Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive destruction of pancreatic beta cells mediated by autoreactive T lymphocytes, resulting in absolute insulin deficiency. Preservation of residual beta-cell function at the time of diagnosis is a critical therapeutic window, as even marginal endogenous insulin secretion - reflected by detectable C-peptide levels - is associated with improved glycemic control, reduced hypoglycemia burden, and decreased long-term vascular complication rates.

This study evaluates the hypothesis that combinatorial immunomodulation - using the AS01B adjuvant system within the Recombinant Zoster Vaccine (RZV; Shingrix, GSK) alongside metabolic and cytoprotective support via a GLP-1 receptor agonist (semaglutide) - can synergistically preserve residual beta-cell function in adults within 100 days of T1D diagnosis. The AS01B adjuvant system activates innate immune pathways that promote regulatory T-cell (Treg) expansion and shift the immunological milieu toward tolerance, while GLP-1 receptor agonism provides direct beta-cell cytoprotection, reduces glucotoxicity, and may suppress autoimmune cytokine signaling.

SHIELD-T1D is a randomized, double-blind, placebo-controlled, parallel-group Phase II clinical trial enrolling 240 adults (18-50 years) diagnosed with T1D within 100 days, with confirmed residual beta-cell function (stimulated C-peptide ≥0.2 nmol/L). Participants are randomized 1:1:1:1 to one of four arms: (1) Shingrix alone, (2) Semaglutide alone, (3) Shingrix + Semaglutide combination, or (4) dual placebo. The primary endpoint is change in 2-hour stimulated C-peptide AUC during a Mixed Meal Tolerance Test (MMTT) from baseline to 12 months.

This phase II randomized, double-blind, placebo-controlled multicenter trial will evaluate the efficacy and safety of the recombinant zoster vaccine (Shingrix) and a glucagon-like peptide-1 (GLP-1) receptor agonist, alone and in combination, for preservation of residual beta-cell function in adults with recent-onset type 1 diabetes. The working hypothesis is that combining AS01 adjuvant-mediated immunomodulation with the metabolic and cytoprotective actions of a GLP-1 receptor agonist will provide dual protection for pancreatic beta cells, slowing autoimmune destruction and improving functional insulin secretion compared with placebo.

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.

Inclusion Criteria:

1. Diagnosis of Type 1 Diabetes (T1D) according to American Diabetes Association (ADA) criteria.
2. Age 18 to 50 years (inclusive) at the time of screening.
3. Randomization within 100 days of the first insulin injection.
4. Confirmed residual beta-cell function, defined as a peak stimulated C-peptide level ≥0.2 nmol/L during a Mixed Meal Tolerance Test (MMTT) performed at screening.
5. Presence of at least one T1D-related autoantibody (GADA, IA-2A, ZnT8A, or ICA).
6. Willingness to comply with intensive insulin therapy and glucose monitoring.
7. Females of childbearing potential must have a negative pregnancy test and agree to use highly effective contraception.

Exclusion Criteria:

1. History of diabetic ketoacidosis (DKA) within 4 weeks of screening.
2. Prior use of any immunotherapy or investigational agents for T1D.
3. Current or prior use of GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT2 inhibitors.
4. History of pancreatitis or medullary thyroid carcinoma.
5. Active or chronic infection (e.g., HIV, Hepatitis B or C, Tuberculosis).
6. Pregnancy or breastfeeding.
7. Significant renal, hepatic, or cardiovascular disease.
8. History of severe allergic reaction to any component of the Recombinant Zoster Vaccine (Shingrix) or semaglutide.
9. Current use of systemic corticosteroids or other immunosuppressive medications.

Placebo injections will be identical in volume, appearance, and administration route. Randomization codes will be held by an independent unblinded pharmacist. Emergency unblinding procedures are available via a 24-hour DSMB-approved unblinding protocol