Preparedness, prevention and control related to zoonotic avian influenza

Abstract

A risk assessment framework was developed to evaluate the zoonotic potential of avian influenza (AI), focusing on virus mutations linked to phenotypic traits related to mammalian adaptation identified in the literature. Virus sequences were screened for the presence of these mutations and their geographical, temporal and subtype-specific trends. Spillover events to mammals (including humans) and human seroprevalence studies were also reviewed. Thirty-four mutations associated with five phenotypic traits (increased receptor specificity, haemagglutinin stability, neuraminidase specificity, enhanced polymerase activity and evasion of innate immunity) were shortlisted. AI viruses (AIVs) carrying multiple adaptive mutations and traits belonged to both low and highly pathogenic subtypes, mainly to A(H9N2), A(H7N9), A(H5N6) and A(H3N8), were sporadic and primarily detected in Asia. In the EU/EEA, H5Nx viruses of clade 2.3.4.4b, which have increased opportunities for evolution due to widespread circulation in birds and occasional cases/outbreaks in mammals, have acquired the highest number of zoonotic traits. Adaptive traits, such as enhanced polymerase activity and immune evasion, were frequently acquired, while receptor-specific mutations remained rare. Globally, human cases remain rare, with the majority overall due to A(H5N1), A(H5N6), A(H7N9) and A(H9N2) that are among the subtypes that tend to have a higher number of adaptive traits. The main drivers of mammalian adaptation include virus and host characteristics, and external factors increasing AIV exposure of mammals and humans to wild and domestic birds (e.g. human activities and ecological factors). Comprehensive surveillance of AIVs targeting adaptive mutations with whole genome sequencing in animals and humans is essential for early detection of zoonotic AIVs and efficient implementation of control measures. All preparedness, preventive and control measures must be implemented under a One Health framework and tailored to the setting and the epidemiological situation; in particular, enhanced monitoring, biosecurity, genomic surveillance and global collaboration are critical for mitigating the zoonotic risks of AIV.

Keywords: avian influenza; birds; highly pathogenic avian influenza (HPAI); mammals; mutations; preparedness; public health.

FIGURE 1

Reported cases of HPAI A(H5Nx) infection by the WOAH (90%) and national authorities (10%) in non‐human mammal families and orders (November 2020 to September 2024).

FIGURE 2

Reported detections of HPAI A(H5Nx) in non‐human mammals per region and per epidemiological season (data from the WOAH–WAHIS). Note that in one single reported detection, one or more infected animal might be included.

FIGURE 3

Distribution of different A(H5N1) clades among reported human cases with available sequences, January 2000 to May 2024.

FIGURE 4

Distribution of reported cases of avian influenza virus in humans by the time of onset or detection from 1997 to 31 October 2024, including subtypes in which more than a total of 10 cases have been reported in humans. The figure includes detections of A(H5N1) due to suspected environmental contamination reported in 2022 (three detections) and 2023 (three detections, one inconclusive). Human cases of A(H5) cases epidemiologically linked to A(H5N1) outbreaks at poultry and dairy cattle farms in the USA in 2024 are included in the number of cases of A(H5N1).

FIGURE 5

Reported cases of avian influenza virus in humans by year of onset or detection and reporting country between 2019 and 31 October 2024, including subtypes for which more than a total of 10 cases have been reported in humans. The figure includes detections of A(H5N1) due to suspected environmental contamination reported by Spain (2) and the USA (1) in 2022, and the United Kingdom (3, 1 inconclusive) in 2023. Human cases of A(H5) cases epidemiologically linked to A(H5N1) outbreaks at poultry and dairy cattle farms in the USA in 2024 are included in the number of cases of A(H5N1).

FIGURE 6

Reported number of cases or detections of avian influenza virus in humans by reporting country between 1997 and 31 October 2024 for (A) subtype A(H5N1) and (B) subtype A(H9N2). The figure includes detections of A(H5N1) due to suspected environmental contamination reported by Spain (2), United Kingdom (3, 1 inconclusive) and USA (1). Human cases of A(H5) epidemiologically linked to A(H5N1) outbreaks at poultry and dairy cattle farms in the USA in 2024 are included in the number of cases of A(H5N1).

