Avian influenza A(H5Nx): Public health knowledge gaps and research needs

Last updated: June 28, 2024

On this page

• Introduction
• Science and surveillance to enable action
• Knowledge generation
• Prioritized knowledge gaps and research needs
• Appendix

Introduction

Outbreaks of avian influenza A(H5N1) in domestic and wild birds and some wild mammals have recently emerged and become widespread in Europe and North, Central and South America, including across Canada. Government authorities in Canada are currently responding to the outbreak of influenza A(H5N1) in farmed birds and wildlife across Canada. Influenza A(H5N1) is a subtype of avian influenza virus that mainly infects birds, but has been found in rare and sporadic human cases globally.

In March 2024, A(H5N1) was detected in dairy cows and their (raw) milk for the first time in the United States.^{Reference 1} During April and May 2024, three human cases of the virus were reported in dairy farm workers in the United States and were attributed to exposure to dairy cattle.^{Reference 2} No cases of A(H5N1) have been detected in humans or dairy cows in Canada, and for the general population in Canada, the likelihood of human infection with avian influenza A(H5N1) clade 2.3.4.4b acquired from livestock (e.g., cattle, goats, swine) in the next three months is very low due to a very low likelihood and level of exposure to infectious virus.

The Public Health Agency of Canada (PHAC)'s role includes preventing and controlling infectious diseases and preparing and responding to health emergencies. This applies to assessing the human health risk of avian influenza, and engaging in risk-appropriate prevention, preparedness, and response activities. The integration of emerging science, including the identification of knowledge gaps and priorities, throughout these activities ensures an evidence-informed approach.

The priority knowledge gaps and research needs synthesized in this document reflect a One Health approach. They are the product of an iterative approach led by the PHAC Office of the Chief Science Officer in collaboration with experts from within PHAC, and members of the PHAC avian influenza A(H5Nx) expert panel, which includes other federal departments (Canadian Food Inspection Agency (CFIA), Health Canada, and Indigenous Services Canada). They were also informed by gaps identified in risk assessment activities domestically and internationally, knowledge synthesis of published and grey literature, and a meeting co-hosted with the Royal Society of Canada. The knowledge gaps and research needs were validated by experts as highly relevant to public health preparedness and response for possible human infection with the current circulating avian influenza virus, and to A(H5Nx) broadly, in Canada. Emerging evidence and transmission scenarios are likely to impact the relevance of these knowledge gaps and this will be considered a living document.

The CFIA has identified complementary science and research gaps to focus Canada's support for science and research on challenges related to the prevention, detection, response and management of highly pathogenic avian influenza (HPAI) in animals.

Science and surveillance to enable action

Pathogen emergence occurs periodically and PHAC, along with its partners in Canada and abroad, are consistently on the lookout for unusual or concerning trends. Influenza A(H5N1) activity has been documented in humans, and cases have been sporadic, with no current evidence of sustained human to human transmission. The recent development of more extensive presence of A(H5N1) in mammals requires additional science and surveillance activities in order to better understand whether this represents a threat to human health. To that end, PHAC is presenting below the current research priorities that will support ongoing risk assessment and responses.

While governmental agencies, provincial/territorial authorities, communities, and academic researchers are actively pursuing several of the gaps presented, there remains significant opportunity for further science and research activities to address these, and other, knowledge gaps by One Health partners. Strategies to address these knowledge gaps and research needs may be achieved through a diversity of approaches. The knowledge gaps and research needs are not intended to privilege specific methodological approaches or research designs.

Knowledge generation

Building science and research capacity using a One Health approach

In Canada, there is a need to understand baseline domestic research strengths, and bolster preparedness and response for A(H5N1), by leveraging knowledge and science capacity gained from the COVID-19 pandemic. A One Health approach can enable conditions for interdisciplinary research at the animal-human-environment interface.

Mechanisms for, and enablers of, science and research in this area include but are not limited to:

• Building system linkages and integrating data across surveillance systems at the human-animal-environment interface.
• Developing One Health research collaborations.
• Leveraging existing research and surveillance networks related to influenza, wastewater, modelling, laboratories, and pandemic preparedness.
• Sharing data, including genomics data, materials and developing standard protocols.

