Evaluating the role of high-dose influenza vaccine in people with Down syndrome under age 65 - PROJECT SUMMARY/ABSTRACT The goal of this planning grant is to prepare for a clinical trial testing our hypothesis that high-dose influenza vaccine (Fluzone) safely improves vaccine response in people with Down syndrome (DS) < 65 years old. Our team of clinicians, scientists, and members of the DS community will work together to finalize clinical trial design, complete start up activities, and design the mechanistic and epidemiological studies needed to learn whether and how high-dose influenza vaccine is more effective than standard immunization. The planned clinical trial addresses an urgent public health need; people with DS are at increased risk of death from respiratory infections, exhibit advanced immune aging, and show an impaired response to influenza immunization compared to people without DS across all ages. High-dose influenza vaccine safely improves response in people without DS, providing a strong rationale for testing in DS. Importantly, it is already standard of care in people > 65 years of age. The proposed randomized-controlled clinical trial will compare safety and efficacy of high-dose to standard- dose influenza vaccine in 111 individuals with DS. The primary endpoint will be vaccine-specific hemagglutinin inhibition responses in serum at 2 weeks post-vaccination. Re-randomization within each arm in the second year will assess reproducibility and quantify any priming effect of high dose immunization. Our R34 Specific Aims are: 1: Develop a protocol and complete study start-up activities to prepare for a randomized-controlled clinical trial of high- vs. standard-dose influenza immunization in DS. Our partnership between the Benaroya Research Institute and Baylor College of Medicine brings expertise in DS clinical care, DS immunology, clinical trial design, vaccine studies, and experience enrolling diverse cohorts. Our team includes expertise in influenza assays and epidemiology, and in developing collaborative research activities with people with DS (co-researchers) and their families. Our team, including co-researchers, will: finalize protocol procedures, educational materials, and consent and assent documents; obtain regulatory approvals; prepare case report forms; and develop plans for data and safety monitoring, site training, and statistical analysis. 2: Finalize mechanistic approaches to complement the primary clinical trial. Embedded studies within the randomized trial are planned to provide deep mechanistic insights into molecular pathways involved in respiratory infections and response to vaccination, including a mechanistic pilot challenge with live attenuated influenza virus vaccine (LAIV). We will finalize sampling methods, timepoints, and assays during the R34 period. 3: Conduct descriptive epidemiology of flu vaccination and flu outcomes and plan our simulation study to complement the primary clinical trial. We have Medicaid and Medicare claims data for all adults with Down syndrome in the US from 2011-2022 (N>130,000). In the R34 phase we will describe demographic and formulation patterns in flu vaccine receipt, and flu-related hospitalization and mortality. We will plan a simulation study to model the impact of the high dose vaccine at the population, incorporating U01 trial outcomes.
