Assessment Of Development Of Resistance To Neuraminidase Inhibitors In A (H5N1) Influenza Viruses Using A Ferret Model
Funder
National Health and Medical Research Council
Funding Amount
$165,546.00
Summary
The neuraminidase (NA) inhibitors are considered the most effective anti-influenza drugs available for both prevention and treatment of influenza virus infection including A(H5N1) viruses. The drugs are effective against all subtypes of influenza A, making them ideal for use in the early months of a pandemic prior to an appropriate vaccine being produced. As a result many countries around the world, including Australia, have stockpiled these drugs (mainly Tamiflu) as part of their pandemic prepa ....The neuraminidase (NA) inhibitors are considered the most effective anti-influenza drugs available for both prevention and treatment of influenza virus infection including A(H5N1) viruses. The drugs are effective against all subtypes of influenza A, making them ideal for use in the early months of a pandemic prior to an appropriate vaccine being produced. As a result many countries around the world, including Australia, have stockpiled these drugs (mainly Tamiflu) as part of their pandemic preparedness plans. However, of concern is the increasing number of recent reports of a higher than expected level of resistance in epidemic influenza being generated against these drugs. A recent isolation of an H5N1 virus from a Vietnamese girl highlights that these viruses can also be resistant to Tamiflu. Within Australia, Tamiflu will be a critical weapon against the initial wave of an influenza pandemic, therefore it is vital that more is known about the propensity of the H5N1 virus to generate resistance, and possibly make these drugs clinically less effective. The aim of the project is to determine the levels, mode and type of resistance that may occur when ferrets are experimentally infected with HP A(H5N1) virus and then treated with NA inhibitors drugs such as Tamiflu. In the event of resistant viruses being isolated following drug pressure from Tamiflu, the strains will then be tested for their sensitivity to the other NA inhibitor drugs Relenza (zanamivir) or the peramivir (a third currently unlicensed NA inhibitor). The results from this cross resistance work will allow strategies to be put into place regarding the administration of an alternative NA inhibitor in the event of a pandemic virus acquiring particular NA mutations which may for example result in Tamiflu resistance. To determine the relative human risk of a NA inhibitor resistant A(H5N1) virus, studies to determine how infectious or transmissible the viruses are would be performed on all resistant strains isolated. NA inhibitor resistant strains demonstrate varying degrees of transmissibility and fitness, therefore it would be beneficial to classify this for any strains generated from this study so as to be in a better position to understand the public health implications if a particular resistant strain was to arise.Read moreRead less
Highly Pathogenic Avian Influenza (HPAI) - Improved Diagnosis With Quality Assurance Of Serological & Molecular Diagnost
Funder
National Health and Medical Research Council
Funding Amount
$249,019.00
Summary
This project aims to produce Quality Assurance (QA) algorithms to ensure accurate diagnosis of highly pathogenic avian influenza (HPAI) using serological and molecular techniques. The project will assess HPAI diagnosis accurately within the setting of other circulating respiratory illnesses, utilising a new HPAI module, ,in combination with existing modules within the Royal College of Pathologists of Australia (RCPA) Serology Quality Assurance Program (SQAP). This will ensure rapid, cost-efficie ....This project aims to produce Quality Assurance (QA) algorithms to ensure accurate diagnosis of highly pathogenic avian influenza (HPAI) using serological and molecular techniques. The project will assess HPAI diagnosis accurately within the setting of other circulating respiratory illnesses, utilising a new HPAI module, ,in combination with existing modules within the Royal College of Pathologists of Australia (RCPA) Serology Quality Assurance Program (SQAP). This will ensure rapid, cost-efficient improvements in diagnostics by utilizing existing infrastructure. The key elements of the project are: Introduction of quality assurance processes to ensure accurate diagnosis and to evaluate existing and developing laboratory testing procedures, test accuracy, and result interpretation; Involvement of human and veterinary laboratories in the QA and development processes; Production of suitable antigenic material through molecular virology as targets for HPAI antibody and molecular diagnostics in QA programs. This will thereby allow large quantities of non-infectious material for HPAI QA assessment of serological and molecular assays around Australia, using baculovirus expressed antigens and cloned gene targets respectively. These projects are designed within a short (<12 month) time frame in order to fulfil the needs of the Australian community in controlling the developing HPAI avian pandemic, and the possible human pandemic. Significant positive outcomes in the next six months are assured by the existence of current QA processes, experience in influenza research already available in the human and animal health laboratories involved, the research records of the groups, and the close existing linkages between the research, QA, diagnostic and avian virology groups.Read moreRead less
Pandemic Influenza Vaccine: Exploiting The Conserved HA Cleavage Site
Funder
National Health and Medical Research Council
Funding Amount
$243,300.00
Summary
Influenza virus needs to cleave its surface spike protein, hemagglutinin or HA, to become mature and infectious. This project is aimed at producing a vaccine that will block the cleavage thus rendering the virus non-infectious. To achieve this, we will use synthetic fragments (called peptides) of the viral HA spike protein mimicking its cleavage site to immunize mice. This will produce specific antibodies that will bind to the cleavage site while the virus is inside the infected cell, thus preve ....Influenza virus needs to cleave its surface spike protein, hemagglutinin or HA, to become mature and infectious. This project is aimed at producing a vaccine that will block the cleavage thus rendering the virus non-infectious. To achieve this, we will use synthetic fragments (called peptides) of the viral HA spike protein mimicking its cleavage site to immunize mice. This will produce specific antibodies that will bind to the cleavage site while the virus is inside the infected cell, thus preventing the viral spike protein from being cleaved and remain immature. This idea is particularly suited to fight the bird flu, as all pathogenic bird influenza viruses cleave HA spike proteins within the infected cell.Read moreRead less
