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Executive Summary
Introduction
Welcome and Opening Remarks
Plenary Sessions
Break-Out Sessions
Integration and Summation Session
Workshop Evaluation and Next Steps
Appendix 1: Planning Committee
Appendix 2: Workshop Participants
Appendix 3: Workshop Agenda
Appendix 4: Plenary Speaker Biographies
Appendix 5: Summary of Break-out Sessions
Appendix 6: Abridged Workshop Evaluation
Appendix 7: Next Steps
Canadian and international vaccine experts and researchers gathered in Ottawa on August 31 and September 1, 2005 to examine the current state of research and make recommendations on national research priorities that will enhance pandemic and inter-pandemic influenza prevention and control strategies for Canada. The event was sponsored and organized by the Public Health Agency of Canada (PHAC) and the Canadian Institutes of Health Research (CIHR) Institute of Infection and Immunity in partnership with the Canadian Association for Immunization Research and Evaluation (CAIRE).
The meeting included plenary sessions in which experts gave an overview of the current knowledge of influenza. Dr. Mark Loeb of McMaster University gave an introductory talk on influenza, which was followed by a summary of current pandemic/inter-pandemic (annual) influenza preparedness and control strategies by Dr. Theresa Tam of the Public Health Agency of Canada. Dr. Fred Aoki of the University of Manitoba spoke about antivirals for influenza control, and Dr. Susan Tamblyn reviewed influenza vaccines. Dr. David Scheifele of the Canadian Association for Immunization Research and Evaluation summarized current Canadian influenza research activities. Dr. Ben Schwartz of the Centers for Disease Control and Prevention highlighted the U.S. influenza research approach, and global influenza research strategies and activities were reviewed by Dr. Klaus Stöhr from the World Health Organization (WHO).
Participants then worked in small groups to identify key gaps in knowledge and research activities needed to enhance influenza prevention and control strategies. The research needs were prioritized, and the top three to five priorities from each break-out group were combined into ten research priority areas in the final integration and summation session. The following research priority areas are explained further in the final report.
Priority Research Areas for Pandemic and Annual Influenza prevention and control
Influenza virus characterization and ecology
Studies are needed on the basic science (virology, immunology, biology) of influenza viruses and the ecological relationships between animal and human viruses. More information concerning influenza subtypes is required to determine the nature and extent of animal reservoirs, and the factors involved in viral modification and acquisition of virulence.
Influenza virus transmission
An enhanced understanding of the influenza virus shedding patterns of infected persons and the means of transmission to susceptible contacts is needed.
Public health preventive measures
Public health research is needed to understand the effectiveness and safety of current public health interventions aimed at preventing infection both in the community and institutions, as well as knowing how populations react to influenza and influenza control.
Improving rapid diagnostic tests
Currently there is a lack of highly accurate and rapid diagnostic tests for influenza, therefore, research aimed at the development of these diagnostics is needed.
Clinical management of influenza patients
It is necessary to better understand the most effective ways to clinically manage and treat influenza patients, particularly the most ill, including new methods to rapidly diagnose influenza.
Development and optimal use of antiviral drugs
Research aimed at the development and use of antivirals in the treatment of individuals with influenza and in the prevention of infection is needed. This includes studies of novel approaches with existing antiviral medications and also research aimed at the development and evaluation of new antiviral agents.
Surge capacity of the health care system
This research gap includes activities aimed at being ready to respond quickly and effectively to increased demand in capacity encountered during annual influenza epidemics and the next pandemic.
More effective and acceptable influenza vaccines
More effective vaccines must be developed using new technologies that trigger the immune system more readily, produce longer lasting protection, produce cross-protection and non-injection delivery methods.
Immunization programs
The differences in vaccination programs across Canada provide a significant opportunity to evaluate various vaccination strategies to control influenza. Population-based data on the uptake, effectiveness and safety of influenza immunization is needed.
Preparation for a pandemic vaccine
Many challenges involved in the preparation, testing, and evaluation of a vaccine in the context of a pandemic are expected. Canada will be responsible for evaluating the pandemic vaccine produced by its domestic manufacturer.
At the conclusion of the two days, participants evaluated the workshop. Overall, participants agreed that the process in developing consensus on research priorities was appropriate, and that the objectives of the workshop were achieved but further priority-setting of the final top ten list is needed. The workshop Planning Committee and workshop participants provided further input to define the research priorities into ten research themes which are included in this report. The findings will be communicated to funding agencies and decision makers in Canada and internationally. Strategic approaches for funding the identified influenza research priorities will be developed and pursued in 2006.
