First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes

: Background : Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by CD8+ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong β-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. Methods: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 μg for priming followed by three further administrations of 25/75/225 μg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. Results: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change − 0.108, − 0.041, − 0.040, and − 0.012, respectively), suggesting no disease progression. Conclusions: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. Trial registration: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016–003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018–003728-35

Prognosis of proliferative lupus nephritis subsets in the Louvain Lupus Nephritis inception Cohort.

ObjectiveThe objective of this paper is to evaluate whether the different International Society of Nephrology/Renal Pathology Society (ISN/RPS) classes of proliferative lupus nephritis (LN) have a distinct baseline presentation, short-term response to immunosuppression (IS) and long-term prognosis.MethodsNinety-eight patients with new onset (first renal biopsy) ISN/RPS proliferative LN (Class III: n = 24; IV-S: n = 23; IV-G: n = 51) were diagnosed at our institution between 1995 and 2012 (Louvain Lupus Nephritis inception Cohort). Their baseline renal parameters, primary response to IS at one year, survival and long-term renal outcome (mean follow-up: 77 months) were compared.ResultsAt baseline, serum creatinine and 24-hour proteinuria were higher in Class IV-G, as was activity index on renal biopsy in Class IV-S and IV-G compared to III. Upon treatment, renal parameters improved with the same kinetics and to the same extent in the three pathological classes. On repeat renal biopsies (n = 43), activity indices dropped similarly. Poor outcomes (death, end-stage renal disease, renal impairment defined by an eGFR <60 ml/min/1.73 m(2)) did not statistically differ between groups, although there was a trend toward more renal impairment at follow-up in Class IV-G compared to IV-S and III. Finally, the presence of even mild chronic lesions on baseline biopsy was clearly predictive of late renal outcome.ConclusionSubsetting proliferative LN into Class III, IV-S and IV-G provides less clinically discriminant prognostic information than baseline chronicity index

Adjuvant system AS02V enhances humoral and cellular immune responses to pneumococcal protein PhtD vaccine in healthy young and older adults: Randomised, controlled trials.

The improved immune response to PhtD vaccine containing the AS02V adjuvant system in comparison to alum suggests that the reduced immune response to vaccines in older adults can be partially restored to the response level observed in young adults. ClinicalTrials.gov identifiers: NCT00307528/NCT01767402

Vaccine adjuvant systems containing monophosphoryl lipid A and QS21 induce strong and persistent humoral and T cell responses against hepatitis B surface antigen in healthy adult volunteers.

A randomised, double-blind study assessing the potential of four adjuvants in combination with recombinant hepatitis B surface antigen has been conducted to evaluate humoral and cell-mediated immune responses in healthy adults after three vaccine doses at months 0, 1 and 10. Three Adjuvant Systems (AS) contained 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21, formulated either with an oil-in-water emulsion (AS02B and AS02V) or with liposomes (AS01B). The fourth adjuvant was CpG oligonucleotide. High levels of antibodies were induced by all adjuvants, whereas cell-mediated immune responses, including cytolytic T cells and strong and persistent CD4(+) T cell response were mainly observed with the three MPL/QS21-containing Adjuvant Systems. The CD4(+) T cell response was characterised in vitro by vigorous lymphoproliferation, high IFN-gamma and moderate IL-5 production. Antigen-specific T cell immune response was further confirmed ex vivo by detection of IL-2- and IFN-gamma-producing CD4(+) T cells, and in vivo by measuring increased levels of IFN-gamma in the serum and delayed-type hypersensitivity (DTH) responses. The CpG adjuvanted vaccine induced consistently lower immune responses for all parameters. All vaccine adjuvants were shown to be safe with acceptable reactogenicity profiles. The majority of subjects reported local reactions at the injection site after vaccination while general reactions were recorded less frequently. No vaccine-related serious adverse event was reported. Importantly, no increase in markers of auto-immunity and allergy was detected over the whole study course. In conclusion, the Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be fundamental to develop effective prophylactic vaccines against complex pathogens, e.g. malaria, HIV infection and tuberculosis, and for special target populations such as subjects with an impaired immune response, due to age or medical conditions

A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein E subunit vaccine candidate in young and older adults

Background. An adjuvanted recombinant varicella zoster virus (VZV) subunit vaccine is being developed for the prevention of herpes zoster and its complications. Methods. In a phase I/II, open-label, randomized, parallel-group study, older adults (50-70 years) received 2 doses 2 months apart of an adjuvanted recombinant glycoprotein E vaccine (HZ/su; n = 45), a live attenuated Oka strain VZV vaccine (OKA; n = 45), or HZ/su and OKA administered concomitantly (n = 45). To evaluate safety prior to administration in older adults, young adults (18-30 years) were vaccinated with 2 doses 2 months apart of HZ/su (n = 10) or OKA (n = 10). Safety and immunogenicity were assessed up to 42 months for older adults immunized with HZ/su and up to 12 months for all others. Results. Few grade 3 events and no severe adverse events were reported. Fatigue, myalgia, headache, and injection site pain were the most common solicited reactions for HZ/su and occurred more frequently than with OKA. CD4(+) T-cell and humoral immune responses were much higher with HZ/su than with OKA and remained elevated until 42 months. Addition of OKA to HZ/su did not increase immunogenicity. Conclusions. In this study, HZ/su adjuvanted subunit vaccine was well tolerated and more immunogenic than a live attenuated VZV vaccine. Clinical Trial registration. NCT00492648 and NCT00492648