This page has only limited features, please log in for full access.
SARS-CoV-2 infection in hospital areas is of a particular concern, since the close interaction between health care personnel and patients diagnosed with COVID-19, which allows virus to be easily spread between them and subsequently to their families and communities. Preventing SARS-CoV-2 infection among healthcare personnel is essential to reduce the frequency of infections and outbreaks during the pandemic considering that they work in high-risk areas. In this research, silver nanoparticles (AgNPs) were tested in vitro and shown to have an inhibitory effect on SARS-CoV-2 infection in cultured cells. Subsequently, we assess the effects of mouthwash and nose rinse with ARGOVIT® silver nanoparticles (AgNPs), in the prevention of SARS-CoV-2 contagion in health workers consider as high-risk group of acquiring the infection in the General Tijuana Hospital, Mexico, a hospital for the exclusive recruitment of patients diagnosed with COVID-19. We present a prospective randomized study of 231 participants that was carried out for 9 weeks (during the declaration of a pandemic). The "experimental" group was instructed to do mouthwash and nose rinse with the AgNPs solution; the "control" group was instructed to do mouthwashes and nose rinse in a conventional way. The incidence of SARS-CoV-2 infection was significantly lower in the "experimental" group (two participants of 114, 1.8%) compared to the "control" group (thirty-three participants of 117, 28.2%), with an 84.8% efficiency. We conclude that the mouth and nasal rinse with AgNPs helps in the prevention of SARS-CoV-2 infection in health personnel who are exposed to patients diagnosed with COVID-19.
Horacio Almanza-Reyes; Sandra Moreno; Ismael Plascencia-López; Martha Alvarado-Vera; Leslie Patrón-Romero; Belén Borrego; Alberto Reyes-Escamilla; Daniel Valencia-Manzo; Alejandro Brun; Alexey Pestryakov; Nina Bogdanchikova. Evaluation of silver nanoparticles for the prevention of SARS-CoV-2 infection in health workers: In vitro and in vivo. PLoS ONE 2021, 16, 1 .
AMA StyleHoracio Almanza-Reyes, Sandra Moreno, Ismael Plascencia-López, Martha Alvarado-Vera, Leslie Patrón-Romero, Belén Borrego, Alberto Reyes-Escamilla, Daniel Valencia-Manzo, Alejandro Brun, Alexey Pestryakov, Nina Bogdanchikova. Evaluation of silver nanoparticles for the prevention of SARS-CoV-2 infection in health workers: In vitro and in vivo. PLoS ONE. 2021; 16 (8):1.
Chicago/Turabian StyleHoracio Almanza-Reyes; Sandra Moreno; Ismael Plascencia-López; Martha Alvarado-Vera; Leslie Patrón-Romero; Belén Borrego; Alberto Reyes-Escamilla; Daniel Valencia-Manzo; Alejandro Brun; Alexey Pestryakov; Nina Bogdanchikova. 2021. "Evaluation of silver nanoparticles for the prevention of SARS-CoV-2 infection in health workers: In vitro and in vivo." PLoS ONE 16, no. 8: 1.
SARS-CoV-2 infection in hospital areas is of a particular concern, since the close interaction between health care personnel and patients diagnosed with COVID-19, which allows virus to be easily spread between them and subsequently to their families and communities. Preventing SARS-CoV-2 infection among healthcare personnel is essential to reduce the frequency of infections and outbreaks during the pandemic considering that they work in high-risk areas. In this research, silver nanoparticles (AgNPs) were tested in vitro and shown to have an inhibitory effect on SARS-CoV-2 infection in cultured cells. Subsequently, we assess the effects of mouthwash and nose rinse with ARGOVIT® silver nanoparticles (AgNPs), in the prevention of SARS-CoV-2 contagion in health workers consider as high-risk group of acquiring the infection in the General Tijuana Hospital, Mexico, a hospital for the exclusive recruitment of patients diagnosed with COVID-19. We present a prospective randomized study of 231 participants that was carried out for 9 weeks (during the declaration of a pandemic). The “experimental” group was instructed to do mouthwash and nose rinse with the AgNPs solution; the “control” group was instructed to do mouthwashes and nose rinse in a conventional way. The incidence of SARS-CoV-2 infection was significantly lower in the “experimental” group (two participants of 114, 1.8%) compared to the “control” group (thirty-three participants of 117, 28.2%), with a 84.8% efficiency. We conclude that the mouth and nasal rinse with AgNPs helps in the prevention of SARS-CoV-2 infection in health personnel who are exposed to patients diagnosed with COVID-19.
Horacio Almanza-Reyes; Sandra Moreno; Ismael Plascencia-López; Martha Alvarado-Vera; Leslie Patrón-Romero; Belén Borrego; Alberto Reyes-Escamilla; Daniel Valencia-Manzo; Alejandro Brun; Alexey Pestryakov; Nina Bogdanchikova. Evaluation of silver nanoparticles for the prevention of SARS-CoV-2 infection in health workers: in vitro and in vivo. 2021, 1 .
