Proceedings of the Influenza Research Priorities Workshop

Appendix 5: Summary of Break-Out Sessions

Session A - Challenges influenza poses in the community
Session B - Challenges influenza poses in the health care setting
Session C - Challenges influenza poses to basic and applied science
Session D - Optimizing influenza vaccines
Session E - Optimizing vaccination programs
Session F - Optimizing the use of antiviral drugs

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Session A
Challenges influenza poses in the community

Knowledge gaps identified:

• Surveillance gaps (defining disease and impact burden; reliable/rapid diagnostics) We know little about the excretion pattern/transmission pattern of influenza virus
• Epidemiological (reviewing/confirming modes of transmission; period of communicability; role of children in spread; why are LTC facilities hit harder and how can we prevent this?; what about other non-LTC facilities?)
• Controlling transmission; role of masks; hand hygiene; closure of schools/events; restriction of travel; contract tracing and quarantine; human-animal interface in the community
• Impact of public education on public behaviour; self-care
• Modeling of economic impact; projected impact of intervention in Canada; "is modeling a good surrogate for research in the community setting?"
• Early containment strategies: Do early pandemic interventions (culling, antivirals, vaccines) work? Stockpiling antivirals
• What special interventions are needed for remote communities?
• How can we engage family physicians, public health practitioners/nurses, other health practitioners, complementary practices?
• Operational/feasibility public health measures - capacity of public health system
• Understand public behaviour in crisis situation using meaningful methodology, determinance of vaccine update
• Ability to predict patterns of spread
• Clear, planned communication (to the public and private sectors) must be addressed; effective risk communication/crisis communication; best methods of mass communication (technology choices)
• Relationship between people buying antivirals and supply
• Clinical management of severe influenza disease (due to short supply issues of vaccine/AV stockpile during pandemic)
• Knowledge about personal and corporate preparedness - what is happening, what is optimal? (personal and public)
• Equity (disparities in access? What are our public values regarding treatment, etc.)

Research priorities brainstorming results:

• What are effective measures to control spread (non-vaccine measures) what are risk groups, transmission patterns, effectiveness of interventions?
• Transmissibility (how influenza spreads); interaction between people (contact networks) Intrafamilial versus institutions versus community
• Social behaviours (consumers and providers) (how people behave now and during a pandemic - is there a difference?, how can we intervene meaningfully? Why is there complacency? Why does widespread panic occur when unwarranted? Why is there resistance among some populations to receive vaccine, and how do we reverse this trend, gain trust, obtain buy-in for both methods, does practice work?) How do people respond to public health interventions?
• Need to understand the impact of current influenza programs, burden/characteristics/diagnosis of disease to establish incidence reduction goals (do more pop-based studies looking at effectiveness of current strategies) using consistent laboratory approaches
• Impact of vaccination program (e.g. school setting)
• How effective are interventions (contract tracing, hand washing, mask use) as a public health control measure during pandemic (what works best to reduce morbidity/mortality?)
• Knowledge of supply, use of non-publicly funded vaccine, feasible practical ways of capturing coverage in a database
• Refining transmission patterns of influenza
• What are the effectiveness of non-medical interventions

Research Priorities Identified in Session A

#1 How do we gather a greater depth of understanding of influenza transmission?

Research response (research activities)

• What are the patterns of spread (who gets it?)
•  Defining shedding patterns
• What is the behaviour of new strains?
• How do current vs. pandemic strains differ?
• Defining infective dose A
• erosol spread vs fomite spread (airborne, droplet, contact)
• What is the impact of setting on transmission? (household/community)

Infrastructure/capacity gaps

• Rapid deployment capacity
• Integrated networks of researchers are needed
• National historical outbreak data needed for modeling

Comments

• Clinical trial comparing N95 mask to standard surgical mask
• This informs pandemic planning activities but also potential to influence/modify annual control efforts

#2 What are the effectiveness of public health interventions/control measures

Research response (research activities)

• Hand washing effectiveness
• Value of using masks
• Value of contact follow up and quarantine
• Value of closing schools/public places
• Value of restricting travel

Infrastructure/capacity gaps

• Take advantage of system opportunities (e.g. school closures during pre-scheduled breaks)
• Public Health human resources are scanty

Comments

• Many are only feasible through modeling

#3 How do populations react to influenza, pandemic influenza, and influenza control measures (Social/behavioural science)

Research response (research activities)