Influenza A(H5N1) is considered both a human and animal pathogen and therefore laboratory facilities must have the appropriate licensing in place in order to acquire this virus under the following legislative and regulatory frameworks:

• Human Pathogens and Toxins Act and its regulations. It is a Risk Group 3 security sensitive biological agent and regulated by PHAC.
• Health of Animals Act and its regulations. It is a Risk Group 3 foreign animal disease pathogen of concern and regulated by CFIA.

PHAC science and surveillance activities

PHAC routinely works in close collaboration with public health system counterparts internationally (e.g., World Health Organization (WHO), United States Centers for Disease Control and Prevention, United Kingdom Health Security Agency), other Government of Canada departments and agencies, and provincial and territorial public health authorities to coordinate and advance science and surveillance activities on emerging public health threats.

PHAC's National Microbiology Laboratory (NML) is a WHO National Influenza Centre and collaborates extensively with the CFIA National Centre for Foreign Animal Disease Laboratory, a World Organization for Animal Health reference laboratory for highly pathogenic avian influenza. The Biosafety Level 3 and 4 laboratory containment facilities at these laboratories are leading and uniquely equipped for the diagnosis and confirmation of A(H5Nx) cases in animals and humans.

The NML supports research and human testing for avian influenza virus including:

• Diagnosis: enhanced reference/diagnostic services of emerging influenza viruses, development of diagnostic test protocols for provincial and territorial partners enabling distributed testing. The NML has worked closely with provinces and territories to ensure that most are able to rapidly detect any human cases of A(H5N1). For areas without established testing, NML will provide rapid testing support if and when needed. The H5 molecular testing at the NML is able to detect the 2.3.4.4b clade of H5 viruses. Most provinces have capacity to test for the new H5 clade. Control RNA has been distributed, and the NML has distributed proficiency tests yearly and the last panel contained samples with avian influenza virus clade 2.3.4.4b A(H5N1) RNA.
• Virus surveillance: whole genome sequencing to monitor viral evolution and detect new strains, assessment of medical countermeasures and match with vaccine strains.
• Research: development of animal models, transmission studies, and vaccine studies. This includes in-progress testing of newer H5N1 and H5N5 viruses in ferrets.
• Wastewater surveillance: early influenza signal detection in a community.
• Modelling: working with other government departments and modelling networks to model bird migration into Canada and transmission among wildlife to understand the potential risk of transmission to humans.
• Quality assurance of provincial and territorial laboratories and testing supports for jurisdictions without labs.

NML also enables the decentralization of testing by the provision of ongoing recommendations on diagnostic protocols and control reagents.

Other science and surveillance areas mobilized by PHAC for A(H5N1):

• Identifying knowledge gaps and research needs.
• Convening and coordinating the:
  • Canadian Public Health Laboratory Network to assure an integrated public health laboratory network response to infectious diseases that encompasses One Health.
  • Emerging Infectious Disease Modelling Initiative network to strengthen collaborative efforts among the academic community and all relevant stakeholders to conduct and coordinate infectious diseases modelling.
  • Pan-Canadian wastewater surveillance network to share information and coordinate studies and testing sites and improve methods and tools.
  • Multi-Agency Steering Committee for Public Health Risks Associated with Avian Influenza A(H5N1) in Canada to describe, anticipate or estimate public health risks, develop recommended actions, and explore future outcomes of risk.
  • Expert Panel on H5Nx to ensure best available science advice and identification of knowledge gaps in an ongoing way.
• More broadly, the FPT Pandemic Preparedness Task Group (under Communicable and Infectious Disease Steering Committee) has been stood up to support partnerships on pandemic preparedness initiatives and progress on shared pandemic preparedness actions to strengthen our collective approach to readiness for future pandemics.
• Leading collaborative human surveillance activities:
  • Providing national case definitions. PT public health authorities are required to report confirmed and probable human cases of A(H5N1) to PHAC within 24 hours. Confirmed cases of A(H5N1) are notifiable under the International Health Regulations (2005).
  • Detecting influenza activity using multiple components to detect and monitor avian influenza cases in humans should they arise (e.g., syndromic surveillance (FluWatchers), laboratory testing and typing, hospitalization data, outbreak reporting).
  • Monitoring public information sources to detect and communicate information about potential public health threats worldwide – including avian influenza cases in humans and animals – through the Global Public Health Intelligence Network.
  • Deploying field epidemiologists at the request of jurisdictions to support surveillance activities as needed.
• Conducting rapid risk assessments and pandemic risk scenario analyses to identify emerging threats, develop recommendations, explore possible risk outcomes, and describe, anticipate or estimate public health risks.
• Conducting and commissioning knowledge syntheses and evidence profiles to address emerging questions by bringing and assessing the best available published scientific literature. This work will help inform future updates to technical guidance documents to ensure they remain evidence-informed.
• Participating as a member of the:
  • Canadian Institutes for Health Research Centre for Research on Pandemic Preparedness and Health Emergencies Steering Committee to influence research funding priorities associated with emerging public health threats, including A(H5N1).
  • Biomanufacturing and Life Sciences Strategy governance to coordinate research and development activities related to vaccines, therapeutics, and diagnostics.

