Total threat to human well being related to the continued HPAI A(H5) outbreaks in poultry and detections in wild birds and cattle stays low
17 April 2024
8 minute learn
This can be a technical abstract of an evaluation of the genomic sequences of viruses related to an outbreak of extremely pathogenic avian influenza (HPAI) A(H5N1) viruses in Texas. This evaluation helps the conclusion that the general threat to most of the people related to the continued HPAI A(H5N1) outbreak has not modified and stays low right now. The genome of the virus recognized from the affected person in Texas is publicly posted in GISAID and has been submitted to GenBank.
The US Facilities for Illness Management and Prevention (CDC) has sequenced the influenza virus genome recognized in a specimen collected from the affected person in Texas who was confirmed to be contaminated with extremely pathogenic avian influenza A(H5N1) [“HPAI A(H5N1)”] virus and in contrast these with HPAI A(H5N1) sequences from cattle, wild birds and poultry. The virus sequences are HA clade 2.3.4.4b HPAI A(H5N1) with every particular person gene phase intently associated to viruses detected in dairy cattle accessible from USDA testing in Texas.
Whereas minor modifications had been recognized within the virus sequence from the affected person specimen in comparison with the viral sequences from cattle, each cattle and human sequences keep primarily avian genetic traits and for essentially the most half lack modifications that may make them higher tailored to contaminate mammals.
The genome for the human isolate had one change (PB2 E627K) that’s identified to be related to viral adaptation to mammalian hosts, and which has been detected earlier than in folks and different mammals contaminated with HPAI A(H5N1) virus and different avian influenza subtypes (e.g., H7N9), however with no proof of onward unfold amongst folks. Viruses can bear modifications in a bunch as they replicate after an infection. Additional, there are not any markers identified to be related to influenza antiviral resistance discovered within the virus sequences from the affected person’s specimen and the virus could be very intently associated to 2 current HPAI A(H5N1) candidate vaccine viruses which can be already accessible to producers, and which may very well be used to make vaccine if wanted.
Total, the genetic evaluation of HPAI A(H5N1) viruses in Texas helps CDC’s conclusion that the human well being threat presently stays low. Extra particulars can be found on this technical abstract beneath:
Technical abstract
Viral RNA extractions obtained from nasopharyngeal swab and conjunctival swab specimens collected from the affected person had been used as template to carry out subsequent era sequencing utilizing Illumina and Oxford Nanopore Applied sciences (ONT) platforms. Codon full consensus sequence was efficiently generated solely from the conjunctival specimen and was assembled utilizing CDC’s Iterative Refinement Meta Assembler (IRMA). Illumina and ONT yielded equivalent sequences on the consensus sequence stage.
In concordance with the rRT-PCR cycle threshold (Ct) values obtained from every specimen (i.e., roughly 18 for the conjunctival specimen and 33 for the nasopharyngeal pattern), viral RNA from the nasopharyngeal pattern did not generate PCR amplicons appropriate for sequencing. Notably, the affected person reported solely conjunctivitis with no respiratory or different signs, which doubtless resulted in decrease viral RNA concentrations detected within the nasopharyngeal pattern and is suggestive of an absence of respiratory an infection within the affected person.
The virus sequence was confirmed to be HA clade 2.3.4.4b HPAI A(H5N1) with every particular person gene phase decided to be intently associated to viruses detected in dairy cattle in Texas. The genotype was labeled as B3.13 (1) and corresponds to the identical genotype described by USDA for the virus detected in Texas cattle (2). This genotype accommodates PA, HA, NA and M gene segments from Eurasian wild chook lineages and PB2, PB1, NP and NS gene segments from American wild chook lineages. Different viruses with this genotype have been sporadically detected in wild birds, poultry and one skunk since November 2023 within the US CDC’s real-time RT-PCR diagnostic check used for the detection of A(H5) virus in human samples has not been impacted by genetic modifications in B3.13 genotype viruses.
The hemagglutinin (HA) gene codes for one of many two floor glycoproteins and is central to species specificity as a result of it’s chargeable for virus attachment and fusion with host cells. Just like the viruses detected in cattle, the evaluation of the HA gene from the human specimen exhibits that it’s intently associated to HPAI A(H5) viruses in HA clade 2.3.4.4b lately detected in wild birds and poultry and lacks amino acid modifications that enhance recognition of mammalian receptors or fusion of the viral membrane with the host endosomal membranes.
The HA can also be the first goal of neutralizing antibodies elicited by an infection or vaccination, and the HA of virus from the human specimen could be very intently associated to the A/Astrakhan/3212/2020-like pre-pandemic candidate vaccine virus (CVV) (IDCDC-RG71A) and the A/American wigeon/South Carolina/22-000345-001/2021-like CVV (IDCDC-RG78A), each of which can be found to vaccine producers (3).
There are solely 4 amino acid modifications (L104M, L115Q, T195I, V210A) between the HA1 of the virus from the Texas case and A/Astrakhan/3212/2020-like CVV and solely two modifications (L115Q, T195I) in comparison with the A/American wigeon/South Carolina/22-000345-001/2021-like CVV. The modifications aren’t in main antigenic epitopes strongly suggesting that antibodies elicited by A/Astrakhan/3212/2020-like and A/American wigeon/South Carolina/22-000345-001/2021-like vaccines can be anticipated to have good cross-reactivity – and due to this fact safety – in opposition to this virus.