FIGURE 7

Reported cases or detections of avian influenza virus in humans by age group and reported outcome between 1 November 2021 and 31 October 2024, including subtypes in which more than 10 cases have been reported in humans. The figure includes detections of A(H5N1) due to suspected environmental contamination reported in 2022 (three detections) and 2023 (three detections, one inconclusive). Human cases of A(H5) cases epidemiologically linked to A(H5N1) outbreaks at poultry and dairy cattle farms in the USA in 2024 are included in the number of cases of A(H5N1).

FIGURE 8

Timeline of human cases by virus subtype and the total number of sequences (avian and mammalian) with a higher number of accumulated traits (3–5). The left y‐axis is the number of human cases; the right y‐axis is the number of virus sequences with mutations affecting three to five traits.

FIGURE 9

Proportion of trait counts (total number of 0–5 accumulated traits per virus) for the different influenza virus subtypes, displayed as a percentage of the total sequences for each subtype (0–2 traits are grouped into the same category, light blue).

FIGURE 10

Proportion (0–1) of each trait across subtypes (34 mutations from subset 1). The total number of sequences containing at least one of the trait‐associated mutations (n) on the total number of sequences (N) per subtype is displayed for each subtype and each trait (n/N) (the first three traits are shown; the other two are shown in Figure 11 for reason of space).

FIGURE 11

Proportion (0–1) of each trait across subtypes (34 mutations from subset 1). The total number of sequences containing at least one of the trait‐associated mutations (n) on the total number of sequences (N) per subtype is displayed for each subtype and each trait (n/N).

FIGURE 12

Proportion of each trait across subtypes (13 mutations, subset 2). The total number of sequences containing at least one of the trait‐associated mutations (n) on the total number of sequences (N) per subtype is displayed for each subtype and each trait (n/N).

FIGURE 13

Proportion of each trait across H5 clades (34 mutations from subset 1). The total number of sequences containing at least one of the trait‐associated mutations (n) on the total number of sequences (N) per subtype is displayed for each subtype and each trait (n/N).

FIGURE 14

Proportion of each trait across H5 clades (13 mutations, subset 2). The total number of sequences containing at least one of the trait‐associated mutations (n) on the total number of sequences (N) per subtype is displayed for each subtype and each trait (n/N).

FIGURE 15

Heat map of the proportion of the 40 shortlisted mutations (subset 1) across subtypes (the 13 mutations, subset 2, are indicated in blue).

FIGURE 16

Heat map of the proportion of the 40 shortlisted mutations (subset 1) across H5 clades (the 13 mutations, subset 2, are indicated in blue).

FIGURE 17

Timeline of the frequency of the 13 mutations (subset 2) in all the analysed viruses plotted over the number of human cases. Each plot represents the timeline (year) of the relative frequency (black line and right y‐axis) of each of the 13 shortlisted mutations (indicated above each graph). The bars represent the number of AIV human cases reported each year, coloured according to the subtype (left y‐axis).

FIGURE 18

Diagram showing goals, objectives and possible related actions about prevention, control and preparedness measures to reduce the risk of AI spread from infected animals to and within fur animal farms.

FIGURE 19

Diagram showing goals, objectives and possible actions related to prevention, control and preparedness measures to reduce the risk of AI spread from infected animals to and within cattle farms.

FIGURE 20

Diagram showing goal, objectives and possible actions related to prevention, control and preparedness measures to reduce the risk of AI transmission to humans in animal farms.

FIGURE 21

Number of sequences in the data set per year, subtypes (upper) and continent (lower).

FIGURE D.1

Number of sequences for each influenza subtype by number of traits (1–5) identified in each sequence.

FIGURE D.2 Frequency of shortlisted mutations across continents.

FIGURE D.3 Frequency of shortlisted mutations across continents.

FIGURE D.4 Frequency of shortlisted mutations across continents.

FIGURE D.5 Timeline of the frequency of the 40 mutations (subset 1) in all the analysed viruses plotted over the number of human cases. Each plot represents the timeline (year) of the relative frequency (black line and right y‐axis) of each of the shortlisted mutations (indicated above each graph). The bars represent the number of AIV human cases reported each year, coloured according to the subtype (left y‐axis).