Pandemic Influenza: Developing A Model To Enhance Preperadness In The Buisness Sector
Funder
National Health and Medical Research Council
Funding Amount
$146,934.00
Summary
Businesses need to undertake pandemic influenza preparedness to protect their staff, suppliers, customers, business and the wider community. The prospect of pandemic influenza has major implications for business continuity and while the instinctive reaction may be that business is able to look after itself, small and medium sized businesses are key to Australia's economic wellbeing and thereby our physical and mental health. We also consider that without appropriate planning, and because of the ....Businesses need to undertake pandemic influenza preparedness to protect their staff, suppliers, customers, business and the wider community. The prospect of pandemic influenza has major implications for business continuity and while the instinctive reaction may be that business is able to look after itself, small and medium sized businesses are key to Australia's economic wellbeing and thereby our physical and mental health. We also consider that without appropriate planning, and because of the economic imperatives, businesses may become a key point for spreading of influenza. Small and medium sized businesses account for more than half the total private sector work-force in Australia. Experience from SARS has demonstrated that health staff spend an inordinate amount of time fielding queries from the business sector faced with an epidemic. By obtaining key information in advance, resources can be readied should a pandemic occur, and the most useful and relevant advice can be developed. The aim of this project is to establish an evidence-based approach to business preparedness for pandemic influenza. We will identify key areas of vulnerability in small and medium-sized businesses which can be targeted to enhance preparedness for pandemic influenza, and thus contribute to control of the spread of pandemic influenza in the community. Focus groups and face-to-face interviews with 200 small or medium businesses owners or managers from a range of sectors will be used to identify the critical issues for consideration pandemic preparedness planning. We will ascertain the range of current knowledge attitudes and beliefs to pandemic influenza, the extent of business continuity planning for pandemic influenza, perceived requirements to support small business to develop pandemic plans, and the most effective approaches to strategic communication and knowledge transfer. Our underlying hypothesis is based on the fact that small and medium sized businesses are inadequately informed and prepared for a pandemic, and that planning to protect staff and critical points in the business can protect both business functioning, and individual and community health. The major outcomes of this project include a self-administered intervention kit that will permit businesses to undertake their own preparedness planning.Read moreRead less
Adapting Pandemic Influenza Interventions And Management To The Newly-emerged Virus
Funder
National Health and Medical Research Council
Funding Amount
$245,098.00
Summary
The Australian Health Management Plan for Pandemic Influenza is based on data from past and current influenza. A newly-emerged influenza strain is likely to differ in some respects. This project will develop practical ways to adapt the management plan to the emerged virus from early pandemic data. It will determine the data needed to do this efficiently, to ensure that Australia receives the greatest benefit from its antiviral drugs, vaccines and other public health interventions introduced.
Segmentation Of The Peripheral Nervous System - The Role Of Axon Guidance Factors.
Funder
National Health and Medical Research Council
Funding Amount
$190,331.00
Summary
Injury to the nervous system results in great loss to the individual and society at large. To repair a damaged nerve pathway so that functional recovery may ensue is the pre-eminent goal of neuroscience research. An understanding of how factors that guide nerve processes coordinate the wiring of the nervous system during development of an embryo will provide an insight into what strategy is required to repair a damaged nerve pathway in the mature nervous system. In this research project we propo ....Injury to the nervous system results in great loss to the individual and society at large. To repair a damaged nerve pathway so that functional recovery may ensue is the pre-eminent goal of neuroscience research. An understanding of how factors that guide nerve processes coordinate the wiring of the nervous system during development of an embryo will provide an insight into what strategy is required to repair a damaged nerve pathway in the mature nervous system. In this research project we propose to investigate what factors guide the formation of the peripheral nervous system which controls the body. We will use a novel model system whereby a whole chick embryo is grown in a culture dish and the developing nerve pathways can be manipulated to discover what are the exact factors that guide nerve processes to wire up pathways to the limbs and other body parts. This research will provide an opportunity to study the basic principles of nerve pathfinding which may then be applied to more complicated circuits within the brain and to the repair of injured nerve pathways.Read moreRead less
Mechanisms Of B Cell Immunodominance To Influenza Virus
Funder
National Health and Medical Research Council
Funding Amount
$617,611.00
Summary
Current influenza vaccines elicit poor protection against viruses undergoing rapid change or emerging from animal reservoirs. We will define the basis for why highly conserved sites of virus vulnerability, such as the hemagglutinin "stem" domain, are poorly targeted by current vaccines and will assess novel hemagglutinin stem-based vaccines in macaque models of human influenza. Our results will guide the rational design of next-generation vaccines for influenza.
