Optimization of an LNP-mRNA vaccine candidate targeting SARS-CoV-2 receptor-binding domain

In 2020, two mRNA-based vaccines, encoding the full length of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, have been introduced for control of the coronavirus disease (COVID-19) pandemic1,2. However, reactogenicity, such as fever, caused by innate immune responses to the vaccine formulation remains to be improved. Here, we optimized a lipid nanoparticle (LNP)-based mRNA vaccine candidate, encoding the SARS-CoV-2 spike protein receptor-binding domain (LNP-mRNA-RBD), which showed improved immunogenicity by removing reactogenic materials from the vaccine formulation and protective potential against SARS-CoV-2 infection in cynomolgus macaques. LNP-mRNA-RBD induced robust antigen-specific B cells and follicular helper T cells in the BALB/c strain but not in the C57BL/6 strain; the two strains have contrasting abilities to induce type I interferon production by dendritic cells. Removal of reactogenic materials from original synthesized mRNA by HPLC reduced type I interferon (IFN) production by dendritic cells, which improved immunogenicity. Immunization of cynomolgus macaques with an LNP encapsulating HPLC-purified mRNA induced robust anti-RBD IgG in the plasma and in various mucosal areas, including airways, thereby conferring protection against SARS-CoV-2 infection. Therefore, fine-tuning the balance between the immunogenic and reactogenic activity of mRNA-based vaccine formulations may offer safer and more efficacious outcomes.

Ultra-rapid high-density mapping system with the phase singularity technique is feasible in identifying rotors and focal sources and predicting AF termination.

INTRODUCTION: Phase singularity (PS) mapping provides additional insight into the AF mechanism and is accurate in identifying rotors. The study aimed to evaluate the feasibility of PS mapping in identifying AF rotors using data obtained from an automatic ultra-rapid high-resolution mapping system with a high-density mini-basket catheter. METHODS: Twenty-three pigs underwent rapid right atrial (RA) pacing (RAP 480 bpm) for 5 weeks before the experiment. During AF, RA endocardial automatic continuous mappings with a mini-basket catheter were generated using an automatic ultra-rapid mapping system. Both fractionation mapping and waveform similarity measurements using a PS mapping algorithm were applied on the same recording signals to localize substrates maintaining AF. RESULTS: Seventeen (74%) pigs developed sustained AF after RAP. Three were excluded because of periprocedural ventricular arrhythmia and corrupted digital data. RA fractionation maps were acquired with 6.17 ± 4.29 minutes mean acquisition time, 13768 ± 12698 acquisition points mapped during AF from 581 ± 387 beats. Fractionation mapping identified extensively distributed (66.7%) RA complex fractionated atrial electrogram (CFAE), whereas the nonlinear analysis identified high similarity index (SI > 0.7) parts in limited areas (23.7%). There was an average of 1.67 ± 0.87 SI sites with 0.43 ± 0.76 rotor/focal source/chamber. AF termination occurred in 11/16 (68.75%) AF events in 14 pigs during ablation targeting max CFAE. There was a higher incidence of rotor/focal source at AF termination sites compared with non-AF termination sites (54.5% vs 0%, P = 0.011). CONCLUSIONS: The data obtained from ultra-rapid high-density automatic mapping is feasible and effective in identifying AF rotors/focal sources using PS technique, and those critical substrates were closely related to AF procedural termination.

Ambient fine particulate matter (PM2.5) exposure is associated with idiopathic ventricular premature complexes burden: A cohort study with consecutive Holter recordings.

BACKGROUND: Epidemiological evidence has shown an association between ambient fine particulate matter (PM2.5) exposure and cardiovascular mortality. Increased ventricular premature complex (VPC) burden can cause left ventricular dilatation and dysfunction. We aimed to investigate the relationship between acute PM2.5 exposure and VPC burden in patients without structural heart disease. METHODS: We reviewed 26 820 patients who underwent 24-hour Holter electrocardiogram (ECG) recordings between 1 Jan 2013 and 1 Dec 2016. We enrolled patients with significant idiopathic (structurally normal heart) VPC burden defined as ≥30 VPCs/h (Lown grade 2) who had at least two Holter ECG recordings. The VPC burden between the studies on high and low PM2.5 exposure dates was compared in 24 and 12 hours time periods. RESULT: Sixty-seven patients (31 men, 56.49 ± 18.35 years) were enrolled. Patients were exposed to 25.63 ± 11.47 and 14.66 ± 7.51 µg/m 3 of PM2.5 during the high and low study dates, respectively. The overall VPC counts (10,490.69 ± 10,681.63/day) and burden (10.22% ± 10.17%) were significantly higher on the days with higher PM2.5 exposure compared with low PM2.5 exposure dates (8293.31 ± 9009.09; P = 0.014% and 9.14% ± 12.73%, P = 0.012, respectively). Compared with low PM2.5 exposure dates, the VPC burden on high exposure dates was significantly higher from 9 am to 9 pm (5.85% ± 6.41% vs 4.84% ± 6.97%; P = 0.025) but not at nocturnal periods. CONCLUSION: Our study demonstrated a significantly higher VPC burden on high PM2.5 exposure date. The burden was increased in the daytime but not at nighttime. This result suggests that daytime PM2.5 exposure may be associated with ventricular arrhythmia burden in the healthy population.

