Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection
- University of Bordeaux, Inria SISTM, UMR 1219, France
- Université Paris-Saclay, Inserm, CEA, France
- Vaccine Research Institute, Inserm U955, France
- Baylor Scott and White Research Institute, United States
- Institut Pasteur, France
- University of Amsterdam, Netherlands
Abstract
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.
Data availability
No unique reagents were generated for this study.Data that support the findings of this study are provided in the source data files of this paper and gather data from 1) the study [Marlin, Nature Com 2021] used in this analysis, which are also directly available online in the section Source data of this related paper (https://www.nature.com/articles/s41467-021-25382-0#Sec17) ; 2) the study [Brouwer, Cell 2021] used in this analysis, which are also available from the corresponding authors of the related paper and 3) the study [Corbett, NEJM 2020] used in this analysis, which are also available online in the section Supplementary Material of the related paper, excel file labelled ("Supplementary Appendix 2"). Data from the main study [Marlin, Nature Com 2021] can also be found in the open-access repository Dryad using the following DOI: https://doi.org/10.5061/dryad.1zcrjdfv7.The original code (mlxtran models and R) as well as model definition files including the full list of parameters used are available and free-of-cost on github (Inria SISTM Team) at the following link: https://github.com/sistm/SARSCoV2modelingNHP.
Article and author information
Author details
Pauline Maisonnasse
Funding
Agence Nationale de la Recherche (ANR-10-LABX-77-01)
- Yves Levy
- Rodolphe Thiébaut
Agence Nationale de la Recherche (ANR-11- 1018 INBS-0008)
- Roger Le Grand
This work was supported by INSERM and the Investissements d'Avenir program, Vaccine Research Institute (VRI), managed by the ANR under reference ANR-10-LABX-77-01. MA has been funded by INRIA PhD grant. The Infectious Disease Models and Innovative Therapies (IDMIT) research infrastructure is supported by the Programme Investissements d'Avenir"
Ethics
Animal experimentation: Cynomolgus macaques (Macaca fascicularis), aged 37-66 months (18 females and 13 males) and originating from Mauritian AAALAC certified breeding centers were used in this study. All animals were housed in IDMIT facilities (CEA, Fontenay-aux-roses), under BSL2 and BSL-3 containment when necessary (Animal facility authorization #D92-032-02, Préfecture des Hauts de Seine, France) and in compliance with European Directive 2010/63/EU, the French regulations and the Standards for Human Care and Use of Laboratory Animals, of the Office for Laboratory Animal Welfare (OLAW, assurance number #A5826-01, US). The protocols were approved by the institutional ethical committee "Comité d'Ethique en Expérimentation Animale du Commissariat à l'Energie Atomique et aux Energies Alternatives" (CEtEA #44) under statement number A20-011. The study was authorized by the "Research, Innovation and Education Ministry" under registration number APAFIS#24434-2020030216532863v1.
Copyright
© 2022, Alexandre et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,270
- views
-
- 302
- downloads
-
- 11
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection
eLife 11:e75427.
https://doi.org/10.7554/eLife.75427
Further reading
-
- Cell Biology
- Immunology and Inflammation
The endothelial blood-brain barrier (BBB) strictly controls immune cell trafficking into the central nervous system (CNS). In neuroinflammatory diseases such as multiple sclerosis, this tight control is, however, disturbed, leading to immune cell infiltration into the CNS. The development of in vitro models of the BBB combined with microfluidic devices has advanced our understanding of the cellular and molecular mechanisms mediating the multistep T-cell extravasation across the BBB. A major bottleneck of these in vitro studies is the absence of a robust and automated pipeline suitable for analyzing and quantifying the sequential interaction steps of different immune cell subsets with the BBB under physiological flow in vitro. Here, we present the under-flow migration tracker (UFMTrack) framework for studying immune cell interactions with endothelial monolayers under physiological flow. We then showcase a pipeline built based on it to study the entire multistep extravasation cascade of immune cells across brain microvascular endothelial cells under physiological flow in vitro. UFMTrack achieves 90% track reconstruction efficiency and allows for scaling due to the reduction of the analysis cost and by eliminating experimenter bias. This allowed for an in-depth analysis of all behavioral regimes involved in the multistep immune cell extravasation cascade. The study summarizes how UFMTrack can be employed to delineate the interactions of CD4+ and CD8+ T cells with the BBB under physiological flow. We also demonstrate its applicability to the other BBB models, showcasing broader applicability of the developed framework to a range of immune cell-endothelial monolayer interaction studies. The UFMTrack framework along with the generated datasets is publicly available in the corresponding repositories.
-
- Immunology and Inflammation
The gut biome, a complex ecosystem of micro- and macro-organisms, plays a crucial role in human health. A disruption in this evolutive balance, particularly during early life, can lead to immune dysregulation and inflammatory disorders. ‘Biome repletion’ has emerged as a potential therapeutic approach, introducing live microbes or helminth-derived products to restore immune balance. While helminth therapy has shown some promise, significant challenges remain in optimizing clinical trials. Factors such as patient genetics, disease status, helminth species, and the optimal timing and dosage of their products or metabolites must be carefully considered to train the immune system effectively. We aim to discuss how helminths and their products induce trained immunity as prospective to treat inflammatory and autoimmune diseases. The molecular repertoire of helminth excretory/secretory products (ESPs), which includes proteins, peptides, lipids, and RNA-carrying extracellular vesicles (EVs), underscores their potential to modulate innate immune cells and hematopoietic stem cell precursors. Mimicking natural delivery mechanisms like synthetic exosomes could revolutionize EV-based therapies and optimizing production and delivery of ESP will be crucial for their translation into clinical applications. By deciphering and harnessing helminth-derived products’ diverse modes of action, we can unleash their full therapeutic potential and pave the way for innovative treatments.
