Appearance of IgG to SARS-CoV-2 in saliva effectively indicates seroconversion in mRNA vaccinated immunocompromised individuals

BackgroundImmunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves the oral cavity, a primary site of infection, is presently unknown. MethodsImmunocompromised individuals (n=404) and healthy controls (n=82) participated in a prospective clinical trial encompassing two doses of the mRNA BNT162b2 vaccine. Immunocompromised individuals included primary immunodeficiencies (PID) and secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL). Saliva and serum samples were collected at four time points from the first vaccine dose until 2 weeks after second dose. SARS-CoV-2 spike specific immunoglobulin G (IgG) responses were quantified by a multiplex bead-based assay in saliva and correlated to paired serum IgG titers determined by Elecsys(R) Anti-SARS-CoV-2 S assay. ResultsIgG responses to the SARS-CoV-2 spike full-length trimeric glycoprotein (Spike-f) and S1 subunit in saliva in the HIV and HSCT/CAR-T groups were comparable to healthy controls. In contrast, PID, SOT, and CLL patients all displayed weaker responses which were mainly influenced by disease parameters or immunosuppressants. Salivary IgG levels strongly correlated with serum IgG titers on days 21 and 35 (rho=0.8079 and 0.7768, p=<0.0001). Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded AUC=0.95, PPV=90.7% for the entire cohort on D35. ConclusionsSaliva conveys humoral responses induced by BNT162b2 vaccination. The predictive power makes it highly suitable for screening low responding/vulnerable groups for revaccination. Trial RegistrationClinicalTrials.gov Identifier: NCT04780659 FundingKnut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, The Swedish Blood Cancer Foundation and the organization for PID patient group in Sweden, and Nordstjernan AB. Center for Medical Innovation (CIMED), the Swedish Medical Research Council and the Stockholm County Council (ALF). GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/21264377v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1428efcorg.highwire.dtl.DTLVardef@b97e88org.highwire.dtl.DTLVardef@224661org.highwire.dtl.DTLVardef@3ab25a_HPS_FORMAT_FIGEXP M_FIG C_FIG

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial

BackgroundPatients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate the safety and efficacy after two doses of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. Methods539 study subjects (449 patients and 90 controls) were included in the clinical trial. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/chimeric antigen receptor T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FindingsAdverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72{middle dot}2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43{middle dot}4%) and CLL (63{middle dot}3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. InterpretationThe results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. The rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups and/or subgroups to improve immunity. FundingKnut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, Swedish Research Council, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

Tocilizumab shortens time on mechanical ventilation and length of hospital stay in patients with severe COVID-19: a retrospective cohort study.

BackgroundHyperinflammation is a key feature of the pathogenesis of COVID-19 with a central role of the interleukin-6 pathway. We aimed to study the impact of the IL-6 receptor antagonist tocilizumab on the outcome of patients admitted to the intensive care unit (ICU) with acute respiratory distress syndrome (ARDS) related to COVID-19. MethodsEighty-seven patients with confirmed SARS-CoV-2 infection and moderate to severe ARDS were included (n tocilizumab = 29, n controls = 58). A matched cohort was created using a propensity score. The primary endpoint was 30-day all-cause mortality, secondary endpoints included ventilation-free days and length of stay. ResultsNo difference was found in 30-day all-cause mortality in patients treated with tocilizumab compared to controls (17.2% vs. 32.8%, p = 0.2; HR = 0.52 [0.19 - 1.39], p = 0.19). Ventilator-free days were 19.0 (IQR 12.5 - 20.0) versus 9 (IQR 0.0 - 18.5; p = 0.04), respectively. A higher rate of freedom from mechanical ventilation at 30 days was achieved in patients receiving tocilizumab (HR 2.83 [1.48 - 5.40], p < 0.002). Median length of stay in ICU and total length of stay were reduced by 8 and 9.5 days in patients treated with tocilizumab. Similar results were obtained in the analysis of the propensity score matched cohort. ConclusionsTreatment of critically ill patients with ARDS due to COVID-19 with tocilizumab was not associated with reduced 30-day all-cause mortality, but shorter duration on ventilatory support as well as shorter overall length of stay in hospital and in ICU.