The world has suddenly been alerted to the threat of pandemic influenza with the recent deaths in Asia of patients and their close contacts from which the avian influenza H5N1 virus has been isolated. Experts believe that it is only a matter of time before this virus mutates and acquires the ability to rapidly spread within the human population. The currently available vaccines have virtually no capacity to prevent infection by a new pandemic virus. Once the virus strikes appropriate vaccines ca ....The world has suddenly been alerted to the threat of pandemic influenza with the recent deaths in Asia of patients and their close contacts from which the avian influenza H5N1 virus has been isolated. Experts believe that it is only a matter of time before this virus mutates and acquires the ability to rapidly spread within the human population. The currently available vaccines have virtually no capacity to prevent infection by a new pandemic virus. Once the virus strikes appropriate vaccines can be made against it but this procedure takes at least 6 months, the time predicted for the virus to have already spread throughout the globe. We are proposing that a vaccine designed to induce killer T cells (called CTLs) that target the conserved regions shared by all influenza viruses, could be used as a preventative measure without prior knowledge of the exact type of virus that will emerge. This sort of vaccine will not prevent against infection but will greatly lessen the severity of the disease. We have already designed a vaccine that that will induce high levels of CTLs that can greatly speed up the clearance of viruses of the type that are currently in the human population, when tested in animal models. However, we predict that a new pandemic virus will be much more vigorous in its growth and so our vaccines will have to be improved to cope with this. This project looks at ways of increasing the number and effectiveness of the CTLs that are induced by our vaccines. This will require an understanding of how we can modulate the function of other specialised cells, dendritic cells and helper T cells, that play a role in starting and maintaining the CTL response, as well as modulating the CTLs themselves.Read moreRead less
Enhancing Australia's Pandemic Influenza Vaccine Output By Increasing The Yeild Of Vaccine From Eggs
Funder
National Health and Medical Research Council
Funding Amount
$251,517.00
Summary
Influenza epidemics cause significant morbidity and mortality, particularly amongst the young and elderly. Unlike other vaccines, a new flu vaccine formulation needs to be prepared each year from the currently circulating strain. This involves a long process of preparing new seed vaccine stock, which is then tested, manufactured and distributed. The situation is even more complicated by the ability of different influenza strains to reassort with others. An example of current major concern is the ....Influenza epidemics cause significant morbidity and mortality, particularly amongst the young and elderly. Unlike other vaccines, a new flu vaccine formulation needs to be prepared each year from the currently circulating strain. This involves a long process of preparing new seed vaccine stock, which is then tested, manufactured and distributed. The situation is even more complicated by the ability of different influenza strains to reassort with others. An example of current major concern is the possibility of deadly avian flu viruses, such as H5N1, to gain the capacity to directly infect humans by recombining with a human strain and thereby starting a new global pandemic. When the next influenza pandemic occurs, the availability of a vaccine will be of the highest priority and early supply of vaccines will save millions of lives. Since vaccination is the only sustainable defense, we face an urgent need to have the capacity to supply large numbers of vaccine doses of influenza vaccines within a short period of time. Currently, the only way of producing flu vaccines is in eggs. The speed of vaccine supply is totally dependant on the yield of vaccine from eggs and the number of eggs that can be processed at any one time. Since there are severe constraints on the number of eggs that can be simultaneously processed, the limiting factor that can be addressed is the actual yield of vaccine per egg. The aim of this project is the develop methods that allow higher levels of vaccine virus to grow in eggs. We will take a multi-pronged approach to enhancing influenza vaccine production that are directed toward increasing the capacity of eggs to promote virus replication, as well as towards the vaccine strain to boost its ability to replicate in the egg. The outcome will be an enhanced capacity for vaccine manufacturers to quickly and effectively expand vaccine supplies which will directly impact on global morbidity and mortality during a flu pandemic.Read moreRead less
Heterosubtypic T Cell-inducing Vaccines For Influenza In Humans
Funder
National Health and Medical Research Council
Funding Amount
$352,307.00
Summary
Bird flu virus poses a large risk to the world if it mutates to become easily spread between people. If this occurs vaccines will be made to the mutated strain but there will be a time lag before these are available. We have been working on a novel vaccine that induces protective T cell immunity to parts of the virus that are common to all influenza strains and will be effective against any new virus. Our information from animal models will be used to create a human vaccine of this type .