Prioritized knowledge gaps and research needs

Knowledge gaps are grouped by key thematic areas. Interdependencies between knowledge generating activities, and the capacity or feasibility to address the gaps, are not described in this document. The knowledge gaps identified are relevant to public health from a One Health perspective, and do not constitute an exhaustive list of all science and research needs related to A(H5Nx).

To inform the next phase of integrated preparedness and risk assessment activities, considering that A(H5N1) is primarily affecting animals at this time, of greatest immediate urgency are knowledge gaps related to:

• Assessment of potential risks from animal products, including milk and other animal products (e.g., raw meat; unpasteurized cheeses).
• Understanding and characterizing A(H5N1) viruses in birds and non-human mammals to detect any potential changes of relevance to public health.
• Enhanced surveillance studies among humans at greatest exposure to infected animals/birds and their by-products (e.g., raw milk) for early detection of potential spillover events and understanding presence of A(H5N1) in these population groups including exposure routes. This includes research to enhance the methods and tools for early detection and understanding the virus (e.g., improving sensitivity and specificity of wastewater testing; development of assays for serological testing).

The above areas are being addressed across departments in the Government of Canada and their partners. From a One Health perspective, using patterns of detection in animals, including outbreaks, may be a promising way of targeting enhanced, active surveillance in humans and may assist in taking a more efficient and integrated One Health approach to surveillance.

Based on recent geographic spread, infections in new species and genetic variability, co-development of surveillance and response plans across sectors would be helpful, with particular emphasis on high-risk exposure settings for humans.

Researchers and scientists across disciplines and domains are encouraged to engage early and co-develop science activities with impacted communities, such as farm operators and those at higher exposure risk to infected animals or who handle and/or consume raw by-products milk or meat, to facilitate receptivity of proposed actions, and promote integration of diverse perspectives. This includes prioritizing equity-informed, culturally appropriate and community-led approaches with populations, including First Nations, Inuit, and Metis communities. Incorporating Sex and Gender Based Plus considerations in the design, conduct, analysis, and interpretation of studies can also be applied as part of a broader equity lens in science and research activities.

Table 1: Priority knowledge gaps and research needs, grouped by theme and subtheme