The Influenza Research Priorities Workshop was held on August 31 and September 1, 2005 at the Delta Ottawa Hotel and Suites in Ottawa, Ontario. The event was sponsored and organized by the Public Health Agency of Canada (PHAC) and the Canadian Institutes of Health Research (CIHR) Institute of Infection and Immunity in partnership with the Canadian Association for Immunization Research and Evaluation (CAIRE), with input from an expert Planning Committee (Appendix 1: Planning Committee). The workshop was attended by over 70 Canadian and international vaccine and influenza experts and researchers (Appendix 2: Workshop Participants) who gathered to make recommendations on national research priorities that will enhance pandemic and inter-pandemic influenza prevention and control strategies. The workshop included plenary sessions in which experts gave participants an overview of the current knowledge of influenza. The plenary sessions were followed by break-out sessions focusing on specific areas for influenza research. In the break-out sessions, participants discussed gaps in knowledge, research activities to help bridge the gaps and identified infrastructure and capacity requirements that are currently lacking. Through consensus, the research was prioritized and the top three to five priorities from each break-out session were presented to the plenary group and then combined in the final integration and summation session (Appendix 3: Workshop Agenda). This discussion resulted in the identification of ten research priority areas that are needed to enhance pandemic and inter-pandemic influenza prevention and control.
Dr. Alan Bernstein, President, Canadian Institutes of Health Research
Dr. Bernstein gave opening remarks and thanked everyone for coming to the meeting, including colleagues from the National Institutes of Health, Centers for Disease Control and Prevention and the World Health Organization. He stated that there is some urgency to set a time-driven research agenda to identify what Canada's role in influenza research can and should be, so that recommendations can be made to the Public Health Agency of Canada, the Canadian Institutes of Health Research and the federal government. He mentioned that he had recently attended a meeting of the Heads of International Research Organizations (HIRO) and that influenza was discussed. He hoped that the participants over the course of the workshop would help define a national research agenda for influenza, so that when he next meets with HIRO, he will be able to discuss Canada's role and ways that the international health agencies can work together to deal with this imminent threat.
Dr. Arlene King, Director, Immunization and Respiratory Infections Division, Public Health Agency of Canada
Dr. King stated that this meeting was originally conceived by the Pandemic Influenza Committee in 2002, but it was delayed because of the outbreaks of Severe Acute Respiratory Syndrome (SARS) in 2002-2003. Ironically, it was the SARS crisis that illustrated the need for strategic and coordinated approach to research and an identification of infrastructure requiring urgent attention before a crisis occurs. The Canadian Immunization Committee has endorsed this workshop as part of the overall research component of the National Immunization Strategy. The Canadian Immunization Committee along with the Pandemic Influenza Committee will be paying close attention to the priorities identified in the meeting, which will serve to guide and inform researchers and research sponsors. Dr. King closed by thanking the Planning Committee and the Immunization and Respiratory Infections Division Secretariat for their many hours in planning and preparing for the workshop.
Workshop Co-chairs: Dr. Theresa Tam, Associate Director, Immunization and Respiratory Infections Division, Public Health Agency of Canada and Dr. David Scheifele, Director, Canadian Association for Immunization Research and Evaluation (CAIRE)
Drs. Tam and Scheifele emphasized the importance of influenza research in prevention and control of influenza and that this key public health issue is critical at this time for Canada and internationally. An overview of the workshop goals and process were provided and participants were encouraged to contribute fully as the outcome of the meeting is expected to be a focused research agenda with key infrastructure gaps identified for Canada.
Plenary speakers (Appendix 4: Plenary Speaker Biographies) gave workshop participants an overview of Canadian and international current knowledge of influenza, including annual and pandemic prevention and control strategies. Highlights of the presentations follow.
Influenza 101
Dr. Mark Loeb, Associate Professor, McMaster University
Dr. Loeb described the influenza virus and how it has evolved during the last century. The virus consists of RNA surrounded by a coat of phospholipids and proteins. Two coat proteins, hemagglutinin (HA) and neuraminidase (NA), are essential for infection of host cells and are used clinically to define specific subtypes of influenza. For example, in influenza A subtype H5N1, of current concern because some experts believe that it may trigger the next pandemic, H5 refers to the specific form of HA and N1 refers to the form of NA. The subtype forms of H and N arise from antigenic drift (mutations in the viral RNA in one subtype) and/or antigenic shift (exchange of viral RNA between subtypes in a secondary host), and are thought to allow viruses, which normally infect birds to infect humans, pigs and other animals.
Dr. Loeb also gave an overview of the communicability, pathogenesis, epidemiology and the immune response to influenza infection in humans. The principle mode of influenza viral transmission in humans appears to be through respiratory droplets resulting from coughing and sneezing; however, more information concerning the modes of transmission and efficacy of infection control is required. Several high risk populations have been identified including the elderly, those living in long-term chronic care facilities and individuals with cardiac and pulmonary disorders; however, Dr. Loeb believes that the list should be re-examined. The human immune response is mostly subtype specific, with HA and NA being the major antigens that are recognized. The immune response to another surface protein, M2 is not subtype specific, suggesting that a robust response to M2 would provide cross-subtype protection. Unfortunately, the natural immune response to M2 is weak.
