Wednesday, December 21, 2022

UK HSA Technical Briefing: Risk Assessment On HPAI H5N1 & Human Infection


Over the past 17 years I've often described HPAI H5 as a virus that - despite sparking a number of serious human infections around the world - isn't quite ready for prime time.  It has only rarely been transmitted from human-to-human, and needs to overcome a number of genetic barriers before it can become a genuine pandemic threat. 

But it keeps trying, and one day it may succeed. 

Over the past year we've witnessed an unprecedented spread of HPAI H5, and continued evolution - and the occasional spillover of the virus into mammals - around the world (see this morning's ECDC/EFSA Avian influenza overview September – December 2022.

Three weeks ago, in UK APHA: Technical risk assessment for avian influenza (human health): influenza A H5N1, we looked at an initial risk assessment by the UK's Animal & Plant Health Agency, which reassuringly found:

`There is no evidence of sustained human-to-human transmission (moderate to high confidence).', they provide a number of caveats, including: 

There is insufficient information to judge the risk of asymptomatic or mild disease due to limited testing in human contacts of infected birds.


There is insufficient information to assess the occurrence of limited human-to-human transmission such as transmission within households. 

As a result, that assessment stated: At present there are no indicators of increasing risk to human health; however, this is a low confidence assessment. They also caution that `The risk assessment is dynamic and requires regular review during this period of unusually high levels of transmission in birds.'

Today we have a much more detailed technical briefing from the UK's Health Security Agency (UKHSA), which - while similarly reassuring - takes the potential threat from HPAI H5 seriously.  Among their findings:

  • They define 6 levels of transmission, and place the UK at Level 3 (Evidence of viral genomic changes that provide an advantage for mammalian infection). 
  • They are also investigating a small number of unsubtypable flu samples (see chart below), although there is no evidence that any of these are HPAI H5. 

  • At present, there are no indicators of increasing risk to human health, however this is a low confidence assessment. 
I've only posted some excerpts from a much longer report.  Follow the link to read it in its entirety. 

Research and analysis
Investigation into the risk to human health of avian influenza (influenza A H5N1) in England: technical briefing 1

Published 21 December 2022
Applies to England

Levels of human health risk related to the outbreak of avian influenza in England
Main data points
Part 1. Risk assessment as of 13 December 2022
Part 2. Epidemiology update
Part 3. Genomic surveillance
Part 4. Planned rapid laboratory assessments and early data
Part 5. Further planned work
Sources and acknowledgments
The UK Health Security Agency (UKHSA) is working with the Animal and Plant Health Agency (APHA) and the Department for Environment, Food and Rural Affairs (Defra) to investigate the risk to human health of avian influenza (influenza A H5N1) in England. 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 13 December 2022 (or as specified in the text) to allow time for analysis.

Levels of human health risk related to the outbreak of avian influenza in England

These risk levels were developed by the Technical Group to help to establish triggers for enhancing assessment and response. The avian influenza outbreak can be considered to fall into one of 6 potential levels of transmission.

Level 0 (Baseline)

Avian influenza circulating in birds within normal bounds of prevalence and with normal epidemiological dynamics.

Level 1

Avian influenza circulating in birds with altered epidemiological dynamics and/or increased prevalence.

Level 2

Level 1 plus detection of spillover into mammals.

Level 3

Evidence of viral genomic changes that provide an advantage for mammalian infection.

Level 4

Sustained transmission in non-human mammalian species or any human detection and mutations in haemagglutinin (HA) which allow transmission. (A single human detection in a person exposed to infected birds, without HA mutations, does not raise the risk level to 4.)

Level 5

Any human-to-human transmission.

 The UK risk is currently assessed as at level 3.

Main data points

Since 1 October 2022, the start of the current reporting year for avian influenza, APHA has notified UKHSA that highly pathogenic avian influenza (HPAI) A(H5N1) has been confirmed in avian species at 130 premises in England. Wild bird testing is undertaken on a geographically representative sample of birds, with 447 influenza A (H5N1) detections at 280 locations in England reported since 1 October 2022. Since the introduction of the poultry housing order on 7 November 2022, numbers of infected premises are decreasing but detections in wild birds continue to suggest high levels of circulating virus in the UK.

From 1 October 2022 to 15 December 2022, health protection systems have recorded 2,085 human exposure episodes (where a person was directly exposed to an infected bird). There is likely to be substantial under ascertainment.

Detailed data on incidents (health protection responses to avian influenza detections) is incomplete. Based on the 29% of incidents for which there is data (1 October 2022 to 13 December 2022), personal protective equipment (PPE) was used in 27.3% of exposures, and antiviral prophylaxis in 15.9% of exposures. Symptoms were reported following 31 (4.3%) exposures, with 24 symptomatic swabs being carried out (77.4% of those eligible). There have been no detections of avian influenza viruses in humans the UK during the current reporting year (from 1 October 2022 to date) and there was one human detection in the UK in the preceding reporting year (1 October 2021 to 30 September 2022).

APHA report that 20 mammals have been retrospectively tested, of which 8 were influenza A (H5N1) positive. Four of these have genome sequences available and all show the presence of a mutation which is associated with potential advantages for mammalian infection. This is very limited data but, together with international data, is suggestive of sporadic mammalian spillover events.

