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Dr. AITOR NOGALES
The Center for Animal Health Research (CISA-INIA), Valdeolmos, 28130 Madrid, Spain

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0 Influenza
0 Innate Immunity
0 Vaccines
0 Viruses
0 virus-host interaction

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Article
Published: 26 August 2021
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Recombinant viruses expressing reporter genes allow visualization and quantification of viral infections and can be used as valid surrogates to identify the presence of the virus in infected cells and animal models. However, one of the limitations of recombinant viruses expressing reporter genes is the use of either fluorescent or luciferase proteins that are used alternatively for different purposes. Vaccinia virus (VV) is widely used as a viral vector, including recombinant (r)VV singly expressing either fluorescent or luciferase reporter genes that are useful for specific purposes. In this report, we engineered two novel rVV stably expressing both fluorescent (Scarlet or GFP) and luciferase (Nluc) reporter genes from different loci in the viral genome. In vitro, these bi-reporter expressing rVV have similar growth kinetics and plaque phenotype than those of the parental WR VV isolate. In vivo, rVV Nluc/Scarlet and rVV Nluc/GFP effectively infected mice and were easily detected using in vivo imaging systems (IVIS) and ex vivo in the lungs from infected mice. We used these bi-reporter expressing rVV to assess viral pathogenesis, infiltration of immune cells in the lungs, and to directly identify the different subsets of cells infected by VV in the absence of antibody staining. Collectively, these rVV expressing two reporter genes open the feasibility to study the biology of viral infections in vitro and in vivo, including host-pathogen interactions and dynamics or tropism of viral infections. Moreover, they represent an excellent approach for the discovery of new prophylactics and/or therapeutics for the treatment of poxvirus infections. IMPORTANCE Despite the eradication of variola virus (VARV), the causative agent of smallpox, poxviruses still represent an important threat to human health due to their possible use as bioterrorism agents and the emergence of zoonotic poxvirus diseases. Recombinant vaccinia viruses (rVV) expressing easily traceable fluorescent or luciferase reporter genes have significantly contributed to the progress of poxvirus research. However, rVV expressing one marker gene have several constraints for in vitro and in vivo studies, since both fluorescent and luciferase proteins impose certain limitations for specific applications. To overcome these limitations, we generated optimized rVV stably expressing both fluorescent (Scarlet or GFP) and luciferase (Nluc) reporter genes to easily track viral infection in vitro and in vivo. This new generation of double reporter-expressing rVV represent an excellent option to study viral infection dynamics in cultured cells and validated animal models of infection, and for the discovery of new poxvirus antiviral treatments.

ACS Style

Kevin Chiem; Maria Lorenzo; Javier Rangel-Moreno; Maria De La Luz Garcia-Hernandez; Jun-Gyu Park; Aitor Nogales; Rafael Blasco; Luis Martínez-Sobrido. Bi-reporter vaccinia virus for tracking viral infections in vitro and in vivo. 2021, 1 .

AMA Style

Kevin Chiem, Maria Lorenzo, Javier Rangel-Moreno, Maria De La Luz Garcia-Hernandez, Jun-Gyu Park, Aitor Nogales, Rafael Blasco, Luis Martínez-Sobrido. Bi-reporter vaccinia virus for tracking viral infections in vitro and in vivo. . 2021; ():1.

Chicago/Turabian Style

Kevin Chiem; Maria Lorenzo; Javier Rangel-Moreno; Maria De La Luz Garcia-Hernandez; Jun-Gyu Park; Aitor Nogales; Rafael Blasco; Luis Martínez-Sobrido. 2021. "Bi-reporter vaccinia virus for tracking viral infections in vitro and in vivo." , no. : 1.

Journal article
Published: 30 June 2021 in Viruses
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Influenza B viruses (IBV) circulate annually, with young children, the elderly and immunocompromised individuals being at high risk. Yearly vaccinations are recommended to protect against seasonally influenza viruses, including IBV. Live attenuated influenza vaccines (LAIV) provide the unique opportunity for direct exposure to the antigenically variable surface glycoproteins as well as the more conserved internal components. Ideally, LAIV Master Donor Viruses (MDV) should accurately reflect seasonal influenza strains. Unfortunately, the continuous evolution of IBV have led to significant changes in conserved epitopes compared to the IBV MDV based on B/Ann Arbor/1/1966 strain. Here, we propose a recent influenza B/Brisbane/60/2008 as an efficacious MDV alternative, as its internal viral proteins more accurately reflect those of circulating IBV strains. We introduced the mutations responsible for the temperature sensitive (ts), cold adapted (ca) and attenuated (att) phenotype of B/Ann Arbor/1/1966 MDV LAIV into B/Brisbane/60/2008 to generate a new MDV LAIV. In vitro and in vivo analysis demonstrated that the mutations responsible of the ts, ca, and att phenotype of B/Ann Arbor/1/1966 MDV LAIV were able to infer the same phenotype to B/Brisbane/60/2008, demonstrating its potential as a new MDV for the development of LAIV to protect against contemporary IBV strains.

ACS Style

Chantelle White; Kevin Chiem; Daniel Perez; Jefferson Santos; Stivalis Cardenas Garcia; Aitor Nogales; Luis Martínez-Sobrido. A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines. Viruses 2021, 13, 1278 .

AMA Style

Chantelle White, Kevin Chiem, Daniel Perez, Jefferson Santos, Stivalis Cardenas Garcia, Aitor Nogales, Luis Martínez-Sobrido. A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines. Viruses. 2021; 13 (7):1278.

Chicago/Turabian Style

Chantelle White; Kevin Chiem; Daniel Perez; Jefferson Santos; Stivalis Cardenas Garcia; Aitor Nogales; Luis Martínez-Sobrido. 2021. "A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines." Viruses 13, no. 7: 1278.