• Fostering compliance with disease reduction recommendations
• Determinants of vaccine uptake by the public during pandemic and inter-pandemic periods
• Determinants of vaccine uptake or antiviral use for health care workers
• Testing messages developed based on risk and crisis communication principles

Comments

• (Impact) May understand determinants, but it may not result in behaviour change
• Could be enhanced in pandemic
• Behaviours could completely change in a pandemic

Session B
Challenges influenza poses in the health care setting

Knowledge gaps identified:

• Transmissibility in health care setting
• Use of prophylactic antivirals in the HCS
• Effectiveness of immunizing HCW in the acute care setting
• Effectiveness of hospital based immunization programs for patients
• Appropriate triggers for isolation
• Effectiveness of infection control measures
• Viral shedding in hospital patients, is it prolonged
• Role of self administration of antivirals

Research Priorities Identified in Session B

#1 Understanding transmission and effective preventive measures in health care settings

Research response (research activities)

• Personnel protective equipment
• Viral shedding
• Role of physical environment
• Efficacy of preventative measures
• Epidemiology of transmissions
• Comparisons of rural versus urban health care settings
• Comparison of health care settings with and without outbreaks

Infrastructure/capacity gaps

• Interdisciplinary
• Lack of transmission models
• Lack of rapid diagnostics

Comments

• Feasible with funding
• Broadly applicable to other viral infections

#2 Clinical management of influenza infection and outcomes

Research response (research activities)

• Appropriate antibiotic use
• Self administration/care
• Use of antivirals and non-prescribed medications (timing)
• Clinical priority setting for treating infection, when support equipment is limited (includes qualitative, ethics)
• Optimizing early detection/treatment
• Ethics of decision making What are the predicators of fatal outcomes
• Special populations
• Education of health care providers
• Management in the rural versus urban setting

Infrastructure/capacity gaps

• Lack of rapid diagnostics

#3 Immunization of (patients and personnel) in the Health Care Settings

Research response (research activities)

• Evaluation of the economics
• Determinants of uptake
• Improving uptake
• Knowledge, attitudes and beliefs
• Ethical issues
• How to overcome barriers
• Evaluation program options (ie not every year)
• Evaluation of efficient delivery systems
• Vaccine safety
• Impact of adverse events on uptake

Infrastructure/capacity gaps

• Need database registries

Comments

• Overcoming the barriers

#4 Evaluating surge capacity, delivery and response in the health care system

Research response (research activities)

• Modelling
• Innovative delivery methods
• Economic analysis
• Quantitative and qualitative
• Impact on health/human resources (absenteeism, staff shortage, moral)

Infrastructure/Capacity Gaps

• Access to data elements

#5 Evaluation of the Utility, determinants and Impact of optimized Diagnostic testing at the individual and population level

Research response (research activities)

• What is the impact of early diagnosis
• Uptake and use of diagnostics at the various levels of health care

Infrastructure/capacity gaps

• Lack of highly accurate diagnostic testing

Comments

• This is a cross cutting priority and applies to all other priorities.

Session C
Challenges influenza poses to basic and applied science

Research priorities brainstorming session:

• Immune correlates of cross reactive immune protection
• Viral evolution
• Strain characterization, surveillance
• Antigenicity versus genetics
• Genetics to disease outcome - properties
• Scientific surveillance - systematic surveillance, human and animal
• Validation of diagnostic tests for swine
• Better vaccines for animal and humans
• Collaboration between influenza experts - animal, human, clinical
• Correlation of advances in human and vet. species
• Improved adjuvants
• Investigating responses in different aged groups
• Genetic differences and disease outcomes - genetic basis for host response
• Predicting disease severity, predicting complications, host response
• Determinants of severe complications - mechanisms, diagnosis, prognosis
• Determinants for transmission between hosts, host switching
• Infectious dose, route of transmission for animals, characterize infection in different species
• Human epidemiology
• Bird migration patterns of infected animals - identify viruses in water fowl, migration
• Animal surveillance and behaviour e.g. migration
• Samples in populations
• Mucosal protection and cross protection
• Cross protection from vaccine - priming and cross reactivity, efficacy of mismatched vaccine
• Induction of cross reactivity
• Would immunizing school children result in herd immunity

Results of brainstorming activity:

• Host (animal and human) response - innate immunity, correlates of protection and cross reactive protection, priming response, immune enhancements, immunopathology, host genetics, better animal and human vaccines, clinical predictors of outcome, natural history of disease and determinants of pathology, high risk groups, age related issues, mucosal immunity
• Influenza genetics - species to species transmission, survival and geographic movement in animal reservoirs and the environment, molecular evolution and population dynamics, genetics of virulence, ecology, viral genomics, determinants of reassortment, effects of vaccination on viral evolution
• Diagnostics and surveillance (animal and humans) - rapid, community, public health, improved diagnostics, full genome sequencing, diagnosis of resistance, virus/host co-evolution, drug resistance, clinical predictors of outcome, systematic surveillance
• Prevention - behavioural, compliance, modes of transmission, infection control programs, universal versus targeted programs, feasibility of achieving herd immunity, animal vaccination
• New viral targets and approaches - accine centres/platform, all serotypes, reverse genetics platforms, animal model facilities, testing, new antivirals, immunomodulator agents, modes of formulation and delivery

Research Priorities Identified in Session C

#1 Diagnostics, surveillance and viral evolution (animal and humans)

Research response (research activities)

• Rapid tests, improved diagnostics, full genome sequencing, diagnosis of drug resistance, virus/host co-evolution, clinical predictors of outcome, systematic surveillance, survival and geographic movement in animal reservoirs and the environment, molecular evolution and population dynamics, species to species transmission, genetics of virulence, ecology, viral genomics, determinants of reassortment, effects of vaccination on viral evolution

Infrastructure/capacity gaps

• Safety and regulatory issues, clinical and animal facilities, P3 labs, bioinformatics, coordination, databases, ethics approval between centres, dissemination of information, public health and clinical care collaboration, coordination between human and animal biology, reference strains - database of viral strains and reagents, access to strains, standardization and validation of assays, biostatistics and modeling, training/new labs (scientific capacity), population modeling

#2 Host (animal and human) response

Research response (research activities)

• Innate immunity, correlates of protection and cross reactive protection, priming response, immune enhancement, immunopathology, host genetics, better animal and human vaccines, clinical predictors of outcome, natural history of disease and determinants of pathology, high risk groups, age related issues, mucosal immunity

Infrastructure/capacity gaps

• Low number of level 3 labs, limited animal models and facilities, interdisciplinary teams linking basic and clinical, collaborative protocols for sampling and sharing of samples, coordinating centres for samples

Comments

• Rapid uptake of findings

#3 Prevention

Research response (research activities)

• Behavioural approaches, compliance, modes of transmission, infection control programs, universal versus targeted vaccine programs, feasibility of achieving herd immunity, animal vaccination

Infrastructure/capacity gaps

• Animal models, P3 labs, randomized trials in communities, funding, methodological problems in evaluation of infection control

#4 New viral targets and approaches

Research response (research activities)

• Vaccine centres/platform - all serotypes, reverse genetics platforms, animal model facilities, testing, new antivirals, immunomodulator agents, modes of formulation and delivery

Infrastructure/capacity gaps

• Need for collaboration, core funding for platforms, P3 facilities, standardized assays

Session D
Optimizing influenza vaccines

Research Priorities Identified in Session D

#1 Improved vaccines and correlates of protection

• Correlates of immunity - cross protection, formulation and delivery, clinical immune response, immunopathology, different populations, novel/better vaccine development, dose sparing, adjuvant use, cross priming, primary immunization, optimize efficacy and effectiveness, route, devices, schedule, ease of use, societal acceptance

Research response (research activities)

• cross protection, formulation and delivery, clinical immune response, immunopathology, different populations, novel/better vaccine development, dose sparing, adjuvant use, cross priming, primary immunization, optimize efficacy and effectiveness, route, devices, schedule, ease of use, societal acceptance

Infrastructure/capacity gaps

• Capacity to do all phases of research on vaccines
• Vaccine centres to do preclinical laboratory testing and clinical testing [immunophenotyping, high throughput, monitor immune and immunopathologic responses, correlates of immunity, linking laboratory with epidemiological and clinical studies (phase 1 to 4 studies)]

Comments

• Population-based surveillance system to identify clinical events, vaccine effectiveness and adverse events - database and management of vaccine efficacy and effectiveness, adverse events
• Standardized protocols for lab assays evaluating efficacy and safety (an integrated lab/clinical system)

# 2 Pandemic preparation

• Pandemic preparation - dry run [from seed lot to requirements for licensure (regulatory approval to support strategy)], modeling (different vaccines with different effectiveness)]