AMA StyleHoracio Almanza-Reyes, Sandra Moreno, Ismael Plascencia-López, Martha Alvarado-Vera, Leslie Patrón-Romero, Belén Borrego, Alberto Reyes-Escamilla, Daniel Valencia-Manzo, Alejandro Brun, Alexey Pestryakov, Nina Bogdanchikova. Evaluation of silver nanoparticles for the prevention of SARS-CoV-2 infection in health workers: in vitro and in vivo. . 2021; ():1.
Chicago/Turabian StyleHoracio Almanza-Reyes; Sandra Moreno; Ismael Plascencia-López; Martha Alvarado-Vera; Leslie Patrón-Romero; Belén Borrego; Alberto Reyes-Escamilla; Daniel Valencia-Manzo; Alejandro Brun; Alexey Pestryakov; Nina Bogdanchikova. 2021. "Evaluation of silver nanoparticles for the prevention of SARS-CoV-2 infection in health workers: in vitro and in vivo." , no. : 1.
Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes an important disease in ruminants, with great economic losses. The infection can be also transmitted to humans; therefore, it is considered a major threat to both human and animal health. In a previous work, we described a novel RVFV variant selected in cell culture in the presence of the antiviral agent favipiravir that was highly attenuated in vivo. This variant displayed 24 amino acid substitutions in different viral proteins when compared to its parental viral strain, two of them located in the NSs protein that is known to be the major virulence factor of RVFV. By means of a reverse genetics system, in this work we have analyzed the effect that one of these substitutions, P82L, has in viral attenuation in vivo. Rescued viruses carrying this single amino acid change were clearly attenuated in BALB/c mice while their growth in an interferon (IFN)-competent cell line as well as the production of interferon beta (IFN-β) did not seem to be affected. However, the pattern of nuclear NSs accumulation was modified in cells infected with the mutant viruses. These results highlight the key role of the NSs protein in the modulation of viral infectivity.
Belén Borrego; Sandra Moreno; Nuria de la Losa; Friedemann Weber; Alejandro Brun. The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice. Viruses 2021, 13, 542 .
AMA StyleBelén Borrego, Sandra Moreno, Nuria de la Losa, Friedemann Weber, Alejandro Brun. The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice. Viruses. 2021; 13 (4):542.
Chicago/Turabian StyleBelén Borrego; Sandra Moreno; Nuria de la Losa; Friedemann Weber; Alejandro Brun. 2021. "The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice." Viruses 13, no. 4: 542.
Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes Rift Valley fever (RVF), a zoonotic disease of wild and domestic ruminants, causing serious economic losses and a threat to human health that could be controlled by vaccination. Though RVF vaccines are available for livestock, no RVF vaccines have been licensed for veterinary use in non-endemic countries nor for human populations in RVF risk areas. In a recent work, we showed that favipiravir, a promising drug with antiviral activity against a number of RNA viruses, led to the extinction of RVFV from infected cell cultures. Nevertheless, certain drug concentrations allowed the recovery of a virus variant showing increased resistance to favipiravir. In this work, we characterized this novel resistant variant both at genomic and phenotypic level in vitro and in vivo. Interestingly, the resistant virus displayed reduced growth rates in C6/36 insect cells but not in mammalian cell lines, and was highly attenuated but still immunogenic in vivo. Some amino acid substitutions were identified in the viral RNA-dependent RNA-polymerase (RdRp) gene and in the virus encoded type I-interferon (IFN-I) antagonist NSs gene, in catalytic core motifs and nuclear localization associated positions, respectively. These data may help to characterize novel potential virulence markers, offering additional strategies for further safety improvements of RVF live attenuated vaccine candidates.
Belén Borrego; Alejandro Brun. A Hyper-Attenuated Variant of Rift Valley Fever Virus Generated by a Mutagenic Drug (Favipiravir) Unveils Potential Virulence Markers. Frontiers in Microbiology 2021, 11, 1 .
AMA StyleBelén Borrego, Alejandro Brun. A Hyper-Attenuated Variant of Rift Valley Fever Virus Generated by a Mutagenic Drug (Favipiravir) Unveils Potential Virulence Markers. Frontiers in Microbiology. 2021; 11 ():1.
Chicago/Turabian StyleBelén Borrego; Alejandro Brun. 2021. "A Hyper-Attenuated Variant of Rift Valley Fever Virus Generated by a Mutagenic Drug (Favipiravir) Unveils Potential Virulence Markers." Frontiers in Microbiology 11, no. : 1.
