Immunogenicity and reactogenicity of intradermal mRNA-1273 SARS-CoV-2 vaccination: a non-inferiority, randomized-controlled trial

Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naive persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naive participants, aged 18-30 years, were randomized (1:1:1) to receive either two doses of 20 mu g mRNA-1273 ID with a standard needle (SN) or the Bella-mu (R) needle (BM), or two doses of 100 mu g IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at -15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488-2150) in the IM and 1263 (951-1676) and 1295 (1020-1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was -13.95% (-24.31 to -3.60) for the ID-SN and -13.04% (-22.78 to -3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease.Host-parasite interactio

Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2-specific CD8(+) T cell responses following COVID-19

Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates(1-6). Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c(+) natural killer (NK) cells and CD4(+) T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38(+)PD1(+)CD4(+) T effector (T-eff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127(+) granulocytes and CD38(+)CD8(+) tissue-resident memory T cells (T-RM). SARS-CoV-2-specific CD8(+) T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Design, upgrade and characterization of the silicon photomultiplier front-end for the AMIGA detector at the Pierre Auger Observatory

AMIGA (Auger Muons and Infill for the Ground Array) is an upgrade of the Pierre Auger Observatory to complement the study of ultra-high-energy cosmic rays (UHECR) by measuring the muon content of extensive air showers (EAS). It consists of an array of 61 water Cherenkov detectors on a denser spacing in combination with underground scintillation detectors used for muon density measurement. Each detector is composed of three scintillation modules, with 10 m$^2$ detection area per module, buried at 2.3 m depth, resulting in a total detection area of 30 m$^2$. Silicon photomultiplier sensors (SiPM) measure the amount of scintillation light generated by charged particles traversing the modules. In this paper, the design of the front-end electronics to process the signals of those SiPMs and test results from the laboratory and from the Pierre Auger Observatory are described. Compared to our previous prototype, the new electronics shows a higher performance, higher efficiency and lower power consumption, and it has a new acquisition system with increased dynamic range that allows measurements closer to the shower core. The new acquisition system is based on the measurement of the total charge signal that the muonic component of the cosmic ray shower generates in the detector.Comment: 40 pages, 33 figure

Direct measurement of the muonic content of extensive air showers between 2×1017\mathbf { 2\times 10^{17}} and 2×1018 \mathbf {2\times 10^{18}}~eV at the Pierre Auger Observatory

The hybrid design of the Pierre Auger Observatory allows for the measurement of the properties of extensive air showers initiated by ultra-high energy cosmic rays with unprecedented precision. By using an array of prototype underground muon detectors, we have performed the first direct measurement, by the Auger Collaboration, of the muon content of air showers between 2×10$^{17}$ and 2×10$^{18}$ eV. We have studied the energy evolution of the attenuation-corrected muon density, and compared it to predictions from air shower simulations. The observed densities are found to be larger than those predicted by models. We quantify this discrepancy by combining the measurements from the muon detector with those from the Auger fluorescence detector at 10$^{17.5}$eV and 10$^{18}$eV. We find that, for the models to explain the data, an increase in the muon density of 38% ±4%(12%) ± (21%)¦(18%) for EPOS-LHC, and of 50%(53%) ±4%(13%) ± (23%)¦(20%) for QGSJetII-04, is respectively needed

Status and performance of the underground muon detector of the Pierre Auger Observatory

The Auger Muons and Infill for the Ground Array (AMIGA) is an enhancement of the Pierre Auger Observatory, whose purpose is to lower the energy threshold of the observatory down to 1016.5 eV, and to measure the muonic content of air showers directly. These measurements will significantly contribute to the determination of primary particle masses in the range between the second knee and the ankle, to the study of hadronic interaction models with air showers, and, in turn, to the understanding of the muon puzzle. The underground muon detector of AMIGA is concomitant to two triangular grids of water-Cherenkov stations with spacings of 433 and 750 m; each grid position is equipped with a 30 m2 plastic scintillator buried at 2.3 m depth. After the engineering array completion in early 2018 and general improvements to the design, the production phase commenced. In this work, we report on the status of the underground muon detector, the progress of its deployment, and the performance achieved after two years of operation. The detector construction is foreseen to finish by mid-2022

A combined fit of energy spectrum, shower depth distribution and arrival directions to constrain astrophysical models of UHECR sources

The combined fit of the measured energy spectrum and distribution of depths of shower maximum of ultra-high-energy cosmic rays is known to constrain the parameters of astrophysical scenarios with homogeneous source distributions. Further measurements show that the cosmic-ray arrival directions agree better with the directions and fluxes of catalogs of starburst galaxies and active galactic nuclei than with isotropy. Here, we present a novel combination of both analyses. For that, a three-dimensional universe model containing a nearby source population and a homogeneous background source distribution is built, and its parameters are adapted using a combined fit of the energy spectrum, depth of shower maximum distribution and energy-dependent arrival directions. The model takes into account a symmetric magnetic field blurring, source evolution and interactions during propagation. We use simulated data, which resemble measurements of the Pierre Auger Observatory, to evaluate the method’s sensitivity. With this, we are able to verify that the source parameters as well as the fraction of events from the nearby source population and the size of the magnetic field blurring are determined correctly, and that the data is described by the fitted model including the catalog sources with their respective fluxes and three-dimensional positions. We demonstrate that by combining all three measurements we reach the sensitivity necessary to discriminate between the catalogs of starburst galaxies and active galactic nuclei