Dr. Loeb closed his remarks by stating that more research is required to understand viral and human host genetics underpinning transmission and pathogenesis of influenza, as well as human influenza transmission and community spread, particularly in children and individuals in health care settings.
Current pandemic/inter-pandemic influenza preparedness and control strategies
Dr. Theresa Tam, Associate Director, Immunization and Respiratory Infections Division, Public Health Agency of Canada
Dr. Tam outlined Canadian public health programs and strategies for the prevention and control of annual influenza. Surveillance programs include monitoring viral presence in specimens sent to selected laboratories and regular reporting of flu-like symptoms by doctor's offices and long-term care facilities. Immunization programs have also been established, and Canada distributes more influenza vaccine per capita than any other country. Vaccine safety monitoring programs have been established, along with programs to guide and educate health care workers and the public. In order to more effectively design immunization programs, Dr. Tam stated that applied public health research in surveillance, vaccine safety and effectiveness monitoring, public attitudes to vaccination, economics, modeling and basic research in the areas of genomics, immunology and new vaccines is required.
Dr. Tam also gave an update on the current pandemic threat stating that while it is difficult to predict the timing of an influenza pandemic, most experts agree that a pandemic is overdue. Conditions in southeast Asia suggest that an influenza A virus (H5N1 or another strain) may develop pandemic qualities sooner rather than later. An overview of the Canadian Pandemic Influenza Plan (CPIP) was given. The plan was published in 2004 and updates are expected in December 2005. Some gaps in knowledge concerning the influenza pandemic that Dr. Tam identified include whether a novel virus of pandemic potential could be contained at its source, the impact that school closures and mask use would have on disease spread, and the optimal strategies and logistics for public health measures for responding to a pandemic.
Obstacles and opportunities for influenza control - antivirals
Dr. Fred Aoki, Professor, Medicine Medical Microbiology and Pharmacology & Therapeutics, University of Manitoba
Dr. Aoki gave an overview of available and new anti-influenza drugs and identified gaps in current knowledge. There are two classes of antiviral drugs: M2 inhibitors (e.g. amantadine) and NA inhibitors (e.g. zanamivir and oseltamivir). Both types are effective against most influenza subtypes, except H5N1, which is resistant to amantadine. NA inhibitors significantly decrease influenza infection rates, moderately decrease the duration of flu symptoms, decrease hospitalization and death rates and are well tolerated. They must be administered within two days following appearance of flu-like symptoms, which may limit their use. Newer antivirals currently being developed include resveratol, T-705 and polymeric versions of zanamivir. Gaps in knowledge that were identified by Dr. Aoki include: whether physicians and health care workers have the knowledge to administer antiviral drugs and whether they and patients will comply with treatment schedules; the bioavailability of the drugs in critically ill patients and infants under one year of age; the efficacy in high risk groups, and in individuals who have had the disease for more than 48 hours; the efficacy of antivirals in reducing non-respiratory disease and the safety of the drugs; and, the development of antiviral resistance when used in the field.
Obstacles and opportunities for influenza control - vaccines
Dr. Susan Tamblyn, Public Health Consultant
Dr. Tamblyn summarized the strengths of the Canadian influenza vaccination program. Some highlights include the fact that Canada has the highest per capita vaccine uptake, our program is publicly funded and delivered by public health, we have a secure supply of annual vaccine and are securing the Canadian production capacity for pandemic vaccines. Unfortunately, we still see overflowing hospitals; outbreaks in schools and health care facilities; frequent, poor vaccine matches; and we lack information about the impact and cost-effectiveness of our vaccination programs. Dr. Tamblyn stated that we need to improve both the vaccine and vaccination programs. New types of vaccines, delivery systems (oral or intranasal instead of injection) and manufacturing methods (cell culture instead of egg production) are required. For pandemic vaccines, dose-sparing strategies, rapid clinical trials and processes for the rapid and large-scale manufacture of vaccines will be required. Different vaccination strategies are currently used in Canada - the traditional high-risk approach, age-based strategies and universal vaccination. Vaccination of school children for both direct and indirect benefit (herd immunity) is an additional promising strategy being studied in the U.S. Dr. Tamblyn suggested that we need a more standardized and organized approach to evaluate the effectiveness and impact of our vaccination programs and develop the evidence needed for program planning. She believes that two new initiatives, the Research Advisory Council of the Canadian Immunization Committee and the Canadian Vaccine Initiative (a proposed virtual network of Canadian scientific expertise from public and non-governmental organizations and the private sector) will help to integrate and improve capacity for vaccine research in Canada.