Rift valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes an important disease in ruminants, with great economic losses. The infection can be also transmitted to humans; therefore it is considered a major threat to both human and animal health. In a previous work, we described a novel RVFV variant selected in cell culture in the presence of the antiviral agent favipiravir that was highly attenuated in vivo. This variant displayed 24 amino acid substitutions in different viral proteins when compared to its parental viral strain, two of them located in the NSs protein that is known to be the major virulence factor of RVFV. By means of a reverse genetics system, in this work we have analyzed the effect that one of these substitutions, P82L, has in viral attenuation in vivo. Rescued viruses carrying this single amino acid change were clearly attenuated in BALB/c mice while their growth in an IFN-competent cell line as well as the production of IFN-β did not seem to be affected. However, the pattern of nuclear NSs accumulation was modified in cells infected with the mutant viruses. These results unveil a new RVFV virulence marker highlighting the multiple ways of NSs protein to modulate viral infectivity.
Belén Borrego; Sandra Moreno; Nuria de la Losa; Friedemann Weber; Alejandro Brun. The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice Not Related with a Type-I IFN Antagonistic Phenotype. 2021, 1 .
AMA StyleBelén Borrego, Sandra Moreno, Nuria de la Losa, Friedemann Weber, Alejandro Brun. The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice Not Related with a Type-I IFN Antagonistic Phenotype. . 2021; ():1.
Chicago/Turabian StyleBelén Borrego; Sandra Moreno; Nuria de la Losa; Friedemann Weber; Alejandro Brun. 2021. "The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice Not Related with a Type-I IFN Antagonistic Phenotype." , no. : 1.
Background Many ruminant diseases of viral aetiology can be effectively prevented using appropriate vaccination measures. For diseases such as Rift Valley fever (RVF) the long inter-epizootic periods make routine vaccination programs unfeasible. Coupling RVF prophylaxis with seasonal vaccination programmes by means of multivalent vaccine platforms would help to reduce the risk of new RVF outbreaks. Methodology/Principal findings In this work we generated recombinant attenuated Rift Valley fever viruses (RVFVs) encoding in place of the virulence factor NSs either the VP2 capsid protein or a truncated form of the non-structural NS1 protein of bluetongue virus serotype 4 (BTV-4). The recombinant viruses were able to carry and express the heterologous BTV genes upon consecutive passages in cell cultures. In murine models, a single immunization was sufficient to protect mice upon RVFV challenge and to elicit a specific immune response against BTV-4 antigens that was fully protective after a BTV-4 boost. In sheep, a natural host for RVFV and BTV, both vaccines proved immunogenic although conferred only partial protection after a virulent BTV-4 reassortant Morocco strain challenge. Conclusions/Significance Though additional optimization will be needed to improve the efficacy data against BTV in sheep, our findings warrant further developments of attenuated RVFV as a dual vaccine platform carrying heterologous immune relevant antigens for ruminant diseases in RVF risk areas.
Sandra Moreno; Eva Calvo-Pinilla; Stephanie Devignot; Friedemann Weber; Javier Ortego; Alejandro Brun. Recombinant Rift Valley fever viruses encoding bluetongue virus (BTV) antigens: Immunity and efficacy studies upon a BTV-4 challenge. PLOS Neglected Tropical Diseases 2020, 14, e0008942 .
AMA StyleSandra Moreno, Eva Calvo-Pinilla, Stephanie Devignot, Friedemann Weber, Javier Ortego, Alejandro Brun. Recombinant Rift Valley fever viruses encoding bluetongue virus (BTV) antigens: Immunity and efficacy studies upon a BTV-4 challenge. PLOS Neglected Tropical Diseases. 2020; 14 (12):e0008942.
Chicago/Turabian StyleSandra Moreno; Eva Calvo-Pinilla; Stephanie Devignot; Friedemann Weber; Javier Ortego; Alejandro Brun. 2020. "Recombinant Rift Valley fever viruses encoding bluetongue virus (BTV) antigens: Immunity and efficacy studies upon a BTV-4 challenge." PLOS Neglected Tropical Diseases 14, no. 12: e0008942.
SUMMARY/ABSTRACTIn a previous work, we showed that favipiravir, a promising drug with antiviral activity against a number of RNA viruses, led to the extinction of RVFV from infected cell cultures. Nevertheless, certain drug concentrations allowed the recovery of a virus variant showing increased resistance to favipiravir. In this work, we characterized this novel resistant variant both at genomic and phenotypic level in vitro and in vivo. Interestingly, the resistant virus displayed reduced growth rates in insect cells and was highly attenuated but still immunogenic in vivo. Some amino acid substitutions were identified in the viral RNA-dependent RNA-polymerase (RdRp) gene and in the encoded IFN antagonist NSs gene, in catalytic core motifs and nuclear localization associated positions respectively. These data may help to characterize novel potential virulence markers, offering additional strategies for further safety improvements of RVF live attenuated vaccine candidates.SIGNIFICANCE STATEMENTLive attenuated virus vaccines usually provide long lasting immune responses upon administration. These vaccines are not recommended for use in immune compromised hosts, due to the presence of uncontrolled residual virulence. Cell culture virus propagation in the presence of mutagenic drugs often results in weakened virus lacking virulence as well as limited spreading capabilities. Here, we have characterized a mutagen-induced RVFV variant (40F-p8) that is not virulent in a highly sensitive mouse strain lacking antiviral response. The observed lack of virulence correlates with the presence of specific mutations along key residues in the viral genome, unveiling potential virulence determinants. Thus, 40F-p8 constitutes the basis for a novel RVFV vaccine strain with additional safety features.
