An mRNA Vaccine against SARS-CoV-2 - Preliminary Report Jackson, Lisa A; Anderson, Evan J; Rouphael, Nadine G ...
New England journal of medicine/The New England journal of medicine,
11/2020, Letnik:
383, Številka:
20
Journal Article
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate ...vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.
We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.
After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer GMT, 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).
Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and ...death from coronavirus disease 2019 (Covid-19) have been associated with an older age.
We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart.
Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells.
In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).
Solid-state electrolytes such as cubic Li6.25Al0.25La3Zr2O12 (LLZO) can enable solid-state batteries, metallic lithium anodes and higher voltage cathodes. However, the stability of cubic LLZO is ...affected by current density. In beta alumina solid electrolyte, microstructural failure was caused by Na dendrite penetration, and was shown to be a function of the fracture toughness, KIC. The relationship between dendrite penetration and KIC indicates electronic failure is related to creation of microstructural damage, and the microstructural damage may be used as an indicator of imminent electronic failure. To monitor microstructural damage during cycling, we developed a non-invasive, in-situ cell monitoring apparatus to help to correlate mechanical stability with Li-ion current density in LLZO. A pulse-echo transducer was integrated into all solid-state Li-LLZO-Li cells. The capability enables the characterization of microscopic inhomogeneities through the careful measurement of changes to the elastic moduli. The elastic moduli and fracture toughness have been previously reported for dense (>99%) specimens, but monitoring of the relative change in moduli during cycling has not been explored. In this study, an acoustic monitoring method is presented to monitor LLZO specimens during cycling.
•Dendrite penetration in solid state electrolytes causes short-circuiting.•Acoustic pulse-echo technique monitors changes in microstructural integrity in-situ.•Can observe dendrite propagation by reduction in stiffness.
Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing ...evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response.
Unique structural and optical properties of atomically thin two-dimensional semiconducting transition metal dichalcogenides enable in principle their efficient coupling to photonic cavities having ...the optical mode volume close to or below the diffraction limit. Recently, it has become possible to make all-dielectric nano-cavities with reduced mode volumes and negligible non-radiative losses. Here, we realise low-loss high-refractive-index dielectric gallium phosphide (GaP) nano-antennas with small mode volumes coupled to atomic mono- and bilayers of WSeFormula: see text. We observe a photoluminescence enhancement exceeding 10Formula: see text compared with WSeFormula: see text placed on planar GaP, and trace its origin to a combination of enhancement of the spontaneous emission rate, favourable modification of the photoluminescence directionality and enhanced optical excitation efficiency. A further effect of the coupling is observed in the photoluminescence polarisation dependence and in the Raman scattering signal enhancement exceeding 10Formula: see text. Our findings reveal dielectric nano-antennas as a promising platform for engineering light-matter coupling in two-dimensional semiconductors.
PO and PN have been newly identified in several oxygen-rich circumstellar envelopes, using the Submillimeter Telescope of the Arizona Radio Observatory. The J = 5 → 4 and J = 6 → 5 transitions of PN ...near 235 and 282 GHz, and the lambda doublets originating in the J = 5.5 → 4.5 and J = 6.5 → 5.5 lines of PO at 240 and 284 GHz, have been detected toward the shells of asymptotic giant branch (AGB) stars TX Cam and R Cas. A similar set of lines has been observed toward the supergiant NML Cyg, and new transitions of these two molecules were also measured toward the AGB star IK Tau. Along with the previous data from VY Canis Majoris (VY CMa), these spectral lines were analyzed using the non-local thermodynamic equilibrium (non-LTE) circumstellar modeling code, ESCAPADE. For the AGB stars, peak abundances found for PN and PO were f ∼ (1-2) × 10−8 and (0.5-1) × 10−7, respectively, while those for the supergiants were f(PN) ∼ (0.3-0.7) × 10−8 and f(PO) ∼ (5-7) × 10−8. PN was well modeled with a spherical radial distribution, suggesting formation near the stellar photosphere, perhaps enhanced by shocks. PO was best reproduced by a shell model, indicating a photochemical origin, except for VY CMa. Overall, the abundance of PO is a factor of 5-20 greater than that of PN. This study suggests that phosphorus-bearing molecules are common in O-rich envelopes, and that a significant amount of phosphorus (>20%) remains in the gas phase.
We invert for the time‐dependent slip history of slow slip events on the Cascadia subduction zone using GPS data from 1998 to 2008. The 16 slip transients have sufficient station coverage to solve ...for the slip distribution on the plate interface. GPS time series are inverted for fault slip using the Extended Network Inversion Filter. Limited station coverage south of Portland (45.5°N latitude) restricts our analysis to events on the northern half of the subduction zone. Slip is resolved at the base of the seismogenic zone and the slip distributions suggest a potential segment boundary near Seattle (47.6°N) that correlates roughly with geologic and tectonic boundaries. Events that initiate to the north and south tend to overlap at about this latitude. We compile statistics on source parameters, such as propagation rate, recurrence interval, and stress drop, which can be used to constrain proposed models of the source mechanics. Over a 10 year period, total strain release from slow slip events is nonuniform along strike with the greatest cumulative slip (27 cm) centered beneath Port Angeles (48.1°N). This slip patch also exhibits the most regular recurrence of Mw ∼6 events relative to other locations along strike. The spatial extent of the slip patch beneath Port Angeles correlates with the along‐strike bend of the Cascadia subduction zone in northwestern Washington, suggesting that plate geometry plays an important role in controlling the along‐strike characteristics of slow slip.
Slow slip and tectonic tremor in subduction zones take place at depths where there is abundant evidence for distributed shear over broad zones (∼10–103 m) composed of rocks with marked differences in ...mechanical properties. Here we model quasi‐dynamic rupture along faults composed of material mixtures characterized by different rate‐and‐state‐dependent frictional properties to determine the parameter regime capable of producing slow slip in an idealized subduction zone setting. Keeping other parameters fixed, the relative proportions of velocity‐weakening (VW) and velocity‐strengthening (VS) materials control the sliding character (stable, slow, or dynamic) along the fault. The stability boundary between slow and dynamic is accurately described by linear analysis of a double spring‐slider system with VW and VS blocks. Our results place bounds on the volume fractions of VW material present in heterogeneous geological assemblages that host slow slip and tremor in subduction zones.
Key Points
Aseismic slip is produced by a balance between frictional heterogeneities
Varying the abundance of heterogeneities produces stable, slow, or fast sliding
Model stability is well described by a double spring‐slider system
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