Current national influenza research activities and gaps
Dr. David Scheifele, Director, Vaccine Evaluation Centre, British Columbia Children's Hospital
Dr. Scheifele gave an overview of recent and current influenza research in Canada. Much of the research in the areas of virology, immunology and vaccine development has been supported by the Canadian Institutes of Health Research (CIHR). CIHR funding to these areas increased five-fold from $329,000 in 2000 to $1.5 million in 2005. The supported research includes modeling of disease control interventions and studying the role of viral mutations in virulence. Also, the Public Health Agency of Canada (PHAC) and CIHR have launched a request for applications to assess and compare Ontario's universal influenza vaccination program with targeted programs. Other federally funded initiatives include the surveillance and analysis of the influenza virus at the PHAC National Microbiology Laboratory, surveillance networks administered by the Immunization and Respiratory Infections Division (PHAC), and monitoring of avian influenza by the Canadian Food Inspection Agency. British Columbia and Québec have strong influenza research programs, but relevant research is also performed in institutions scattered throughout the country. Individuals in networks such as Canadian Network for Vaccines and Immunotherapeutics (CANVAC) and Canadian Association for Immunization Research and Evaluation (CAIRE) have trials centers, which perform research to develop and assess influenza vaccines. Overall, there is substantial scientific expertise available across a wide range of settings and disciplines, but little of it is fully committed to influenza. Dr. Scheifele stated that while no drastic changes are warranted, investments to stabilize strategically important areas and methods to coordinate research (e.g. request for proposals) and provide an overview of current influenza research activities are needed.
Global influenza research strategies and activities
Dr. Klaus Stöhr, Team Coordinator, Department of Communicable Disease Surveillance and Response, Global Influenza Programme, WHO
Dr. Stöhr emphasized the urgent need to plan, prepare and conduct research to better respond to the next influenza pandemic. His remarks were mainly focused on H5N1, but are applicable to other pandemic strains that may emerge. He stated that we need to know: the likelihood and outcome of reassortment between H5N1 and human and pig influenza viruses; whether the source and pathways of transmission from animals to humans can be controlled; more about the clinical effects of H5N1 infection in humans and if antivirals and H5N1 vaccines could be used to slow down or avert a pandemic. Dr. Stöhr stated that it is estimated that the current stockpiles of antivirals are only sufficient to treat 2% of the world's population. Also, production of a strain-specific vaccine would take at least a year with current production methods, only 5% of the world's population would have access to the vaccine. Therefore, it is critical to determine the most effective non-pharmaceutical measures to slow down the spread of infection. In addition, antigen-sparing methods and improved methods for vaccine production are essential to increase surge capacity during annual and pandemic outbreaks of influenza. A research goal that may take longer to achieve, but would be very worthwhile to pursue, is to develop a cross-subtype influenza vaccine that would alleviate many of the problems associated with surge capacity. Dr. Stöhr closed by stating that although research costs money, investment in influenza research now will save many lives and much more money in the future.
U.S. influenza research strategies and activities
Dr. Ben Schwartz, National Vaccine Program Office, Centers for Disease Control and Prevention
Dr. Schwartz summarized some of the influenza research that is currently being performed in the United States. There are several research foci within the Department of Health and Human Services Agencies including the National Institutes of Health Research (NIH), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC) and Office of Public Health Emergency Preparedness. NIH funding for influenza research related to basic science and development of diagnostics, vaccines and antivirals has increased 5 fold over the past four years, and is estimated to reach US$119 million dollars in 2005. Critical research infrastructure includes the NIH vaccine treatment and evaluation units that are currently running, for example, H5N1 vaccine clinical trials; the CDC's Thailand Emerging Infections Program, which is conducting epidemiological studies and supporting outbreak investigations in Thailand; NIH National Institute of Allergy and Infectious Diseases influenza genome project, which has released the sequence of 300 human influenza isolates; and the NIH National Institute of General Medical Sciences Models of Infectious Disease Agents Study with the goal to model real or anticipated disease outbreaks to assist policy makers, which recently published models of strategies to contain an outbreak of a novel influenza strain in southeast Asia.
Dr. Schwartz also provided highlights of current vaccine research aimed at reducing the time to produce a pandemic vaccine, developing strategies to increase the number of doses produced via improved egg-free methods and use of adjuvants, and developing conserved antigen vaccines that could be stockpiled. Antiviral research to develop treatment regimes for infants and the severely ill and to develop new antivirals is also ongoing. Dr. Schwartz concluded by stating that influenza pandemic preparedness is a Department of Health and Human Services Agency and U.S. government priority and he predicted that the budget to support influenza pandemic preparedness would increase substantially in the next year.
Closing Remarks: Day 1
Dr. Paul Gully, Deputy Chief Public Health Officer, Public Health Agency of Canada
Dr. Gully stated that the Public Health Agency of Canada is pleased to have organized and supported, along with the CIHR and CAIRE, this important workshop. He thanked the plenary speakers for their excellent summaries of influenza research and for identifying many of the current gaps in knowledge. He noted that Canada was one of the first countries to start pandemic planning, and today, even with greater public awareness of the influenza pandemic threat, few countries are thinking about what has to be done to prevent or lessen the burden that influenza places on human health, society and the economy. Dr. Gully told the participants that their recommendations will have relevance both nationally and internationally. He closed by stating that he hoped participants would apply the knowledge they gained through the meeting to their own jurisdictions.
