultation with the variety of stakeholders involved in these questions if pandemic plans are to smoothly deal with future crises in an ethically and legally sound manner.

Legal rights during pandemics : federalism, rights and public health laws - a view from Australia

Pandemic influenza will cause significant social and economic disruption. Legal frameworks can play an important role in clarifying the rights and duties of individuals, communities and governments for times of crisis. In addressing legal frameworks, there is a need for jurisdictional clarity between different levels of government in responding to public health emergencies. Public health laws are also informed by our understandings of rights and responsibilities for individuals and communities, and the balancing of public health and public freedoms. Consideration of these issues is an essential part of planning for pandemic influenza.

A systematic review of community-based interventions for emerging zoonotic diseases in Southeast Asia

Background Southeast Asia has been at the epicentre of recent epidemics of emerging and re-emerging zoonotic diseases. Community-based surveillance and control interventions have been heavily promoted but the most effective interventions have not been identified. Objectives This review evaluated evidence for the effectiveness of community-based surveillance interventions at monitoring and identifying emerging infectious disease; the effectiveness of community-based control interventions at reducing rates of emerging infectious disease; and contextual factors that influence intervention effectiveness. Inclusion criteria Participants Communities in Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand and Viet Nam. Types of intervention(s) Non-pharmaceutical, non-vaccine, and community-based surveillance or prevention and control interventions targeting rabies, Nipah virus , dengue, SARS or avian influenza. Types of outcomes Primary outcomes: measures: of infection or disease; secondary outcomes: measures of intervention function. Types of studies Original quantitative studies published in English. Search strategy Databases searched (1980 to 2011): PubMed, CINAHL, ProQuest, EBSCOhost, Web of Science, Science Direct, Cochrane database of systematic reviews, WHOLIS, British Development Library, LILACS, World Bank (East Asia), Asian Development Bank. Methodological quality Two independent reviewers critically appraised studies using standard Joanna Briggs Institute instruments. Disagreements were resolved through discussion. Data extraction A customised tool was used to extract quantitative data on intervention(s), populations, study methods, and primary and secondary outcomes; and qualitative contextual information or narrative evidence about interventions. Data synthesis Data was synthesised in a narrative summary with the aid of tables. Meta-analysis was used to statistically pool quantitative results. Results Fifty-seven studies were included. Vector control interventions using copepods, environmental cleanup and education are effective and sustainable at reducing dengue in rural and urban communities, whilst insecticide spraying is effective in urban outbreak situations. Community-based surveillance interventions can effectively identify avian influenza in backyard flocks, but have not been broadly applied. Outbreak control interventions for Nipah virus and SARS are effective but may not be suitable for ongoing control. Canine vaccination and education is more acceptable than culling, but still fails to reach coverage levels required to effectively control rabies. Contextual factors were identified that influence community engagement with, and ultimately effectiveness of, interventions. Conclusion Despite investment in community-based disease control and surveillance in Southeast Asia, published evidence evaluating interventions is limited in quantity and quality. Nonetheless this review identified a number of effective interventions, and several contextual factors influencing effectiveness. Identification of the best programs will require comparative evidence of effectiveness acceptability, cost-effectiveness and sustainability.

The duty to report disease outbreaks : of interest or value? Lessons from H5N1

Since the severe acute respiratory syndrome outbreak in 2003, it has been argued that there has been a substantial revision to the norm dictating the behaviour of states in the event of a disease outbreak. This article examines the evolution of the norm to ‘report and verify’ disease outbreaks and evaluates the extent to which this revised norm has begun to guide state behaviour. Examination of select East Asian countries affected by human infections of the H5N1 (avian influenza) virus strain reveals the need to further understand the mutually constitutive relationship between the value attached to prompt reporting against the capacity to report, and how states manage both in fulfilling their duty to report.

Vulnerability : an issue for law and policy in pandemic planning?

The 2009 H!Nl 'swine flu' pandemic was the first influenza pandemic of the twenty-first centmy. Unlike the first influenza pandemic of the twentieth century, the so-called 'Spanish flu' which killed millions of people worldwide, the 2009 pandemic was relatively mild. While the mildness of the 2009 pandemic meant that the 'Yorld was spared from the impact of a high-mortality event that would cause widespread social and economic disruption, the 2009 pandemic did provide an opportunity to road-test pandemic readiness. In other work we have assessed Australia's pandemic plans and emergency management legislation, finding that both provide flexible and adaptive forms of regulation that are capable of adapting to the scale and severity of a pandemic or other public health emergency. 1 In this chapter we consider whether pandemic planning adequately addresses the needs of vulnerable individuals and groups, both within countries and between them. Central to this is the question of whether vulnerability is itself a useful concept for both law and policy, and if so, the implications of expressly incorporating the concept of vulnerability into pandemic planning.