Themes and sub themes	Priority knowledge gap or research need topic area
Theme 1: Identification, description, and characterization of A(H5Nx) pathogens
Pathogen identification, description and characterization	Characterize the biology and behaviour of influenza A(H5Nx) viruses in birds and non-human mammals to inform assessment and mitigation of risk to humans.Footnote a Understand virological and genomic factors (including reassortment) that may impact the ability of the viruses to infect humans.Footnote a Understand innate and adaptive immunity to influenza A(H5Nx) in humans, including antigen/antibody and cellular immune responses and antigenic crossover with other influenza viruses.
Epidemiology, surveillance and testing	Describe the epidemiology of A(H5Nx) via surveillance and testing activities at the human-animal-environment interface (distribution, frequency, clinical spectrum, transmission parameters, etc.). Define factors relating to susceptibility and transmission parameters of different mammalian species and humans to A(H5Nx) viruses to understand the potential risk and impact on human health.Footnote a Enable comparison of international and domestic epidemiological parameters and human case information, including comparing sequencing, to determine key changes in virus evolution and inform public health guidance. Assess seroprevalence and human exposure in different populations including groups at higher risk of occupational exposure to infected animals.Footnote a
Theme 2: Methods and tools to advance public health action
Detection and diagnosis	Enhance methods and tools for early detection of human cases in populations at increased risk of exposure, and enhanced surveillance (for example in wastewater or serosurveys). Understand the broader landscape of testing modalities and develop/deploy new molecular (including genomics) and serological methods for rapid detection as well as assess their effectiveness and performance.
Modelling	Undertake modelling to inform the development of risk scenarios of A(H5Nx) human-to-human transmission and interventions. In the event of increases in human cases, use modelling to forecast health system capacity for managing human cases of A(H5Nx), including pan-Canadian healthcare demand for various medical countermeasures.
Theme 3: Evidence-based interventions
Pharmaceutical public health interventions: Therapeutics	Assess safety, effectiveness and relative advantages/disadvantages of different therapeutics and treatments against human A(H5Nx) infection (including options meant for chemoprophylaxis, and treatment) and support the development of novel therapeutics. Evaluate mechanisms to reduce the emergence of resistance to antivirals.
Pharmaceutical public health interventions: Vaccines	Understand the effectiveness and safety of human A(H5Nx) vaccines as well as implementation/intervention strategies, in different populations.
Non pharmaceutical public health interventions	Evaluate how protective measures and interventions such as the use of personal protective equipment (PPE), ventilation/air filtration, and cleaning/disinfection impact transmission.
Behavioural and Social Sciences	Describe the behavioural factors influencing human interactions with different types of animals and geographic and cultural variation in human-animal contacts.Footnote a Understand factors affecting adherence to preventative public health measures to reduce exposure to A(H5Nx) and how they influence transmission rates. Define factors contributing to misconceptions and trust in public health or expert advice to inform public health guidance, communications and interventions.

A more comprehensive list of knowledge gaps follows below; many of which would only become relevant in the context of a large-scale spillover event in humans, or significant human-to-human transmission. Those marked with footnote "a" were most consistently assessed as being relevant to improving understanding of the assessment of risk related to spillover into humans at higher risk due to potential exposure, and in which scientific activities are deemed to be best initiated early.

Theme 1: Pathogen identification, description, and characterization of A(H5Nx)

Biological and virological characterization, including genomic monitoring, phenotypic characterization and understanding mechanisms of transmission

Characterize the biology and behaviour of influenza A(H5Nx) viruses in birds and non-human mammals to inform assessment and mitigation of risk of transmission to humans ^{Footnote a}

• Are circulating viruses in birds and non-human mammals, including ruminants, evolving such that A(H5Nx) infectiousness, transmissibility, virulence, disease severity and progression, and immunity, are impacted? ^{Footnote a}
• What viral genomic markers/profiles have been associated with the above changes in the currently circulating strains? What are the profiles that indicate the highest potential for direct mammal-to-mammal spread? ^{Footnote a}
• What is the virus survivability in different environments as influenced by the complex relationship of biological, physical and environmental factors? ^{Footnote a}
• What are the risks and consequences of reassortment between H5Nx and other endemic influenza viruses in other species, including swine and humans?^{Footnote a}
• What are the host response characteristics in wildlife (avian and mammalian hosts) that experience severe disease vs asymptomatic infection, including in remote areas?^{Footnote a}

Understand virological and genomic factors (including reassortment) that may impact the ability of the viruses to infect humans^{Footnote a}

• What are the genomic mutations/characteristics of A(H5Nx) that have the potential for functional impacts on human health (e.g., infectiousness, transmissibility, virulence, disease severity and progression, immunity, and susceptibility to antivirals and medical countermeasures)?^{Footnote a}
• What mutations and virological characteristics are conducive to sustained human-to-human transmission?^{Footnote a}
• What is the pathogenicity and transmissibility of circulating A(H5Nx) strains and what implications does it have on risk to human health?^{Footnote a}
• What is the infectious dose in humans and the types of exposure necessary (e.g., exposure to infected animals, contaminated environment, consumption of raw milk or products made with raw milk, virus survival in human gastrointestinal fluids) to induce infection in humans following contact with infected birds and mammals?^{Footnote a}
• What are the risk factors for human infection with A(H5Nx) and most impacted groups? ^{Footnote a}
• What is the risk of A(H5Nx) transmission between livestock on affected farms, and to companion animals and other domestic species? ^{Footnote a}
• What is the degree of virus shedding by infected cows and other mammals (symptomatic and asymptomatic) and virus survivability in milk, raw milk cheese, animal waste (mucus and manure), and the duration of shedding and incubation and infectious period? Is avian influenza A(H5N1) present in muscle of infected cattle or other mammals? ^{Footnote a}
• Is there evidence of novel tissue tropism and pathology (e.g. neuroinvasive disease)?^{Footnote a}
• What is the immunopathology of disease and are there immunomodulatory targets that are druggable?^{Footnote a}