Six break-out sessions were held during the workshop. Three were held concurrently on Day 1, and three concurrent sessions were held on Day 2. The purpose of the six break-out sessions was to focus appropriate expertise in specific areas of pandemic and inter-pandemic disease prevention and control in order to identify research priorities and gaps in infrastructure and capacity. The six break-out sessions were on the following themes:
Workshop participants were carefully assigned to break-out sessions by the Planning Committee. Each break-out group consisted of experts in the specific area addressed in the break-out session along with researchers having a diverse range of knowledge and expertise. Sessions were led by moderators, and had a rapporteur and note-taker to document the discussion.
In the break-out sessions, moderators provided the group with a brief high-level review of the existing knowledge gaps in Canada/internationally in a particular area of disease prevention and control, guided by the question "what are the important unanswered research questions that Canadian research should address in this area?" Participants then participated in a brainstorming session on the key research priorities, aimed at reducing the burden of disease in Canada. Moderators then guided the identification of the key three to five research priorities, through consensus, from the brainstormed list. Each priority was further described by identifying examples of research activities and infrastructure/capacity gaps that currently exist. A five-point Likert relevancy scale was used by the group to assign criteria/rationale for each research priority. The criteria and rationale were:
The top three to five research priorities, infrastructure and capacity gaps, and criteria and rationale for each break-out group were then presented to all of the workshop participants in subsequent plenary sessions (Appendix 5: Summary of Break-out Sessions).
Challenges influenza poses in the community
Moderators: Drs. Ian Gemmill and Karen Grimsrud
The focus of this break-out group was research pertaining to disease risk and impact assessment, as well as influenza prevention and control strategies in the community. Suggested topics for discussion included: epidemiologic and risk factor assessment, economic impact, animal to human transmission, health care system interventions, public health/vaccine interventions to control or limit the spread of influenza.
Challenges influenza poses in the health care setting
Moderators: Drs. Gary Garber and Mark Loeb
This break-out group discussed research in the clinical setting such as diagnosis, patient treatment and management (other than antivirals), infection control, ambulatory care issues, health care system interventions, clinical trials and other clinical research capacity.
Challenges influenza poses to basic and applied science
Moderators: Drs. Guy Boivin and Earl Brown
Here the emphasis was on basic and applied research on influenza such as rapid diagnostics, animal models, virulence factors, correlates of protection and transmissibility of animal influenza viruses.
Optimizing influenza vaccines
Moderators: Drs. Joanne Langley and Brian Ward
This break-out group discussed influenza vaccine-related research opportunities including novel vaccine development, increasing vaccine immunogenicity and effectiveness, adjuvants and other dose-sparing strategies, forecasting vaccine strains and vaccinating populations before a pandemic (evidence for cross-protection).
Optimizing vaccination programs
Moderators: Drs. Gaston De Serres and Susan Tamblyn
Research pertaining to immunization program issues such as assessing program effectiveness, disease impact of vaccination programs, economic impact, vaccine safety, ethical issues, communications and public opinion research was discussed in this break-out session.
Optimizing the use of antiviral drugs
Moderator: Dr. Todd Hatchette
This break-out group discussed research on antiviral and other therapeutic drugs for influenza including novel therapeutics, effectiveness of antivirals for treatment and prophylaxis, drug safety, drug resistance, economic impact, ethical issues, communications and public opinion research.
Facilitators: Drs. Lorne Babiuk and Scott Halperin
During the final Integration and Summation session of Day 2, the complete list of key research priorities identified by all of the break-out groups was provided to all participants. The purpose of this session was to further prioritize the research priorities identified by the break-out groups to form a list of the most important national research priorities.
During the integration and summation session, workshop participants, with the guidance of the facilitators, combined the top priorities identified in the break-out sessions into ten research priority areas and identified what new capacity or infrastructure is needed. Further discussion is needed to determine who the key stakeholders, clients, funders are for this research.
Following the workshop, the Planning Committee and workshop participants reviewed this report to expand upon the information and put the priorities into context using the discussion material from the break-outs.
The following 10 priorities are not listed in any order.
Influenza virus characterization and ecology
Background/rationale
Much remains to be learned about the basic science of influenza viruses and the ecological relationships between animal and human viruses. Rapid advances are being made on many fronts, with potential applications to disease prevention and control.
Key research needs
Relevance
Basic research informs both pandemic and inter-pandemic situations and has global application for improvements in national and international disease control and prevention. Basic research on influenza is a global enterprise to which Canadian researchers have contributed with grant support. This research is essential for ongoing collaboration and contribution toward international efforts in pandemic preparedness.
Feasibility/infrastructure required
Canada has a small number of scientists active in this area of research. A limiting factor is the requirement for researchers to have Level 3 biological containment facilities to work with dangerous strains, such as H5N1 avian virus. Only a few such facilities exist in Canada because of the high costs involved, with just one or two able to house infected animals for study. A major new animal facility is currently under construction with Canada Foundation for Innovation (CFI) support.