Belén Borrego; Alejandro Brun. A hyper-attenuated variant of Rift Valley fever virus (RVFV) generated by a mutagenic drug (favipiravir) unveils potential virulence markers. 2020, 1 .
AMA StyleBelén Borrego, Alejandro Brun. A hyper-attenuated variant of Rift Valley fever virus (RVFV) generated by a mutagenic drug (favipiravir) unveils potential virulence markers. . 2020; ():1.
Chicago/Turabian StyleBelén Borrego; Alejandro Brun. 2020. "A hyper-attenuated variant of Rift Valley fever virus (RVFV) generated by a mutagenic drug (favipiravir) unveils potential virulence markers." , no. : 1.
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.
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 StyleEva 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 StyleEva 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.
In vitro neutralizing antibodies have been often correlated with protection against Rift Valley fever virus (RVFV) infection. We have reported previously that a single inoculation of sucrose-purified modified vaccinia Ankara (MVA) encoding RVFV glycoproteins (rMVAGnGc) was sufficient to induce a protective immune response in mice after a lethal RVFV challenge. Protection was related to the presence of glycoprotein specific CD8+ cells, with a low-level detection of in vitro neutralizing antibodies. In this work we extended those observations aimed to explore the role of humoral responses after MVA vaccination and to study the contribution of each glycoprotein antigen to the protective efficacy. Thus, we tested the efficacy and immune responses in BALB/c mice of recombinant MVA viruses expressing either glycoprotein Gn (rMVAGn) or Gc (rMVAGc). In the absence of serum neutralizing antibodies, our data strongly suggest that protection of vaccinated mice upon the RVFV challenge can be achieved by the activation of cellular responses mainly directed against Gc epitopes. The involvement of cellular immunity was stressed by the fact that protection of mice was strain dependent. Furthermore, our data suggest that the rMVA based single dose vaccination elicits suboptimal humoral immune responses against Gn antigen since disease in mice was exacerbated upon virus challenge in the presence of rMVAGnGc or rMVAGn immune serum. Thus, Gc-specific cellular immunity could be an important component in the protection after the challenge observed in BALB/c mice, contributing to the elimination of infected cells reducing morbidity and mortality and counteracting the deleterious effect of a subneutralizing antibody immune response.
Elena López-Gil; Sandra Moreno; Javier Ortego; Belén Borrego; Gema Lorenzo; Alejandro Brun. MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses. Vaccines 2020, 8, 82 .
AMA StyleElena López-Gil, Sandra Moreno, Javier Ortego, Belén Borrego, Gema Lorenzo, Alejandro Brun. MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses. Vaccines. 2020; 8 (1):82.
Chicago/Turabian StyleElena López-Gil; Sandra Moreno; Javier Ortego; Belén Borrego; Gema Lorenzo; Alejandro Brun. 2020. "MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses." Vaccines 8, no. 1: 82.
Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks.
Belén Borrego; Ana I. de Ávila; Esteban Domingo; Alejandro Brun. Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir. Antimicrobial Agents and Chemotherapy 2019, 63, e00669-19 .
AMA StyleBelén Borrego, Ana I. de Ávila, Esteban Domingo, Alejandro Brun. Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir. Antimicrobial Agents and Chemotherapy. 2019; 63 (8):e00669-19.
Chicago/Turabian StyleBelén Borrego; Ana I. de Ávila; Esteban Domingo; Alejandro Brun. 2019. "Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir." Antimicrobial Agents and Chemotherapy 63, no. 8: e00669-19.
Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.
Belén Borrego; Ana Isabel De Ávila; Esteban Domingo; Alejandro Brun. Lethal mutagenesis of Rift Valley fever virus induced by favipiravir. 2019, 601344 .
AMA StyleBelén Borrego, Ana Isabel De Ávila, Esteban Domingo, Alejandro Brun. Lethal mutagenesis of Rift Valley fever virus induced by favipiravir. . 2019; ():601344.
Chicago/Turabian StyleBelén Borrego; Ana Isabel De Ávila; Esteban Domingo; Alejandro Brun. 2019. "Lethal mutagenesis of Rift Valley fever virus induced by favipiravir." , no. : 601344.
