Effects of Age on Lipid Nanoparticle Delivery and mRNA Vaccination

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PROJECT ABSTRACT The goal of this research is to study the influence of age on the delivery processes required for lipid nanoparticle-mediated mRNA vaccination, with a long-term goal of improving vaccination outcomes in the elderly. In the next thirty years, our elderly population will double, exceeding 1.6 billion people worldwide. Unfortunately, a declining immune system makes elderly people susceptible to an array of deadly infectious diseases, placing additional burdens on global healthcare, particularly during epidemics and pandemics such as Ebola and SARS-CoV-2. There is a real need for effective prophylactics that protect vulnerable populations. Messenger RNA (mRNA) has emerged as a revolutionary platform that has catalyzed the fastest development of vaccines in history and bolstered the fight against SARS-CoV-2. However, early data suggest that these vaccines elicit an age-dependent immune response. The diminished antibody response of these vaccines in the elderly can substantially curtail their duration of protection. There is an urgent need to understand mRNA delivery as a function of age and develop potent and safe vaccines that can protect people across all age groups. While other researchers are examining age-related immune system impairment, this research is unique because it will determine age-related effects on the lipid nanoparticle (LNP) mRNA delivery process. This will enable the decoupling of impaired delivery and diminished immune responses on mRNA vaccination in the elderly. I am well-poised to conduct this research, given my preliminary data and the expertise of the Whitehead and Weissman labs with LNP delivery, immunology, and vaccinology. Although measuring post-vaccination infection rates and antibody titers as a function of age is important, these endpoints do not capture the effect of age on critical intermediate steps during mRNA vaccination. I hypothesize that differences in delivery contribute to reductions in mRNA-induced immunity. To test this hypothesis, I will determine to what extent age affects lipid nanoparticle mRNA delivery endpoints (Aim 1) and immune responses (Aim 2), allowing the two to be decoupled. In Aim 1, I will determine the efficacy, biodistribution, targeted cell population, immunogenicity, and toxicity of five top-performing lipid nanoparticles following intramuscular injection in young and old mice of both sexes. In Aim 2, I will elucidate the impact of age on the immune response of mRNA-LNPs. From Aim 2.1, we will select a top-performing LNP to investigate further in a vaccine kinetics study (Aim 2.2). Aims 1 and 2 combined will reveal LNP structures that confer the most robust immune response in young and old mice and aid the development of more efficacious mRNA vaccines for the elderly. This work is innovative because we will study how age impacts the process of nanoparticle delivery, which has not been conducted comprehensively for mRNA-LNPs. In the long term, our discoveries will have clinical significance because they will help tailor the design of LNP delivery systems for the elderly.