Understand innate and adaptive immunity to influenza A(H5Nx) in humans, including antigen/antibody and cellular immune responses and antigenic crossover with other influenza viruses

• What is the antigenic crossover between influenza A(H5Nx) and other Influenza viruses (natural infection or from vaccination)?^{Footnote a}
• What are the correlates of seroprotection for influenza A(H5Nx)?
• What is the immune response in individuals with mild or asymptomatic A(H5Nx) infection?

Epidemiology, surveillance and testing

Describe the epidemiology (prevalence, mortality rate and distribution) of A(H5Nx) via surveillance, and testing activities at the human-animal-environment interface (e.g., in wild birds, wild mammals, and domestic animals)

• What are the frequency, distribution, and characteristics of symptomatic and asymptomatic A(H5Nx) infection in wild birds, wild mammals, domestic animals, and feral cat colonies, including modes of transmission, incubation and infectious periods, clinical presentation, and severity? ^{Footnote a}
• How can integrated wildlife and animal surveillance systems be combined to identify geographical areas and settings with increased risk of human exposure? ^{Footnote a}
• What are the types of human interactions with animals that increase risk of human exposure and implications for preventive public health guidance?^{Footnote a}

Define factors relating to the susceptibility and transmission parameters of different mammalian species and humans to A(H5Nx) viruses (e.g., clinical signs, incubation period, contagious period, virus shedding) to understand the potential risk to and impact on human health^{Footnote a}

• In different species of mammals and birds, what clinical and virological factors are associated with increased susceptibility to influenza A(H5Nx) infection in humans? How do these differ across species?
• What are the modes of transmission of A(H5Nx) within and between species? What factors contribute to spillover events from one species to the next, including from mammals to humans?
• How do animal (commercial, domestic or wildlife) control/containment measures and animal vaccination strategies modify human health risk?^{Footnote a}
• How does A(H5Nx) transmission to or between companion animals and other domestic animals change human health risk? ^{Footnote a}

Enable comparison of international and domestic baseline epidemiological parameters and human case information, including comparing sequencing data between reported human cases to determine key changes in virus differences between clades and subtypes, to understand the disease in severe and mild/asymptomatic human cases and inform public health guidance and interventions

• What is the prevalence, mortality rates, and geographic distribution of influenza A(H5Nx) cases, clusters and outbreaks in humans, including an understanding of asymptomatic infection?
• What is the incubation period, infectious period and reproductive rate of A(H5Nx) in humans?
• What is the clinical presentation and course of infection (including long lasting impacts) and spectrum of disease severity of A(H5Nx) infections in known human cases?^{Footnote a}
• How does clinical presentation of A(H5Nx) infection in other species relate to presentation in humans?
• How does the risk of infection vary by mode of transmission to humans (e.g., exposure to companion animals, consumption of raw meat, eggs or milk and milk products, and contact with fomites including contaminated farming equipment)? ^{Footnote a}

Assess seroprevalence and human exposure in different populations including groups at higher risk of occupational exposure to infected animals (e.g., poultry or livestock farmers, hunters, those who work at zoos, and wildlife care rehabilitation workers, municipal and parks employees, hunters/trappers, those living in rural/remote settings, contacts of cases)^{Footnote a}

• Developing a sensitive and specific serologic assay to enable the detection of asymptomatic infection in exposed groups.
• What is the level of population immunity in high-risk groups and in the general population?
• What is the risk of human exposure to A(H5Nx) in high-risk occupational groups and/or other at-risk communities (e.g., poultry or livestock farmers, hunters, those who work at zoos, and wildlife care rehabilitation workers, municipal and parks employees, hunters/trappers, those living in rural/remote settings, contacts of cases)?

