• La unión de ribavirina y remdesivir consigue eliminar de forma rápida el virus al inducir un exceso de mutaciones en su genoma que le impiden multiplicarse con eficacia
• El trabajo abre nuevas posibilidades de tratamiento en pacientes vulnerables que no consiguen eliminar el virus

Una investigación liderada por científicos del Consejo Superior de Investigaciones Científicas (CSIC) encuentra una combinación novedosa de dos fármacos que es eficaz frente al virus causante de la covid-19. La ribavirina, un agente antiviral de amplio espectro, y el remdesivir, un agente efectivo aprobado frente a la covid-19, consiguen extinguir el virus rápidamente cuando se usan en combinación. El estudio, publicado en la revista British Journal of Pharmacology, abre nuevas posibilidades de tratamiento para la supresión efectiva del SARS-CoV-2, especialmente en aquellos pacientes vulnerables que no consiguen eliminar el virus.

Celia Perales, investigadora del CSIC en el Centro Nacional de Biotecnología (CNB-CSIC) y colaboradora del Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), apunta a que “aunque en la actualidad la infección por SARS-CoV-2 no reviste la misma gravedad que al comienzo de la pandemia, en pacientes vulnerables como los inmunodeprimidos, es importante disponer de nuevas combinaciones de fármacos para combatirlo”. 

NPJ Vaccines. 2024 Mar 6;9(1):53.

• La publicación coincide con el cuarto aniversario de la declaración de la pandemia por la OMS.
• Se trata de un diario de a bordo de la investigación realizada en el centro tras la aparición del SARS-CoV-2.

Han pasado cuatro años desde que la Organización Mundial de la Salud (OMS) elevara la emergencia causada por el patógeno más famoso de este siglo, el SARS-CoV-2, al nivel de pandemia por los datos alarmantes referidos a su propagación y gravedad. El nuevo virus revolucionó cualquier ámbito de la sociedad sin excepción. Para la ciencia, supuso todo un desafío a la par que una oportunidad difícil de comparar con cualquier otro evento acontecido.

El Consejo Superior de Investigaciones Científicas (CSIC), a través de su editorial, recoge la experiencia de uno de sus centros, el Centro Nacional de Biotecnología (CNB-CSIC), durante los dos años posteriores a esta declaración. Se trata del libro El reto del SARS-CoV-2. Un relato sobre el esfuerzo colectivo del Centro Nacional de Biotecnología en la investigación acerca del nuevo coronavirus, escrito por la periodista y comunicadora Leyre Flamarique e ilustrado por la investigadora del CNB-CSIC Alicia Calvo-Villamañán.

Mario Mellado, director del CNB-CSIC remarca el objetivo del libro: “Hemos querido recoger de manera clara no solo los resultados científicos del trabajo realizado en la pandemia, sino la parte más humana de la investigación, ya que todo nuestro personal se volcó en colaborar y aportar su granito de arena en la búsqueda de soluciones desde los distintos ámbitos de conocimiento del centro”.

• El estudio ha revelado la aparición incipiente de variantes de coronavirus con propiedades biológicas alteradas en pacientes de COVID-19

• Estas mutaciones, hasta ahora inadvertidas por su baja proporción en los pacientes infectados, han sido detectadas gracias a una técnica de secuenciación ultra-profunda

Equipos del Consejo Superior de Investigaciones Científicas (CSIC), de la Universidad Politécnica de Madrid y de la Fundación Jiménez Díaz han revelado en pacientes de COVID-19 la aparición incipiente de variantes de coronavirus con propiedades biológicas alteradas.

El estudio utilizó muestras de virus aislados de pacientes de la primera ola de COVID-19 en Madrid, sobre las que se aplica una técnica de secuenciación ultra-profunda para identificar mutaciones presentes en muy baja proporción. En cada paciente infectado se hallaron multitud de mutaciones cuya relación de parentesco se analizó mediante mapas de redes neuronales. Este procedimiento, basado en técnicas de computación avanzada, permite visualizar en forma de mapas tridimensionales las secuencias con distintas mutaciones, la distancia evolutiva entre secuencias y la frecuencia con la que se encuentran en cada paciente.