Journal article
Published: 20 May 2021 in Microorganisms
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The influenza A virus (IAV) PA-X protein is a virulence factor that selectively degrades host mRNAs leading to protein shutoff. This function modulates host inflammation, antiviral responses, cell apoptosis, and pathogenesis. In this work we describe a novel approach based on the use of bacteria and plasmid encoding of the PA-X gene under the control of the bacteriophage T7 promoter to identify amino acid residues important for A/Brevig Mission/1/1918 H1N1 PA-X’s shutoff activity. Using this system, we have identified PA-X mutants encoding single or double amino acid changes, which diminish its host shutoff activity, as well as its ability to counteract interferon responses upon viral infection. This novel bacteria-based approach could be used for the identification of viral proteins that inhibit host gene expression as well as the amino acid residues responsible for inhibition of host gene expression.

ACS Style

Kevin Chiem; Luis Martinez-Sobrido; Aitor Nogales; Marta DeDiego. Amino Acid Residues Involved in Inhibition of Host Gene Expression by Influenza A/Brevig Mission/1/1918 PA-X. Microorganisms 2021, 9, 1109 .

AMA Style

Kevin Chiem, Luis Martinez-Sobrido, Aitor Nogales, Marta DeDiego. Amino Acid Residues Involved in Inhibition of Host Gene Expression by Influenza A/Brevig Mission/1/1918 PA-X. Microorganisms. 2021; 9 (5):1109.

Chicago/Turabian Style

Kevin Chiem; Luis Martinez-Sobrido; Aitor Nogales; Marta DeDiego. 2021. "Amino Acid Residues Involved in Inhibition of Host Gene Expression by Influenza A/Brevig Mission/1/1918 PA-X." Microorganisms 9, no. 5: 1109.

Preprint content
Published: 23 April 2021
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Influenza A virus (IAV) PA-X protein is a virulence factor that selectively degrades host mRNAs leading to protein shutoff. This function modulates host inflammation, antiviral responses, cell apoptosis, and pathogenesis. In this work we describe a novel approach based on the use of bacteria and a plasmid encoding the PA-X gene under the control of the bacteriophage T7 promoter to identify amino acid residues important for A/Brevig Mission/1/1918 H1N1 PA-X’s shutoff activity. Using this system, we have identified PA-X mutants encoding single or double amino acid changes, which diminish its host shutoff activity, as well as its ability to counteract interferon responses upon viral infection. This novel bacteria-based approach could be used for the identification of viral proteins that inhibit host gene expression as well as the amino acid residues responsible for inhibition of host gene expression.

ACS Style

Kevin Chiem; Luis Martinez-Sobrido; Aitor Nogales; Marta L. DeDiego. Amino acid residues involved in inhibition of host gene expression by influenza A/Brevig Mission/1/1918 PA-X. 2021, 1 .

AMA Style

Kevin Chiem, Luis Martinez-Sobrido, Aitor Nogales, Marta L. DeDiego. Amino acid residues involved in inhibition of host gene expression by influenza A/Brevig Mission/1/1918 PA-X. . 2021; ():1.

Chicago/Turabian Style

Kevin Chiem; Luis Martinez-Sobrido; Aitor Nogales; Marta L. DeDiego. 2021. "Amino acid residues involved in inhibition of host gene expression by influenza A/Brevig Mission/1/1918 PA-X." , no. : 1.

Journal article
Published: 17 April 2021 in Viruses
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The influenza A virus (IAV) is able to infect multiple mammalian and avian species, and in humans IAV is responsible for annual seasonal epidemics and occasional pandemics of respiratory disease with significant health and economic impacts. Studying IAV involves laborious secondary methodologies to identify infected cells. Therefore, to circumvent this requirement, in recent years, multiple replication-competent infectious IAV expressing traceable reporter genes have been developed. These IAVs have been very useful for in vitro and/or in vivo studies of viral replication, identification of neutralizing antibodies or antivirals, and in studies to evaluate vaccine efficacy, among others. In this report, we describe, for the first time, the generation and characterization of two replication-competent influenza A/Puerto Rico/8/1934 H1N1 (PR8) viruses where the viral non-structural protein 1 (NS1) was substituted by the monomeric (m)Cherry fluorescent or the NanoLuc luciferase (Nluc) proteins. The ΔNS1 mCherry was able to replicate in cultured cells and in Signal Transducer and Activator of Transcription 1 (STAT1) deficient mice, although at a lower extent than a wild-type (WT) PR8 virus expressing the same mCherry fluorescent protein (WT mCherry). Notably, expression of either reporter gene (mCherry or Nluc) was detected in infected cells by fluorescent microscopy or luciferase plate readers, respectively. ΔNS1 IAV expressing reporter genes provide a novel approach to better understand the biology and pathogenesis of IAV, and represent an excellent tool to develop new therapeutic approaches against IAV infections.

ACS Style

Aitor Nogales; Michael Schotsaert; Raveen Rathnasinghe; Marta DeDiego; Adolfo García-Sastre; Luis Martinez-Sobrido. Replication-Competent ΔNS1 Influenza A Viruses Expressing Reporter Genes. Viruses 2021, 13, 698 .

AMA Style

Aitor Nogales, Michael Schotsaert, Raveen Rathnasinghe, Marta DeDiego, Adolfo García-Sastre, Luis Martinez-Sobrido. Replication-Competent ΔNS1 Influenza A Viruses Expressing Reporter Genes. Viruses. 2021; 13 (4):698.

Chicago/Turabian Style

Aitor Nogales; Michael Schotsaert; Raveen Rathnasinghe; Marta DeDiego; Adolfo García-Sastre; Luis Martinez-Sobrido. 2021. "Replication-Competent ΔNS1 Influenza A Viruses Expressing Reporter Genes." Viruses 13, no. 4: 698.