Theme 2: Methods and tools to advance public health action

Detection and diagnosis

Enhance methods and tools for early detection of human cases in populations at increased risk of exposure, and enhanced surveillance (e.g., in wastewater or serosurveys)

• What is the level of under-detection of mild and sub-clinical human infections, limiting our understanding of avian and/or animal exposures associated with asymptomatic or mild infections? ^{Footnote a}

Understand the broader landscape of testing modalities and develop/deploy new molecular (including genomics) and serological methods for rapid detection as well as assess their effectiveness and performance

• What is the best testing strategy for individuals presenting with non-respiratory symptoms (for example, conjunctival versus nasopharangeal swabs)?
• What is the effectiveness of new molecular and/or serological methods for rapid detection of novel influenza viruses?
• In addition to diagnostic tests - used where evidence of symptoms/illness is/are present, do we have screening tests available that could be used to test asymptomatic animals and humans - that are highly sensitive and specific?
• What diagnostic assays need to be developed? Can new assays differentiate between antibodies produced due to an infection from those produced due to vaccination?
• What are the barriers to participation of population segments in enhanced surveillance, including in occupational and industry settings? What are effective strategies to overcome these barriers?

Modelling

Undertake modelling to inform the development of risk scenarios of A(H5Nx) human-to-human transmission and interventions

• What are the potential pandemic risk scenarios associated with avian and non-human mammal-to-human transmission?
• What are the potential pandemic risk scenarios associated with human-to-human transmission, considering environmental factors such as weather, population displacement, and community housing (e.g., arrival of asylum seekers)?
• What is the likelihood of a pandemic risk scenario?
• In the event of human-to-human transmission, what is the risk of continued transmission and importation of human cases, estimates of disease severity and transmission parameters (e.g., reproduction number and generation time), and the effectiveness of interventions including available antiviral treatments?
• What is the potential impact of pharmaceutical and non-pharmaceutical health interventions on A(H5Nx) epidemiology and other societal impacts?
• What is the available economic modelling of interventions to prevent mammal-to-human and human-to-human transmission?

In the event of increases in human cases, use modelling to forecast health system capacity for managing human cases of A(H5Nx), including pan-Canadian healthcare demand for various medical countermeasures (e.g., drugs, diagnostics, personal protective equipment (PPE), medical devices), including impact of imported cases

• Based on the pandemic risk scenarios, what are the pan-Canadian needs for healthcare access and supplies (e.g., hospitalization, PPE, medical devices, etc)?

Theme 3: Evidence-based interventions

Pharmaceutical public health interventions: vaccines and therapeutics

Assess safety, effectiveness and relative advantages/disadvantages of different therapeutics and treatments against human A(H5Nx) infection (including options meant for chemoprophylaxis, and treatment) and support the development of novel therapeutics (e.g., antiviral drugs) to treat human A(H5Nx) infection

• What existing therapeutics approved for use in humans can be repurposed for use against A(H5Nx) infection (e.g., immunomodulators)?
• What is the comparative effectiveness of different therapeutics for use against human A(H5Nx) infection?
• Are there novel therapeutics (antivirals or immunotherapies) for preventing and treating human A(H5Nx) infection in development? How effective and safe are they?
• What are the treatment indications and roles of combination therapy for the treatment of serious infection (e.g., in individuals who are ventilated)?
• What are the most effective antiviral intervention strategies and trigger points for antiviral deployment?
• What is the effectiveness and safety of combining different therapeutic agents or combining vaccines and therapeutics in the treatment and prevention of A(H5Nx) infection? This includes understanding potential synergistic or antagonistic effects between different therapeutics.

Evaluate mechanisms to reduce the emergence of A(H5Nx) resistance to antivirals

• What are effective mechanisms to reduce the emergence of A(H5Nx) antiviral resistance?
• What is the value of combination therapy in reducing the likelihood of emerging resistance?
• How can sequencing capacity be leveraged to establish surveillance for emerging resistance (e.g. coupling to antiviral deployment)?
• Are there novel broad-spectrum therapeutics (antivirals or immunotherapies) in development to provide a higher genetic barrier to resistance? How effective and safe are they?

