Pathobiology of an NS1-Truncated H3N2 Swine Influenza Virus Strain in Pigs

Vandoorn, Elien; Stadejek, Wojciech; Parys, Anna; Chepkwony, Sharon; Chiers, Koen; Reeth, Kristien Van

doi:10.1128/jvi.00519-22

Cited by 5 publications

(18 citation statements)

References 34 publications

(62 reference statements)

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“…This advantage has been broadly used to generate LAIV by introducing specific amino acid substitutions, or deletions, in the viral genome (Martinez-Sobrido et al, 2018;Rodriguez et al, 2018b;Blanco-Lobo et al, 2019;Hilimire et al, 2020). For instance, IAV encoding truncated versions of NS1 or where the NS1 sequence was completely removed (DNS1) have been generated and used as potential LAIV candidates in multiple animal species (Quinlivan et al, 2005;Solorzano et al, 2005;Richt et al, 2006;Vincent et al, 2007;Wang et al, 2008;Chambers et al, 2009;Steel et al, 2009;Kappes et al, 2012;Choi et al, 2015;Jang et al, 2016;Na et al, 2016;Chen et al, 2017;Nogales et al, 2017b;Jang et al, 2018;Nicolodi et al, 2019;Lee et al, 2021;Vandoorn et al, 2022a), or to study IAV infections (Nogales et al, 2021a), including the contribution of NS1, and its domains, in viral pathogenesis (Nogales et al, 2017a;Nogales et al, 2017c;Chauche et al, 2018;Nogales et al, 2018a;Nogales et al, 2018b;Nogales et al, 2021b). Because NS1 is the main countermeasure against cellular antiviral responses, the recovery of NS1 truncated or deficient viruses can be challenging, since these viruses have limited ability to inhibit the cellular innate immune responses induced during viral infection Kochs et al, 2007;Hale et al, 2008;Nogales et al, 2018b;Nogales et al, 2019b).…”

Section: Reverse Genetics Techniques For the Development Of Iav Vacci...mentioning

confidence: 99%

“…Because of IAV NS1's ability to modulate cellular immune responses and inhibit IFN production (Figure 4), multiple vaccine approaches based on the use of modified NS1 proteins as a means for virus attenuation have been developed and assessed (Quinlivan et al, 2005;Solorzano et al, 2005;Richt et al, 2006;Vincent et al, 2007;Wang et al, 2008;Chambers et al, 2009;Steel et al, 2009;Kappes et al, 2012;Choi et al, 2015;Sridhar et al, 2015;Jang et al, 2016;Na et al, 2016;Chen et al, 2017;Hoft et al, 2017;Nogales et al, 2017b;Nogales et al, 2017e;Jang et al, 2018;Nicolodi et al, 2019;Lee et al, 2021;Vandoorn et al, 2022a). NS1 deficient or truncated IAV have been considered as promising LAIV because they replicate poorly in IFN-competent hosts (Figure 5), while they are able to induce a strong and protective immune response against WT forms of the virus (Quinlivan et al, 2005;Solorzano et al, 2005;Richt et al, 2006;Vincent et al, 2007;Wang et al, 2008;Chambers et al, 2009;Steel et al, 2009;Kappes et al, 2012;Choi et al, 2015;Sridhar et al, 2015;Jang et al, 2016;Na et al, 2016;Chen et al, 2017;Hoft et al, 2017;Nogales et al, 2017b; Nogales et al, 2017e;…”

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

“…Importantly, NS1 deficient and/or truncated viruses can grow in appropriated substrates such as IFN-deficient cells (e.g., Vero cells) or systems with an undeveloped IFN system (e.g., 5-6 day-old chicken embryonated eggs) Vlecken et al, 2013), required for vaccine production (Bardiya and Bae, 2005;Barrett et al, 2009;Hussain et al, 2010;Perdue et al, 2011;Jin and Chen, 2014). Another advantage of LAIV based on NS1 deficient or truncated viruses is their ability to induct robust both humoral and cellular immune responses (Quinlivan et al, 2005;Solorzano et al, 2005;Richt et al, 2006;Vincent et al, 2007;Wang et al, 2008;Chambers et al, 2009;Steel et al, 2009;Kappes et al, 2012;Choi et al, 2015;Sridhar et al, 2015;Jang et al, 2016;Na et al, 2016;Chen et al, 2017;Hoft et al, 2017;Nogales et al, 2017b;Nogales et al, 2017e;Jang et al, 2018;Nicolodi et al, 2019;Lee et al, 2021;Vandoorn et al, 2022a). While humoral responses are highly important against homologous IAV strains, cellular responses could provide cross-protection against heterologous strains (Nogales et al, 2017e;Korenkov et al, 2018;Rodriguez et al, 2018b;Krammer, 2019;Rodriguez et al, 2019;Smith et al, 2019).…”

