Evaluation of Raxtozinameran Vaccination in Children with Elevated Genetic Risk for Type 1 Diabetes: Impact on Islet Autoantibody Incidence

The primary objective of this study is to evaluate whether **vaccination** of children with an elevated genetic risk for **Type 1 Diabetes** against COVID-19, starting from 6 months of age, reduces the cumulative incidence of islet autoantibodies or Type 1 Diabetes during childhood. This is clinically relevant as it explores the potential of COVID-19 vaccination to mitigate the onset of autoimmune conditions in genetically predisposed children, potentially altering the disease trajectory and improving long-term health outcomes.

Secondary objectives include:

• Determining whether COVID-19 vaccination similarly reduces the cumulative incidence of multiple islet autoantibodies in childhood.
• Assessing whether the vaccination reduces the cumulative incidence of Type 1 Diabetes in childhood.
• Evaluating whether the vaccination reduces the cumulative incidence of celiac disease-associated transglutaminase autoantibodies in childhood.

The clinical trial involves a total of **267 participants** who are children aged between 3 and 4 months at the time of enrollment. The study population includes both **male and female** subjects, with a focus on those with a high genetic risk (>10%) of developing islet autoantibodies by age 6 years, as determined by a specific HLA DR/DQ genotype, polygenic risk score, and first-degree family history of type 1 diabetes. Participants are required to have written informed consent signed by their custodial parent(s). The trial aims to assess whether vaccination against COVID-19 from 6 months of age can reduce the cumulative incidence of islet autoantibodies or type 1 diabetes in childhood. The trial population was selected based on these criteria, and it includes a **vulnerable population** due to the young age of the participants. No specific lifestyle considerations such as diet or physical activity are mentioned for this study.

The clinical trial is designed to evaluate the efficacy of a **COVID-19 mRNA vaccine** in reducing the incidence of islet autoantibodies or type 1 diabetes in children with a high genetic risk. This is a randomized, double-blind, controlled trial involving the administration of the Comirnaty Omicron XBB.1.5 vaccine, with a placebo group receiving a 0.9% sodium chloride solution. The trial is set to commence in April 2024 and is expected to conclude by October 2029, with a maximum treatment period of 14 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age between 3 and 4 months, a high genetic risk for developing islet autoantibodies, and signed informed consent from custodial parents. Following randomization, participants will receive either the vaccine or placebo via injection. The primary endpoint is the time to development of persistent confirmed islet autoantibodies or type 1 diabetes, while secondary endpoints include the time to development of multiple islet autoantibodies or transglutaminase autoantibodies.

Follow-up visits will be scheduled to monitor the participants' health and collect data on the development of autoantibodies or type 1 diabetes. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last until the trial's end date unless early termination is warranted. Conditions for early termination include adverse reactions or withdrawal of consent. The trial's design ensures rigorous assessment of the vaccine's impact on the targeted pediatric population, contributing valuable insights into preventive strategies for type 1 diabetes.

The clinical trial involves the administration of **Comirnaty Omicron XBB.1.5**, a COVID-19 mRNA vaccine (nucleoside modified), which is formulated as a **concentrate for dispersion for injection**. The active substance in this vaccine is **raxtozinameran**, a nucleic acid-based compound. The vaccine is administered via injection, with a dosage of 3 micrograms per dose. The maximum daily dose is 3 micrograms, and the total dose over the treatment period is capped at 9 micrograms. The treatment period extends up to 14 days. The vaccine is manufactured by BioNTech Manufacturing GmbH and is authorized under the marketing authorization number EU/1/20/1528/024. The vaccine is not a pediatric formulation and is not classified as an orphan drug.

In addition to the experimental vaccine, the study utilizes a **0.9% Sodium Chloride solution for injection (saline)** as a non-experimental treatment. This saline solution serves as a placebo in the trial. The pharmaceutical form and active substance details for the saline solution are not specified. The saline is used to maintain the blinding of the study and ensure that participants and investigators are unaware of the treatment allocation. The administration route and dosing schedule for the saline solution are not detailed in the provided data.

Efficacy in this clinical trial will be assessed through the measurement of specific endpoints related to the development of **type 1 diabetes** and associated autoantibodies. The primary efficacy outcome is defined as the elapsed time from random treatment assignment to the development of persistent confirmed islet autoantibodies or type 1 diabetes. Secondary endpoints include the elapsed time to the development of persistent confirmed multiple islet autoantibodies, the onset of type 1 diabetes, and the emergence of persistent confirmed transglutaminase autoantibodies.

The trial aims to determine whether vaccination of children with elevated genetic risk for type 1 diabetes against COVID-19 from 6 months of age can reduce the cumulative incidence of islet autoantibodies or type 1 diabetes during childhood. The efficacy parameters will be collected and analyzed over the course of the trial, with specific timepoints for assessment not explicitly detailed in the provided data. The trial is expected to conclude by October 2029, with recruitment starting in April 2024.