Cardiac delivery of modified mRNA using lipid nanoparticles: Cellular targets and biodistribution after intramyocardial administration.

Despite research efforts being made towards preserving (or even regenerating) heart tissue after an ischemic event, there is a lack of resources in current clinical treatment modalities for patients with acute myocardial infarction that specifically address cardiac tissue impairment. Modified messenger RNA (modRNA) presents compelling properties that could allow new therapeutic strategies to tackle the underlying molecular pathways that ultimately lead to development of chronic heart failure. However, clinical application of modRNA for the heart is challenged by the lack of effective and safe delivery systems. Lipid nanoparticles (LNPs) represent a well characterized class of RNA delivery systems, which were recently approved for clinical usage in mRNA-based COVID-19 vaccines. In this study, we evaluated the potential of LNPs for cardiac delivery of modRNA. We tested how variations in C12-200 modRNA-LNP composition affect transfection levels and biodistribution after intramyocardial administration in both healthy and myocardial-infarcted mice, and determined the targeted cardiac cell types. Our data revealed that LNP-mediated modRNA delivery outperforms the current state of the art (modRNA in citrate buffer) upon intramyocardial administration in mice, with only minor differences among the formulations tested. Furthermore, we determined both in vitro and in vivo that the cardiac cells targeted by modRNA-LNPs include fibroblasts, endothelial cells and epicardial cells, suggesting that these cell types could represent targets for therapeutic interference with these LNP formulations. These outcomes may serve as a starting point for LNP development specifically for therapeutic mRNA cardiac delivery applications.

Antibodies to Haemophilus influenzae serotype b in the Netherlands a few years after the introduction of routine vaccination.

We assessed antibodies to the capsular polysaccharide of Haemophilus influenzae type b (HibPS) in the Dutch population a few years after a mass vaccination against H. influenzae (Hib) was begun. We observed sharp declines in the geometric mean titer (GMT) and the prevalence of HibPS antibodies at levels of < or =0.15 microg/mL in children who had received 4 doses of vaccine: from 8.65 microg/mL (prevalence, 99.4%) after 0-2 months to 0.8 microg/mL (prevalence, 83.3%) after 27-29 months. In adult groups, both the prevalence of HibPS antibodies and the GMT declined significantly with increasing age but remained high (prevalence, > or =83.7%; GMT, 0.73 > or = microg/mL). We conclude that the overall immunity in the Dutch population seems satisfactory. We draw our conclusions from the current serosurveillance study and from the sharp decline in invasive Hib disease noted after the introduction of vaccination. The key questions for the future are (1) whether Hib and cross-reacting organisms will circulate sufficiently to provide natural reexposure, and (2) how long memory immunity will persist after vaccination without reexposure.