• It is a monoclonal antibody with both prophylactic and therapeutic action, isolated from blood samples of a patient infected with SARS-CoV-2 during the first wave of the pandemic.
• The antibody has been designed and developed by researchers from the National Centre for Biotechnology, Hospital del Mar Research Institute, the IrsiCaixa AIDS Research Institute,  and the Center for Genomic Regulation.
• This new treatment has been patented pending commercial development. The results of the work have been published in Nature Communications journal.

A study by the National Centre for Biotechnology, belonging to the Spanish National Research Council (CNB-CSIC), Hospital del Mar Research Institute, the IrsiCaixa AIDS Research Institute –a center jointly promoted by the "la Caixa" Foundation and the Department of Health of the Government of Catalonia–, and the Protein Technologies Unit of the Center for Genomic Regulation (CRG) has led to the development of a new antibody that is active against all existing variants of SARS-CoV-2, including the Omicron subvariants currently circulating. It is a monoclonal antibody, a protein from the immune system developed in the laboratory, called 17T2. The work, in which a scientific team from the CIBER of Infectious Diseases (CIBERINFEC) also participated, has just been published by the journal Nature Communications.

 Antiviral Res. 2023 Dec:220:105760. Epub 2023 Nov 21.

A Gómez-Carballa, G Albericio, J Montoto-Louzao, P Pérez, D Astorgano, I Rivero-Calle, F Martinón-Torres, M Esteban, A Salas, J García-Arriaza

Abstract

Unravelling the molecular mechanism of COVID-19 vaccines through transcriptomic pathways involved in the host response to SARS-CoV-2 infection is key to understand how vaccines work, and for the development of optimized COVID-19 vaccines that can prevent the emergence of SARS-CoV-2 variants of concern (VoCs) and future outbreaks. In this study, we investigated the effects of vaccination with a modified vaccinia virus Ankara (MVA)-based vector expressing the full-length SARS-CoV-2 spike protein (MVA-S) on the lung transcriptome from susceptible K18-hACE2 mice after SARS-CoV-2 infection. One dose of MVA-S regulated genes related to viral infection control, inflammation processes, T-cell response, cytokine production and IFN-γ signalling. Down-regulation of Rhcg and Tnfsf18 genes post-vaccination with one and two doses of MVA-S may represent a mechanism for controlling infection immunity and vaccine-induced protection. One dose of MVA-S provided partial protection with a distinct lung transcriptomic profile to healthy animals, while two doses of MVA-S fully protected against infection with a transcriptomic profile comparable to that of non-vaccinated healthy animals. This suggests that the MVA-S booster generates a robust and rapid antigen-specific immune response preventing virus infection. Notably, down-regulation of Atf3 and Zbtb16 genes in mice vaccinated with two doses of MVA-S may contribute to vaccine control of innate immune system and inflammation processes in the lungs during SARS-CoV-2 infection. This study shows host transcriptomic mechanisms likely involved in the MVA-S vaccine-mediated immune response against SARS-CoV-2 infection, which could help in improving vaccine dose assessment and developing novel, well-optimized SARS-CoV-2 vaccine candidates against prevalent or emerging VoCs.

 DOI: 10.1016/j.antiviral.2023.105760

ACS Nano. 2023 Nov 8.

V Castro, AJ Pérez-Berna, G Calvo, E Pereiro, P Gastaminza

Abstract

Plus-strand RNA viruses are proficient at remodeling host cell membranes for optimal viral genome replication and the production of infectious progeny. These ultrastructural alterations result in the formation of viral membranous organelles and may be observed by different imaging techniques, providing nanometric resolution. Guided by confocal and electron microscopy, this study describes the generation of wide-field volumes using cryogenic soft-X-ray tomography (cryo-SXT) on SARS-CoV-2-infected human lung adenocarcinoma cells. Confocal microscopy showed accumulation of double-stranded RNA (dsRNA) and nucleocapsid (N) protein in compact perinuclear structures, preferentially found around centrosomes at late stages of the infection. Transmission electron microscopy (TEM) showed accumulation of membranous structures in the vicinity of the infected cell nucleus, forming a viral replication organelle containing characteristic double-membrane vesicles and virus-like particles within larger vesicular structures. Cryo-SXT revealed viral replication organelles very similar to those observed by TEM but indicated that the vesicular organelle observed in TEM sections is indeed a vesiculo-tubular network that is enlarged and elongated at late stages of the infection. Overall, our data provide additional insight into the molecular architecture of the SARS-CoV-2 replication organelle.

Keywords: SARS-CoV-2; cryo-SXT; microscopy; vesiculo-tubular network; viral replication.

DOI: 10.1021/acsnano.3c07265

 Front Immunol. 2022 Sep 12;13:995235.

P Pérez , D Astorgano, G Albericio, S Flores, PJ Sánchez-Cordón, J Luczkowiak, R Delgado, JM Casasnovas, Mariano Esteban, Juan García-Arriaza

Abstract

Current coronavirus disease-19 (COVID-19) vaccines are administered by the intramuscular route, but this vaccine administration failed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection in the upper respiratory tract, mainly due to the absence of virus-specific mucosal immune responses. It is hypothesized that intranasal (IN) vaccination could induce both mucosal and systemic immune responses that blocked SARS-CoV-2 transmission and COVID-19 progression. Here, we evaluated in mice IN administration of three modified vaccinia virus Ankara (MVA)-based vaccine candidates expressing the SARS-CoV-2 spike (S) protein, either the full-length native S or a prefusion-stabilized [S(3P)] protein; SARS-CoV-2-specific immune responses and efficacy were determined after a single IN vaccine application. Results showed that in C57BL/6 mice, MVA-based vaccine candidates elicited S-specific IgG and IgA antibodies in serum and bronchoalveolar lavages, respectively, and neutralizing antibodies against parental and SARS-CoV-2 variants of concern (VoC), with MVA-S(3P) being the most immunogenic vaccine candidate. IN vaccine administration also induced polyfunctional S-specific Th1-skewed CD4+ and cytotoxic CD8+ T-cell immune responses locally (in lungs and bronchoalveolar lymph nodes) or systemically (in spleen). Remarkably, a single IN vaccine dose protected susceptible K18-hACE2 transgenic mice from morbidity and mortality caused by SARS-CoV-2 infection, with MVA-S(3P) being the most effective candidate. Infectious SARS-CoV-2 viruses were undetectable in lungs and nasal washes, correlating with high titers of S-specific IgGs and neutralizing antibodies against parental SARS-CoV-2 and several VoC. Moreover, low histopathological lung lesions and low levels of pro-inflammatory cytokines in lungs and nasal washes were detected in vaccinated animals. These results demonstrated that a single IN inoculation of our MVA-based vaccine candidates induced potent immune responses, either locally or systemically, and protected animal models from COVID-19. These results also identified an effective vaccine administration route to induce mucosal immunity that should prevent SARS-CoV-2 host-to-host transmission.

Keywords: MVA; S protein; SARS-CoV-2; immunogenicity; intranasal delivery; mice; protective efficacy; vaccine candidates.

doi: 10.3389/fimmu.2022.995235. eCollection 2022.

 PLoS Pathog. 2022 Jul 11;18(7):e1010631.

T Ginex, C Marco-Marín, M Wieczór, CP Mata, J Krieger, P Ruiz-Rodriguez, ML López-Redondo, C Francés-Gómez, R Melero , CO Sánchez-Sorzano, M Martínez, N Gougeard  A Forcada-Nadal, S Zamora-Caballero, R Gozalbo-Rovira, C Sanz-Frasquet, R Arranz, J Bravo, V Rubio, A Marina , IBV-Covid19-Pipeline; R Geller, I Comas, C Gil, M Coscolla  M Orozco  JL Llácer, Jose-Maria Carazo

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

doi: 10.1371/journal.ppat.1010631.