Safety and immunogenicity of a replication-deficient H5N1 influenza virus vaccine lacking NS1

Nicolodi, Christina; Groiss, Franz; Киселев, О. И.; Wolschek, Markus; Seipelt, Joachim; Muster, Thomas

doi:10.1016/j.vaccine.2019.05.013

Cited by 19 publications

(24 citation statements)

References 33 publications

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“…We also provide evidence for its therapeutic potential as a prophylactic to protect against acute respiratory infections caused by IFN-sensitive viruses including the causative agent of COVID-19 pandemic. ΔNS1 viruses are being clinically developed as live attenuated influenza virus vaccines and in clinical trials they have shown to induce protective antibodies and no adverse responses in human volunteers 21–23 . Here we show that ΔNS1 viruses have the potential to induce immediate protection against viral infection prior to the induction of specific long-lasting protective adaptive immune responses 69, 70 .…”

Section: Discussionmentioning

confidence: 99%

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Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine

Rathnasinghe

Salvatore

Zheng

et al. 2021

Preprint

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The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

“…Consistent with its function, deletion of NS1 in recombinant IAV results in a live attenuated and highly immunogenic IAV. As a result, IAV with impaired NS1 function are currently used as vaccines against swine influenza in pigs 20 and they are under clinical consideration as live attenuated human influenza virus vaccines 21–23 .…”

Section: Introductionmentioning

confidence: 99%

Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine

Rathnasinghe

Salvatore

Zheng

et al. 2021

Preprint

Self Cite

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“…As a result of such processes, these proteins are often considered important virulence factors that contribute to the design of live attenuated vaccines. For example, nonstructural protein 1 (NS1) of the influenza virus plays a crucial role in replication and pathogenesis by suppressing apoptosisassociated specklike protein ubiquitination; thus, vaccination with a live attenuated H5N1 influenza vaccine lacking NS1 is safe (22)(23)(24). The virion host shutoff (vhs) protein is the key regulator of the induced early host shutoff response, and herpes simplex viruses with vhs deleted have been proposed as live attenuated vaccines (25,26).…”

Section: Discussionmentioning

confidence: 99%

A conserved region of nonstructural protein 1 from alphacoronaviruses inhibits host gene expression and is critical for viral virulence

Shen

Wang

Yang

et al. 2019

Journal of Biological Chemistry

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Coronaviruses are enveloped, single-stranded RNA viruses that are distributed worldwide. They include transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and the human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), many of which seriously endanger human health and well-being. Only alphacoronaviruses and betacoronaviruses harbor nonstructural protein 1 (nsp1), which performs multiple functions in inhibiting antiviral host responses. The role of the C terminus of betacoronavirus nsp1 in virulence has been characterized, but the location of the alphacoronavirus nsp1 region that is important for virulence remains unclear. Here, using TGEV nsp1 as a model to explore the function of this protein in alphacoronaviruses, we demonstrate that alphacoronavirus nsp1 inhibits host gene expression. Solving the crystal structure of full-length TGEV at 1.85-Å resolution and conducting several biochemical analyses, we observed that a specific motif (amino acids 91-95) of alphacoronavirus nsp1 is a conserved region that inhibits host protein synthesis. Using a reverse-genetics system based on CRISPR/ Cas9 technology to construct a recombinant TGEV in which this specific nsp1 motif was altered, we found that this mutation does not affect virus replication in cell culture but significantly reduces TGEV pathogenicity in pigs. Taken together, our findings suggest that alphacoronavirus nsp1 is an essential virulence determinant, providing a potential paradigm for the development of a new attenuated vaccine based on modified nsp1.

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“…After an intranasal monovalent dose, results revealed its safety and tolerability. Moreover, 75% of the participants displayed seroconversion after one immunization and IgA serum levels were increased after a second immunization [125].…”

Section: Ns1-modified Virus As Vaccinesmentioning

confidence: 99%

The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection

Rosário‐Ferreira

Preto

Melo

et al. 2020

IJMS

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Influenza (flu) is a contagious viral disease, which targets the human respiratory tract and spreads throughout the world each year. Every year, influenza infects around 10% of the world population and between 290,000 and 650,000 people die from it according to the World Health Organization (WHO). Influenza viruses belong to the Orthomyxoviridae family and have a negative sense eight-segment single-stranded RNA genome that encodes 11 different proteins. The only control over influenza seasonal epidemic outbreaks around the world are vaccines, annually updated according to viral strains in circulation, but, because of high rates of mutation and recurrent genetic assortment, new viral strains of influenza are constantly emerging, increasing the likelihood of pandemics. Vaccination effectiveness is limited, calling for new preventive and therapeutic approaches and a better understanding of the virus–host interactions. In particular, grasping the role of influenza non-structural protein 1 (NS1) and related known interactions in the host cell is pivotal to better understand the mechanisms of virus infection and replication, and thus propose more effective antiviral approaches. In this review, we assess the structure of NS1, its dynamics, and multiple functions and interactions, to highlight the central role of this protein in viral biology and its potential use as an effective therapeutic target to tackle seasonal and pandemic influenza.

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Safety and immunogenicity of a replication-deficient H5N1 influenza virus vaccine lacking NS1

Cited by 19 publications

References 33 publications

Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine

Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine

A conserved region of nonstructural protein 1 from alphacoronaviruses inhibits host gene expression and is critical for viral virulence

The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection

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