Journal article
Published: 14 April 2021 in Journal of Virology
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PA-X is a non-structural protein of influenza A virus (IAV), which is encoded by the polymerase acidic (PA) N-terminal region that contains a C-terminal +1 frameshifted sequence. IAV PA-X protein modulates virus-induced host innate immune responses and viral pathogenicity via suppression of host gene expression or cellular shutoff, through cellular mRNA cleavage. Highly pathogenic avian influenza viruses (HPAIV) of the H5N1 subtype naturally infect different avian species, they have an enormous economic impact in the poultry farming, and they also have zoonotic and pandemic potential, representing a risk to human public health. In the present study, we describe a novel bacteria-based approach to identify amino acid residues in the PA-X protein of the HPAIV A/Viet Nam/1203/2004 H5N1 that are important for its ability to inhibit host protein expression or cellular shutoff activity. Identified PA-X mutants displayed a reduced shutoff activity as compared to that of the wild-type (WT) A/Viet Nam/1203/2004 H5N1 PA-X protein. Notably, this new bacteria-based screening allowed us to identify amino acid residues widely distributed over the entire N-terminal region of PA-X. Furthermore, we found that some of the residues affecting A/Viet Nam/1203/2004 H5N1 PA-X host shutoff activity also affect PA polymerase activity in a minigenome assay. This information could be used for the rational design of new and more effective compounds with antiviral activity against IAV. Moreover, our results demonstrate the feasibility of using this bacteria-based approach to identify amino acid residues important for the activity of viral proteins to inhibit host gene expression. IMPORTANCE Highly pathogenic avian influenza viruses (HPAIV) continue to pose a huge threat to global animal and human health. Despite of the limited genome size of Influenza A virus (IAV), the virus encodes eight main viral structural proteins and multiple accessory non-structural proteins, depending on the IAV type, subtype or strain. One of the IAV accessory proteins, PA-X, is encoded by the polymerase acidic (PA) protein and is involved in pathogenicity through the modulation of IAV-induced host inflammatory and innate immune responses. However, the molecular mechanism(s) of IAV PA-X regulation of the host immune response is not well understood. In this work, we used, for the first time, a bacteria-based approach for the identification of amino acids important for the ability of IAV PA-X to induce host shutoff activity and describe novel residues relevant for its ability to inhibit host gene expression, and their contribution in PA polymerase activity.

ACS Style

Kevin Chiem; Darío López-García; Javier Ortego; Luis Martinez-Sobrido; Marta L. DeDiego; Aitor Nogales. Identification of amino acid residues required for inhibition of host gene expression by influenza A/Viet Nam/1203/2004 H5N1 PA-X. Journal of Virology 2021, 1 .

AMA Style

Kevin Chiem, Darío López-García, Javier Ortego, Luis Martinez-Sobrido, Marta L. DeDiego, Aitor Nogales. Identification of amino acid residues required for inhibition of host gene expression by influenza A/Viet Nam/1203/2004 H5N1 PA-X. Journal of Virology. 2021; ():1.

Chicago/Turabian Style

Kevin Chiem; Darío López-García; Javier Ortego; Luis Martinez-Sobrido; Marta L. DeDiego; Aitor Nogales. 2021. "Identification of amino acid residues required for inhibition of host gene expression by influenza A/Viet Nam/1203/2004 H5N1 PA-X." Journal of Virology , no. : 1.

Review
Published: 25 December 2020 in Microorganisms
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Bluetongue virus (BTV), the prototype member of the genus Orbivirus (family Reoviridae), is the causative agent of an important livestock disease, bluetongue (BT), which is transmitted via biting midges of the genus Culicoides. To date, up to 29 serotypes of BTV have been described, which are classified as classical (BTV 1–24) or atypical (serotypes 25–27), and its distribution has been expanding since 1998, with important outbreaks in the Mediterranean Basin and devastating incursions in Northern and Western Europe. Classical vaccine approaches, such as live-attenuated and inactivated vaccines, have been used as prophylactic measures to control BT through the years. However, these vaccine approaches fail to address important matters like vaccine safety profile, effectiveness, induction of a cross-protective immune response among serotypes, and implementation of a DIVA (differentiation of infected from vaccinated animals) strategy. In this context, a wide range of recombinant vaccine prototypes against BTV, ranging from subunit vaccines to recombinant viral vector vaccines, have been investigated. This article offers a comprehensive outline of the live viral vectors used against BTV.

ACS Style

Luis Jiménez-Cabello; Sergio Utrilla-Trigo; Eva Calvo-Pinilla; Sandra Moreno; Aitor Nogales; Javier Ortego; Alejandro Marín-López. Viral Vector Vaccines against Bluetongue Virus. Microorganisms 2020, 9, 42 .

AMA Style

Luis Jiménez-Cabello, Sergio Utrilla-Trigo, Eva Calvo-Pinilla, Sandra Moreno, Aitor Nogales, Javier Ortego, Alejandro Marín-López. Viral Vector Vaccines against Bluetongue Virus. Microorganisms. 2020; 9 (1):42.

Chicago/Turabian Style

Luis Jiménez-Cabello; Sergio Utrilla-Trigo; Eva Calvo-Pinilla; Sandra Moreno; Aitor Nogales; Javier Ortego; Alejandro Marín-López. 2020. "Viral Vector Vaccines against Bluetongue Virus." Microorganisms 9, no. 1: 42.

Journal article
Published: 02 October 2020 in International Journal of Molecular Sciences
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Bluetongue virus (BTV) and African horse sickness virus (AHSV) are vector-borne viruses belonging to the Orbivirus genus, which are transmitted between hosts primarily by biting midges of the genus Culicoides. With recent BTV and AHSV outbreaks causing epidemics and important economy losses, there is a pressing need for efficacious drugs to treat and control the spread of these infections. The polyanionic aromatic compound aurintricarboxylic acid (ATA) has been shown to have a broad-spectrum antiviral activity. Here, we evaluated ATA as a potential antiviral compound against Orbivirus infections in both mammalian and insect cells. Notably, ATA was able to prevent the replication of BTV and AHSV in both cell types in a time- and concentration-dependent manner. In addition, we evaluated the effect of ATA in vivo using a mouse model of infection. ATA did not protect mice against a lethal challenge with BTV or AHSV, most probably due to the in vivo effect of ATA on immune system regulation. Overall, these results demonstrate that ATA has inhibitory activity against Orbivirus replication in vitro, but further in vivo analysis will be required before considering it as a potential therapy for future clinical evaluation.