Arboviruses are arthropod-borne viruses that exhibit worldwide distribution and are a constant threat, not only for public health but also for wildlife, domestic animals, and even plants. To study disease pathogenesis and to develop efficient and safe therapies, the use of an appropriate animal model is a critical concern. Adult mice with gene knockouts of the interferon α/β (IFN-α/β) receptor (IFNAR(−/−)) have been described as a model of arbovirus infections. Studies with the natural hosts of these viruses are limited by financial and ethical issues, and in some cases, the need to have facilities with a biosafety level 3 with sufficient space to accommodate large animals. Moreover, the number of animals in the experiments must provide results with statistical significance. Recent advances in animal models in the last decade among other gaps in knowledge have contributed to the better understanding of arbovirus infections. A tremendous advantage of the IFNAR(−/−) mouse model is the availability of a wide variety of reagents that can be used to study many aspects of the immune response to the virus. Although extrapolation of findings in mice to natural hosts must be done with care due to differences in the biology between mouse and humans, experimental infections of IFNAR(−/−) mice with several studied arboviruses closely mimics hallmarks of these viruses in their natural host. Therefore, IFNAR(−/−) mice are a good model to facilitate studies on arbovirus transmission, pathogenesis, virulence, and the protective efficacy of new vaccines. In this review article, the most important arboviruses that have been studied using the IFNAR(−/−) mouse model will be reviewed.
Alejandro Marín-Lopez; Eva Calvo-Pinilla; Sandra Moreno; Sergio Utrilla Trigo; Aitor Nogales; Alejandro Brun; Erol Fikrig; Javier Ortego. Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor. Viruses 2019, 11, 35 .
AMA StyleAlejandro Marín-Lopez, Eva Calvo-Pinilla, Sandra Moreno, Sergio Utrilla Trigo, Aitor Nogales, Alejandro Brun, Erol Fikrig, Javier Ortego. Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor. Viruses. 2019; 11 (1):35.
Chicago/Turabian StyleAlejandro Marín-Lopez; Eva Calvo-Pinilla; Sandra Moreno; Sergio Utrilla Trigo; Aitor Nogales; Alejandro Brun; Erol Fikrig; Javier Ortego. 2019. "Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor." Viruses 11, no. 1: 35.
The aim of this work was to evaluate the immunogenicity and efficacy of DNA and MVA vaccines encoding the RVFV glycoproteins Gn and Gc in an ovine model of RVFV infection. Adult sheep of both sexes were challenged 12 weeks after the last immunization and clinical, virological, biochemical and immunological consequences, were analyzed. Strategies based on immunization with homologous DNA or heterologous DNA/MVA prime-boost were able to induce a rapid in vitro neutralizing antibody response as well as IFNγ production after in vitro virus specific re-stimulation. In these animals we observed reduced viremia levels and less clinical signs when compared with mock-immunized controls. In contrast, sheep inoculated with a homologous MVA prime-boost showed increased viremia correlating with the absence of detectable neutralizing antibody responses, despite of inducing cellular responses after the last immunization. However, faster induction of neutralizing antibodies and IFNγ production after challenge were found in this group when compared to the mock vaccinated group, indicative of a primed immune response. In conclusion, these results suggest that vaccination strategies based on DNA priming were able to mount and maintain specific anti-RVFV glycoprotein immune responses upon homologous or heterologous booster doses, warranting further optimization in large animal models of infection.
Gema Lorenzo; Elena López-Gil; Javier Ortego; Alejandro Brun. Efficacy of different DNA and MVA prime-boost vaccination regimens against a Rift Valley fever virus (RVFV) challenge in sheep 12 weeks following vaccination. Veterinary Research 2018, 49, 1 -12.
AMA StyleGema Lorenzo, Elena López-Gil, Javier Ortego, Alejandro Brun. Efficacy of different DNA and MVA prime-boost vaccination regimens against a Rift Valley fever virus (RVFV) challenge in sheep 12 weeks following vaccination. Veterinary Research. 2018; 49 (1):1-12.
Chicago/Turabian StyleGema Lorenzo; Elena López-Gil; Javier Ortego; Alejandro Brun. 2018. "Efficacy of different DNA and MVA prime-boost vaccination regimens against a Rift Valley fever virus (RVFV) challenge in sheep 12 weeks following vaccination." Veterinary Research 49, no. 1: 1-12.
Bluetongue virus (BTV) is the causative agent of bluetongue disease (BT), which affects domestic and wild ruminants. At the present, 27 different serotypes have been documented. Vaccination has been demonstrated as one of the most effective methods to avoid viral dissemination. To overcome the drawbacks associated with the use of inactivated and attenuated vaccines we engineered a new recombinant BTV vaccine candidate based on proteins VP2, VP7, and NS1 of BTV-4 that were incorporated into avian reovirus muNS-Mi microspheres (MS-VP2/VP7/NS1) and recombinant modified vaccinia virus Ankara (rMVA). The combination of these two antigen delivery systems in a heterologous prime-boost vaccination strategy generated significant levels of neutralizing antibodies in IFNAR(-/-) mice. Furthermore, this immunization strategy increased the ratio of IgG2a/IgG1 in sera, indicating an induction of a Th1 response, and elicited a CD8 T cell response. Immunized mice were protected against lethal challenges with the homologous serotype 4 and the heterologous serotype 1 of BTV. All these results support the strategy based on microspheres in combination with rMVAs as a promising multiserotype vaccine candidate against BTV.
