Research and analysis

Influenza A(H1N2)v: rapid technical assessment

Published 11 December 2023

Applies to England

The UK Health Security Agency (UKHSA) with the Animal and Plant Health Agency (APHA) and the Worldwide Influenza Centre (WIC) at the Francis Crick Institute is undertaking standard investigations following the first human detection of an influenza virus not previously known to cause human infection.

This briefing is produced to share data useful to other public health investigators and academic partners undertaking related work. It includes early evidence and preliminary analyses which may be subject to change.

Data reported in the technical briefing is as of 4 December 2023 (or as specified in the text) to allow time for analysis.

Situation update

A human case of influenza A (H1N2)v clade 1B.1.1 was detected in England through routine community respiratory virus surveillance. The case is an otherwise well person over 75 years of age, who recovered fully. Although the virus was similar to those detected in pigs in England and the case lives in a region of England containing pig farms, no direct contact between the index case and any animal was reported.

UKHSA with APHA and Defra, the Francis Crick Institute, local NHS partners and the local authority therefore investigated:

1. To determine the source of infection, backwards contact tracing and assessment of potential locations for animal to human spillover in the vicinity of the case were undertaken. Although the case lives in an area of the country which contains pig farms and in proximity to sites containing animals (including a veterinary facility and a live auction market) no direct link or chain of transmission could be identified between the case and any animal. Environmental sampling is ongoing.

2. To identify any potential human to human transmission: contact tracing, polymerase chain reaction (PCR) testing and serology are being used. One household contact and one other contact were symptomatic but their symptoms had already resolved by the time they were identified, and therefore they were not tested whilst unwell. At the time of testing, one of these contacts had a non-influenza respiratory pathogen detected although its significance is unclear given timing with respect to symptoms. To date, no further cases have been detected through the investigations including follow-up of contacts (including precautionary follow up of the contacts of symptomatic contacts). Serological assessment is ongoing.

3. To rule out any local community transmission, enhanced surveillance is being conducted (community and hospital). Following the index case, no further cases have been detected to date through enhanced surveillance through local GP practices (Table 1) and hospital trusts, but this will continue for a further 4 weeks.

Table 1. Enhanced primary care sentinel surveillance swabbing 1 October to 5 December 2023

Coinfections are reported for both subtypes. Count includes index case. Row numbers are cumulative, so each row includes the counts from the row above.

Setting	Total tests in period	Total influenza positive	Influenza subtyped: A	Influenza subtyped: H1N1	Influenza subtyped: H3N2	Influenza subtyped: H1N2v	Influenza subtyped: B	Percentage positive
Practice of index case	115	1	0	0	0	1*	0	0.87
Nearest 5 practices	140	1	0	0	0	1*	0	0.71
Region	279	1	0	0	0	1*	0	0.36
England	4,629	57	0	30	21	1*	6	1.23

*This is the index case

Source: UKHSA/RCGP Research and Surveillance Centre

Exploratory studies have also been initiated to improve knowledge of spillover risk and to develop capability for future events, including an assessment of the potential of wastewater testing, environmental studies of potential spillover locations, and protocols for surveillance of occupational groups with relevant animal exposure. Work is also ongoing to assess the ability of currently available diagnostic assays to detect this strain.

This report provides a summary of the assessment that UKHSA makes for novel or emerging influenza viruses. Data used for the assessment was provided by UKHSA, APHA, and the Worldwide Influenza Centre at the Francis Crick Institute.

Genomic characterisation of the virus

The virus is influenza A(H1N2) and as this detection has occurred in a human, it is referred to as A(H1N2)v. The haemagglutinin gene sequence is of the H1 subtype and very closely related to viruses that have been detected in British pigs in 2022 and 2023. These viruses cluster genetically within the 1B.1.1 HA lineage which arose when seasonal influenza viruses from humans were introduced into pigs, likely in the 1980s, and they have continued to circulate and diversify in pigs to the present day. Different 1B lineage genetic subgroups circulate in different parts of Europe. The neuraminidase (N2) and the internal gene segments also all show a very close relationship to contemporary 1B.1.1 swine influenza A viruses in Great Britain. The internal genes originated from the H1pdm09 virus but have diverged significantly from their human ancestor: the relative risk in relation to replication in humans has yet to be determined. There is no evidence of a new reassortment.

Phylogenetically, the human case viral genome clusters closely with contemporary swine viruses from the surrounding region.