Measurement of the cosmic-ray energy spectrum above 2.5 x 10(18) eV using the Pierre Auger Observatory

We report a measurement of the energy spectrum of cosmic rays for energies above 2.5×10$^{18}$ eV based on 215,030 events recorded with zenith angles below 60°. A key feature of the work is that the estimates of the energies are independent of assumptions about the unknown hadronic physics or of the primary mass composition. The measurement is the most precise made hitherto with the accumulated exposure being so large that the measurements of the flux are dominated by systematic uncertainties except at energies above 5×10$^{19}$ eV. The principal conclusions are (1) The flattening of the spectrum near 5×10$^{18}$ eV, the so-called “ankle,” is confirmed. (2) The steepening of the spectrum at around 5×10$^{Z19}$ eV is confirmed. (3) A new feature has been identified in the spectrum: in the region above the ankle the spectral index γ of the particle flux (∝E$^{−γ }$) changes from 2.51±0.03 (stat)±0.05 (syst) to 3.05±0.05 (stat)±0.10 (syst) before changing sharply to 5.1±0.3 (stat)±0.1 (syst) above 5×10$^{19}$ eV. (4) No evidence for any dependence of the spectrum on declination has been found other than a mild excess from the Southern Hemisphere that is consistent with the anisotropy observed above 8×10$^{18}$ eV

Performance of the 433 m surface array of the Pierre Auger Observatory

The Pierre Auger Observatory, located in western Argentina, is the world’s largest cosmic-ray observatory. While it was originally built to study the cosmic-ray flux above 1018.5 eV, several enhancements have reduced this energy threshold. One such enhancement is a surface array composed of a triangular grid of 19 water-Cherenkov detectors separated by 433 m (SD-433) to explore the energies down to about 1016 eV. We are developing two research lines employing the SD-433. Firstly, we will measure the energy spectrum in a region where previous experiments have shown evidence of the second knee. Secondly, we will search for ultra-high energy photons to study PeV cosmic-ray sources residing in the Galactic center. In this work, we introduce the SD-433 and we show that it is fully efficient above 5×1016 eV for hadronic primaries with θ < 45°. Using seven years of data, we present the parametrization of the lateral distribution function of measured signals. Finally, we show that an angular resolution of 1.8° (0.5°) can be attained at the lowest (highest) primary energies. Our study lays the goundmark for measurements in the energy range above 1016 eV by utilizing the SD-433 and thus expanding the scientific output of the Auger surface detector

Features of the energy spectrum of cosmic rays above 2.5×1018 eV using the pierre auger observatory

We report a measurement of the energy spectrum of cosmic rays above 2.5×10$^{18}$ eV based on 215 030 events. New results are presented: at about 1.3×10$^{19}$ eV, the spectral index changes from 2.51±0.03(stat)±0.05(syst) to 3.05±0.05(stat)±0.10(syst), evolving to 5.1±0.3(stat)±0.1(syst) beyond 5×10$^{19}$ eV, while no significant dependence of spectral features on the declination is seen in the accessible range. These features of the spectrum can be reproduced in models with energy-dependent mass composition. The energy density in cosmic rays above 5×10$^{18}$ eV is [5.66±0.03(stat)±1.40(syst)]×10$^{53}$ erg Mpc$^{-3}$

Search for upward-going showers with the Fluorescence Detector of the Pierre Auger Observatory

Given its operation time and wide field of view, the Fluorescence Detector (FD) of the Pierre Auger Observatory is sufficiently sensitive to detect upward-going events when used in monocular mode. Upward-going air showers are a possible interpretation of the recent events reported by the ANITA Collaboration in the energy range above 1017 eV. The Pierre Auger FD data can be used to support or constrain this interpretation. If confirmed, it would require either new phenomena or significant modifications to the standard model of particle physics. To prepare this search, a set of quality selection criteria was defined by using 10% of the available FD data from 14 years of operation. This subset was mainly used to clean the data from improperly labelled laser events that had been used to monitor the quality of the atmosphere. The potential background for this search consists of cosmic-ray induced air showers with specific geometric configurations which, in a monocular reconstruction, can be reconstructed erroneously as upward-going events. To distinguish candidates from these false positives, to calculate the exposure, and to estimate the expected background, dedicated simulations for signal (upward-going events) and background (downward-going events) have been performed. The detector exposure is large enough to strongly constrain the interpretation of ANITA anomalous events. Preliminary results of the analysis after unblinding the data set are presented