SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

High-Precision Ramsey-Comb Spectroscopy at Deep Ultraviolet Wavelengths

High-precision spectroscopy in systems such as molecular hydrogen and helium ions is very interesting in view of tests of quantum electrodynamics and the proton radius puzzle. However, the required deep ultraviolet and shorter wavelengths pose serious experimental challenges. Here we show Ramsey-comb spectroscopy in the deep ultraviolet for the first time, thereby demonstrating its enabling capabilities for precision spectroscopy at short wavelengths. We excite Kr84 in an atomic beam on the two-photon 4p6→4p55p[1/2]0 transition at 212.55 nm. It is shown that the ac-Stark shift is effectively eliminated, and combined with a counterpropagating excitation geometry to suppress Doppler effects, a transition frequency of 2 820 833 101 679(103) kHz is found. The uncertainty of our measurement is 34 times smaller than the best previous measurement, and only limited by the 27 ns lifetime of the excited state

High-energy, high-repetition-rate picosecond pulses from a quasi-CW diode-pumped Nd:YAG system

We report on a high-power quasi-CW pumped Nd:YAG laser system, producing 130 mJ, 64 ps pulses at 1064 nm wavelength with a repetition rate of 300 Hz. Pulses from a Nd:YV

Characterization of a chip-based bioreactor for three-dimensional cell cultivation via magnetic resonance imaging

We describe the characterization of a chip-based platform (3D-KITChip) for the three-dimensional cultivation of cells under perfusion conditions via magnetic resonance imaging (MRI). Besides the chip, the microfluidic system is comprised of a bioreactor housing, a medium supply, a pump for generating active flow conditions as well as a gas mixing station. The closed circulation loop is ideally suited for a characterization via MRI since the small bioreactor setup with active perfusion, driven by the pump from outside the coils, not only is completely MRI-compatible but also can be transferred into the magnetic coil of an experimental animal scanner. We have found that the two halves of the chip inside the bioreactor are homogeneously perfused with cell culture medium both with and without cells inside the 3D-KITChip. In addition, the homogeneity of perfusion is nearly independent from the flow rates investigated in this study, and furthermore, the setup shows excellent washout characteristics after spiking with Gadolinium-DOTA which makes it an ideal candidate for drug screening purposes. We, therefore, conclude that the 3D-KITChip is well suited as a platform for high-density three-dimensional cell cultures, especially those requiring a defined medium flow and/or gas supply in a precisely controllable three dimensional environment, like stem cells

Differential contributions of set-shifting and monitoring to dual-task interference

It is commonly argued that complex behaviour is regulated by a number of “executive functions” which work to co-ordinate the operation of disparate cognitive systems in the service of an overall goal. However, the identity, roles, and interactions of specific putative executive functions remain contentious, even within widely accepted tests of executive function. The authors present two experiments that use dual-task interference to provide further support for multiple distinct executive functions and to establish the differential contributions of those functions in two relatively complex executive tasks – Random Generation and the Wisconsin Card Sorting Test. Results are interpreted in terms of process models of the complex executive tasks

Quantum Mechanical Studies of DNA and LNA

Quantum mechanical (QM) methodology has been employed to study the structure activity relations of DNA and locked nucleic acid (LNA). The QM calculations provide the basis for construction of molecular structure and electrostatic surface potentials from molecular orbitals. The topologies of the electrostatic potentials were compared among model oligonucleotides, and it was observed that small structural modifications induce global changes in the molecular structure and surface potentials. Since ligand structure and electrostatic potential complementarity with a receptor is a determinant for the bonding pattern between molecules, minor chemical modifications may have profound changes in the interaction profiles of oligonucleotides, possibly leading to changes in pharmacological properties. The QM modeling data can be used to understand earlier observations of antisense oligonucleotide properties, that is, the observation that small structural changes in oligonucleotide composition may lead to dramatic shifts in phenotypes. These observations should be taken into account in future oligonucleotide drug discovery, and by focusing more on non RNA target interactions it should be possible to utilize the exhibited property diversity of oligonucleotides to produce improved antisense drugs