Among the challenges that researchers face are obtaining access to new viral strains and reagents from international and domestic sources, obtaining bioinformatics and statistical support for genomic studies and building collaborations across disciplines (e.g. virology, immunology, veterinary, public health and clinical researchers should collaborate in studying animal to human transmission issues).
Capacity development in the area of basic science research is critical, and efforts into training new scientists must be enhanced. In addition to human resource capacity-building is the need to collaborate and share essential support services, to provide suitable laboratory facilities, and collaborate internationally.
Influenza virus transmission
Background/rationale
Knowledge gaps currently exist in the understanding of virus shedding patterns of infected persons and the pathways of transmission to susceptible contacts. This information is essential for effective disease avoidance and infection control measures.
Key research needs
Relevance
This research was considered urgent as it applies to both inter-pandemic and pandemic periods and has global application. It has the potential to improve annual control efforts and inform pandemic planning and may be applicable to other viral respiratory infections. This research is critical, since the main line of defense in a pandemic situation will be prevention of transmission - we must know more about the modes of transmission in order to inform appropriate protective measures for the population. This research area can be addressed by investigators in any country as the issues are not unique to Canada.
Feasibility/infrastructure required
This type of research has seldom been conducted in Canada. No CIHR-funded study has examined influenza virus shedding and transmission but a major CIHR-funded project is examining the epidemiology of respiratory infections (including influenza) in the elderly. The research methods to describe shedding and transmission are feasible for Canadian investigators with collaboration between specialists in infectious diseases, public health and virology.
Public health preventive measures
Background/rationale
More insight is needed into "non-pharmaceutical" interventions to reduce exposure to influenza and avoid infection. In a pandemic situation, most of the population will have only disease avoidance measures to rely upon to reduce their risk of infection, given the limited supplies of antiviral drugs and the likelihood of delayed availability of pandemic influenza vaccine. Effective disease avoidance measures are particularly important in health care settings, as the SARS experience demonstrated.
Key research needs
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has global application, but the issues are not specific to Canada. It has potential to inform pandemic planning and also to influence annual control efforts. Insights could be rapidly implemented to decrease the burden of disease and may also apply to other respiratory viruses. These insights are urgently needed, as this research deals with the first line of defense against influenza.
Feasibility/infrastructure required
This type of research has seldom been conducted in Canada: no CIHR-funded studies have addressed this aspect of influenza. The research methods required are challenging and costly. They typically require large, prospective, cohort studies with controlled interventions and laboratory-documented effects conducted by integrated networks of interdisciplinary researchers over several influenza seasons. Mathematical modeling offers a new approach to estimating the effects of interventions, an area in which Canada has some expertise (and CIHR has funded a study), but the building of models requires accurate observational data. Hospital-based intervention studies are more readily feasible than population-based studies because they can take advantage of the existing infection control personnel.
Improving rapid diagnostic tests
Background/rationale
Until recently, influenza diagnosis has mainly consisted of clinical assessment, with only a small proportion of cases confirmed by viral culture or serologic tests. Imprecision of clinical diagnosis has hampered disease management (e.g. the use of anti-influenza drugs) and confounded epidemiologic studies. Increasing the availability of rapid diagnostic tests holds promise of improved virus detection and epidemiologic assessment, disease management, vaccine effectiveness measurement and disease epidemiology, making their further development and evaluation of cross-cutting importance.
Key research needs
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has national application but is not unique to Canada. It will inform pandemic planning and influence annual strategies and evaluations, and insights could be rapidly implemented to guide case management. Workshop participants considered such research to be urgent and of cross-cutting importance, since the advanced technology would provide better tools for accurate and timely diagnosis of influenza or other lower respiratory tract infections.
Feasibility/infrastructure required
This type of research is readily feasible in Canada, given the existing infrastructure in applied diagnostic research, hospital-based virus identification methods and clinical studies management. Test evaluation requires collaboration between clinical investigators (such as a network of infectious diseases specialists), clinical virologists and health services researchers. CIHR has funded a study of PCR-based rapid diagnosis of influenza.
Clinical management of influenza patients
Background/rationale
About 20% of the Canadian population suffers from influenza in a typical season, which for most communities lasts only 6-8 weeks. Consequently many people become ill in a short period, straining the capacity of the health care system at all levels. Thousands of infected people die of influenza-related complications. A much larger proportion of the population will be affected in a pandemic, with many becoming severely ill or dying.
While preventive measures (i.e. antiviral drugs, vaccine) are available, they are ordinarily targeted at the most vulnerable and offer incomplete protection. Effective clinical management of influenza sufferers, particularly the most ill, is a central component of the strategy to cope with influenza.
