Development of an innovative adenovirus-inspired self-assembling vaccine platform rapidly adaptable to coronaviruses and other emergent viruses

The COVID-19 pandemic clearly shows how emergent diseases can cause severe global health and economic problems. We must be prepared to react swiftly against new pathogenic agents and this requires the development of vaccines that are safe, efficient in the long-term and easily adaptable with a short revision time. To this end, the COVID-19 mRNA and adenoviral vector vaccines have been spectacular successes, permitting rapid vaccination across the world in an unprecedented manner. Here we report the design of a new adenovirus-derived vaccine technology based on non-infectious pseudo-viral nanoparticles from the serotype 3 human adenovirus. Each nanoparticle comprises sixty identical proteins that assemble to form a 30 nm diameter spherical particle. A sequence has been engineered into the surface of this protein that enables the display of a covalently-bound target antigens. To demonstrate the efficiency of this approach, we added the SARS-CoV 2 spike protein receptor binding domain (RBD), that interacts with host cell ACE2 receptors, to the surface of the nanoparticles. We first showed that the glycosylated RBD retained its ACE2-binding function when displayed on nanoparticles. We then measured the in vivo humoral response of our vaccine candidate in mice and observed a strong antibody response after the prime injection; further levels were achieved following a second booster injection. In mice preimmunized with underivatized adenoviral nanoparticles, we tested if adenovirus seroprevalence, as frequently observed in humans, was detrimental to the RBD-mediated protection provided by our vaccine candidate. Interestingly, a strong anti-coronaviral response was still observed suggesting that existing circulating anti-adenovirus antibodies are not deleterious to our vaccine platform. We then performed pseudo-CoV 2 neutralization assays and obtained higher ID50 values than observed with COVID-19 convalescent sera, thus showing the high potential efficacy of our vaccine platform. This new vaccine technology is a tool that is easily adaptable to future SARS-CoV 2 variants and, more generally, to future emergent viruses and pathogens

Apport de la fibroscopie bronchique en hématologie : étude prospective monocentrique

Introduction. Over the past decade, outcome of patients with hematological diseases has been improved through new intensive treatment regimens. Intensive care has also increased the risk of infectious diseases, which are a major cause of morbidity and mortality for these patients. An important prognostic factor is the time to introduce effective treatment. Microbiological identification can sometimes be difficult and delay the introduction of effective treatment. In this study, we evaluated the interest of bronchoscopy and bronchoalveolar lavage (BAL) in hematological patients with dyspnea. Methods. We prospectively included all patients followed up for hematological malignancies at the Grenoble-Alpes University Hospital who underwent bronchoscopy for dyspnea between October 2019 and October 2020. Demographic, clinical and radiological characteristics of these patients are collected. We present the usefulness of invasive respiratory sampling in the diagnostic and therapeutic strategies. We also evaluated the impact of pneumopathy on survival and the continuation of hematological treatment. Results. A total of fifty bronchoscopy, performed in 44 patients, were collected. Among these patients, twenty-one had acute myeloid leukemia and sixteen received an allogeneic stem cell transplantation (HSCT), ten of them within 100 days of the respiratory episode. A diagnosis was made for 38 pneumopathies, 34 of which were of infectious origin. Invasive respiratory samples combined with non-invasive examinations allowed a diagnosis for 27 pneumopathies (23 infectious and 4 non-infectious). Eighteen cases of pneumonia were diagnosed based on BAL alone (17 infectious and 1 non-infectious). Therapeutic modification following BAL was noted for 31 pneumopathies (62%). Conclusion. For patient suffered from hematological malignancies associated with pneumonia, bronchoscopy plays an important role in diagnostic and therapeutic strategies.Introduction. Au cours des dernières décennies, la survie des patients atteints d’hémopathie maligne a été améliorée grâce à de nouveaux schémas thérapeutiques intensifs. Ces soins intensifs augmentent également le risque de maladies infectieuses. De ce fait, les complications infectieuses sont une cause majeure de morbi-mortalité chez ces patients et les infections pulmonaires sont parmi les plus fréquentes. Matériels et Méthodes. Nous avons inclus prospectivement tous les patients suivis pour une hémopathie maligne au CHU de Grenoble-Alpes (CHU-GA) et bénéficiant d’une fibroscopie bronchique dans le bilan diagnostique d’une pneumopathie, entre octobre 2019 et octobre 2020. Les caractéristiques démographiques, cliniques radiologiques de ces patients sont recueillies. L’utilité des prélèvements respiratoires invasifs dans les stratégies diagnostique et thérapeutique sont présentés. Nous avons également évalué l'impact de la pneumopathie sur la survie et la poursuite du traitement hématologique. Résultats. Un total de cinquante fibroscopies bronchiques, réalisées chez 44 patients est recueilli. Parmi ces patients, vingt et un présentent une leucémie aigüe myéloïde et seize ont bénéficié d’une allogreffe de cellules souches hématopoïétiques (CSH) dont 10 dans les 100 jours précédant l’épisode respiratoire. Un diagnostic est établi pour 38 des pneumopathies dont 34 d’origines infectieuses. L’association des prélèvements respiratoires invasifs aux examens non invasifs a permis d’évoquer un diagnostic pour 27 pneumopathies (23 infectieuses et 4 non infectieuses). Pour dix-huit pneumopathies, le diagnostic repose sur les résultats du LBA seul (17 infectieuses et 1 non infectieuse). Une modification thérapeutique à la suite du LBA est constatée pour 31 pneumopathies (62%). Conclusion. La fibroscopie bronchique joue un rôle important dans le diagnostic étiologique et dans la prise en charge des patients d’hématologie présentant une pneumopathie

Evaluation of a Prototype of a Novel Galactomannan Sandwich Assay Using the VIDAS® Technology for the Diagnosis of Invasive Aspergillosis

International audienceObjectives To evaluate the analytical and clinical performance of a prototype of a VIDAS ® Galactomannan (GM) unitary test (bioMérieux, Marcy l’Etoile, France) and compare to that of the Platelia™ Aspergillus Ag assay (Bio-Rad, CA, USA). Methods Repeatability, reproducibility, and freeze-thaw stability of VIDAS ® GM were evaluated. Sera from patients at risk of IA were concurrently tested with both the VIDAS ® GM and Platelia™ Aspergillus Ag assays. Correlations between the two assays were assessed by Passing Bablok (PB) regression and performance by ROC analysis. Results The correlations between the VIDAS ® GM indexes after one and two cycles of freezing/thawing were r=1.00 and r=0.989, respectively. The coefficients of variation for negative, low-positive, and positive sera were 13%, 6%, and 5% for repeatability and 14.4%, 7.2%, and 5.5% for reproducibility. Overall, 126 sera were tested with both assays (44 fresh and 82 frozen). The correlation between VIDAS ® GM and Platelia™ Aspergillus Ag was r=0.798. The areas under the curve of the ROC analyses were 0.892 and 0.894, for VIDAS ® GM and Platelia™ Aspergillus Ag, respectively. Conclusions This new VIDAS ® GM prototype assay showed adequate analytical and clinical performance and a good correlation with that of Platelia™ Aspergillus Ag with 126 sera, although these results need to be confirmed in a larger prospective and multicentric study. As for the other VIDAS ® assays, VIDAS ® GM is a single-sample automated test using a solid reagent strip and receptacle. It is easy to use and suitable for rapid on-demand test results

Elicitation of potent SARS-CoV-2 neutralizing antibody responses through immunization with a versatile adenovirus-inspired multimerization platform

International audienceVirus-like particles (VLPs) are highly suited platforms for protein-based vaccines. In the present work, we adapted a previously designed non-infectious adenovirus-inspired 60-mer dodecahedric VLP (ADDomer) to display a multimeric array of large antigens through a SpyTag/SpyCatcher system. To validate the platform as a potential COVID-19 vaccine approach, we decorated the newly designed VLP with the glycosylated receptor binding domain (RBD) of SARS-CoV-2. Cryoelectron microscopy structure revealed that up to 60 copies of this antigenic domain could be bound on a single ADDomer particle, with the symmetrical arrangements of a dodecahedron. Mouse immunization with the RBD decorated VLPs already showed a significant specific humoral response following prime vaccination, greatly reinforced by a single boost. Neutralization assays with SARS-CoV-2 spike pseudo-typed virus demonstrated the elicitation of strong neutralization titers, superior to those of COVID-19 convalescent patients. Notably, the presence of pre-existing immunity against the adenoviral-derived particles did not hamper the immune response against the antigen displayed on its surface. This plug and play vaccine platform represents a promising new highly versatile tool to combat emergent pathogens

Elicitation of potent SARS-CoV-2 neutralizing antibody responses through immunization using a versatile adenovirus-inspired multimerization platform

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown that vaccine preparedness is critical to anticipate a fast response to emergent pathogens with high infectivity. To rapidly reach herd immunity, an affordable, easy to store and versatile vaccine platform is thus desirable. We previously designed a non-infectious adenovirus-inspired nanoparticle (ADDomer), and in the present work, we efficiently decorated this original vaccine platform with glycosylated receptor binding domain (RBD) of SARS-CoV-2. Cryo-Electron Microscopy structure revealed that up to 60 copies of this antigenic domain were bound on a single ADDomer particle with the symmetrical arrangements of a dodecahedron. Mouse immunization with the RBD decorated particles showed as early as the first immunization a significant anti-coronavirus humoral response, which was boosted after a second immunization. Neutralization assays with spike pseudo-typed-virus demonstrated the elicitation of strong neutralization titers. Remarkably, the existence of pre-existing immunity against adenoviral-derived particles enhanced the humoral response against SARS-CoV-2. This plug and play vaccine platform revisits the way of using adenovirus to combat emergent pathogens while potentially taking advantage of the adenovirus pre-immunity