It is currently difficult to know the proportion of children immunized during thE sars-cOv-2 epidemic. Moreover, there is still uncertainty about whether adaptive immune responses to SARS-CoV-2 are protective. Such knowledge is of immediate relevance, as it will provide insights into immunity of SARS-CoV-2 infection and thus help define future immunization strategies. On the other hand, SARS-Cov-2 is associated with an overall higher rate of medical complications in immunocom¬promised patients than in the general population. However, the clinical significance of SARS-CoV-2 varies among different immunocompromised populations, and this is related to the individ¬ual degree and type of immunosuppression. Thus, the quantitative and qualitative evaluation of specific B and T cell responses in COVID-19-infected children with either acquired or iatrogenic disruption of their immune system is needed. So, we plan to analyze the anti-SARS-CoV-2 humoral and memory T cell responses, in children with different levels/type of immunosuppression and healthy controls seen in 4 University Hospitals in Paris, in order to determine and compare the quantity and quality of their SARS-CoV-2 specific humoral and memory T cell responses. Children will be prospectively enrolled a case-controlled cohort at the time of usual referring for their pathology and additional blood samples will be collected during blood sample needed for the conventional care of the patient. Several groups of immunosuppressed children (children with HIV infection, Hematologic Malignancy treated by conventional chemotherapy or allogenic stem cell transplantation, inflammatory bowel disease treated by anti-TNF, idiopathic juvenile arthritis treated by methotrexate, children treated by renal transplantation) and subjects considered as control (consultation in pediatric surgery department) will be included. Humoral specific responses will be evaluated by the quantification of SARS-CoV-2 antidodies (IgG and IgM) (Chimiluminescence) and of the SARS-CoV-2 neutralizing antibodies (pseudovirus neutralization assay). Ex vivo SARS-CoV-2-memory T cell responses will be evaluated on frozen cell, in a subgroup of patients with specific antibody, using intracellular cytokine staining (IFN, IL2, TNF) followed by multiparameter Flow Cytometry. In the absence of detection of specific T cells after ex vivo analysis, in vitro analysis of memory T cells responses will be performed by IFN- ELISpot assay after 11 days of stimulation with specific peptides. Patients inclusion, main objective analysis (rate of patients with humoral immunization against SARS-CoV-2 in different group of immunosuppressed children in comparison to control children), and secondary objective analysis (anti-SARS-CoV-2 Humoral and cellular T cell responses, link between anti-SARS-CoV-2 humoral and cellular immune responses) will be performed in 12 months. Such specific study of the pediatric population is particularly important in order to determine their potential for individual and collective protection, especially in immunosuppressed children. These immune parameters will allow to deeply assessing for each child the risk of infection in relation to the persistence of the circulation of the virus. Moreover, with regards to collective benefits, this study should make it possible to adapt the level of protection needed by these children at higher risk of infection by SARS-CoV-2. Finally, the vaccination of immunocompromised patients is an important priority. The 2009 H1N1 influenza pandemic had further highlight the need of immunocompromised individuals to generate a protective and sustained immune response. So, additional researchs to characterize specific immune responses are important in populations receiving varying immunosuppressive regimens. This study should help to adapt future vaccine strategies against SARS-CoV-2 when they will be available.

To date, dynamics of transmission of Multi-Drug Resistant Enterobacteriaceae (MDR-E, including Extended-Spectrum Beta-Lactamase and Carbapenemase-Producing Enterobacteriaceae) have been mainly studied in hospitals. Several studies suggest, however, that MDR-E spread widely in the community through human-to-human transmission. This multidisciplinary project will, using microbiology, epidemiology and mathematical modeling techniques: 1) estimate transmission rates of MDR-E from an index case to his/her household members, and 2) identify the epidemiological and microbiological factors associated with transmission (genomic characteristics of strains, relative faecal abundance, influence of the microbiota). Knowledge gained will inform decision makers and scientists with respect to the impact of control strategies to specifically control the spread of multidrug-resistant microorganisms in the community.

Major depressive disorders (MDD) are severe disorders with heterogeneous clinical presentations that affect up to 20% of the general population. Response rate to antidepressant drugs is only 40 to 50%, leading to the use of drug combinations and development of alternative therapeutics such as light therapy (LT). In meta-analyses, LT has comparable efficacy to antidepressants as a first line treatment of MDD with and without seasonal pattern (SP). Also, LT has the advantage of being effective in improving both sleep, alertness and circadian rhythms, which may be altered in MDD, contrary to antidepressant drugs that target mainly mood. To date, no studies directly evaluated both subjective (questionnaire, sleep diary) and objective markers (actigraphy, night EEG, polysomnography, multiple sleep latency test, melatonin, cortisol, ERG, Pupillometry, measure of corneal light exposure, 7T MRI) of sleep, wake, biological rhythms, and light signaling pathway in all patients with MDD with and without SP. Our hypothesis is that MDD is composed of more homogeneous entities with specific biomarkers on the retina-brain pathways of mood-photic regulation, and so may show differences regarding response to LT. Our objectives are thus to characterize patients suffering from MDD with and without SP, comparing markers on retina-brain pathways of mood-photic regulation at baseline, during and after LT, examining therapeutic response and evolution markers, in order to identify the signature of response to LT and subgroups of responders. We will carry out a multi-centre clinical trial of 173 patients with MDD with and without SP (ratio 1:1) treated 4 weeks with LT with these multimodal approaches and a comparison with 80 healthy controls regarding characteristics and environmental light input. In parallel, photoreceptive and neural pathways mediating the antidepressant effect of LT will be studied in mouse models of MDD exposed to light therapy.

No treatment for traumatic brain injury (TBI) patients has yet provided prolonged neurorestorative effects. Sustained TBI-induced neuroinflammation (NI) is associated with poor outcomes and a growing body of evidence suggests a link between NI and post-TBI neurodegenerative disorders (ND). Thus, modulation of NI offers a promising therapeutic window for interventions aimed at improving the prognosis of TBI. In this context immunomodulation (IM) via mesenchymal stromal cell (MSC)-based therapies have been investigated in various animal models of brain injury and are currently investigated in human to treat various ND through NI modulation but not yet in the specific setting of TBI. These data shown good safety record. In this human multi-centre double-arm double-blind placebo randomized study, we hypothesize that iterative IV injection of Wharton's jelly of the umbilical cord (WJ-UC-MSC) prevents NI and brain lesions exacerbation through IM and thus improve neuroclinical status. We will include 68 patients with severe TBI (Glasgow score<12 within the 48 first hours, brain lesion on CT scan, need for intracranial pressure monitoring) unresponsive to verbal commands 5 days after sedation discontinuation. They will be randomized to receive either 3 injections 1 week apart of WJ-UC-MSC or placebo. Primary outcome will be NI quantified by [18F]-DPA-714 signal intensity measured by dynamic quantitative PET-MRI at 6 months. A clinical evaluation will be performed at 6 and 12 months. We also plan to study early immune response to WJ-UC-MSC using deep immunophenotyping (flow cytometry analysis), next generation sequencing and digital PCR, on blood samples performed between first and second injection. Finally, we will seek for predictive biomarkers by studying transcriptomic and epigenomic peripheral blood mononuclear cells phenotype, on blood samples performed before first and third injections and at 6 months, in order to implement post-TBI personalized medicine.