Key research needs
(See also: Development and optimal use of antiviral drugs, and Surge capacity of the health care system)
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has global application. It will inform pandemic planning and influence annual coping strategies. Insights could be rapidly implemented to save lives and reduce the burden on the health care system by shortening or avoiding hospitalizations. Workshop participants considered such research to be urgently needed.
Feasibility/infrastructure required
This type of research is readily feasible in Canada. It requires formalization and support of emerging networks of researchers in primary care and infectious diseases and integration with existing CIHR-funded expert groups in respiratory diseases. No CIHR-funded studies have directly addressed this aspect of influenza. The recent increase in availability of rapid diagnostic tests in many tertiary care centers has created new opportunities for well-designed intervention studies.
Development and optimal use of antiviral drugs
Background/rationale
Several available medications have activity against influenza viruses and are useful for avoiding (prophylaxis) and treating infection. Canada is investing in a large stockpile of an antiviral drugs to mitigate the effects of pandemic infection until a vaccine becomes available and thereafter. Concerns with this approach include possible reduction of drug effectiveness against avian strains and an emergence of a resistant strain with widespread use. Many uncertainties exist regarding the treatment of severe or complicated cases.
Key research needs
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has global application. Insights could be rapidly implemented to improve patient outcomes and curb disease spread. This urgent research would help to ensure that optimal use is made of the large federal investment in an anti-viral drug.
Feasibility/infrastructure required
This research would be feasible in Canada if infrastructure was enhanced. A limited number of researchers in several centers have conducted industry-sponsored anti-influenza drug studies, providing a core of expertise. A larger network of investigators would need to be established and supported, drawing upon the expertise of primary care, infectious disease and public health researchers, and clinical virologists. CIHR has not funded trials of anti-influenza drugs to date but has funded the development of tests for drug resistance. With development of greater capability to evaluate anti-influenza drugs, more industry-sponsored research on newer agents would be attracted to and conducted in Canada. The drug evaluation network could also evaluate immunoglobulin preparations or anti-inflammatory agents, for example.
Surge capacity of the health care system
Background/rationale
The annual increase in health care utilization during influenza outbreaks stresses the capacity of emergency rooms and hospitals. Disease prevention programs reduce morbidity and the need for care but are only partly effective, as substantial morbidity continues to occur. In a pandemic, demands on health care facilities will occur on an unprecedented scale. Learning how to increase the "surge capacity" of the health care system is a key coping strategy.
Key research needs
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has national application. It has the potential to influence annual control efforts and to inform pandemic planning. Insights could be rapidly implemented to cope better with the annual burden of disease and would also apply to epidemics caused by other infectious diseases. Workshop participants considered such research to be urgently needed.
Feasibility/infrastructure required
Influenza-related health care utilization research has been conducted on a modest scale by several groups of Canadian researchers, none with funding specific to influenza. A key requirement is greater access to administrative databases within the health care system, to track utilization of outpatient and inpatient services. Increasing utilization of rapid diagnostic tests will improve recognition of influenza cases and their specific health care needs.
More effective and acceptable influenza vaccines
Background/rationale
Workshop participants were mindful of the limited effectiveness of the "standard" trivalent, inactivated, egg-derived influenza vaccines. Although 70% to 90% of healthy adults can be protected when circulating and vaccine strains closely match, the protection rates for those most likely to suffer illness complications (e.g. young children, seniors) are substantially lower. Of all the vaccines currently provided in public programs, influenza vaccines are the least effective. The standard type of vaccine will offer limited protection against a pandemic strain such as avian influenza, because of the added challenges involved in eliciting (primary) immune responses to a previously unseen virus. To meet the growing expectations of the general public, more effective vaccines must be developed using new technologies that engage the immune system more reliably. Alternatives to annual injections would thus be a welcome advance. The virus is a moving target and annual changes in vaccine strain are frequently required.
Key research needs
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has global application. It is especially relevant to the domestically produced influenza vaccine on which Canada will rely in the event of a pandemic. Insights could be rapidly applied to annual programs, improving their effectiveness and encouraging greater public participation in them.
Feasibility/infrastructure required
This type of research is readily feasible in Canada, as this country is one of the few with a domestic influenza vaccine manufacturer (ID Biomedical). A working relationship has been established between the federal government and this company to make preparations for a pandemic. The company has promising new influenza vaccine technologies in development and could be encouraged to collaborate with other Canadian innovators to assess additional options for enhancing vaccine effectiveness, such as new adjuvant strategies. CIHR has funded a study of needle-free vaccines for respiratory viruses, including influenza. Canada has the capacity to develop and test new vaccines in animal models of infection. Canada also has a number of skilled vaccine evaluation centers, which will be needed to test new candidate vaccines in people. While these centers currently cooperate in an expanding network, infrastructure support is needed to ensure that a fully functional network will be available when needed. Canada has a number of experts in influenza immunology whose expertise will be needed to evaluate responses to new products and develop standardized tests. In summary, Canada has all of the required elements to pursue this important area of research, but infrastructure investment is required.