Alejandro Marín-López; Eva Calvo-Pinilla; Diego Barriales; Gema Lorenzo; Javier Benavente; Alejandro Brun; Jose Manuel Martínez-Costas; Javier Ortego. Microspheres-prime/rMVA-boost vaccination enhances humoral and cellular immune response in IFNAR(−/−) mice conferring protection against serotypes 1 and 4 of bluetongue virus. Antiviral Research 2017, 142, 55 -62.
AMA StyleAlejandro Marín-López, Eva Calvo-Pinilla, Diego Barriales, Gema Lorenzo, Javier Benavente, Alejandro Brun, Jose Manuel Martínez-Costas, Javier Ortego. Microspheres-prime/rMVA-boost vaccination enhances humoral and cellular immune response in IFNAR(−/−) mice conferring protection against serotypes 1 and 4 of bluetongue virus. Antiviral Research. 2017; 142 ():55-62.
Chicago/Turabian StyleAlejandro Marín-López; Eva Calvo-Pinilla; Diego Barriales; Gema Lorenzo; Javier Benavente; Alejandro Brun; Jose Manuel Martínez-Costas; Javier Ortego. 2017. "Microspheres-prime/rMVA-boost vaccination enhances humoral and cellular immune response in IFNAR(−/−) mice conferring protection against serotypes 1 and 4 of bluetongue virus." Antiviral Research 142, no. : 55-62.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR −/− ) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is responsible for hemorrhagic diseases in humans, with a high mortality rate. There is no FDA-approved vaccine, and there are still gaps in our knowledge of the immune responses to infection. The recently developed mouse models mimic human CCHF disease and are useful to study the immunogenicity and the protection by vaccine candidates. Our study shows that mice vaccinated with a specific DNA vaccine were fully protected. Importantly, we show that neutralizing antibodies are not sufficient for protection against CCHFV challenge but that an extra Th1-specific cellular response is required. Moreover, we describe the identification of five conserved B-cell epitopes, of which only one was previously known, that could be of great importance for the development of diagnostics tools and the improvement of vaccine candidates.
Jorma Hinkula; Stéphanie Devignot; Sara Åkerström; Helen Karlberg; Eva Wattrang; Sándor Bereczky; Mehrdad Mousavi-Jazi; Christian Risinger; Gunnel Lindegren; Caroline Vernersson; Janusz Paweska; Petrus Jansen van Vuren; Ola Blixt; Alejandro Brun; Friedemann Weber; Ali Mirazimi. Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice. Journal of Virology 2017, 91, 1 .
AMA StyleJorma Hinkula, Stéphanie Devignot, Sara Åkerström, Helen Karlberg, Eva Wattrang, Sándor Bereczky, Mehrdad Mousavi-Jazi, Christian Risinger, Gunnel Lindegren, Caroline Vernersson, Janusz Paweska, Petrus Jansen van Vuren, Ola Blixt, Alejandro Brun, Friedemann Weber, Ali Mirazimi. Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice. Journal of Virology. 2017; 91 (10):1.
Chicago/Turabian StyleJorma Hinkula; Stéphanie Devignot; Sara Åkerström; Helen Karlberg; Eva Wattrang; Sándor Bereczky; Mehrdad Mousavi-Jazi; Christian Risinger; Gunnel Lindegren; Caroline Vernersson; Janusz Paweska; Petrus Jansen van Vuren; Ola Blixt; Alejandro Brun; Friedemann Weber; Ali Mirazimi. 2017. "Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice." Journal of Virology 91, no. 10: 1.
Schmallenberg virus (SBV) is an RNA virus of the Bunyaviridae family, genus Orthobunyavirus that infects wild and livestock species of ruminants. While inactivated and attenuated vaccines have been shown to prevent SBV infection, little is known about their mode of immunity; specifically, which components of the virus are responsible for inducing immunological responses in the host. As previous DNA vaccination experiments on other bunyaviruses have found that glycoproteins, as well as modified (i.e. ubiquitinated) nucleoproteins (N) can confer immunity against virulent viral challenge, constructs encoding for fragments of SBV glycoproteins G and G, as well as ubiquitinated and non-ubiquitinated N were cloned in mammalian expression vectors, and vaccinated intramuscularly in IFNAR mice. Upon viral challenge with virulent SBV, disease progression was monitored. Both the ubiquitinated and non-ubiquitinated nucleoprotein candidates elicited high titers of antibodies against SBV, but only the non-ubiquitinated candidate induced statistically significant protection of the vaccinated mice from viral challenge. Another construct encoding for a putative ectodomain of glycoprotein G (segment aa. 678-947) also reduced the SBV-viremia in mice after SBV challenge. When compared to other experimental groups, both the nucleoprotein and G-ectodomain vaccinated groups displayed significantly reduced viremia, as well as exhibiting no clinical signs of SBV infection. These results show that both the nucleoprotein and the putative G-ectodomain can serve as protective immunological targets against SBV infection, highlighting that viral glycoproteins, as well as nucleoproteins are potent targets in vaccination strategies against bunyaviruses.
