SHIELD-T1D: Shingrix and GLP-1 Agonist for Beta-Cell Preservation in Recent-Onset Type 1 Diabetes. (SHIELD-T1D)

The immune pathogenesis of T1D involves a failure of central and peripheral immune tolerance, with autoreactive CD4+ and CD8+ T cells targeting beta-cell autoantigens including GAD65, IA-2, and ZnT8. The window between seroconversion and overt hyperglycemia - and particularly the honeymoon phase immediately following diagnosis - represents an optimal period for immune intervention while sufficient beta-cell mass persists.

The Recombinant Zoster Vaccine (RZV; Shingrix) contains the AS01B adjuvant system (MPL + QS-21 in a liposomal formulation), which potently activates plasmacytoid dendritic cells and promotes generation of antigen-specific and bystander Tregs. Preclinical and clinical evidence from autoimmune contexts suggests AS01B may recalibrate the Th1/Treg balance relevant to T1D pathology. Critically, RZV is already FDA-approved with an established safety profile, enabling accelerated clinical translation.

GLP-1 receptor agonists (GLP-1 RAs), including semaglutide, exert pleiotropic beta-cell protective effects beyond glucose lowering: they enhance beta-cell proliferation, reduce endoplasmic reticulum stress, inhibit cytokine-induced apoptosis (IL-1β, TNF-α, IFN-γ), and may modulate macrophage and T-cell activation states. Emerging data suggest GLP-1 RAs reduce insulitis markers in NOD mouse models and improve C-peptide preservation in early T1D.

The combination strategy employed in SHIELD-T1D leverages complementary mechanisms: immune re-education (Shingrix/AS01B) to reduce autoimmune attack while providing metabolic rescue and direct cytoprotection (semaglutide) to maximize survival of existing beta cells.

4.2.2 Study Population and Setting The study will recruit adults aged 18-50 years with recent-onset T1D (diagnosed within 100 days per ADA criteria) from tertiary diabetes referral centers and academic medical centers. Multi-center enrollment across a minimum of three geographically diverse sites is planned to ensure population representativeness and adequate recruitment velocity.

4.2.3 Intervention Strategy Shingrix (RZV) will be administered intramuscularly (0.5 mL per dose) at Months 0 and 2. Semaglutide (Ozempic®, Novo Nordisk) will be administered subcutaneously once weekly, with a 4-week dose escalation from 0.25 mg/week to 0.5 mg/week, maintained for the 24-month treatment period. Matching placebos (saline injection for RZV; identical-volume subcutaneous saline for semaglutide) will be used for blinded arms. All participants receive standard-of-care insulin therapy throughout the study.

4.2.4 Immunological Mechanistic Sub-studies Longitudinal immunophenotyping using high-dimensional flow cytometry will characterize peripheral blood Tregs (CD4+CD25+FOXP3+), effector memory T cells, and antigen-specific responses to GAD65 and IA-2 at baseline, 6, 12, and 24 months. Multiplex cytokine panels (IL-2, IL-6, IL-10, IL-17A, IL-21, TNF-α, IFN-γ, TGF-β) will assess the systemic immunological milieu. These data will provide mechanistic validation and identify predictive biomarkers of treatment response.

Adults aged 18-50 years with a diagnosis of type 1 diabetes within the preceding 100 days, at least one diabetes-associated autoantibody (GAD65, IA-2, or ZnT8), and residual beta-cell function (stimulated C-peptide ≥ 0.2 nmol/L during a mixed-meal tolerance test [MMTT]) will be enrolled. After screening and confirmation of eligibility, participants will be randomized in a 1:1:1:1 ratio to receive: (1) Shingrix plus GLP-1 placebo, (2) GLP-1 receptor agonist plus Shingrix placebo, (3) Shingrix plus GLP-1 receptor agonist, or (4) double placebo.

Shingrix will be administered as two 0.5 mL intramuscular doses given two months apart (months 0 and 2) according to the standard schedule used for prevention of herpes zoster. The GLP-1 receptor agonist (e.g., once-weekly semaglutide) will be administered subcutaneously using a titration regimen consistent with the approved dosing schedule for adults, with matching placebo injections in the control arms. All participants will receive optimized intensive insulin therapy and standardized diabetes education.

Participants will be followed for 24 months after randomization. Study visits during the first 6 months will occur monthly to monitor safety, glycemic control, adherence, and study drug administration. Subsequently, visits will occur at least every 3 months through month 24. Key efficacy assessments will include serial MMTTs at baseline and predefined follow-up visits (e.g., months 6, 12, 18, and 24) to quantify stimulated C-peptide area under the curve (AUC), HbA1c, and insulin dose requirements. Immunologic assessments (e.g., T-regulatory cell frequency, multifunctional CD4+ T cell profiles, and cytokine signatures) will be performed on stored peripheral blood mononuclear cells at baseline and selected follow-up timepoints.

The primary hypothesis is that combination therapy with Shingrix plus GLP-1 receptor agonist will result in superior preservation of beta-cell function, as measured by 2-hour MMTT-stimulated C-peptide AUC at 12 months, compared with placebo. Secondary hypotheses include improved glycemic control, lower total daily insulin dose, and favorable immunologic modulation with acceptable safety and tolerability in all active treatment arms versus placebo.