Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Mediation of transitional B cell maturation in the absence of functional Bruton's tyrosine kinase.

X-linked immune-deficient (Xid) mice, carrying a mutation in Bruton's tyrosine kinase (Btk), have multiple B cell lineage differentiation defects. We now show that, while Xid mice showed only mild reduction in the frequency of the late transitional (T2) stage of peripheral B cells, the defect became severe when the Xid genotype was combined with either a CD40-null, a TCRbeta-null or an MHC class II (MHCII)-null genotype. Purified Xid T1 and T2 B cells survived poorly in vitro compared to wild-type (WT) cells. BAFF rescued WT but not Xid T1 and T2 B cells from death in culture, while CD40 ligation equivalently rescued both. Xid transitional B cells ex vivo showed low levels of the p100 protein substrate for non-canonical NF-kappaB signalling. In vitro, CD40 ligation induced equivalent activation of the canonical but not of the non-canonical NF-kappaB pathway in Xid and WT T1 and T2 B cells. CD40 ligation efficiently rescued p100-null T1 B cells from neglect-induced death in vitro. These data indicate that CD40-mediated signals, likely from CD4 T cells, can mediate peripheral transitional B cell maturation independent of Btk and the non-canonical NF-kappaB pathway, and thus contribute to the understanding of the complexities of peripheral B cell maturation.

Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.

BACKGROUND: Enteric fever caused by Salmonella Typhi remains a major public health problem in developing countries. Typbar-TCV is a single-dose typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine for persons ≥6 months of age. METHODS: Six hundred fifty-four healthy subjects aged 2-45 years enrolled in a double-blind, randomized controlled trial (RCT) received a single dose of Typbar-TCV or comparator "Vi polysaccharide" (Typbar), and 327 healthy subjects aged 6-23 months received a single dose of Typbar-TCV in an open-label trial (OLT); both received single- or multidose presentations from different lots. After 2 years, subsets in each group received a booster dose. The primary objective included analysis of geometric mean titer (GMTs) and 4-fold rise of anti-Vi serum immunoglobulin G (IgG) enzyme-linked immunosorbent assay titers over baseline (seroconversion [SCN]) 42 days after immunization. RESULTS: Typbar-TCV recipients in the RCT attained higher anti-Vi IgG GMTs 42 days after immunization (SCN, 97%; GMT, 1293 [95% confidence interval {CI}, 1153-1449]) than recipients of Typbar (SCN, 93%; GMT, 411 [95% CI, 359-471]) (P < .001). Typbar-TCV was highly immunogenic in the OLT (SCN, 98%; GMT, 1937 [95% CI, 1785-2103]). Two years after vaccination, anti-Vi titers remained higher in Typbar-TCV subjects (GMT, 82 [95% CI, 73-92]); and exhibited higher avidity (geometric mean avidity index [GMAI], 60%) than in Typbar recipients (GMT, 46 [95% CI, 40-53]; GMAI 46%) in the RCT (P < .001). OLT Typbar-TCV recipients achieved GMT of 48 (95% CI, 42-55) and GMAI of 57%. Typbar-TCV induced multiple IgG subclasses and strong booster responses in all ages. No serious vaccine-attributable adverse events were observed. CONCLUSIONS: Single-dose Typbar-TCV is well tolerated and induces robust and long-lasting serum anti-Vi IgG across age groups. CLINICAL TRIALS REGISTRATION: CTRI/2011/08/001957, CTRI/2014/01/004341.

Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection.

Chronic viral infections incapacitate adaptive immune responses by "exhausting" virus-specific T cells, inducing their deletion and reducing productive T-cell memory. Viral infection rapidly induces death receptor CD95 (Fas) expression by dendritic cells (DCs), making them susceptible to elimination by the immune response. Lymphocytic choriomeningitis virus (LCMV) clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black6/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from noninfected mice to preinfected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of antiviral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans to achieve the clearance of persistent viruses.

Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic ß-cells.

Several cytotoxic mechanisms have been attributed to T cells participating in ß-cell death in type 1 diabetes. However, sensitivity of ß-cells to these mechanisms in vitro and in vivo is likely to be different. Moreover, CD4⁺ and CD8⁺ T cells may use distinct mechanisms to cause ß-cell demise that possibly involve activation of third-party cytotoxic cells. We used the transfer of genetically modified diabetogenic T cells into normal, mutant, and bone marrow chimeric recipients to test the contribution of major cytotoxic mechanisms in ß-cell death. We found that 1) the killing of ß-cells by CD4⁺ T cells required activation of the recipient's own cytotoxic cells via tumor necrosis factor-α (TNF-α); 2) CD8⁺ T-cell cytotoxic mechanisms destroying ß-cells were limited to perforin and Fas ligand, as double knockouts of these molecules abrogated the ability of T cells to cause diabetes; and 3) individual CD8⁺ T-cell clones chose their cytotoxic weaponry by a yet unknown mechanism and destroyed their targets via either Fas-independent or Fas-dependent (~40% of clones) pathways. Fas-dependent destruction was assisted by TNF-α.

NKG2D signaling on CD8⁺ T cells represses T-bet and rescues CD4-unhelped CD8⁺ T cell memory recall but not effector responses.

CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8(+) T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8(+) T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4(+) T cells in a CD4-dependent influenza model and rescues HIV-specific CD8(+) T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8(+) T cells from their pathophysiological fate and may provide therapeutic benefits.

A superantigen interacts with leishmanial infection in antigen-presenting cells to regulate cytokine commitment of responding CD4 T cells.

Germ-line retroviral insertions in vertebrate genomes are implicated in the modulation of host immune responses. We demonstrate that CBA/J mice, which carry the proviral integrants mammary tumor virus locus 6 (Mtv6) and mammary tumor virus locus 7 (Mtv7), are less resistant to infection with the protozoan pathogen Leishmania major compared with closely related but Mtv6-negative and Mtv7-negative CBA/CaJ mice. Although both strains generated comparable L. major-specific CD4 T cell frequencies, T cells from CBA/J mice made much less interferon γ (IFN-γ). L. major-infected CBA/CaJ dendritic cells primed L. major-specific and allospecific IFN-γ-producing CD4 T cells better in vivo and in vitro, respectively, than CBA/J dendritic cells did. L. major susceptibility appeared to be associated with Mtv7, and v-Sag-7 superantigen expression and L. major infection together reduced the ability of an antigen-presenting cell line to prime alloresponder CD4 T cells for IFN-γ commitment. These data show that an endogenous superantigen can interact with L. major infection to alter antigen-presenting cell properties and modulate T cell cytokine commitment, with implications for human susceptibility to infectious diseases.