HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We ...performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4
T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg
and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg
of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log
copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml
. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.
This study examined the correlations between invulnerability, narcissism, self-esteem, delinquency, and aggression in a sample of at-risk adolescents. Participants were 213, 16–18 year-olds (169 ...male, 44 female). As expected, narcissism and invulnerability were related to delinquency and aggression. However, maladaptive narcissism predicted unique variance in delinquency and relational aggression. A negative effect for self-esteem emerged for predicting delinquency when controlling for narcissism and perceived invulnerability. The distributions of narcissism and invulnerability indicated that these constructs may not, as a rule, be elevated in such youth. Some preliminary implications for the role of these variables in adolescent problem behaviors are presented.
The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of ...comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.
Despite being a staple of our science, the process of pre-publication peer review has few agreed-upon standards defining its goals or ideal execution. As a community of reviewers and authors, we ...assembled an evaluation format and associated specific standards for the process as we think it should be practiced. We propose that we apply, debate, and ultimately extend these to improve the transparency of our criticism and the speed with which quality data and ideas become public.
Despite being a staple of our science, the process of pre-publication peer review has few agreed-upon standards defining its goals or ideal execution. As a community of reviewers and authors, we assembled an evaluation format and associated specific standards for the process as we think it should be practiced. We propose that we apply, debate, and ultimately extend these to improve the transparency of our criticism and the speed with which quality data and ideas become public.
Significance Patients with the autoimmune disease systemic lupus erythematosus (SLE) develop pathogenic antibodies against their own “self”-antigens. The development of such autoantibodies is thought ...in part to require help from CD4 ⁺ T cells that also recognize the same self-antigens and direct autoantibody production. In this study, antigen-specific CD4 ⁺ T cells in lupus are identified and tracked for the first time using tetramers containing peptides from the spliceosomal protein U1-70. The proportion of circulating, tetramer-positive CD4 ⁺ cells correlates with the presence of U1-70–specific autoantibodies, and antigen-specific T cells are directly implicated in disease activity by their production of the proinflammatory cytokine IL-17. The role of these cells in disease pathology makes them candidate targets for therapeutic intervention.
Antigen-specific CD4 ⁺ T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E ᵏ–containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4 ⁺ T-cell populations in MRL/ lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine ¹⁴⁰. The frequency of CD4 ⁺ T cells specific for U1-70(131-150):I-E ᵏ (without phosphorylation) correlates with disease severity and anti–U1-70 autoantibody production. These T cells also express RORγt and produce IL-17A. Furthermore, the U1-70–specific CD4 ⁺ T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen-specific CD4 ⁺ T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease.
In North America, both messenger RNA (mRNA) vaccines, Pfizer-BioNTech BNT162b2, and Moderna mRNA-1273, each utilizing a 2-dose regimen, have started to be administered to individuals.
We evaluated ...the quantitative serologic antibody response following administration of either a single dose or both doses of an mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in a cohort of 98 participants (88 healthcare workers HCW and 10 solid organ transplant SOT recipients). Antibody levels were compared across 3 immunoassays: Elecsys Anti-SARS-CoV-2 S (Roche Diagnostics), SARS-CoV-2 TrimericS IgG (DiaSorin), and SARS-CoV-2 IgG II Quant (Abbott).
Among HCW, sensitivity ranged from 100% (Roche), 99% (Abbott) and 98% (DiaSorin). The SARS-CoV-2 IgG II Quant and SARS-CoV-2 TrimericS IgG assays showed good agreement with a Pearson correlation coefficient of R = 0.95. Pearson correlation coefficients of R = 0.82 and 0.83 were obtained for Elecsys Anti-SARS-CoV-2 S vs SARS-CoV-2 TrimericS IgG and SARS-CoV-2 IgG II Quant vs Elecsys Anti-SARS-CoV-2 S, respectively. Significant differences in antibody levels between HCW and SOT recipients were observed. A decrease in antibody levels from time of vaccine administration to blood draw was evident. Among those with a second dose, an increase in antibody levels with increased time between administration of the first and second dose was observed.
The absolute values generated from each of the assay platforms are not interchangeable. Antibody levels differed with increased time between vaccine administration and with increased time between administration of the first and second dose. Further, significant differences in antibody levels between HCW and SOT recipients were observed.
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