The neuraminidase (NA) gene encodes the opposite floor protein of the virus. The foremost function of the NA is to launch new progeny virions from an contaminated cell by enzymatically cleaving sialic acid receptors, which aids virus unfold to uninfected cells inside an contaminated host. The enzymatic exercise of NA is inhibited by one class of antiviral medicine which can be FDA-approved for remedy of influenza (i.e., NA inhibitors).
Evaluation of the N1 NA gene from the Texas human specimen confirmed that it didn’t have any identified or suspected markers of lowered susceptibility to this class of antivirals, which incorporates oseltamivir. Moreover, the NA has a full-length stalk which is according to viruses that naturally flow into in wild birds. In earlier HPAI A(H5N1) virus outbreaks and zoonoses the NA stalk area typically had deletions (e.g., a 20 amino acid deletion at positions 49–68 relative to A/goose/Guangdong/1/1996) that enhances replication and/or pathogenesis in terrestrial poultry and mice (4-6).
Evaluation of the opposite gene segments (PB2, PB1, PA, NP, M, NS) was additionally performed. No identified or suspected markers of lowered susceptibility to antiviral compounds that focus on the PA (i.e., baloxavir marboxil) or M2 (i.e., amantadine, rimantadine) had been discovered.
Along with the HA and NA, the RNA transcription and replication complicated (PB2, PB1, PA, NP) even have species-specific determinants that affect environment friendly replication in people and different mammals, significantly polymerase primary protein 2 (PB2). The PB1, PA and NP lacked markers of mammalian adaptation. The PB2 of the human specimen had a change of PB2 E627K in comparison with the PB2 genes of viruses accessible from USDA detections in Texas dairy cattle and sometimes present in A(H5N1) viruses circulating in wild birds. This mutation is, nonetheless, generally present in people and different mammals which can be contaminated with HPAI A(H5N1) viruses and is known to be related to mammalian adaptation as a result of it improves RNA polymerase exercise and replication effectivity in mammalian cells; based mostly on experimental research in mice, guinea pigs and ferrets, it has the potential to affect pathogenesis or transmission in contaminated mammals (7-8).
Regardless of earlier identification of PB2 E627K in human instances of HPAI A(H5N1) virus, there isn’t any proof of onward transmission amongst people after an infection with viruses containing this mutation. You will need to notice that this substitution has not been seen in accessible PB2 genes from viruses circulating in wild birds and poultry or within the lately described cattle viruses detected in Texas, suggesting the mutation might have been acquired within the affected person throughout the growth of conjunctivitis. Viruses can bear modifications in a bunch as they replicate after an infection, and it’s not unusual or shocking for HPAI A(H5N1) viruses to bear this and different polymerase gene modifications in contaminated sufferers (9). Extra information from A(H5N1) virus-infected animals from the premises the place the particular person was doubtless uncovered is required to help this speculation.
The protein merchandise from the M (M1 and M2) and NS (N1 and N2) genes lacked markers related to mammalian adaptation. Collectively, epidemiologic, and viral genomic analyses point out that this case represents a single zoonotic occasion and whereas the HA lacked modifications more likely to improve transmission to mammals, it did purchase substitutions in PB2 more likely to improve replication in mammals, which illustrates that now we have to stay vigilant and proceed to characterize zoonotic viruses.
Total, the genomic evaluation of the virus from this human case doesn’t change CDC’s threat evaluation associated to the HPAI A(H5) clade 2.3.4.4b viruses. The general threat to human well being related to the continued HPAI A(H5) outbreaks in poultry and detections in wild birds and cattle stays low.
Word: HPAI A(H5) viruses, predominantly HPAI A(H5N1) clade 2.3.4.4b viruses, have been circulating globally in wild birds within the U.S. since late 2021. These viruses have brought about outbreaks in business and yard poultry, with spillover leading to sporadic infections in mammals.
References
- GenoFLU. GitHub – USDA-VS/GenoFLU: Influenza information pipeline to automate genotyping project
- United States of America – Influenza A viruses of excessive pathogenicity (Inf. with) (non-poultry together with wild birds) (2017-) – Comply with up report 44. https://wahis.woah.org/#/in-review/4451?fromPage=event-dashboard-url
- World Well being Group. 2024. Genetic and antigenic traits of zoonotic influenza A viruses and growth of candidate vaccine viruses for pandemic preparedness. February 2024. https://cdn.who.int/media/docs/default-source/influenza/who-influenza-recommendations/vcm-northern-hemisphere-recommendation-2024-2025/202402_zoonotic_vaccinvirusupdate.pdf?sfvrsn=70150120_4
- Stech O, Veits J, Abdelwhab EM, Wessels U, Mettenleiter TC, Stech J. 2015. The Neuraminidase Stalk Deletion Serves as Main Virulence Determinant of H5N1 Extremely Pathogenic Avian Influenza Viruses in Rooster. Sci Rep 5:13493.
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