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

“…Therefore, as broadly protective vaccines are needed, LAIV typically are a better option to protect against heterologous strains than inactivated influenza vaccines (IIV) (Sridhar et al, 2015;Hoft et al, 2017;Nogales et al, 2017e). Recombinant swine (Solorzano et al, 2005;Richt et al, 2006;Vincent et al, 2007;Kappes et al, 2012;Lee et al, 2021;Vandoorn et al, 2022a), equine (Quinlivan et al, 2005;Chambers et al, 2009;Na et al, 2016), canine (Nogales et al, 2017b), and avian (Wang et al, 2008;Steel et al, 2009;Choi et al, 2015;Jang et al, 2016;Chen et al, 2017;Jang et al, 2018;Nicolodi et al, 2019) IAV with different partial truncations or deficient in NS1 have been generated and proposed as potential LAIV in different animal models of infection, including mice (Talon et al, 2000b;Quinlivan et al, 2005;Steel et al, 2009;Pica et al, 2012;Choi et al, 2015;Na et al, 2016;Nogales et al, 2017b), pigs (Richt et al, 2006;Vincent et al, 2007;Kappes et al, 2012;Lee et al, 2021;Vandoorn et al, 2022a), horses (Chambers et al, 2009), and birds (Wang et al, 2008;Steel et al, 2009;Jang et al, 2016;Chen et al, 2017;Jang et al,...…”

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

“…However, this possibility is highly unlikely in the case of NS1 truncated or deficient viruses based on their reduced in vivo replication, although additional work will be required to completely discard this possibility. Likewise, the possibility of NS1 truncated or deficient viruses to reassort with IAV strains in the field is also improbable based on their limited in vivo replication (Talon et al, 2000b;Quinlivan et al, 2005;Richt et al, 2006;Vincent et al, 2007;Wang et al, 2008;Chambers et al, 2009;Steel et al, 2009;Kappes et al, 2012;Pica et al, 2012;Choi et al, 2015;Jang et al, 2016;Na et al, 2016;Chen et al, 2017;Nogales et al, 2017b;Jang et al, 2018;Lee et al, 2021;Vandoorn et al, 2022a). However, recent studies related with the use of a LAIV encoding an NS1 truncated protein to prevent swine influenza virus has shown that this risk cannot be completely discarded (Mancera Gracia et al, 2020;Sharma et al, 2020), highlighting the importance of IAV surveillance to detect emerging IAV strains with LAIV genes after vaccination campaigns to rule out the potential reassortment between viruses in the vaccine and natural circulating isolates.…”

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

See 4 more Smart Citations

Live attenuated influenza A virus vaccines with modified NS1 proteins for veterinary use

Nogales

DeDiego

Martínez-Sobrido

2022

Front. Cell. Infect. Microbiol.

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Influenza A viruses (IAV) spread rapidly and can infect a broad range of avian or mammalian species, having a tremendous impact in human and animal health and the global economy. IAV have evolved to develop efficient mechanisms to counteract innate immune responses, the first host mechanism that restricts IAV infection and replication. One key player in this fight against host-induced innate immune responses is the IAV non-structural 1 (NS1) protein that modulates antiviral responses and virus pathogenicity during infection. In the last decades, the implementation of reverse genetics approaches has allowed to modify the viral genome to design recombinant IAV, providing researchers a powerful platform to develop effective vaccine strategies. Among them, different levels of truncation or deletion of the NS1 protein of multiple IAV strains has resulted in attenuated viruses able to induce robust innate and adaptive immune responses, and high levels of protection against wild-type (WT) forms of IAV in multiple animal species and humans. Moreover, this strategy allows the development of novel assays to distinguish between vaccinated and/or infected animals, also known as Differentiating Infected from Vaccinated Animals (DIVA) strategy. In this review, we briefly discuss the potential of NS1 deficient or truncated IAV as safe, immunogenic and protective live-attenuated influenza vaccines (LAIV) to prevent disease caused by this important animal and human pathogen.

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Section: Reverse Genetics Techniques For the Development Of Iav Vacci...mentioning

confidence: 99%

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

Section: Ns1 Truncated or Deficient Viruses As Laivmentioning

confidence: 99%

See 3 more Smart Citations

Live attenuated influenza A virus vaccines with modified NS1 proteins for veterinary use

Nogales

DeDiego

Martínez-Sobrido

2022

Front. Cell. Infect. Microbiol.