Understand the effectiveness and safety of human A(H5Nx) vaccines as well as implementation and intervention strategies, in different populations

• What is the anticipated demand of human A(H5Nx) vaccines?
• What are the mechanisms to support vaccine uptake/confidence (e.g., ease of administration, minimizing pain) and understand vaccine effectiveness in different populations (i.e., post-administration studies)?
• What is the effectiveness of various vaccination implementation strategies (universal, targeted to high-risk groups and populations with a high burden of disease concentration, pre- or post-exposure, ring vaccination, etc.)?
• What is the effectiveness of different dose strategies (dose schedule, number of doses, sparing strategies)?
  • Is dose-sparing possible given that inactivated avian influenza virus vaccines have historically demonstrated poor immunogenicity and required high antigen content and/or adjuvant?
  • Is dose priming with a different, but related, avian influenza vaccine effective due to reliance on high antigen content/adjuvants?
• Given the risk of highly pathogenic avian influenza viruses being embryo-lethal, can the H5Nx virus strains of interest be propagated efficiently in eggs to create vaccine bulk? If not, are there any antigen-like strains that could be propagated more efficiently?
  • What is the anticipated impact to vaccine effectiveness due to pivoting to a related strain?
  • What is the threshold for making the switch in strain propagation?
• Which vaccine platforms are best suited for protection against influenza A(H5N1)/A(H5Nx)? What are the comparative safety, immunogenicity, efficacy and effectiveness profiles of different human A(H5Nx) vaccines?
• What are the safety profiles of human A(H5Nx) vaccines?
  • Are there new adverse events that need to be monitored?
• What is the interaction between seasonal influenza vaccine and human A(H5Nx) vaccines? What is the contribution of pre-existing or cross-protective immunity from seasonal or other vaccines against influenza A(H5Nx) vaccines and any resultant impacts, if any, on the safety and efficacy of human A(H5N1) vaccines?
• What is the safety, immunogenicity, efficacy, and effectiveness of A(H5Nx) vaccines in special populations (e.g., children, older adults, pregnant individuals, immunocompromised individuals)?

Non-pharmaceutical public health interventions

Evaluate how protective measures and interventions such as the use of personal protective equipment (PPE), ventilation/air filtration, and cleaning/disinfection impact transmission

• How do ventilation and air filtration impact A(H5Nx) transmission in high-exposure occupational settings for humans?
• How effective is PPE against zoonotic A(H5Nx) transmission in high-risk occupational settings?
• What is the pan-Canadian variability of PPE and biosecurity standards and requirements in various occupational settings?
• What is the availability of protective measures in backyard flocks compared to commercial facilities and how are they implemented?
• What is the level of adherence to and what factors facilitate adherence to use of protective measures and PPE, including in occupational settings/environments?
• What are the most critical factors to consider when selecting appropriate PPE for individuals working in environments with potential exposure and for use in special populations?
• What are the most effective disinfectants for eliminating the virus from various surfaces?
• Are there any novel technologies or approaches being developed to enhance the efficacy of protection, cleaning, and disinfection methods?

Behavioural and social sciences

Describe the frequency of and behavioural factors influencing human interactions with different types of animals and geographic and cultural variation in human-animal contacts^{Footnote a}

• How do Canadians interact with and what is the exposure level to animals of concern?
• What are the behavioural, cultural, socioeconomic, climate change, geographical, land-use (or planning) factors at the community level that can increase spillover potential, including among Indigenous communities?
• What are the challenges, concerns, and needs of the public, and specifically Indigenous communities, to inform the development of appropriate guidance and improve knowledge translation on A(H5Nx) infection prevention and control?
• How can we support community-level preparedness for avian influenza in equity-seeking populations?

Understand factors affecting adherence to preventative public health measures to reduce exposure to A(H5Nx) and how they influence transmission rates

• What are the barriers/facilitators of personal protective equipment adherence among humans at risk of exposure (e.g., poultry or livestock farmers, hunters, those who work at zoos, and wildlife care rehabilitation workers, municipal and parks employees, hunters/trappers, those living in rural/remote settings), and how can uptake be improved? ^{Footnote a}
• What are the barriers/facilitators to biosecurity and emergency response adherence among animal health sectors (e.g., poultry farms, livestock farms, others?)? ^{Footnote a}
• How do we most effectively engage populations at increased risk of exposure to A(H5Nx) viruses to achieve adherence with risk mitigation measures?^{Footnote a}
• What are the barriers/facilitators to testing/participation in surveillance among humans at risk of exposure, and how can uptake be improved?
• Among humans at risk of exposure (e.g., poultry or livestock farmers, hunters, those who work at zoos, and wildlife care rehabilitation workers, municipal and parks employees, hunters/trappers, those living in rural/remote settings) what are the barriers/facilitators to the following: a) immunization with seasonal human influenza vaccine; b) immunization with a vaccine against A(H5Nx) virus(es); and, c) acceptance of antiviral prophylaxis?^{Footnote a}
• What is the knowledge, attitudes and beliefs of populations at increased risk of exposure to A(H5Nx) viruses? The general population?