Hani Boshra; Diego Charro; Gema Lorenzo; Isbene Sánchez; Beatriz Lazaro; Alejandro Brun; Nicola G.A. Abrescia. DNA vaccination regimes against Schmallenberg virus infection in IFNAR −/− mice suggest two targets for immunization. Antiviral Research 2017, 141, 107 -115.
AMA StyleHani Boshra, Diego Charro, Gema Lorenzo, Isbene Sánchez, Beatriz Lazaro, Alejandro Brun, Nicola G.A. Abrescia. DNA vaccination regimes against Schmallenberg virus infection in IFNAR −/− mice suggest two targets for immunization. Antiviral Research. 2017; 141 ():107-115.
Chicago/Turabian StyleHani Boshra; Diego Charro; Gema Lorenzo; Isbene Sánchez; Beatriz Lazaro; Alejandro Brun; Nicola G.A. Abrescia. 2017. "DNA vaccination regimes against Schmallenberg virus infection in IFNAR −/− mice suggest two targets for immunization." Antiviral Research 141, no. : 107-115.
In this work we have tested the potential antiviral activity of silver nanoparticles formulated as Argovit™ against Rift Valley fever virus (RVFV). The antiviral activity of Argovit was tested on Vero cell cultures and in type-I interferon receptor deficient mice (IFNAR −/− mice) by two different approaches: (i) different dilutions of Argovit were added to previously infected cells or administrated to animals infected with a lethal dose of virus; (ii) virus was pre-incubated with different dilutions of Argovit before inoculation in mice or cells. Though the ability of silver nanoparticles to control an ongoing RVFV infection in the conditions tested was limited, the incubation of virus with Argovit before the infection led to a reduction of the infectivity titers both in vitro and in vivo. These results reveal the potential application of silver nanoparticles to control the infectivity of RVFV, which is an important zoonotic pathogen.
Belén Borrego; Gema Lorenzo; Josué D. Mota-Morales; Horacio Almanza-Reyes; Francisco Mateos; Elena López-Gil; Nuria de la Losa; Vasily A. Burmistrov; Alexey Pestryakov; Alejandro Brun; Nina Bogdanchikova. Potential application of silver nanoparticles to control the infectivity of Rift Valley fever virus in vitro and in vivo. Nanomedicine: Nanotechnology, Biology and Medicine 2016, 12, 1185 -1192.
AMA StyleBelén Borrego, Gema Lorenzo, Josué D. Mota-Morales, Horacio Almanza-Reyes, Francisco Mateos, Elena López-Gil, Nuria de la Losa, Vasily A. Burmistrov, Alexey Pestryakov, Alejandro Brun, Nina Bogdanchikova. Potential application of silver nanoparticles to control the infectivity of Rift Valley fever virus in vitro and in vivo. Nanomedicine: Nanotechnology, Biology and Medicine. 2016; 12 (5):1185-1192.
Chicago/Turabian StyleBelén Borrego; Gema Lorenzo; Josué D. Mota-Morales; Horacio Almanza-Reyes; Francisco Mateos; Elena López-Gil; Nuria de la Losa; Vasily A. Burmistrov; Alexey Pestryakov; Alejandro Brun; Nina Bogdanchikova. 2016. "Potential application of silver nanoparticles to control the infectivity of Rift Valley fever virus in vitro and in vivo." Nanomedicine: Nanotechnology, Biology and Medicine 12, no. 5: 1185-1192.
Rift Valley Fever virus (RVFV) causes recurrent outbreaks of acute life-threatening human and livestock illness in Africa and the Arabian Peninsula. No licensed vaccines are currently available for humans and those widely used in livestock have major safety concerns. A ‘One Health’ vaccine development approach, in which the same vaccine is co-developed for multiple susceptible species, is an attractive strategy for RVFV. Here, we utilized a replication-deficient chimpanzee adenovirus vaccine platform with an established human and livestock safety profile, ChAdOx1, to develop a vaccine for use against RVFV in both livestock and humans. We show that single-dose immunization with ChAdOx1-GnGc vaccine, encoding RVFV envelope glycoproteins, elicits high-titre RVFV-neutralizing antibody and provides solid protection against RVFV challenge in the most susceptible natural target species of the virus-sheep, goats and cattle. In addition we demonstrate induction of RVFV-neutralizing antibody by ChAdOx1-GnGc vaccination in dromedary camels, further illustrating the potency of replication-deficient chimpanzee adenovirus vaccine platforms. Thus, ChAdOx1-GnGc warrants evaluation in human clinical trials and could potentially address the unmet human and livestock vaccine needs.
George M. Warimwe; Joseph Gesharisha; B. Veronica Carr; Simeon Otieno; Kennedy Otingah; Daniel Wright; Bryan Charleston; Edward Okoth; Lopez-Gil Elena; Gema Lorenzo; El-Behiry Ayman; Naif K. Alharbi; Musaad A. Al-Dubaib; Alejandro Brun; Sarah C. Gilbert; Vishvanath Nene; Adrian Hill. Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever. Scientific Reports 2016, 6, 20617 .