Immunization programs
Background/rationale
Workshop participants were reminded that Canada is a world leader in annual per capita utilization of influenza vaccine. Moreover, Ontario is a world leader in offering influenza vaccine to all residents (universal program), whereas other provinces have programs that target groups at highest risk of disease complications, with differing delivery strategies. It should follow that Canada is a world leader in evaluating the effectiveness of annual influenza programs but this has not been the case - little has been done to evaluate programs. Recently, two Requests for Proposals invited comparison of the effectiveness of the universal immunization program in Ontario to targeted immunization programs in other provinces or comparable countries.
Key research needs
Relevance
This research is relevant to both inter-pandemic and pandemic periods and has global application. Insights could be rapidly implemented to increase program effectiveness and reduce the burden of disease. Participants considered such research to be urgently needed.
Feasibility/infrastructure required
Canada is uniquely positioned to measure the effectiveness of its highly subscribed influenza vaccination programs, both targeted and universal, however the infrastructure needed to do this requires substantial development.
The main challenge in evaluating influenza immunization programs (or any immunization program) lies in the inability to obtain and link administrative databases, or registries, at the individual level. Currently, there is no reliable or consistent method to obtain information on vaccination status of individuals or clinical data, such as health outcomes. Electronic provincial immunization registries will provide information on immunization status, but have not been implemented across Canada at this time. The widening availability of rapid diagnostic tests will assist with capturing clinical data for the hospital contacts. Some provinces can link required data presently but the process is slow. Community-level comparisons of the impact of program strategies offer a manageable alternative but have not been undertaken in Canada. Public health departments are typically understaffed and ill-prepared to undertake evaluation research, explaining the lack of studies to date. Investment in developing this capacity is essential as these public programs should be continuously evaluated and improved. CIHR has funded a study of the impact of influenza on pregnant women.
Preparation for a pandemic vaccine
Background/rationale
Canada will be responsible for evaluating the pandemic vaccine produced by its domestic manufacturer. Many challenges are involved in preparing, testing and evaluating a vaccine in the context of a pandemic. It is desirable to anticipate as many of the challenges and identify remedies as possible, to save time and avoid missteps during an outbreak.
Key research needs
Relevance
This research is central to Canada's security of vaccine supply since we must be well prepared to assess the domestic product on which the country will rely. Efficient preparations will help to ensure a minimum delay in vaccine becoming available for general use. Testing prototype vaccines (such as H5N1 avian influenza) in advance of a pandemic will provide valuable insights regarding safety, dosing and formulation, reducing the potential for unanticipated difficulties and consequent delays. Participants considered such research to be urgent and of high priority.
Feasibility/infrastructure required
The Public Health Agency of Canada has contracted with the domestic manufacturer to ensure vaccine supply during a pandemic and to produce and evaluate a prototype H5N1 avian influenza vaccine. To facilitate clinical trials now and in the future, a network of vaccine evaluation centers needs to be established, including experts in assessing immune responses to influenza. Extensive pre-planning is needed to reduce response time for clinical trials, including prior approval of detailed protocols by the regulatory agency and research ethics boards of participating centers, negotiation of contracts between the trials sponsor and centers, training of key personnel and development of reliable methods for data and logistics management. Plans should encompass phase 1 and 2 trials conducted prior to approval for use and phase 4 studies during use (to assess safety and effectiveness). The latter may require access to health care databases, requiring consideration of privacy concerns. Creating this infrastructure will also position Canadian researchers to evaluate other vaccines of strategic or economic importance.
Closing Remarks: Day 2
Dr. David Scheifele, Director, Canadian Association for Immunization Research and Evaluation
Dr. Scheifele commented that follow-up meetings will be required to address infrastructure gaps and the feasibility of the research described in each priority area. It will be important to identify research that builds on the strengths of the Canadian research community. Consideration will be given to research that is being performed in other countries so that research and resources are not duplicated. Related to this is a need for a repository for information on current influenza research. Dr. Sheifele stated that it is possible that the Canadian Vaccine Initiative might play a role in this repository. He then closed the workshop by thanking the participants for their contributions.
At the conclusion of the two days, participants evaluated the workshop. Overall, participants agreed that the overall process in developing consensus on research priorities was appropriate, and that the objectives of the workshop were achieved, but further priority-setting of the final top ten list is needed (Appendix 6: Abridged Workshop Evaluation). The workshop Planning Committee and workshop participants provided further input to define the research priorities into ten research themes which are included in this final report. The findings will then be communicated to funding agencies and decision makers in Canada and internationally (Appendix 7: Next Steps). Strategic approaches for funding the identified influenza research priorities will be developed and pursued in 2006.
Appendix 1: Planning Committee
Appendix 2: Workshop Participants
Appendix 3: Workshop Agenda
Appendix 4: Plenary Speaker Biographies
Appendix 5: Summary of Break-out Sessions
Appendix 6: Abridged Workshop Evaluation
Appendix 7: Next Steps