ACS Style

Celia Alonso; Sergio Utrilla-Trigo; Eva Calvo-Pinilla; Luis Jiménez-Cabello; Javier Ortego; Aitor Nogales. Inhibition of Orbivirus Replication by Aurintricarboxylic Acid. International Journal of Molecular Sciences 2020, 21, 7294 .

AMA Style

Celia Alonso, Sergio Utrilla-Trigo, Eva Calvo-Pinilla, Luis Jiménez-Cabello, Javier Ortego, Aitor Nogales. Inhibition of Orbivirus Replication by Aurintricarboxylic Acid. International Journal of Molecular Sciences. 2020; 21 (19):7294.

Chicago/Turabian Style

Celia Alonso; Sergio Utrilla-Trigo; Eva Calvo-Pinilla; Luis Jiménez-Cabello; Javier Ortego; Aitor Nogales. 2020. "Inhibition of Orbivirus Replication by Aurintricarboxylic Acid." International Journal of Molecular Sciences 21, no. 19: 7294.

Journal article
Published: 18 September 2020 in Viruses
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Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection.

ACS Style

Desarey Morales Vasquez; Jun-Gyu Park; Ginés Ávila-Pérez; Aitor Nogales; Juan Carlos De La Torre; Fernando Almazan; Luis Martinez-Sobrido. Identification of Inhibitors of ZIKV Replication. Viruses 2020, 12, 1041 .

AMA Style

Desarey Morales Vasquez, Jun-Gyu Park, Ginés Ávila-Pérez, Aitor Nogales, Juan Carlos De La Torre, Fernando Almazan, Luis Martinez-Sobrido. Identification of Inhibitors of ZIKV Replication. Viruses. 2020; 12 (9):1041.

Chicago/Turabian Style

Desarey Morales Vasquez; Jun-Gyu Park; Ginés Ávila-Pérez; Aitor Nogales; Juan Carlos De La Torre; Fernando Almazan; Luis Martinez-Sobrido. 2020. "Identification of Inhibitors of ZIKV Replication." Viruses 12, no. 9: 1041.

Journal article
Published: 30 July 2020 in npj Vaccines
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Rift Valley fever (RVF) and bluetongue (BT) are two important ruminant diseases transmitted by arthropods. Both viruses have shown important geographic spread leading to endemicity of BT virus (BTV) in Africa and Europe. In this work, we report a dual vaccine that simultaneously induces protective immune responses against BTV and RVFV based on modified vaccinia Ankara virus (MVA) expressing BTV proteins VP2, NS1, or a truncated form of NS1 (NS1-Nt), and RVFV Gn and Gc glycoproteins. IFNAR(−/−) mice immunized with two doses of MVA-GnGc-VP2 developed a significant neutralizing antibody response against BTV-4 and RVFV. Furthermore, the homologous prime-boost immunization with MVA-GnGc-NS1 or MVA-GnGc-NS1-Nt triggered neutralizing antibodies against RVFV and NS1-specific cytotoxic CD8+ T cells in mice. Moreover, all mice immunized with MVA-GnGc-NS1 or MVA-GnGc-NS1-Nt remained healthy after lethal challenge with RVFV or BTV-4. The homologous prime-boost vaccination with MVA-GnGc-NS1, which was the best immunization strategy observed in mice, was assayed in sheep. Clinical signs and viremia were absent or highly reduced in vaccinated sheep after challenge with BTV-4 or RVFV. These results indicate that MVA-GnGc-NS1 vaccination elicits immune protection against RVFV and BTV in sheep.

ACS Style

Eva Calvo-Pinilla; Alejandro Marín-López; Sandra Moreno; Gema Lorenzo; Sergio Utrilla Trigo; Luis Jiménez-Cabello; Julio Benavides; Aitor Nogales; Rafael Blasco; Alejandro Brun; Javier Ortego. A protective bivalent vaccine against Rift Valley fever and bluetongue. npj Vaccines 2020, 5, 70 .

AMA Style

Eva Calvo-Pinilla, Alejandro Marín-López, Sandra Moreno, Gema Lorenzo, Sergio Utrilla Trigo, Luis Jiménez-Cabello, Julio Benavides, Aitor Nogales, Rafael Blasco, Alejandro Brun, Javier Ortego. A protective bivalent vaccine against Rift Valley fever and bluetongue. npj Vaccines. 2020; 5 (1):70.

Chicago/Turabian Style

Eva Calvo-Pinilla; Alejandro Marín-López; Sandra Moreno; Gema Lorenzo; Sergio Utrilla Trigo; Luis Jiménez-Cabello; Julio Benavides; Aitor Nogales; Rafael Blasco; Alejandro Brun; Javier Ortego. 2020. "A protective bivalent vaccine against Rift Valley fever and bluetongue." npj Vaccines 5, no. 1: 70.

