Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses

IntroductionCOVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood.MethodsHere, we studied the humoral and cellular immune responses of fully vaccinated individuals who subsequently experienced breakthrough infection due to the Delta variant of SARS-CoV-2 and correlated them with the severity of the disease.ResultsIn this study, an effective humoral response alone was not sufficient to induce effective immune protection against severe breakthrough infection, which also required effective cell-mediated immunity to SARS-CoV-2. Patients who did not require oxygen had significantly higher specific (p=0.021) and nonspecific (p=0.004) cellular responses to SARS-CoV-2 at the onset of infection than those who progressed to a severe form.DiscussionKnowing both humoral and cellular immune response could allow to adapt preventive strategy, by better selecting patients who would benefit from additional vaccine boosters.Trial registration numbershttps://clinicaltrials.gov, identifier NCT04355351; https://clinicaltrials.gov, identifier NCT04429594

Th17-Immune Response in Patients With Membranous Nephropathy Is Associated With Thrombosis and Relapses: Th17-Immune Response in Patients With Membranous Nephropathy Is Associated With Thrombosis and Relapses

International audienceExciting times for the field of renal autoimmune diseases have begun. In 2021, for the first time, two new drugs belimumab (1) and voclosporin ( 2) are approved for the treatment of lupus nephritis (LN) (1, 2). Other novel targeted therapies demonstrate clinical efficacy in large, randomized trials, such as avacopan for ANCA-associated vasculitis (AAV) (3), imlifidase for Goodpasture’s disease and iptacopan for IgA nephropathy (IgAN). Pathogenic molecules are specifically targeted by new drugs that help to uncover novel aspects of disease mechanisms leading to glomerulonephritis. Simultaneously, the field is boosted by novel big data technologies on the single cell levels such as high-sensitive multi-color flow cytometry, single-cell genomics (single-cell RNA sequencing - scRNAseq), single cell metabolomics and proteomics. The novel treatment options in renal autoimmune diseases almost simultaneously require new immunomonitoring tools. ‘Immunomonitoring’includes the wide range of approaches to monitoring immune responses by the cellular immune system (e.g. T-cells, B-cells, plasma cells, dendritic cells, neutrophils etc.), or by the humoral immune system (e.g. cytokines, (auto-)antibodies, urinary markers, etc.). Monitoring relevant immune responses in patients with renal autoimmune diseases helps us to better understand a) the underpinning immunological pathophysiology of these diseases; b) the beneficial effects of novel treatments on autoimmunity; and c) can potentially help doctors and patients guide a personalized treatment strategy, adding information on immunological (non-)response to a clinical (non-) response treatment and on disease prognosis. In the present Research Topic, we have been able to collect for you a vast amount of research addressing novel ways and the roleof immunomonitoring in the broad range of renal autoimmune disease including LN, AAV, IgAN, idiopathic membranous nephropathy (iMN) and complement-mediated disease (CMD)

Th17-Immune Response in Patients With Membranous Nephropathy Is Associated With Thrombosis and Relapses

International audienceAlternative strategies targeting dysregulated cytokine balance could be considered for these patients at high risk of relapse

Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients

Background Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.Methods Previously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (NCT02799901). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.Results Seventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2–28.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-α and interferon-γ (IFN-γ) (1136 pg/mL vs 5558 pg/mL, p<0.0001; and 3894 pg/mL vs 17 129 pg/mL, p=0.02, respectively). Responders exhibited increasing cytokine levels from baseline to week 6. Non-responders had lower interleukin 17A (IL-17A) levels at baseline than responders (7 pg/mL vs 32 pg/mL, p=0.03), and lower IFN-γ levels at week 6 (3.3 ng/mL vs 14.5 ng/mL, p=0.03). A lower level of IL-17A at week 2 and a lower level of IFN-γ at week 6 correlated with worse PFS (p=0.04 and p=0.04 respectively). At baseline, patients who developed irAEs had higher IL-6 levels (19.3 ng/mL vs 9.2 ng/mL, p=0.03) and higher IL-17A levels (52.5 pg/mL vs 2.5 pg/mL, p=0.009) than those without irAEs.Conclusions Our findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy

Low T Cell Responsiveness in the Early Phase of COVID-19 Associates with Progression to Severe Pneumonia in Kidney Transplant Recipients

Kidney transplant (KT) recipients are at increased risk of developing severe forms of COVID-19. Little is known about the immunological mechanisms underlying disease severity in these patients receiving T-cell targeting immunosuppressive drugs. We investigated the relationship between T cell responsiveness at the beginning of the infection and the risk of subsequent progression to respiratory failure. We performed a multicentric prospective study in KT recipients with a positive RT-PCR COVID-19 test and only mild symptoms at inclusion. Blood samples were collected at baseline in a cell culture system containing T cell stimuli. We assessed T cell responsiveness by computing the ratio between the levels of Th1, Th2, Th17 and Treg cytokines produced after polyclonal stimulation and the number of blood lymphocytes. We then used an unsupervised classification approach to stratify patients into low and high T cell responders and a penalized logistic regression to evaluate the association between T cell responsiveness and progression to severe pneumonia. Forty-five patients were included. All patients who progressed to severe pneumonia (24.4%, n = 11) were low T cell responders at baseline (p = 0.01). In multivariate analysis, low T cell responsiveness at baseline was the main risk factor for subsequent progression to severe pneumonia. This study provides novel insights into the mechanisms underlying COVID-19 severity in organ transplant recipients and data of interest to clinicians managing immunosuppressive drugs in these patients

Optimization of Rituximab Therapy in Adult Patients With PLA2R1-Associated Membranous Nephropathy With Artificial Intelligence

International audienceIntroduction: Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 μg/ml at month-3) is a risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients’ characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission.Methods: Rituximab concentrations were measured at month-3 in 92 sera from adult patients with primary membranous nephropathy, split into a training (75%) and a testing set (25%). A forward-backward machine-learning procedure determined the best combination of variables to predict rituximab underdosing in the training data set, which was tested in the test set. The performances were evaluated for accuracy, sensitivity, and specificity in 10-fold cross-validation training and test sets.Results: The best variables combination to predict rituximab underdosing included age, gender, body surface area (BSA), anti-phospholipase A2 receptor type 1 (anti-PLA2R1) antibody titer on day-0, serum albumin on day-0 and day-15, and serum creatinine on day-0 and day-15. The accuracy, sensitivity, and specificity were respectively 79.4%, 78.7%, and 81.0% (training data set), and 79.2%, 84.6% and 72.7% (testing data set). In both sets, the algorithm performed significantly better than chance (P < 0.05). Patients with an initial high probability of underdosing experienced a longer time to remission with higher rituximab cumulative doses required to achieved remission.Conclusion: This algorithm could allow for early intensification of rituximab regimen in patients at high estimated risk of underdosing to increase the likelihood of remission

Image_2_Low baseline IFN-γ response could predict hospitalization in COVID-19 patients.jpeg

The SARS-CoV-2 infection has spread rapidly around the world causing millions of deaths. Several treatments can reduce mortality and hospitalization. However, their efficacy depends on the choice of the molecule and the precise timing of its administration to ensure viral clearance and avoid a deleterious inflammatory response. Here, we investigated IFN-γ, assessed by a functional immunoassay, as a predictive biomarker for the risk of hospitalization at an early stage of infection or within one month prior to infection. Individuals with IFN-γ levels below 15 IU/mL were 6.57-times more likely to be hospitalized than those with higher values (p65 years, and no vaccination were independently associated with hospitalization. In addition, we found a significant inverse correlation between low IFN-γ response and high level of IL-6 in plasma (Spearman’s rho=-0.38, p=0.003). Early analysis of the IFN-γ response in a contact or recently infected subject with SARS-CoV-2 could predict hospitalization and thus help the clinician to choose the appropriate treatment avoiding severe forms of infection and hospitalization.</p