Preparing Queensland pharmacists to vaccinate – Australia’s first pharmacists immunisation pilot

In November 2013, the Queensland Department of Health announced its intention to pilot pharmacists vaccination for influenza in the 2014 Flu season. The Pharmaceutical Society of Australia Queensland Branch was tasked with development of an appropriate training program for the pilot.

Australia’s first Pharmacist Immunisation Pilot - who did pharmacists inject?

The Queensland Pharmacist Immunisation Pilot is Australia’s first to allow pharmacists vaccination. The pilot ran between April 1st 2014 and August 31st 2014, with pharmacists administering influenza vaccination during the flu season. METHODS Participant demographics and previous influenza vaccination experiences were recorded using GuildCare software. Participants also completed a ‘post-vaccination satisfaction survey’ following their influenza vaccination. RESULTS A total of 11,475 participant records were analysed. Females accounted for 63% of participants, with the majority of participants aged between 45 – 64 years (53%). Overall, 49% of participants had been vaccinated before, the majority at a GP clinic (60%). Most participants reported receiving their previous influenza vaccination from a nurse (61%). Interestingly, 1% thought a pharmacist had administered their previous vaccination, while 7% were unsure which health professional had administer it. It was also of note that approximately 10% of all participants were eligible to receive a free vaccination from the National Immunisation Program, but still opted to receive their vaccine in a pharmacy. Over 8,000 participants took part in the post-vaccination survey, 93% were happy to receive their vaccination from a pharmacy in the future while 94% would recommend this service to other people. The remaining 7% and 6% respectively had omitted to fill in those questions. DISCUSSION Participants were overwhelmingly positive in their response to the pharmacist vaccination pilot. These findings have helped pave the way for expanding the scope of practice for pharmacists with the aim to increase vaccination rates across the state.

The Australian prehospital pandemic risk perception study and an examination of new public health roles in pandemic response for ambulance services

This report is one of a series of products resulting from a National Health and Medical Research Council (NHMRC) Urgent Research Grant – Pandemic Influenza [No 409973]. The research targeted two key aspects of planning and preparedness for a human influenza pandemic, namely:

Using DNA as a drug - bioprocessing and delivery strategies

DNA may take a leading role in a future generation of blockbuster therapeutics. DNA has inherent advantages over other biomolecules such as protein, RNA and virus-like particles including safety, production simplicity and higher stability at ambient temperatures. Vaccination is the principal measure for preventing influenza and reducing the impact of pandemics; however, vaccines take up to 8-9 months to produce, and the global production capacity is woefully low. With production times as short as 2 weeks, improved safety and stability, bioprocess engineering developments, and the ability to perform numerous therapeutic roles, DNA has the potential to meet the demands of emerging and existing diseases. DNA is experiencing sharp growths in demand as indicated by its use in gene therapy trials and DNA vaccine related patents. Of particular interest for therapeutic use is plasmid DNA (pDNA), a form of non-genomic DNA that makes use of cellular machinery to express proteins or antigens. The production stages of fermentation and downstream purification are considered in this article. Forward looking approaches to purifying and delivering DNA are reported, including affinity chromatography and nasal inhalation. The place that pDNA may take in the preparation for and protection against pandemics is considered. If DNA therapeutics and vaccines prove to be effective, the ultimate scale of production will be huge which shall require associated bioprocess engineering research and development for purification of this large, unique biomolecule.

Inorganic-organic composite particle as a staged delivery platform for plasmid DNA-based biopharmaceuticals

Infectious diseases such as SARS, influenza and bird flu may spread exponentially throughout communities. In fact, most infectious diseases remain major health risks due to the lack of vaccine or the lack of facilities to deliver the vaccines. Conventional vaccinations are based on damaged pathogens, live attenuated viruses and viral vectors. If the damage was not complete, the vaccination itself may cause adverse effects. Therefore, researchers have been prompted to prepare viable replacements for the attenuated vaccines that would be more effective and safer to use. DNA vaccines are generally composed of a double stranded plasmid that includes a gene encoding the target antigen under the transcriptional directory and control of a promoter region which is active in cells. Plasmid DNA (pDNA) vaccines allow the foreign genes to be expressed transiently in cells, mimicking intracellular pathogenic infection and inducing both humoral and cellular immune responses. Currently, because of their highly evolved and specialized components, viral systems are the most effective means for DNA delivery, and they achieve high efficiencies (generally >90%), for both DNA delivery and expression. As yet, viral-mediated deliveries have several limitations, including toxicity, limited DNA carrying capacity, restricted target to specific cell types, production and packing problems, and high cost. Thus, nonviral systems, particularly a synthetic DNA delivery system, are highly desirable in both research and clinical applications.