The Accuracy and Clinical Applicability of a Sensor Based Electromagnetic Non-fluoroscopic Catheter Tracking System

BACKGROUND AND OBJECTIVES@#The differences between electromagnetic-based mapping (EM) and impedance-based mapping (IM) in 3D anatomical reconstruction have not been fully clarified. We aimed to investigate the anatomical accuracy between EM (MediGuide™) and IM (EnSite Velocity™) systems.@*METHODS@#We investigated 15 consecutive patients (10 males, mean age 58±9 years) who underwent pulmonary veins (PVs) isolation for paroxysmal atrial fibrillation (PAF). Contrast-enhanced computed tomography (CT) image of the left atrium (LA) was acquired before ablation and the 3D geometry of the LA was constructed using EM during ablation procedure. We measured the 4 PV angles between the main trunk of each PV and the posterior LA after field scaling. Additionally, the posterior LA surface area was measured. The variables were compared to those of CT-based geometry. A control group of 40 patients who underwent conventional PVs isolation using IM were also evaluated.@*RESULTS@#The actual and relative changes of EM and CT-based geometry in all PV angles and posterior LA were significantly smaller compared to those of IM and CT-based geometry. Intraclass correlation coefficient (ICC) between EM and CT-based geometry were 0.871 (right superior pulmonary vein [RSPV]), 0.887 (right inferior pulmonary vein [RIPV]), 0.853 (left superior pulmonary vein [LSPV]), 0.911 (left inferior pulmonary vein [LIPV]), and 0.833 (posterior LA). On the other hand, ICC between IM and CT-based geometry were 0.548 (RSPV), 0.639 (RIPV), 0.691 (LSPV), 0.706 (LIPV), and 0.568 (posterior LA).@*CONCLUSIONS@#Image integration with EM enables high accurate visualization of cardiac anatomy compared to IM in PAF ablation.

The Accuracy and Clinical Applicability of a Sensor Based Electromagnetic Non-fluoroscopic Catheter Tracking System

BACKGROUND AND OBJECTIVES: The differences between electromagnetic-based mapping (EM) and impedance-based mapping (IM) in 3D anatomical reconstruction have not been fully clarified. We aimed to investigate the anatomical accuracy between EM (MediGuide™) and IM (EnSite Velocity™) systems. METHODS: We investigated 15 consecutive patients (10 males, mean age 58±9 years) who underwent pulmonary veins (PVs) isolation for paroxysmal atrial fibrillation (PAF). Contrast-enhanced computed tomography (CT) image of the left atrium (LA) was acquired before ablation and the 3D geometry of the LA was constructed using EM during ablation procedure. We measured the 4 PV angles between the main trunk of each PV and the posterior LA after field scaling. Additionally, the posterior LA surface area was measured. The variables were compared to those of CT-based geometry. A control group of 40 patients who underwent conventional PVs isolation using IM were also evaluated. RESULTS: The actual and relative changes of EM and CT-based geometry in all PV angles and posterior LA were significantly smaller compared to those of IM and CT-based geometry. Intraclass correlation coefficient (ICC) between EM and CT-based geometry were 0.871 (right superior pulmonary vein [RSPV]), 0.887 (right inferior pulmonary vein [RIPV]), 0.853 (left superior pulmonary vein [LSPV]), 0.911 (left inferior pulmonary vein [LIPV]), and 0.833 (posterior LA). On the other hand, ICC between IM and CT-based geometry were 0.548 (RSPV), 0.639 (RIPV), 0.691 (LSPV), 0.706 (LIPV), and 0.568 (posterior LA). CONCLUSIONS: Image integration with EM enables high accurate visualization of cardiac anatomy compared to IM in PAF ablation.