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

Last updated: May 13, 2024

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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 StatesReference 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.

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:

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:

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:

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):

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:

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
Understand virological and genomic factors (including reassortment) that may impact the ability of the viruses to infect humansFootnote 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 (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)
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 healthFootnote 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
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

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)
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 (e.g., drugs, diagnostics, personal protective equipment (PPE), medical devices), including impact of imported cases

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
Evaluate mechanisms to reduce the emergence of A(H5Nx) resistance to antivirals
Understand the effectiveness and safety of human A(H5Nx) vaccines as well as implementation and 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 frequency of and behavioural factors influencing human interactions with different types of animals and geographic and cultural variation in human-animal contactsFootnote a
Understand factors affecting adherence to preventative public health measures to reduce exposure to A(H5Nx) and how they influence transmission rates
Define the risk factors (including but not limited to medical, social, and behavioural), associated with A(H5Nx) to inform public health guidance and interventions

Appendix

Key sources

Key sources consulted include:

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:

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

Footnote a

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.

Return to footnote a

References

Reference 1

Burrough ER, Magstadt DR, Petersen B, Timmermans SJ, Gauger PC, Zhang J, et al. Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Emerg Infect Dis. 2024 Jul [cited 2024 May 13]. https://doi.org/10.3201/eid3007.240508

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Reference 2

Technical Report: Highly Pathogenic Avian Influenza A(H5N1) Viruses updated June 5 2024. Available from https://www.cdc.gov/flu/avianflu/spotlights/2023-2024/h5n1-technical-report-06052024.htm

Return to reference 2

Reference 3

Adapted from Science Council. Our definition of science [Internet]. N.d. [cited 2024 May 13]. Available from: https://sciencecouncil.org/about-science/our-definition-of-science/

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Reference 4

Adapted from Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. 2018. [cited 2024 May 13]. Available from: https://ethics.gc.ca/eng/documents/tcps2-2018-en-interactive-final.pdf

Return to reference 4

Reference 5

Adapted from the One health joint plan of action (2022-2026): working together for the health of humans, animals plants and the environment. Available from: One health joint plan of action (2022‒2026): working together for the health of humans, animals, plants and the environment (who.int)

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