There are no obvious features of concern in the mutations seen in the human case viral genome compared to swine genomes, although some differences are of unknown significance.

The NP segment of the A(H1N2)v human sequence contains the G101D mutation and several others when compared to the 2009 pandemic H1N1 virus. These mutations are also present in swine samples closely related to the recent human A(H1N2)v case. These mutations, particularly G101D, are potentially re-adaptations to swine, re-sensitising NP to the human restriction factor MxA (and possibly BTN3A3). This likely results in the virus being sensitive to these human restriction factors, and preliminarily suggests that these sites have not been selected for to regain resistance, as might be expected during longer term human circulation.

The A(H1N2)v clade 1B.1.1 genome sequence from the index case has been made publicly available by UKHSA (GISAID accession EPI_ISL_18548251; NCBI GenBank accession: SUB14002372).

Genomes from contemporary swine influenza cases have been made available on the Global Initiative on Sharing All Influenza Data (GISAID) by APHA:

• EPI_ISL_18543639
• EPI_ISL_18586964
• EPI_ISL_18586963
• EPI_ISL_18586962
• EPI_ISL_18586961
• EPI_ISL_18586960
• EPI_ISL_18586959
• EPI_ISL_18586958
• EPI_ISL_18586957
• EPI_ISL_18586956
• EPI_ISL_18586955
• EPI_ISL_18586954
• EPI_ISL_18586953
• EPI_ISL_18586952
• EPI_ISL_18586951
• EPI_ISL_18586950

These genomes are from multiple counties across Great Britain.

There is no live virus isolate from the human case. Genomic assessments were undertaken using the complete genome from the human case (GISAID isolate ID: EPI_ISL_18548251, NCBI GenBank: SUB140.02372) and phenotypic assessments were undertaken using a surrogate closely related virus isolate from swine (GISAID isolate ID: EPI_ISL_18543639).

Figure 1 shows a phylogeny of the HA segment for global A(H1) representative swine influenza sequences. The clades containing sequences from the 1A and 1C lineages have been collapsed and the 1B subgroups are labelled. Sequences are coloured by country of submission. The clade containing the sequence from the UK index case is indicated by the red diamond at the root of the clade.

Figure 1. Phylogeny of representative global A(H1) swine sequence data and sequence data from the UK index case

The H1 1A and 1C clades have been collapsed and 1B subgroups are labelled. Sequences are coloured by country of submission. The clade containing the UK index case is indicated by a red diamond at the root of the clade.

Supplementary data is not available for this figure.

Rapid assessment of the virus

Rapid assessment: influenza A(H1N2)v 1B.1.1 (first human case)

Epidemiology in animals

Clade 1B.1.1 is endemic in pigs in Great Britain and likely to be the dominant virus circulating (69% of all swine influenza genomes 2014-2023). Ancestral and related clades are present in Europe but 1B.1.1 is distinct to Great Britain (‘moderate confidence’). Surveillance is clinical and voluntary (GB Pig Disease Surveillance Dashboard). Based on historic data there is no clear indication of a recent change in levels of transmission (‘low confidence’).

Exposure of the UK human population to swine A(H1N2)

The general population has a very low risk of exposure to this virus in pigs. Those directly exposed to pigs regularly (for example, through occupation) may have a higher risk of exposure to this virus. The case resides in a region containing a high density of pig farms. East Anglia, Yorkshire and Humber regions have the highest densities of pigs, and a high proportion of commercially kept pigs compared with other regions in GB. UKHSA together with APHA and local authorities is undertaking investigative work on sites where exposures may occur such as markets, abattoirs and farms.

Propensity to infect humans

There is no data. UKHSA monitors influenza at the human/animal interface through targeted surveillance and will extend the current study on farms affected by avian influenza to include a pilot sample of pig farms.

Human to human transmission

There is no virologically confirmed human-to-human transmission. The human case viral genome is closely related to circulating viruses in pigs (‘moderate confidence’) and the mutational profile where it can be interpreted is consistent with a hypothesis of recent emergence (‘low confidence’).

The presence of a case without direct contact with animals, and the presence of a symptomatic household contact, mean that some limited degree of human-to-human transmission may have occurred (‘low confidence’).

No onwards transmission has been detected through PCR testing of contacts (‘low confidence’; given the normal surveillance lag time in identifying the influenza variant, most testing was relatively late compared to potential exposure and serological assessment is in process and may change this assessment).