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Intramuscular prime/intranasal boost vaccination to induce sterilizing immunity against influenza A virus infection

Avanthay,

Garcia-Nicolas,

Ruggli

et al. 2024

Preprint

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The most commonly used influenza vaccines are made from inactivated viruses and are administered via the intramuscular route. Although these vaccines can protect from severe lower respiratory tract disease, they do not completely prevent virus replication in the upper respiratory tract, and this may lead to virus excretion and dissemination. Therefore, nasally administered live-attenuated influenza vaccines (LAIV) that induce mucosal immunity have been developed, but finding an optimal balance between sufficient attenuation and immunogenicity remained challenging. These problems apply to both human and swine influenza vaccines. We have recently developed an LAIV candidate based on the 2009 pandemic H1N1 virus which encodes a truncated NS1 protein and lacks PA-X protein expression (NS1(1-126)-ΔPAX). This virus showed a blunted replication and elicited a strong innate immune response. In the present study, we took advantage of the pig animal model to evaluate this vaccine candidate in vivo and to identify a strategy for its improvement. Nasal infection of pigs with the NS1(1-126)-ΔPAX LAIV candidate did not cause disease but was associated with prolonged virus shedding from the upper respiratory tract. To increase safety of the vaccine candidate, we developed a novel prime/boost vaccination strategy consisting of a haemagglutinin-encoding propagation-defective vesicular stomatitis virus replicon vaccine for primary immunization via the intramuscular route, and the NS1(1-126)-ΔPAX LAIV for secondary immunization via the nasal route. This immunization strategy significantly reduced LAIV shedding, increased the production of specific serum IgG, neutralizing antibodies, Th1 memory cells, and induced virus-specific mucosal IgG and IgA. Of particular note, the immune response induced by this vaccination strategy completely blocked replication of the homologous challenge virus in the respiratory tract, indicating that sterilizing immunity was achieved. In summary, our novel intramuscular prime/intranasal boost vaccine combines the features of high efficacy and safety which are urgently needed to combat influenza epidemics and pandemics.

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Amino acid 138 in the HA of a H3N2 subtype influenza A virus increases affinity for the lower respiratory tract and alveolar macrophages in pigs

Cardenas,

Seibert,

Cowan

et al. 2024

PLoS Pathog

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Influenza A virus (FLUAV) infects a wide range of hosts and human-to-swine spillover events are frequently reported. However, only a few of these human viruses have become established in pigs and the host barriers and molecular mechanisms driving adaptation to the swine host remain poorly understood. We previously found that infection of pigs with a 2:6 reassortant virus (hVIC/11) containing the hemagglutinin (HA) and neuraminidase (NA) gene segments from the human strain A/Victoria/361/2011 (H3N2) and internal gene segments of an endemic swine strain (sOH/04) resulted in a fixed amino acid substitution in the HA (A138S, mature H3 HA numbering). In silico analysis revealed that S138 became predominant among swine H3N2 virus sequences deposited in public databases, while 138A predominates in human isolates. To understand the role of the HA A138S substitution in the adaptation of a human-origin FLUAV HA to swine, we infected pigs with the hVIC/11A138S mutant and analyzed pathogenesis and transmission compared to hVIC/11 and sOH/04. Our results showed that the hVIC/11A138S virus had an intermediary pathogenesis between hVIC/11 and sOH/04. The hVIC/11A138S infected the upper respiratory tract, right caudal, and both cranial lobes while hVIC/11 was only detected in nose and trachea samples. Viruses induced a distinct expression pattern of various pro-inflammatory cytokines such as IL-8, TNF-α, and IFN-β. Flow cytometric analysis of lung samples revealed a significant reduction of porcine alveolar macrophages (PAMs) in hVIC/11A138S-infected pigs compared to sOH/04 while a MHCIIlowCD163neg population was increased. The hVIC/11A138S showed a higher affinity for PAMs than hVIC/11, noted as an increase of infected PAMs in bronchoalveolar lavage fluid (BALF), and showed no differences in the percentage of HA-positive PAMs compared to sOH/04. This increased infection of PAMs led to an overexpression of granulocyte-monocyte colony-stimulating factor (GM-CSF) stimulation but a reduced expression of peroxisome proliferator-activated receptor gamma (PPARγ) in the sOH/04-infected group. Analysis using the PAM cell line 3D4/21 revealed that the A138S substitution improved replication and apoptosis induction in this cell type compared to hVIC/11 but at lower levels than sOH/04. Overall, our study indicates that adaptation of human viruses to the swine host involves an increased affinity for the lower respiratory tract and alveolar macrophages.

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Pathobiology of an NS1-Truncated H3N2 Swine Influenza Virus Strain in Pigs

Cited by 5 publications

References 34 publications

Live attenuated influenza A virus vaccines with modified NS1 proteins for veterinary use

Live attenuated influenza A virus vaccines with modified NS1 proteins for veterinary use

Intramuscular prime/intranasal boost vaccination to induce sterilizing immunity against influenza A virus infection

Amino acid 138 in the HA of a H3N2 subtype influenza A virus increases affinity for the lower respiratory tract and alveolar macrophages in pigs

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