Milieu intérieur: Defining the boundaries of a healthy immune response for improved vaccination strategies

Abstract

Immune responses in human populations are highly variable, with this variability presenting challenges for vaccine design. As such a better understanding of the factors that determine this variability will help in the development of precision vaccination strategies. The Milieu Interieur consortium was established to address this challenge through a definition of the normal boundaries of a healthy immune response, and the characterization of their genetic and environmental determinants. To do this we have implemented standardized tools for monitoring functional immune responses at the proteomic and transcriptional level, which have been applied to a 1,000 healthy donor cohort. This approach has recently allowed us to quantify the extent of genetic control of cellular variability and transcriptional responses to infection. Initial findings on the influence of age, sex, and genetics may already be included in considerations for improved vaccine development, and ongoing analysis will further define the factors behind inter-individual variability in diverse immune responses. This approach will help to guide the development of the next generation of vaccines that will take into account differences in populations and eventually individuals.

Keywords: DNA; Genetic associations; Healthy donors; Immunity; Immunomonitoring; Systems Immunology; adjuvants; immune modulators; influenza; molecular biology; vaccinology.

Figure 1.

PCA defined by the eigenvectors and eigenvalues as based on the four-cytokine (IFN-β, IFN-γ, IL-1β, and TNF-α) induced mRNA expression data of the 44 genes that were defined to capture the optimal signature. Ellipses representing 95% confidence interval (CI) were constructed and replaced the individual samples. Projected sample vectors of TLR stimuli (shown in red) for each of the 25 donors (FSL, ODN, pIC), individually projected onto the first 2 PC vectors, using the 44 selected genes. PC1 is on the X axis, and PC2 on the Y axis. (From Urrutia et al, Cell Reports 2016¹³ using the paper R Shiny application at https://www.synapse.org/ – !Synapse:syn7059574).

Figure 2.

Age specific decline of IFNγ gene expression following stimulation with E. coli, BCG, S. aurues, and C. albicans, but not SEB. Each dot represents an individual of the 1,000 donor MI cohort as stratified by age, and IFNγ gene expression measured by Nanostring. (Adapted from Piasecka et al, PNAS 2018¹⁶ using the R Shiny application at http://www.misage.pasteur.fr).