No other cases have been detected through UKHSA enhanced community surveillance, including amongst 133 acute respiratory illness patients swabbed between 1 October and 1 December at the nearest 5 RCGP sentinel practices. This is the first ever detection of a non-human influenza strain through RCGP surveillance.

Influenza A(H1N2) sporadic human cases have been detected internationally, usually with direct links to swine, although these are not within the same specific clade.

Severity of disease

No conclusions can be drawn from a single case.

Antigenic characteristics

Based on rapid assessments undertaken by Worldwide Influenza Centre (WIC, FCI), currently available H1 subtype 1B lineage candidate vaccine viruses (CVVs) for prepandemic preparedness, would be unlikely to afford protection against the H1 1B.1.1 swine influenza A viruses detected in the UK.

Additionally, based on a small panel of UK sera taken pre- and post- vaccination with the 2023 to 2024 influenza vaccine, the current seasonal influenza vaccine will likely not afford protection against the H1 1B.1.1 swine influenza A viruses detected in the UK. Further assessment is underway.

Antiviral susceptibility

Based on both genomic and in vitro assessment, the swine virus (A/swine/England/045393/2022) is susceptible to Oseltamivir, Zanamivir and Baloxavir Marboxil (‘high confidence’).

Testing by the Fluorescent (MUNANA) Neuraminidase Inhibition Assay gave IC50s as follows: Oseltamivir 1.62 (approximately 2-fold higher than seasonal median), zanamivir 2.8 (approximately 3-fold higher than seasonal median). The EC50 for Baloxavir Marboxil is 0.24.

Sources and acknowledgments

Data sources

Data on the case and contact investigation and local human health surveillance and studies is provided by UKHSA.

Data relating to animal health surveillance and investigations taking place across England is provided by APHA

Data for antigenicity and antiviral sensitivity analyses was generated by the Francis Crick Institute.

Genomic analyses include data obtained from GISAID.

Authors of this report

Kate Agami, Paula Blomquist, Ashley Banyard, Ian Brown, Alexander Byrne, Meera Chand, Katy Davidson, Eileen Gallagher, Natalie Groves, Ruth Harvey, Susan Hopkins, Joe James, Beatrix Kele, Angie Lackenby, Nicola Lewis, Jamie Lopez Bernal, Ben Mollett, Isabel Oliver, Thomas Peacock, Richard Pebody, Steven Riley, Helen Roberts, Roberto Vivancos, Nick Watkins, Conall Watson, William Welfare, Deborah Williamson, Maria Zambon.

H1N2 Technical Group

The H1N2 Technical Group includes members with expertise in clinical infectious diseases, clinical research, epidemiology, genomics and virology:

• Meera Chand (Chair), UKHSA
• Alex Byrne, APHA
• Allan Bennett, UKHSA
• Amanda Bradley Stewart, PHS
• Andrew Hayward, UKHSA
• Andrew Rambaut, University of Edinburgh
• Angie Lackenby, UKHSA
• Ashley Banyard, APHA
• Ashley Otter, UKHSA
• Barry Atkinson, UKHSA
• Bassam Hallis, UKHSA
• Chris Williams, PHW
• Conall Watson, UKHSA
• Deborah Williamson, UKHSA
• Eileen Gallagher, UKHSA
• Emma Thomson, University of Glasgow and LSHTM
• Erik Volz, Imperial College London
• Gavin Dabrera, UKHSA
• Helen Roberts, Defra
• Ian Brown, APHA
• Isabel Oliver, UKHSA
• James Gilbert, UKHSA
• Jamie Lopez Bernal, UKHSA
• Joe James, APHA
• Kimberly Marsh, PHS
• Luke Hounsome, UKHSA
• Maria Zambon, UKHSA
• Mark O’Doherty, HSCNI
• Michael Lockhart, PHS
• Natalie Groves, UKHSA
• Nicholas Loman, UKHSA and University of Birmingham
• Nick Watkins, UKHSA
• Nicola Lewis, Francis Crick Institute
• Paula Blomquist, UKHSA
• Richard Myers, UKHSA
• Richard Pebody, UKHSA
• Richard Puleston, UKHSA
• Roberto Vivancos, UKHSA
• Ruth Harvey, Francis Crick Institute
• Steven Riley, UKHSA
• Susan Hopkins, UKHSA
• Thomas Peacock, Pirbright Institute
• Victoria Hall, UKHSA
• Wendy Barclay, Imperial College London
• Will Welfare, UKHSA
• Yper Hall, UKHSA