Journal article
Published: 29 June 2020 in Vaccines
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The sequence of non-structural protein NS1 of bluetongue virus (BTV), which contains immunodominant CD8+ T cell epitopes, is highly conserved among BTV serotypes, and has therefore become a major tool in the development of a universal BTV vaccine. In this work, we have engineered multiserotype BTV vaccine candidates based on recombinant chimpanzee adenovirus (ChAdOx1) and modified vaccinia virus Ankara (MVA) vectors expressing the NS1 protein of BTV-4 or its truncated form NS1-Nt. A single dose of ChAdOx1-NS1 or ChAdOx1-NS1-Nt induced a moderate CD8+ T cell response and protected IFNAR(-/-) mice against a lethal dose of BTV-4/MOR09, a reassortant strain between BTV-1 and BTV-4, although the animals showed low viremia after infection. Furthermore, IFNAR(-/-) mice immunized with a single dose of ChAdOx1-NS1 were protected after challenge with a lethal dose of BTV-8 in absence of viremia nor clinical signs. Additionally, the heterologous prime-boost ChAdOx1/MVA expressing NS1 or NS1-Nt elicited a robust NS1 specific CD8+ T cell response and protected the animals against BTV-4/MOR09 even 16 weeks after immunization, with undetectable levels of viremia at any time after challenge. Subsequently, the best immunization strategy based on ChAdOx1/MVA-NS1 was assayed in sheep. Non-immunized animals presented fever and viremia levels up to 104 PFU/mL after infection. In contrast, although viremia was detected in immunized sheep, the level of virus in blood was 100 times lower than in non-immunized animals in absence of clinical signs.

ACS Style

Sergio Utrilla Trigo; Luis Jiménez-Cabello; Ruymán Alonso-Ravelo; Eva Calvo-Pinilla; Alejandro Marín-López; Sandra Moreno; Gema Lorenzo; Julio Benavides; Sarah Gilbert; Aitor Nogales; Javier Ortego. Heterologous Combination of ChAdOx1 and MVA Vectors Expressing Protein NS1 as Vaccination Strategy to Induce Durable and Cross-Protective CD8+ T Cell Immunity to Bluetongue Virus. Vaccines 2020, 8, 346 .

AMA Style

Sergio Utrilla Trigo, Luis Jiménez-Cabello, Ruymán Alonso-Ravelo, Eva Calvo-Pinilla, Alejandro Marín-López, Sandra Moreno, Gema Lorenzo, Julio Benavides, Sarah Gilbert, Aitor Nogales, Javier Ortego. Heterologous Combination of ChAdOx1 and MVA Vectors Expressing Protein NS1 as Vaccination Strategy to Induce Durable and Cross-Protective CD8+ T Cell Immunity to Bluetongue Virus. Vaccines. 2020; 8 (3):346.

Chicago/Turabian Style

Sergio Utrilla Trigo; Luis Jiménez-Cabello; Ruymán Alonso-Ravelo; Eva Calvo-Pinilla; Alejandro Marín-López; Sandra Moreno; Gema Lorenzo; Julio Benavides; Sarah Gilbert; Aitor Nogales; Javier Ortego. 2020. "Heterologous Combination of ChAdOx1 and MVA Vectors Expressing Protein NS1 as Vaccination Strategy to Induce Durable and Cross-Protective CD8+ T Cell Immunity to Bluetongue Virus." Vaccines 8, no. 3: 346.

Review article
Published: 27 June 2020 in Current Opinion in Virology
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Influenza A viruses (IAVs) represent a serious concern globally because they are capable of rapid spread and cause severe disease in humans and other animals. The development and implementation of plasmid-based reverse genetics approaches have allowed the manipulation and recovery of recombinant IAVs from complementary DNA copies of the viral genome. Furthermore, IAV reverse genetics have provided researchers an efficient and powerful platform to introduce specific changes in the viral genome with the final goal of studying IAV biology, designing more effective vaccine strategies, and to reduce the rates of incidence and mortality associated with viral infections. In this review, we briefly discuss IAV reverse genetics and their applications to prevent IAV infections.

ACS Style

Luis Martinez-Sobrido; Marta L DeDiego; Aitor Nogales. AGL2017-82570-RReverse genetics approaches for the development of new vaccines against influenza A virus infections. Current Opinion in Virology 2020, 44, 26 -34.

AMA Style

Luis Martinez-Sobrido, Marta L DeDiego, Aitor Nogales. AGL2017-82570-RReverse genetics approaches for the development of new vaccines against influenza A virus infections. Current Opinion in Virology. 2020; 44 ():26-34.

Chicago/Turabian Style

Luis Martinez-Sobrido; Marta L DeDiego; Aitor Nogales. 2020. "AGL2017-82570-RReverse genetics approaches for the development of new vaccines against influenza A virus infections." Current Opinion in Virology 44, no. : 26-34.

Research article
Published: 14 April 2020 in PLOS Pathogens
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The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.

ACS Style

Luis Martinez-Sobrido; Pilar Blanco Lobo; Laura Rodriguez; Theresa Fitzgerald; Hanyuan Zhang; Phuong Nguyen; Christopher S. Anderson; Jeanne Holden-Wiltse; Sanjukta Bandyopadhyay; Aitor Nogales; Marta L. DeDiego; Brian R. Wasik; Benjamin L. Miller; Carole Henry; Patrick C. Wilson; Mark Y. Sangster; John J. Treanor; David J. Topham; Lauren Byrd-Leotis; David A. Steinhauer; Richard D. Cummings; Jasmina M. Luczo; Stephen M. Tompkins; Kaori Sakamoto; Cheryl A. Jones; John Steel; Anice C. Lowen; Shamika Danzy; Hui Tao; Ashley L. Fink; Sabra L. Klein; Nicholas Wohlgemuth; Katherine J. Fenstermacher; Farah El Najjar; Andrew Pekosz; Lauren Sauer; Mitra K. Lewis; Kathryn Shaw-Saliba; Richard E. Rothman; Zhen-Ying Liu; Kuan-Fu Chen; Colin R. Parrish; Ian E. H. Voorhees; Yoshihiro Kawaoka; Gabriele Neumann; Shiho Chiba; Shufang Fan; Masato Hatta; Huihui Kong; Gongxun Zhong; Guojun Wang; Melissa B. Uccellini; Adolfo García-Sastre; Daniel R. Perez; Lucas M. Ferreri; Sander Herfst; Mathilde Richard; Ron Fouchier; David Burke; David Pattinson; Derek J. Smith; Victoria Meliopoulos; Pamela Freiden; Brandi Livingston; Bridgett Sharp; Sean Cherry; Juan Carlos Dib; Guohua Yang; Charles Russell; Subrata Barman; Richard J. Webby; Scott Krauss; Angela Danner; Karlie Woodard; Malik Peiris; R. A. P. M. Perera; M. C. W. Chan; Elena A. Govorkova; Bindumadhav M. Marathe; Philippe N. Q. Pascua; Gavin Smith; Yao-Tsun Li; Paul G. Thomas; Stacey Schultz-Cherry. Characterizing Emerging Canine H3 Influenza Viruses. PLOS Pathogens 2020, 16, e1008409 .