AMA StyleGeorge M. Warimwe, Joseph Gesharisha, B. Veronica Carr, Simeon Otieno, Kennedy Otingah, Daniel Wright, Bryan Charleston, Edward Okoth, Lopez-Gil Elena, Gema Lorenzo, El-Behiry Ayman, Naif K. Alharbi, Musaad A. Al-Dubaib, Alejandro Brun, Sarah C. Gilbert, Vishvanath Nene, Adrian Hill. Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever. Scientific Reports. 2016; 6 (1):20617.
Chicago/Turabian StyleGeorge M. Warimwe; Joseph Gesharisha; B. Veronica Carr; Simeon Otieno; Kennedy Otingah; Daniel Wright; Bryan Charleston; Edward Okoth; Lopez-Gil Elena; Gema Lorenzo; El-Behiry Ayman; Naif K. Alharbi; Musaad A. Al-Dubaib; Alejandro Brun; Sarah C. Gilbert; Vishvanath Nene; Adrian Hill. 2016. "Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever." Scientific Reports 6, no. 1: 20617.
Bluetongue virus (BTV) replicates in lymphoid tissues where infected mononuclear leukocytes secrete proinflammatory and vasoactive mediators that can contribute to bluetongue (BT) pathogenesis. Using the well-characterized IFNAR(-/-) mice animal model, we have now studied the histopathology and dynamics of leukocyte populations in different target tissues (spleen, thymus, and lung) during BTV-4 infection by histological and immunohistochemical techniques. The spleen and thymus of BTV-4 infected mice showed severe lymphoid depletion on H&E stained sections. This finding was confirmed by IHC, showing moderate decreased immunopositivity against CD3 in the thymus, and scarce immunoreactivity against CD3 and CD79 in the rest of the white pulp in the spleen, together with an increase in MAC387 immunostaining. BTV-4 infection also induced the expression of active caspase-3 in the spleen, where apoptotic debris was observed by H&E. A dramatic increase in iNOS immunoreactivity associated to necrotic areas of the white pulp was observed, being less noticeable in the thymus and the lung. The induction of pro-inflammatory cytokines in tissues where BTV replicates was evaluated by measuring transcript levels by RT-qPCR. BTV-4 infection led to enhance transcription of IFN-γ, TNF, IL-6, IL-12-p40, and IL-1β mRNA in the thymus, spleen and lung, correlating with the level of virus replication in these tissues. Disease progression and pathogenesis in IFNAR(-/-) mice closely mimics hallmarks of bluetongue disease in ruminants. IFNAR(-/-) mice are a good choice to facilitate a faster advance in the field of orbiviruses.
Alejandro Marín-López; Roberto Bermúdez; Eva Calvo-Pinilla; Sandra Moreno; Alejandro Brun; Javier Ortego. Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4. International Journal of Biological Sciences 2016, 12, 1448 -1460.
AMA StyleAlejandro Marín-López, Roberto Bermúdez, Eva Calvo-Pinilla, Sandra Moreno, Alejandro Brun, Javier Ortego. Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4. International Journal of Biological Sciences. 2016; 12 (12):1448-1460.
Chicago/Turabian StyleAlejandro Marín-López; Roberto Bermúdez; Eva Calvo-Pinilla; Sandra Moreno; Alejandro Brun; Javier Ortego. 2016. "Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4." International Journal of Biological Sciences 12, no. 12: 1448-1460.
A high number of infectious diseases affecting livestock and companion animals are caused by pathogens of viral etiology. Ensuring the maximum standards of quality and welfare in animal production requires developing effective tools to halt and prevent the spread of those infectious diseases affecting animal husbandry. To date, one of the best strategies is to implement vaccination policies whenever possible. However many of the currently manufactured vaccines relies in classical vaccine technologies (killed or attenuated vaccines) which, under some circumstances, may not be optimal in terms of safety or adequate for widespread application in disease-free countries at risk of disease introduction. One step ahead is needed to improve and adapt vaccine manufacturing to the use of new generation vaccine technologies already tested in experimental settings. Here we present in the context of animal viral diseases of veterinary interest, an overview of some current vaccine technologies that can be approached for virus pathogens with a brief insight in the type of immunity elicited.
Alejandro Brun. Vaccines and Vaccination for Veterinary Viral Diseases: A General Overview. Methods in Molecular Biology 2016, 1349, 1 -24.
AMA StyleAlejandro Brun. Vaccines and Vaccination for Veterinary Viral Diseases: A General Overview. Methods in Molecular Biology. 2016; 1349 ():1-24.
Chicago/Turabian StyleAlejandro Brun. 2016. "Vaccines and Vaccination for Veterinary Viral Diseases: A General Overview." Methods in Molecular Biology 1349, no. : 1-24.