Research response (research activities)

• Dry run - from seed lot to requirements for licensure (regulatory approval to support strategy)
• Modeling - use of vaccine(s) for different populations in different situations

Infrastructure/capacity gaps

• Capacity to do all phases of research on vaccines
• Vaccine centres to do preclinical laboratory testing and clinical testing [immunophenotyping, high throughput, monitor immune and immunopathologic responses, correlates of immunity, linking laboratory with epidemiological and clinical studies (phase 1 to 4 studies)]
• Population-based surveillance system to identify clinical events, vaccine effectiveness and adverse events - database and management of vaccine efficacy and effectiveness, adverse events
• Standardized protocols for lab assays evaluating efficacy and safety (an integrated lab/clinical system)

Additional comments

• Roles and responsibilities
• Identify opportunities and mechanisms for effective interactions between academia government and industry in developing vaccine priorities
• This group recommends that influenza should be the Canadian Vaccine Initiative priority
• Need clear regulatory pathways for dealing with novel vaccines

Session E
Optimizing vaccination programs

Knowledge gaps identified:

• Population level impact of annual vaccination programs
  • Are there additional high risk groups e.g. pregnant women?
• Monitoring uptake, effectiveness and safety
  • Vaccine coverage in our targeted groups and at P/T/local level
  • Most effective delivery strategies for target groups including HCWs
  • Rapid assessment of vaccine effectiveness
  • Rapid assessment of vaccine safety issues
  • Vaccine safety in pregnancy and young children
• What strategies should we use for our annual program?
  • Phase 2 evaluation of the Ontario universal program
  • Can we use P/T variations to evaluate different program strategies?
  • Does immunization of school children decrease community transmission?
  • Does vaccination of HCWs and close contacts make a difference?
• Cost-effectiveness of new programs/strategies
• Consumer and provider KAB re flu vaccination
• Pandemic vaccination strategies e.g. priming with H5 vaccine, choosing priority groups

Research Priorities Identified in Session E

#1 Comparing alternative vaccination program strategies to control influenza

Research response (research activities)

• Evaluate Ontario universal program in comparison to targeted programs
• Does vaccination of school children decrease transmission in different age groups?
• Does health care worker immunization reduce transmission?
• Evaluation to include drugs, health care utilization, morbidity and mortality, effect on transmission, coverage, outbreaks, workplace and school absenteeism.
• What level of coverage is needed to reduce transmission?
• Use modelling approach for missing data

Infrastructure/capacity gaps

• Administrative databases (e.g. access, compatibility)
• Individual level vaccination and diagnostic data

# 2 Population based rapid assessment of vaccine effectiveness and safety, both annual and pandemic

Research response (research activities)

• Short term and long term safety of vaccine in specific populations
• Development of methodologies and capacity for assessment, including rapid assessment of safety and effectiveness
• Population based impact (mortality and morbidity)
• Economic benefit, or not
• Assess the carry over protection of vaccination over more than one year

Infrastructure/capacity gaps

• Human resources (e.g. rapid analytical capability)
• Administrative database
• Data sharing agreements
• Role of ethics boards Who funds? Availability of rapid funding mechanisms is essential

Comments

• Privacy concerns
• Conflict of interest issues
• What is surveillance versus what is research

#3 How do we increase vaccination coverage rates in the general population

Research response (research activities)

• Evaluate barriers to vaccination (e.g. at individual, institutional and societal levels)
• Evaluate interventions to increase vaccination coverage such as policy approaches, social marketing and messaging
• How can we predict pandemic vaccination behaviour in consumers and health care providers?
• Will a priming strategy with a pandemic strain be acceptable to the public, health care providers and targeted groups?
• Operational issues to deliver vaccination programs rapidly and efficiently
• In the absence of immunization registries what are the alternatives to measure coverage?

Infrastructure/capacity gaps

• Ability to measure and assess vaccine coverage (registries)
• Supply issues

Comments

• Research on pandemic uptake and behaviour to be done pre pandemic

Session F
Optimizing the use of antiviral drugs

Knowledge gaps identified:

• New approaches vs existing approaches
• Knowledge and Attitudes
  • MD / HCW / Patients
    • Acceptance
    • Compliance
    • Public opinion
  • Education strategies
• Pharmacology
  • Bioavailability in critically ill patients
  • Infants
• Prophylaxis efficacy
  • Special populations - school outbreaks
  • How does this influence antibody response to infection
• Treatment efficacy
  • In high risk groups
  • Patients with severe or neurological disease
  • > 48 hrs
  • Can we predict who will fail
  • What are the appropriate regimens in HPAI
  • Treatment of the critically ill
  • Treatment at hospital admission
• Safety
  • Long term prophylaxis
• Resistance
  • What is the incidence in "field" conditions
  • What drives resistance
    • Dose / duration / compliance
• New approaches
  • Treatment / prophylaxis / non-conventional
• Pandemic Questions
  • How to optimize use
  • How to deploy / store
  • Can they abort a pandemic

Research priorities brainstorming results:

• Treatment at hospital admission
• Treatment in ICU - formulations (severely ill patients). Adjunctive tx for severely ill patients. Treatment of special populations (children under the age of 1; immunocompromised patients; resistance)
• Identification of AV which are effective after 48 hours
• Time to deliver a response in LTC/hospital facilities (how long does it take to get the drug, how effective is it vs. vaccination programs?)
• Treatment reducing the duration of infectiousness
• Treatment in hospital and follow up (natural history of critically ill patients)
• Impact of treatment on viral titres
• Treatment of severe infection
• Treatment of community acquired infection, rapid access to AV
• Stage of viral replication - understanding differences between virus (infectious dose)
• Pharmacokinetic study regarding use of existing capsules (new adjunctive therapy)
• Operationalize strategies for public health response
• Years with mismatch of vaccines - should we px in LTC (outbreak control)
• Methodology - clinical dx differs in elderly versus children
• Better surrogate markers of treatment - prognosis - who will likely end up in hospitals
• Better data on outcomes post-flu (clinical dx and epi tools)
• Lab issues: Linkage between funding agency and research to use information to decide in pandemic situation - need PCR-based methodology, more integrated testing system (INFRAST. Gap)
• Px of elderly - better outcomes/evaluation of outbreak
• Role of post-exposure px in hospital, outbreak management in LTC
• Test hypothesis that children are a reservoir and impact on families
• Study previously healthy and immunocompromised hosts or special populations (onset of tx; other outcomes)
• Develop a response plan to shutdown an annual outbreak; Infrastructure needs for stopping an outbreak in community
• Duration of treatment
• Co-administration of antibiotics

Research Priorities Identified in Session F

#1 Research into the management (treatment/rapid diagnosis) of severely ill individuals

Research response (research activities)

• Study the role of adjunctive therapy
• Combined therapies
• Resistance among special populations
• Special populations (children, elderly); immunocompromised patients
• Adjunctive treatments
• Rapid dx, improved access
• Assessment of viral shedding
• Outcome criteria (length of stay, ventilation)
• Severity markers/markers of response
• Dose/duration of therapy

Infrastructure/capacity gaps

• Lack of surveillance capacity
• Require clinical trials network
• Ethics and contractual issues must be timely, reduce bureaucratic burden
• Technology/databases

Comments

• FEASIBILITY requires Clinical Trials Network and $$$

#2 Novel approaches using existing medications or new agents (conventional or non-conventional)

Research response (research activities)

• Development and evaluation of new AV agents
• Develop clinical trials networks
• Ethics discussions
• Role of adjunctive therapies
• Health services research to improve drug delivery
• Optimal dose and duration/delivery of existing AV

Infrastructure/capacity gaps

• Clinical trials network

Comments

• Commercially available, novel agents
• Adjunctive therapies

#3 Optimal dose and duration/delivery of existing Antivirals

Research response (research activities)

• Various populations
• Different virusus
• Effect on resistance
• Parenteral vs. oral therapy vs. nebulized PK/PD studies

Infrastructure/capacity gaps

• Clinical trials network

Comments

• Cross-cutting issue

#4 Utility of Antivirals as a preventive tool

Research response (research activities)

• Efficacy/optimal duration in high risk populations
• Efficacy in LTC facilities
• Post-exposure Px of contacts
• Management of outbreaks
• Px of school children
• Effect on transmission
• Effect on antibody response
• Effect on viral evolution/shedding
• Resistance
• KAB of HCW, patients, MDs (Px issues)
• Cost-effectiveness
• Modeling of impact (need data)
• Optimal dose and duration/delivery of existing AV

Infrastructure/capacity gaps

• Clinical/Public Health network