Define the risk factors (including but not limited to medical, social, and behavioural), associated with A(H5Nx) to inform public health guidance and interventions

• What factors contribute to misconceptions and lack of trust in public health authorities in the animal/wildlife sectors? What factors contribute to misconceptions and lack of trust in public health authorities among Indigenous communities reliant on country foods, hunting/trapping?
• What factors contribute to the potential for misinformation and disinformation associated with varying H5Nx risk scenarios?
• Evaluate the types of information (scientific evidence and beyond) and economic factors that influence public health decision-making by policy makers, communities, and individuals during health emergencies.

Appendix

Key sources

Key sources consulted include:

• PHAC Pandemic risk scenario analysis: Influenza A(H5Nx) clade 2.3.4.4b virus and related future novel viruses (2023-07-27)
• PHAC Rapid risk assessment: Avian influenza A(H5N1) clade 2.3.4.4b (2023-07-27)
• Rapid risk assessment update: Avian influenza A(H5N1) clade 2.3.4.4b in livestock, public health implications for Canada (2024-04-26)
• McMaster Health Forum Living Evidence Profile: Examining what is known about the emergence, transmission and spectrum of the burden of disease of avian influenza A(H5Nx) subtypes (version 7.1, 2024-01-12)
• McMaster Health Forum Rapid Evidence Profile: Identifying features and impacts of public health strategies that can be used to prevent, reduce and/or mitigate avian influenza spillover to humans (2024-01-12)
• United Kingdom Health Security Agency technical briefing (2023-07-14)
• PHAC H5N1 scenario and action planning documents
• Interdepartmental briefing documents from the Canadian Food Inspection Agency and Environment and Climate Change Canada
• Royal Society of Canada One Health meeting H5N1: Evolving Situation, Evolving Science meeting materials
• Meeting records of discussion from the PHAC Expert Panel on Avian Influenza A(H5Nx).

Methods

The list of identified priority knowledge gaps was developed by synthesizing inputs from sources noted above and was validated by PHAC and extramural scientists and researchers through their participation in the PHAC Expert Panel on Avian Influenza A(H5Nx). The validation process resulted in a high degree of concurrence amongst experts on key public health criteria, including:

• Relevance to phase of emergency: initiation of research to address the gap was deemed appropriate during preparedness and response phases.
• Relevance to pandemic preparedness: addressing the gap would be generalizable to broader pandemic preparedness beyond A(H5Nx).
• Impact on dimensions of risk assessment: addressing the gap would impact public health decision-making and action impacting risk of sporadic or widespread A(H5Nx) human-spillover and pandemic.

The methodological objective was not to achieve absolute consensus among all sources and experts consulted, but to identify the priority knowledge gaps and research needs expected to have the greatest relevance to preparedness and response for possible human infection with the current circulating avian influenza virus, and to A(H5Nx) broadly, in Canada.

Definitions

Science: The pursuit and application of knowledge and understanding of the natural and social world following a systematic methodology based on evidence.^{Reference 3} This includes a continuum of creative and systematic activities directly related to the generation, advancement, dissemination and application of scientific and technological knowledge. In the context of this report, this may include knowledge syntheses, operational/implementation research, applied research, and observational and intervention studies.

Research: Any undertaking intended to extend knowledge through a discipline's inquiry or systematic investigation.^{Reference 4}

One Health: "an integrated, unifying approach that aims to sustainably balance and optimize the health of humans, animals, plants and ecosystems. It recognizes the health of humans, domestic and wild animals, plants and the wider environment (including ecosystems) are closely linked and interdependent. The approach mobilizes multiple sectors, disciplines and communities at varying levels of society to work together to foster well-being and tackle threats to health and ecosystems, while addressing the collective need for clean water, energy and air, safe and nutritious food, taking action on climate change, and contributing to sustainable development."^{Reference 5}

Footnotes

References