Porcine #influenza #mAbs to #H3, #H5, and #H7 hemagglutinins recognize H3 egg adapted site and target the HA stem

 

Abstract

Introduction

Monoclonal antibodies (mAbs) are critical tools for elucidating viral evolution, informing vaccine design, and developing antiviral therapeutics. Large-animal models, such as the pig, that closely mirror human immune responses are essential for understanding influenza immunity.

Methods

Pigs were either infected or sequentially immunized with influenza viruses and monoclonal antibodies directed against H3, H5, and H7 influenza virus haemagglutinins were isolated. Antibody specificity, breadth, epitope targeting (head versus stem), neutralizing capacity, and Fc-mediated activity were assessed across influenza subtypes.

Results

Pigs generated both strain-specific and broadly reactive mAbs targeting haemagglutinin head and stem epitopes. An H3-specific mAb (H3–57) selectively recognized the egg-adapted L194P mutation associated with reduced human vaccine effectiveness. H5 and H7 immunization induced neutralizing antibodies, including cross-group stem mAbs reactive with H1, H3, and H5 haemagglutinins. Fc-mediated activity correlated with antibody binding strength rather than epitope location.

Conclusions

These findings demonstrate that pigs mount antibody responses closely resembling those observed in humans, including recognition of conserved stem epitopes and adaptive head mutations. Porcine mAbs represent powerful new tools for dissecting influenza immunity, guiding vaccine design, and enhancing pandemic preparedness using a physiologically relevant large-animal model.

Source: 

Link: https://academic.oup.com/discovimmunology/article/5/1/kyag006/8503709

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Host-specific functional #evolution of #seal #influenza A virus #NS1 protein following #avian-to-seal #transmission

 

ABSTRACT

Marine mammals, particularly seals, are susceptible to both avian and human influenza A viruses (IAVs), making them potential intermediates for zoonotic virus emergence. In recent decades, repeated transmissions of avian influenza viruses (AIVs) from wild aquatic birds, their natural reservoir, have caused significant mortality in seals. Defining the molecular determinants of viral adaptation in marine mammals, and their implications for replication in human cells, is therefore essential. The non-structural protein 1 (NS1) of AIV, a key antagonist of the interferon (IFN) response, plays a central role in host adaptation. Here, we analyzed NS1 proteins from seal influenza viruses (H3, H4, H5, H7, and H10 subtypes) and their closest avian relatives isolated between 1980 and 2023, and evaluated their function in seal, avian, and human cells. Phylogenetic analysis confirmed multiple bird-to-seal transmission events. Seal-derived NS1 proteins generally contained few strain-specific amino acid substitutions and showed comparable expression and IFN antagonism to their avian precursors. A notable exception was the seal H10N7 virus isolated in 2014 in Northeastern Europe, which harbored three previously uncharacterized substitutions at NS1 amino acid residues 94, 104, and 171. These amino acid substitutions markedly altered NS1 properties to enhance protein stability, suppress IFN induction, mediate host transcription shut-off, and increase polymerase activity in human cells, without affecting NS1 expression or reducing virus replication in avian cells. Overall, these results reveal how NS1 undergoes host-specific functional evolution following avian-to-seal transmission and provide mechanistic insight into the adaptation of influenza A viruses to mammalian hosts.

IMPORTANCE

Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds but occasionally infect mammals, including seals, where they can cause severe outbreaks. Seals are of particular concern because they can harbor both avian and human influenza viruses, creating opportunities for reassortment and the emergence of novel zoonotic strains. Understanding how AIVs adapt to mammalian hosts is therefore critical for anticipating and mitigating future influenza threats. Here, we investigated the role of the NS1 protein, a key viral factor that suppresses host immune responses, in seal-derived AIVs. Overall, NS1 expression and function were conserved across different subtypes and host cells. However, we identified unique amino acid substitutions in the NS1 of a seal H10N7 virus that enhanced protein stability, interferon antagonism, and viral adaptation in human cells. These findings illustrate how minor changes in NS1 protein can drive host adaptation and underscore the need for continued surveillance of AIVs in seals.

Source: 

Link: https://journals.asm.org/doi/full/10.1128/jvi.01650-25?af=R

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#Portugal - #Influenza A #H7 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

 

{By Alexis Lours - Own work, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=138694692}

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A wild yellow legged gull in Madeira.

Source: WOAH, https://wahis.woah.org/#/in-review/6888

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Divergent #antibody-mediated #population #immunity to #H5, #H7 and #H9 subtype potential #pandemic #influenza viruses

 

Abstract

Influenza continues to cause significant mortality globally and possesses substantial pandemic potential. Assessing pandemic risk requires a clear understanding of existing population immunity. Leveraging a unique large-scale cohort of human sera, we evaluated total and neutralising antibody-mediated immunity to multiple haemagglutinin (HA) proteins, including those from subtypes with high pandemic potential. Our analysis reveals that population immunity is heterogeneous, with distinct age-dependent differences in responses to H5, H7, and H9 avian influenza subtypes. These shifts align with historical circulation patterns of seasonal H1N1 and H3N2 human viruses. Notably, H7 viruses are primarily neutralised through head domain epitopes, while H5 viruses are targeted mainly via stem epitopes, although in both instances some neutralisation occurred via receptor binding site-adjacent epitopes. Furthermore, H7 responses were dominated by non-glycan-targeted IgG2 antibodies, whereas H5 responses were primarily IgG1-mediated. These findings highlight varying levels of susceptibility to influenza across the population, supporting vaccination approaches informed by exposure history.

Competing Interest Statement

CPT has received lecture fees from Moderna.

Funding Statement

J.S.B. was supported by funding from the Biotechnology and Biological Sciences Research Council (BBSRC) doctoral training programme grant [grant number BB/M011224/1]. R.S. is funded by a Medical Research Council Impact Accelerator Account grant [grant ref MR/X502674/1]. RG was funded by The Institute for Global Pandemic Planning at the University of Warwick, UK, as part of a philanthropically supported doctoral programme. K.C. was funded via the Medical Research Council doctoral training programme grant [MC_UP_A025_1011]. L.H. was funded by a Defence and Science Technology Laboratory grant [grant ref RQ31692]. U.O. and C.P.T. acknowledge funding from the British Council ISFP scheme [grant number 47650215]. N.C.R. is supported by a Royal Society Dorothy Hodgkin Research Fellowship [grant number DHR00620].

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.09.08.25335309v1

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