Mucosal SARS-CoV-2 vaccination of rodents elicits superior systemic T central memory function and cross-neutralising antibodies against variants of concern.

BACKGROUND: COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subsequent transmission, are still needed. METHODS: Here we tested an intranasal (I.N.) vaccination with the receptor binding domain of Spike antigen of SARS-CoV-2 (S-RBD) in combination with the mucosal adjuvant mastoparan-7 compared with the sub-cutaneous (S.C.) route, adjuvanted by either M7 or the gold-standard adjuvant, alum, in mice, for immunological read-outs. The same formulation delivered I.N. or S.C. was tested in hamsters to assess efficacy. FINDINGS: I.N. vaccination improved systemic T cell responses compared to an equivalent dose of antigen delivered S.C. and T cell phenotypes induced by I.N. vaccine administration included enhanced polyfunctionality (combined IFN-γ and TNF expression) and greater numbers of T central memory (TCM) cells. These phenotypes were T cell-intrinsic and could be recalled in the lungs and/or brachial LNs upon antigen challenge after adoptive T cell transfer to naïve recipients. Furthermore, mucosal vaccination induced antibody responses that were similarly effective in neutralising the binding of the parental strain of S-RBD to its ACE2 receptor, but showed greater cross-neutralising capacity against multiple variants of concern (VOC), compared to S.C. vaccination. I.N. vaccination provided significant protection from lung pathology compared to unvaccinated animals upon challenge with homologous and heterologous SARS-CoV-2 strains in a hamster model. INTERPRETATION: These results highlight the role of nasal vaccine administration in imprinting an immune profile associated with long-term T cell retention and diversified neutralising antibody responses, which could be applied to improve vaccines for COVID-19 and other infectious diseases. FUNDING: This study was funded by Duke-NUS Medical School, the Singapore Ministry of Education, the National Medical Research Council of Singapore and a DBT-BIRAC Grant.

Factors associated with psychological distress during the coronavirus disease 2019 (COVID-19) pandemic on the predominantly general population: A systematic review and meta-analysis.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) outbreak has escalated the burden of psychological distress. We aimed to evaluate factors associated with psychological distress among the predominantly general population during the COVID-19 pandemic. METHODS: We searched PubMed, EMBASE, Scopus, Cochrane Library, PsycINFO, and World Health Organization COVID-19 databases (Dec 2019-15 July 2020). We included cross-sectional studies that reported factors associated with psychological distress during the COVID-19 pandemic. Primary outcomes were self-reported symptoms of anxiety and depression. Random-effects models were used to pool odds ratios (OR) and 95% confidence intervals (CI). The protocol was registered in PROSPERO (#CRD42020186735). FINDINGS: We included 68 studies comprising 288,830 participants from 19 countries. The prevalence of anxiety and depression was 33% (95% CI: 28%-39%) and 30% (26%-36%). Women versus men (OR: 1.48 [95% CI: 1.29-1.71; I2 = 90.8%]), younger versus older (< versus ≥35 years) adults (1.20 [1.13-1.26]; I2 = 91.7%), living in rural versus urban areas (1.13 [1.00-1.29]; I2 = 82.9%), lower versus higher socioeconomic status (e.g. lower versus higher income: 1.45 [1.24-1.69; I2 = 82.3%]) were associated with higher anxiety odds. These factors (except for residential area) were also associated with higher depression odds. Furthermore, higher COVID-19 infection risk (suspected/confirmed cases, living in hard-hit areas, having pre-existing physical or mental conditions) and longer media exposure were associated with higher odds of anxiety and depression. INTERPRETATION: One in three adults in the predominantly general population have COVID-19 related psychological distress. Concerted efforts are urgently needed for interventions in high-risk populations to reduce urban-rural, socioeconomic and gender disparities in COVID-19 related psychological distress.

Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism.

We show that both supplemental and ambient magnetic fields modulate myogenesis. A lone 10 min exposure of myoblasts to 1.5 mT amplitude supplemental pulsed magnetic fields (PEMFs) accentuated in vitro myogenesis by stimulating transient receptor potential (TRP)-C1-mediated calcium entry and downstream nuclear factor of activated T cells (NFAT)-transcriptional and P300/CBP-associated factor (PCAF)-epigenetic cascades, whereas depriving myoblasts of ambient magnetic fields slowed myogenesis, reduced TRPC1 expression, and silenced NFAT-transcriptional and PCAF-epigenetic cascades. The expression levels of peroxisome proliferator-activated receptor γ coactivator 1α, the master regulator of mitochondriogenesis, was also enhanced by brief PEMF exposure. Accordingly, mitochondriogenesis and respiratory capacity were both enhanced with PEMF exposure, paralleling TRPC1 expression and pharmacological sensitivity. Clustered regularly interspaced short palindromic repeats-Cas9 knockdown of TRPC1 precluded proliferative and mitochondrial responses to supplemental PEMFs, whereas small interfering RNA gene silencing of TRPM7 did not, coinciding with data that magnetoreception did not coincide with the expression or function of other TRP channels. The aminoglycoside antibiotics antagonized and down-regulated TRPC1 expression and, when applied concomitantly with PEMF exposure, attenuated PEMF-stimulated calcium entry, mitochondrial respiration, proliferation, differentiation, and epigenetic directive in myoblasts, elucidating why the developmental potential of magnetic fields may have previously escaped detection. Mitochondrial-based survival adaptations were also activated upon PEMF stimulation. Magnetism thus deploys an authentic myogenic directive that relies on an interplay between mitochondria and TRPC1 to reach fruition.-Yap, J. L. Y., Tai, Y. K., Fröhlich, J., Fong, C. H. H., Yin, J. N., Foo, Z. L., Ramanan, S., Beyer, C., Toh, S. J., Casarosa, M., Bharathy, N., Kala, M. P., Egli, M., Taneja, R., Lee, C. N., Franco-Obregón, A. Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism.