Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.Initiative for the creation of a Vaccine Research InstituteInfrastructure nationale pour la modélisation des maladies infectieuses humaine

Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates

Chest X-ray (CXR), computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) are noninvasive imaging techniques widely used in human and veterinary pulmonary research and medicine. These techniques have recently been applied in studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-exposed non-human primates (NHPs) to complement virological assessments with meaningful translational readouts of lung disease. Our review of the literature indicates that medical imaging of SARS-CoV-2-exposed NHPs enables high-resolution qualitative and quantitative characterization of disease otherwise clinically invisible and potentially provides user-independent and unbiased evaluation of medical countermeasures (MCMs). However, we also found high variability in image acquisition and analysis protocols among studies. These findings uncover an urgent need to improve standardization and ensure direct comparability across studies

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication i

Bordetella pertussis infection study in a non-human primate model of whooping cough : in vivo imaging contribution

La coqueluche est une pathologie due à la bactérie Bordetella pertussis qui touche les voies respiratoires des patients infectés causant toux, leucocytose, fièvre, et dont les symptômes peuvent aller jusqu’au décès chez les individus les plus à risque (nouveau-nés et enfants immunodéprimés en particulier). Ciblée par différents programmes vaccinaux depuis de nombreuses années, cette pathologie sévit à nouveau dans de nombreux pays développés où le nombre de cas augmente fortement depuis la fin des années 2000. Cette résurgence montre la nécessité de développer de nouvelles stratégies afin de comprendre les mécanismes de l’infection par B. pertussis. Dans ce contexte, la recherche préclinique apparaît comme essentielle pour comprendre la physiopathologie de la coqueluche. De nombreux modèles animaux ont été décrits pour l’étude de la coqueluche mais aucun de ces modèles ne permet de reproduire l’ensemble du spectre des symptômes cliniques de la pathologie, notamment la toux. Cependant, au cours des dernières années un modèle d’infection par Bordetella pertussis chez le jeune babouin a été développé aux Etats-Unis et permet de reproduire la pathologie observée chez l’homme, notamment concernant la toux et la transmission. Ce modèle semble ainsi très prometteur pour l’étude de la physiopathologie de la coqueluche.Cependant, de nombreuses inconnues subsistent dans ce modèle, notamment concernant la colonisation bactérienne et les interactions entre la bactérie et l’hôte. Nous avons ainsi cherché dans cette étude à évaluer d’une part l’impact de différents facteurs comme l’âge des animaux, la dose d’infection ainsi que la voie d’exposition sur la pathologie déclarée par les babouins suite à l’infection par la souche B1917 de B. pertussis afin de pouvoir proposer un parallèle avec les données cliniques disponibles. Nous avons également développé l’utilisation de techniques d’imagerie in vivo comme l’endomicroscopie confocale couplée à la bronchoscopie afin d’étudier la localisation et la cinétique de colonisation et certaines interactions du pathogène dans le tractus respiratoire inférieur au cours de la pathologie. Cette étude nous a ainsi permis d’approfondir les connaissances de physiopathologie de la coqueluche dans ce modèle babouin et consolidera cet outil précieux pour l’évaluation des futures stratégies de prévention contre cette pathologie.Whooping cough, or pertussis, is a respiratory disease caused by Bordetella pertussis bacterial colonization of human airways. Main symptoms are cough, leukocytosis, fever and may even be lethal for some patients (e.g. newborn infants and immuno-deficient patients). Despite a good vaccination coverage worldwide against pertussis, whooping cough cases have been re-increasing in several developed countries in the past twenty years. This resurgence points out the crucial need to develop new control strategies and to better understand pertussis pathophysiology, notably using appropriate animal models. Numerous preclinical models including mice, rats, rabbits and swine have been described for B. pertussis infection studies. However, none of these models reproduce the full spectrum of clinical pertussis symptoms, especially cough. The recent baboon model of whooping cough described in the last few years in the US appears to be a very relevant model for pertussis pathophysiology studies as these animals reproduced all clinical symptoms as observed in humans including cough.However, many aspects of bacterial colonization and interactions with the host have yet to be described in this model.We have then evaluated diverse parameters such as animal age, the inoculum dose and the exposition route on the pathology symptoms and immune responses developed by baboons following B. pertussis B1917 strain inoculation in order to draw a parallel with human clinical data. We also developed in this model in vivo imaging techniques like confocal endomicroscopy coupled with bronchoscopy in order to evaluate bacterial colonization kinetics, localization and some interactions in the lower respiratory tract of infected baboons. Then, this study brought additional data on whooping cough physiopathology in this baboon model, which will be crucial for evaluating future prevention strategies against pertussis diseas

Durable immunogenicity, adaptation to emerging variants, and low-dose efficacy of an AAV-based COVID-19 vaccine platform in macaques

International audienc

Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection

International audienceThe definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication

A case study to dissect immunity to SARS-CoV-2 in a neonate nonhuman primate model

International audienceMost children are less severely affected by coronavirus-induced disease 2019 (COVID-19) than adults, and thus more difficult to study progressively. Here, we provide a neonatal nonhuman primate (NHP) deep analysis of early immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in blood and mucosal tissues. In addition, we provide a comparison with SARS-CoV-2-infected adult NHP. Infection of the neonate resulted in a mild disease compared with adult NHPs that develop, in most cases, moderate lung lesions. In concomitance with the viral RNA load increase, we observed the development of an early innate response in the blood, as demonstrated by RNA sequencing, flow cytometry, and cytokine longitudinal data analyses. This response included the presence of an antiviral type-I IFN gene signature, a persistent and lasting NKT cell population, a balanced peripheral and mucosal IFN-γ/IL-10 cytokine response, and an increase in B cells that was accompanied with anti-SARS-CoV-2 antibody response. Viral kinetics and immune responses coincided with changes in the microbiota profile composition in the pharyngeal and rectal mucosae. In the mother, viral RNA loads were close to the quantification limit, despite the very close contact with SARS-CoV-2-exposed neonate. This pilot study demonstrates that neonatal NHPs are a relevant model for pediatric SARS-CoV-2 infection, permitting insights into the early steps of anti-SARS-CoV-2 immune responses in infants

Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection

Posté sur BioRxiv le 01 novembre 2021International audienceThe definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication

SARS-CoV-2 mechanistic correlates of protection: insight from modelling response to vaccines

Posté sur BioRxiv le 01 novembre 2021The definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication

Computed tomography and [18F]-FDG PET imaging provide additional readouts for COVID-19 pathogenesis and therapies evaluation in non-human primates

Non-human primates (NHPs) are particularly relevant as preclinical models for SARS-CoV-2 infection and nuclear imaging may represent a valuable tool for monitoring infection in this species. We investigated the benefit of computed X-ray tomography (CT) and [18F]-FDG positron emission tomography (PET) to monitor the early phase of the disease in a large cohort (n = 76) of SARS-CoV-2 infected macaques. Following infection, animals showed mild COVID-19 symptoms including typical lung lesions. CT scores at the acute phase reflect the heterogeneity of lung burden following infection. Moreover, [18F]-FDG PET revealed that FDG uptake was significantly higher in the lungs, nasal cavities, lung-draining lymph nodes, and spleen of NHPs by 5 days postinfection compared to pre-infection levels, indicating early local inflammation. The comparison of CT and PET data from previous COVID-19 treatments or vaccines we tested in NHP, to this large cohort of untreated animals demonstrated the value of in vivo imaging in preclinical trials