No abstract

Background In the phase 1–2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. Methods In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. Results Covid-19–related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P=0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody–positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was −0.71 log 10 copies per milliliter (95% confidence interval [CI], −0.90 to −0.53) in the 1200-mg group and −0.86 log 10 copies per milliliter (95% CI, −1.00 to −0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. Conclusions REGEN-COV reduced the risk of Covid-19–related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629 .)

Background REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. Methods We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase–quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). Results Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>10 4 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. Conclusions Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318 .)

T o regulate the immune response and dampen the potential for autoimmunity, the immune system has evolved several mechanisms to down-regulate and control the outgrowth and differentiation of activated CD4 ϩ T cells. One level of control, mediated during the initial interaction of the CD4 ϩ T cell with MHC͞peptide complexes on the surface of antigen-presenting cells, determines whether T cell activation, anergy, or apoptosis will ensue (1-3). A second level of control, mediated by cytokines, regulates the growth and differentiation of activated CD4 ϩ T cells. Different cytokines secreted by CD4 ϩ or CD8 ϩ T cells either stimulate or inhibit CD4 ϩ T cell proliferation and determine whether a naïve T helper (TH) precursor cell differentiates as an IFN-␥-producing TH1 cell or as an IL-4-and IL-10-producing TH2 cell (4-6). A third level of control resides in the regulatory T cells including both CD4 ϩ (7) and CD8 ϩ (8) T cell populations. For example, ample data demonstrate the ability of CD8 ϩ T cells to regulate CD4 ϩ T cell responses (9-13). These effects of CD8 ϩ T cells have been mostly attributed, in recent years, to the CD8 ϩ T cells' secretion of cytokines (14).In addition to identifying cytokines as potential effectors of immune regulation by CD8 ϩ T cells, other studies have identified specific cognate interactions between regulatory CD8 ϩ T cells and activated CD4 ϩ T cells. For example, during antigen-or superantigen-driven CD4 ϩ T cell responses in vivo, CD8 ϩ T cells emerge that specifically regulate CD4 ϩ T cells in a T cell antigen receptor (TCR) V␤-specific manner (15, 16). These CD8 ϩ T cells preferentially recognize antigen-activated CD4 ϩ T cell clones expressing certain TCR V␤ molecules and are restricted by the class I-b MHC molecule Qa-1. Unlike conventional MHC class I-a molecules, Qa-1 molecules are expressed only at low levels on resting T cells but are increased after antigen activation (17). These data are consistent with a model of specific immunoregulation in which after antigen activation CD4 ϩ T cells express membrane Qa-1͞TCRV␤ motifs that are recognized by the ␣␤ TCR expressed by precursor regulatory CD8 ϩ T cells. These CD8 ϩ T cells are induced to differentiate and down-regulate CD4 ϩ T cells expressing the particular Qa-1͞TCRV␤ motifs.A prediction of this model is that Qa-1-restricted, V␤-specific regulatory CD8 ϩ T cells will be induced by ''vaccination'' of animals with antigen-activated CD4 ϩ T cells, using T cell vaccination (TCV) protocols known to prevent autoimmune disease in animal models (18,19). In this regard, we have shown that Qa-1-restricted, V␤-specific CD8 ϩ cytotoxic T cell lines are induced by TCV (16). Moreover, we isolated a CD8 ϩ T hybridoma clone from a T cell-vaccinated mouse that preferentially recognizes CD4 ϩ V␤8 ϩ but not CD4 ϩ V␤6 ϩ myelin basic protein (MBP)-reactive clones in a Qa-1-restricted fashion (16). In this current study, we further confirmed this prediction by investigating an experimental autoimmune encephalomyelitis (EAE) model system in wh...

Vaccination of mice with activated autoantigen-reactive CD4 ؉ T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8 ؉ regulatory T cells that are specific for pathogenic CD4 ؉ T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8 ؉ T cells emerge that preferentially lyse and regulate activated autologous CD4؉ T cells in a T cell receptor (TCR) V␤-specific manner. This TCR V␤-specific regulation is not observed in ␤ 2 -microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar V␤8-specific Qa-1-restricted CD8 ؉ T cells are also induced by TCV with activated CD4 ؉ V␤8 ؉ T cells. These CD8 ؉ T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR V␤8. Further, CD8؉ T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4 ؉ V␤8 ؉ T cell clone specifically recognize other CD4 ؉ T cells and T cell tumors that express V␤8 and the syngeneic Qa-1 a but not the allogeneic Qa-1 b molecule. Thus, V␤-specific Qa-1-restricted CD8 ؉