Process engineering aspects of plasmid-based biopharmaceuticals production : tackling the threatening vaccine shortages to prevent global pandemics

Infectious diseases such as SARS, influenza and bird flu have the potential to cause global pandemics; a key intervention will be vaccination. Hence, it is imperative to have in place the capacity to create vaccines against new diseases in the shortest time possible. In 2004, The Institute of Medicine asserted that the world is tottering on the verge of a colossal influenza outbreak. The institute stated that, inadequate production system for influenza vaccines is a major obstruction in the preparation towards influenza outbreaks. Because of production issues, the vaccine industry is facing financial and technological bottlenecks: In October 2004, the FDA was caught off guard by the shortage of flu vaccine, caused by a contamination in a US-based plant (Chiron Corporation), one of the only two suppliers of US flu vaccine. Due to difficulties in production and long processing times, the bulk of the world's vaccine production comes from very small number of companies compared to the number of companies producing drugs. Conventional vaccines are made of attenuated or modified forms of viruses. Relatively high and continuous doses are administered when a non-viable vaccine is used and the overall protective immunity obtained is ephemeral. The safety concerns of viral vaccines have propelled interest in creating a viable replacement that would be more effective and safer to use.

Rapid-response vaccines - does DNA offer a solution?

In responding to future influenza pandemics and other infectious agents, plasmid DNA overcomes many of the limitations of conventional vaccine production approaches.

Using DNA as a drug : challenges and opportunities for process engineers

The maturing of the biotechnology industry and a focus on productivity has seen a shift from discovery science to small-scale bench-top research to higher productivity, large scale production. Health companies are aggressively expanding their biopharmaceutical interests, an expansion which is facilitated by biochemical and bioprocess engineering. An area of continuous growth is vaccines. Vaccination will be a key intervention in the case of an influenza pandemic. The global manufacturing capacity for fast turn around vaccines is currently woefully inadequate at around 300 million shots. As the prevention of epidemics requires > 80 % vaccination, in theory the world should currently be aiming for the ability to produce around 5.3 billion vaccines. Presented is a production method for the creation of a fast turn around DNA vaccine. A DNA vaccine could have a production time scale of as little as two weeks. This process has been harnessed into a pilot scale production system for the creation of a pre-clinical grade malaria vaccine in a collaborative project with the Coppel Lab, Department of Microbiology, Monash University. In particular, improvements to the fermentation, chromatography and delivery stages will be discussed. Consideration will then be given as to how the fermentation stage affects the mid and downstream processing stages.

Marginal costs of hospital-acquired conditions : information for priority-setting for patient safety programmes and research

Objective: To estimate the relative inpatient costs of hospital-acquired conditions. Methods: Patient level costs were estimated using computerized costing systems that log individual utilization of inpatient services and apply sophisticated cost estimates from the hospital's general ledger. Occurrence of hospital-acquired conditions was identified using an Australian ‘condition-onset' flag for diagnoses not present on admission. These were grouped to yield a comprehensive set of 144 categories of hospital-acquired conditions to summarize data coded with ICD-10. Standard linear regression techniques were used to identify the independent contribution of hospital-acquired conditions to costs, taking into account the case-mix of a sample of acute inpatients (n = 1,699,997) treated in Australian public hospitals in Victoria (2005/06) and Queensland (2006/07). Results: The most costly types of complications were post-procedure endocrine/metabolic disorders, adding AU$21,827 to the cost of an episode, followed by MRSA (AU$19,881) and enterocolitis due to Clostridium difficile (AU$19,743). Aggregate costs to the system, however, were highest for septicaemia (AU$41.4 million), complications of cardiac and vascular implants other than septicaemia (AU$28.7 million), acute lower respiratory infections, including influenza and pneumonia (AU$27.8 million) and UTI (AU$24.7 million). Hospital-acquired complications are estimated to add 17.3% to treatment costs in this sample. Conclusions: Patient safety efforts frequently focus on dramatic but rare complications with very serious patient harm. Previous studies of the costs of adverse events have provided information on ‘indicators’ of safety problems rather than the full range of hospital-acquired conditions. Adding a cost dimension to priority-setting could result in changes to the focus of patient safety programmes and research. Financial information should be combined with information on patient outcomes to allow for cost-utility evaluation of future interventions.