Some clinical and regional public health laboratories undertake influenza subtyping and refer influenza A which is unsubtypable by standard clinical assays to UKHSA for characterisation.
From 1 January 2022 to 8 December 2022, 44 samples were referred to UKHSA as unsubtypable and of these 18 were seasonal H1 or H3 viruses, 11 had no virus detected, 6 had a low viral load precluding further characterisation, and 9 are still being characterised.
Assessment of the sensitivity and completeness of this system for the detection of novel influenza viruses is being undertaken.
Part 1. Risk assessment as of 13 December 2022

This assessment is based on reports made from APHA and other partners to UKHSA. Data sharing is being established but UKHSA has not viewed the current data in full.
UK virus population

There is an increase in confirmed cases of influenza A infected birds (high confidence). In 2022, there has been year-round maintenance of influenza infection in indigenous wild birds which represents a change compared to the usual seasonal pattern in which infections die out over the summer. Compared to the previous risk assessment of 11 November 2022, there are a reducing number of infected premises following the introduction of the national housing order for farmed poultry, but still high levels of detections in dead wild birds.

Influenza A H5N1 is the predominant influenza virus subtype detected in wild birds and farmed flocks in the UK (high confidence). There is diversity within the UK population of H5N1 viruses with 11 genotypes detected since October 2021, including some reassortment with low pathogenic avian influenza viruses (LPAIVs). However, 7 of these genotypes have constituted a limited number of detections. The dominant circulating genotypes since October 2021 are AIV09 and AIV07-B2. Since October 2022, AIV09 is the predominant genotype. Another currently detected genotype in poultry is AIV48 which includes genes from gull-associated influenza viruses.

Genomic surveillance is proportionate for poultry outbreaks (a genome is generated for every affected premise). There is a limited genomic surveillance sampling in wild birds. APHA select birds to test and report that testing is distributed in time and space with host species consideration. There is very limited surveillance of mammals. Genomic data lags 7 to 10 days behind date of sample collection for poultry and currently longer for mammals.

Extent of human exposure in the UK

Owing to the disease burden in birds there is an increased interface between humans and infected birds (high confidence). In particular the high number of wild birds and domestic flocks with influenza A infection, especially where personal protective equipment is not worn, increases the likelihood of human exposures to this virus (moderate confidence).

Propensity to cause mammalian and human infection

Available surveillance data reported by APHA do not suggest widespread mammalian adaptation of this virus (low to moderate confidence).

Mutations known to be advantageous in mammalian infections are infrequent in the available genomic data from avian viruses however these data are lagging. APHA report that there isgoog_1016748401 evidence of direct spill over from birds into some ‘scavenger’ wild mammalian species within the UK (and others noted outside the UK). In the UK 8 mammals, out of a total of 20 targeted from samples collected during 2021 to 2022 and retrospectively tested by APHA, were positive for influenza A (H5N1).

The species affected (foxes and otters) are presumed to have direct high-level exposure to infected birds based on feeding behaviour and food preferences. The 4 available influenza genomes from these positive mammals all show the PB2 E627K substitution. This mutation is known to be acquired rapidly after infection of a mammalian host in some influenza viruses and is associated with enhanced polymerase activity.

The rapid and consistent acquisition of the PB2 mutation in mammals may imply this virus has a propensity to cause zoonotic infections and further assessment should be made of the properties of this mutation. There is also recent confirmed transmission of a virus similar to the AIV48 genotype between mink in Spain, but the published genomes available show no evidence of significant HA mutation.

There is incomplete genotype to phenotype understanding and genomic data must be supplemented by in vitro and animal model studies.

There have been 4 instances of influenza A H5N1 detection in humans (1 UK, 1 USA, 2 Spain) between December 2021 and December 2022. There is limited asymptomatic testing of human contacts of bird cases in the UK and international surveillance is variable. Nevertheless, by comparison with other zoonotic infections including influenza viruses, these data suggest that zoonotic infections are infrequent (low confidence).
Ability to cause (a) severe infection and (b) asymptomatic infection in humans

There are no detected severe human cases associated with Influenza A H5N1 (clade in the UK or internationally. There is insufficient information to judge the risk of asymptomatic or mild disease due to limited testing in human contacts of infected birds.

Human-to-human transmission

There is no evidence of sustained human to human transmission (moderate to high confidence). Subtyping surveillance in the NHS or through NHS referral to UKHSA is incomplete and could delay detection. There is insufficient information to assess the occurrence of limited human to human transmission such as transmission within households.

The current H5N1 viruses in UK birds react well against antisera raised against an available Influenza A(H5) World Health Organization (WHO) candidate vaccine virus (CVV) (A/Astrakhan/3212/2020), developed for pandemic preparedness and coordinated by WHO.

The avian influenza outbreak in the UK is assessed as at risk level 3 although there is limited mammalian surveillance data. At present, there are no indicators of increasing risk to human health, however this is a low confidence assessment. The risk assessment is dynamic and requires regular review during this period of unusually high levels of transmission in birds with mammalian spillover. In vitro and animal model data are required. Enhancements to mammalian and human asymptomatic infection surveillance are both in preparation.

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