AMA Style

Luis Martinez-Sobrido, Pilar Blanco Lobo, Laura Rodriguez, Theresa Fitzgerald, Hanyuan Zhang, Phuong Nguyen, Christopher S. Anderson, Jeanne Holden-Wiltse, Sanjukta Bandyopadhyay, Aitor Nogales, Marta L. DeDiego, Brian R. Wasik, Benjamin L. Miller, Carole Henry, Patrick C. Wilson, Mark Y. Sangster, John J. Treanor, David J. Topham, Lauren Byrd-Leotis, David A. Steinhauer, Richard D. Cummings, Jasmina M. Luczo, Stephen M. Tompkins, Kaori Sakamoto, Cheryl A. Jones, John Steel, Anice C. Lowen, Shamika Danzy, Hui Tao, Ashley L. Fink, Sabra L. Klein, Nicholas Wohlgemuth, Katherine J. Fenstermacher, Farah El Najjar, Andrew Pekosz, Lauren Sauer, Mitra K. Lewis, Kathryn Shaw-Saliba, Richard E. Rothman, Zhen-Ying Liu, Kuan-Fu Chen, Colin R. Parrish, Ian E. H. Voorhees, Yoshihiro Kawaoka, Gabriele Neumann, Shiho Chiba, Shufang Fan, Masato Hatta, Huihui Kong, Gongxun Zhong, Guojun Wang, Melissa B. Uccellini, Adolfo García-Sastre, Daniel R. Perez, Lucas M. Ferreri, Sander Herfst, Mathilde Richard, Ron Fouchier, David Burke, David Pattinson, Derek J. Smith, Victoria Meliopoulos, Pamela Freiden, Brandi Livingston, Bridgett Sharp, Sean Cherry, Juan Carlos Dib, Guohua Yang, Charles Russell, Subrata Barman, Richard J. Webby, Scott Krauss, Angela Danner, Karlie Woodard, Malik Peiris, R. A. P. M. Perera, M. C. W. Chan, Elena A. Govorkova, Bindumadhav M. Marathe, Philippe N. Q. Pascua, Gavin Smith, Yao-Tsun Li, Paul G. Thomas, Stacey Schultz-Cherry. Characterizing Emerging Canine H3 Influenza Viruses. PLOS Pathogens. 2020; 16 (4):e1008409.

Chicago/Turabian Style

Luis Martinez-Sobrido; Pilar Blanco Lobo; Laura Rodriguez; Theresa Fitzgerald; Hanyuan Zhang; Phuong Nguyen; Christopher S. Anderson; Jeanne Holden-Wiltse; Sanjukta Bandyopadhyay; Aitor Nogales; Marta L. DeDiego; Brian R. Wasik; Benjamin L. Miller; Carole Henry; Patrick C. Wilson; Mark Y. Sangster; John J. Treanor; David J. Topham; Lauren Byrd-Leotis; David A. Steinhauer; Richard D. Cummings; Jasmina M. Luczo; Stephen M. Tompkins; Kaori Sakamoto; Cheryl A. Jones; John Steel; Anice C. Lowen; Shamika Danzy; Hui Tao; Ashley L. Fink; Sabra L. Klein; Nicholas Wohlgemuth; Katherine J. Fenstermacher; Farah El Najjar; Andrew Pekosz; Lauren Sauer; Mitra K. Lewis; Kathryn Shaw-Saliba; Richard E. Rothman; Zhen-Ying Liu; Kuan-Fu Chen; Colin R. Parrish; Ian E. H. Voorhees; Yoshihiro Kawaoka; Gabriele Neumann; Shiho Chiba; Shufang Fan; Masato Hatta; Huihui Kong; Gongxun Zhong; Guojun Wang; Melissa B. Uccellini; Adolfo García-Sastre; Daniel R. Perez; Lucas M. Ferreri; Sander Herfst; Mathilde Richard; Ron Fouchier; David Burke; David Pattinson; Derek J. Smith; Victoria Meliopoulos; Pamela Freiden; Brandi Livingston; Bridgett Sharp; Sean Cherry; Juan Carlos Dib; Guohua Yang; Charles Russell; Subrata Barman; Richard J. Webby; Scott Krauss; Angela Danner; Karlie Woodard; Malik Peiris; R. A. P. M. Perera; M. C. W. Chan; Elena A. Govorkova; Bindumadhav M. Marathe; Philippe N. Q. Pascua; Gavin Smith; Yao-Tsun Li; Paul G. Thomas; Stacey Schultz-Cherry. 2020. "Characterizing Emerging Canine H3 Influenza Viruses." PLOS Pathogens 16, no. 4: e1008409.

Journal article
Published: 17 March 2020 in Journal of Virology
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Influenza viruses are highly contagious pathogens and are a major threat to human health. Vaccination remains the most effective tool to protect humans against influenza infection. However, vaccination does not always guarantee complete protection against drifted or, more noticeably, shifted influenza viruses. Although U.S. Food and Drug Administration (FDA) drugs are approved for the treatment of influenza infections, influenza viruses resistant to current FDA antivirals have been reported and continue to emerge. Therefore, there is an urgent need to find novel antivirals for the treatment of influenza viral infections in humans, a search that could be expedited by repurposing currently approved drugs. In this study, we assessed the influenza antiviral activity of 10 compounds previously shown to inhibit mammarenavirus infection. Among them, eight drugs showed antiviral activities, providing a new battery of drugs that could be used for the treatment of influenza infections.

ACS Style

Jun-Gyu Park; Ginés Ávila-Pérez; Aitor Nogales; Pilar Blanco-Lobo; Juan C. de la Torre; Luis Martínez-Sobrido. Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses. Journal of Virology 2020, 94, 1 .

AMA Style

Jun-Gyu Park, Ginés Ávila-Pérez, Aitor Nogales, Pilar Blanco-Lobo, Juan C. de la Torre, Luis Martínez-Sobrido. Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses. Journal of Virology. 2020; 94 (7):1.

Chicago/Turabian Style

Jun-Gyu Park; Ginés Ávila-Pérez; Aitor Nogales; Pilar Blanco-Lobo; Juan C. de la Torre; Luis Martínez-Sobrido. 2020. "Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses." Journal of Virology 94, no. 7: 1.

Editorial
Published: 17 March 2020 in Pathogens
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Influenza virus infections represent a serious public health problem causing contagious respiratory disease and substantial morbidity and mortality in humans, resulting in a considerable economic burden worldwide. Notably, the number of deaths due to influenza exceeds that of any other known pathogen. Moreover, influenza infections can differ in their intensity, from mild respiratory disease to pneumonia, which can lead to death. Articles in this Special Issue have addressed different aspects of influenza in human health, and the advances in influenza research leading to the development of better therapeutics and vaccination strategies, with a special focus on the study of factors associated with innate or adaptive immune responses to influenza vaccination and/or infection.

ACS Style

Aitor Nogales; Marta L. DeDiego. Influenza Virus and Vaccination. Pathogens 2020, 9, 220 .

AMA Style

Aitor Nogales, Marta L. DeDiego. Influenza Virus and Vaccination. Pathogens. 2020; 9 (3):220.

Chicago/Turabian Style

Aitor Nogales; Marta L. DeDiego. 2020. "Influenza Virus and Vaccination." Pathogens 9, no. 3: 220.

Article
Published: 25 February 2020 in mBio
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Lassa virus (LASV) infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever (LF) cases. Licensed LF vaccines are not available, and anti-LF therapy is limited to off-label use of the nucleoside analog ribavirin with uncertain efficacy. We describe the generation of a novel live-attenuated LASV vaccine candidate. This vaccine candidate is based on mutating wild-type (WT) LASV in a key region of the viral genome, the glycoprotein precursor (GPC) gene. These mutations do not change the encoded GPC but interfere with its production in host cells. This mutated LASV (rLASV-GPC/CD) behaves like WT LASV (rLASV-WT) in cell culture, but in contrast to rLASV-WT, does not cause disease in inoculated guinea pigs. Guinea pigs immunized with rLASV-GPC/CD were protected against an otherwise lethal exposure to WT LASV. Our results support the testing of this candidate vaccine in nonhuman primate models ofLF.

ACS Style

Yingyun Cai; Chengjin Ye; Benson Cheng; Aitor Nogales; Masaharu Iwasaki; Shuiqing Yu; Kurt Cooper; David X. Liu; Randy Hart; Ricky Adams; Tyler Brady; Elena N. Postnikova; Jonathan Kurtz; Marisa St Claire; Jens H. Kuhn; Juan Carlos de la Torre; Luis Martínez-Sobrido. A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene. mBio 2020, 11, 1 .

AMA Style

Yingyun Cai, Chengjin Ye, Benson Cheng, Aitor Nogales, Masaharu Iwasaki, Shuiqing Yu, Kurt Cooper, David X. Liu, Randy Hart, Ricky Adams, Tyler Brady, Elena N. Postnikova, Jonathan Kurtz, Marisa St Claire, Jens H. Kuhn, Juan Carlos de la Torre, Luis Martínez-Sobrido. A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene. mBio. 2020; 11 (1):1.

Chicago/Turabian Style

Yingyun Cai; Chengjin Ye; Benson Cheng; Aitor Nogales; Masaharu Iwasaki; Shuiqing Yu; Kurt Cooper; David X. Liu; Randy Hart; Ricky Adams; Tyler Brady; Elena N. Postnikova; Jonathan Kurtz; Marisa St Claire; Jens H. Kuhn; Juan Carlos de la Torre; Luis Martínez-Sobrido. 2020. "A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene." mBio 11, no. 1: 1.

Journal article
Published: 02 February 2020 in Viruses
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Although seasonal influenza vaccines block most predominant influenza types and subtypes, humans still remain vulnerable to waves of seasonal and new potential pandemic influenza viruses for which no immunity may exist because of viral antigenic drift and/or shift. Previously, we described a human monoclonal antibody (hMAb), KPF1, which was produced in human embryonic kidney 293T cells (KPF1-HEK) with broad and potent neutralizing activity against H1N1 influenza A viruses (IAV) in vitro, and prophylactic and therapeutic activities in vivo. In this study, we produced hMAb KPF1 in tobacco plants (KPF1-Antx) and demonstrated how the plant-produced KPF1-Antx hMAb possesses similar biological activity compared with the mammalian-produced KPF1-HEK hMAb. KPF1-Antx hMAb showed broad binding to recombinant HA proteins and H1N1 IAV, including A/California/04/2009 (pH1N1) in vitro, which was comparable to that observed with KPF1-HEK hMAb. Importantly, prophylactic administration of KPF1-Antx hMAb to guinea pigs prevented pH1N1 infection and transmission in both prophylactic and therapeutic experiments, substantiating its clinical potential to prevent and treat H1N1 infections. Collectively, this study demonstrated, for the first time, a plant-produced influenza hMAb with in vitro and in vivo activity against influenza virus. Because of the many advantages of plant-produced hMAbs, such as rapid batch production, low cost, and the absence of mammalian cell products, they represent an alternative strategy for the production of immunotherapeutics for the treatment of influenza viral infections, including emerging seasonal and/or pandemic strains.

ACS Style

Jun-Gyu Park; Chengjin Ye; Michael S. Piepenbrink; Aitor Nogales; Haifeng Wang; Michael Shuen; Ashley J. Meyers; Luis Martinez-Sobrido; James J. Kobie. A Broad and Potent H1-Specific Human Monoclonal Antibody Produced in Plants Prevents Influenza Virus Infection and Transmission in Guinea Pigs. Viruses 2020, 12, 167 .

AMA Style

Jun-Gyu Park, Chengjin Ye, Michael S. Piepenbrink, Aitor Nogales, Haifeng Wang, Michael Shuen, Ashley J. Meyers, Luis Martinez-Sobrido, James J. Kobie. A Broad and Potent H1-Specific Human Monoclonal Antibody Produced in Plants Prevents Influenza Virus Infection and Transmission in Guinea Pigs. Viruses. 2020; 12 (2):167.

Chicago/Turabian Style

Jun-Gyu Park; Chengjin Ye; Michael S. Piepenbrink; Aitor Nogales; Haifeng Wang; Michael Shuen; Ashley J. Meyers; Luis Martinez-Sobrido; James J. Kobie. 2020. "A Broad and Potent H1-Specific Human Monoclonal Antibody Produced in Plants Prevents Influenza Virus Infection and Transmission in Guinea Pigs." Viruses 12, no. 2: 167.

Journal article
Published: 31 January 2020 in Journal of Virology
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Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.

ACS Style

Andrew Smith; Laura Rodriguez; Maya El Ghouayel; Aitor Nogales; Jeffrey M. Chamberlain; Katherine Sortino; Emma Reilly; Changyong Feng; David J. Topham; Luis Martínez-Sobrido; Stephen Dewhurst. A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus. Journal of Virology 2020, 94, 1 .

AMA Style

Andrew Smith, Laura Rodriguez, Maya El Ghouayel, Aitor Nogales, Jeffrey M. Chamberlain, Katherine Sortino, Emma Reilly, Changyong Feng, David J. Topham, Luis Martínez-Sobrido, Stephen Dewhurst. A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus. Journal of Virology. 2020; 94 (4):1.

Chicago/Turabian Style

Andrew Smith; Laura Rodriguez; Maya El Ghouayel; Aitor Nogales; Jeffrey M. Chamberlain; Katherine Sortino; Emma Reilly; Changyong Feng; David J. Topham; Luis Martínez-Sobrido; Stephen Dewhurst. 2020. "A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus." Journal of Virology 94, no. 4: 1.

Journal article
Published: 29 January 2020 in Pathogens
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Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.

ACS Style

Thomas A. Hilimire; Aitor Nogales; Kevin Chiem; Javier Ortego; Luis Martinez-Sobrido. Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine. Pathogens 2020, 9, 86 .

AMA Style

Thomas A. Hilimire, Aitor Nogales, Kevin Chiem, Javier Ortego, Luis Martinez-Sobrido. Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine. Pathogens. 2020; 9 (2):86.

Chicago/Turabian Style

Thomas A. Hilimire; Aitor Nogales; Kevin Chiem; Javier Ortego; Luis Martinez-Sobrido. 2020. "Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine." Pathogens 9, no. 2: 86.

Journal article
Published: 16 January 2020 in Scientific Reports
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Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family that has been known to circulate for decades causing mild febrile illness. The more recent ZIKV outbreaks in the Americas and the Caribbean associated with congenital malformations and Guillain-Barré syndrome in adults have placed public health officials in high alert and highlight the significant impact of ZIKV on human health. New technologies to study the biology of ZIKV and to develop more effective prevention options are highly desired. In this study we demonstrate that direct delivery in mice of an infectious ZIKV cDNA clone allows the rescue of recombinant (r)ZIKV in vivo. A bacterial artificial chromosome containing the sequence of ZIKV strain Paraiba/2015 under the control of the cytomegalovirus promoter was complexed with a commercial transfection reagent and administrated using different routes in type-I interferon receptor deficient A129 mice. Clinical signs and death associated with ZIKV viremia were observed in mice. The rZIKV recovered from these mice remained fully virulent in a second passage in mice. Interestingly, infectious rZIKV was also recovered after intraperitoneal inoculation of the rZIKV cDNA in the absence of transfection reagent. Further expanding these studies, we demonstrate that a single intraperitoneal inoculation of a cDNA clone encoding an attenuated rZIKV was safe, highly immunogenic, and provided full protection against lethal ZIKV challenge. This novel in vivo reverse genetics method is a potentially suitable delivery platform for the study of wild-type and live-attenuated ZIKV devoid of confounding factors typical associated with in vitro systems. Moreover, our results open the possibility of employing similar in vivo reverse genetic approaches for the generation of other viruses and, therefore, change the way we will use reverse genetics in the future.

ACS Style

Gines Ávila-Pérez; Aitor Nogales; Jun-Gyu Park; Desarey Morales Vasquez; David A. Dean; Michael Barravecchia; Daniel Perez; Fernando Almazán; Luis Martínez-Sobrido. In vivo rescue of recombinant Zika virus from an infectious cDNA clone and its implications in vaccine development. Scientific Reports 2020, 10, 1 -14.

AMA Style

Gines Ávila-Pérez, Aitor Nogales, Jun-Gyu Park, Desarey Morales Vasquez, David A. Dean, Michael Barravecchia, Daniel Perez, Fernando Almazán, Luis Martínez-Sobrido. In vivo rescue of recombinant Zika virus from an infectious cDNA clone and its implications in vaccine development. Scientific Reports. 2020; 10 (1):1-14.

Chicago/Turabian Style

Gines Ávila-Pérez; Aitor Nogales; Jun-Gyu Park; Desarey Morales Vasquez; David A. Dean; Michael Barravecchia; Daniel Perez; Fernando Almazán; Luis Martínez-Sobrido. 2020. "In vivo rescue of recombinant Zika virus from an infectious cDNA clone and its implications in vaccine development." Scientific Reports 10, no. 1: 1-14.