The effect of inflammation, SARS-CoV-2 infection, age and mental health on serotonin, and kynurenine and catecholamine pathway metabolites.

BACKGROUND: A high prevalence of mental disorders following COVID-19 has been described. It is therefore essential to elucidate underlying biological mechanisms linking SARS-CoV-2 infection and mental health. The kynurenine and catecholamine metabolic pathways are modulated by inflammation and can affect systemic levels of serotonin and dopamine. Their activity may hence link physical disorders with mental health. We investigated factors that affect kynurenine and catecholamine pathway activity in SARS-CoV-2 infection and recovery. METHODS: The cross-sectional SIMMUN (n = 165) and longitudinal INCOV cohort (n = 167, Su et al. 2022) were analyzed. Demographic and clinical characteristic, inflammatory markers, SARS-CoV-2 infection, symptoms of depression and anxiety (HADS), and mental stress (PSS-4) served as explanatory variables. Blood serotonin and markers of kynurenine (kynurenine/tryptophan ratio), and catecholamine pathway activity (dopamine 3-O-sulfate, phenylalanine/tyrosine ratio) were modeled by multi-parameter linear regression. RESULTS: In the SIMMUN cohort, the inflammatory marker neopterin (ß = 0.47 [95% CI: 0.34-0.61]), SARS-CoV-2-positivity (0.42 [0.16-0.68]), mental stress (0.18 [0.055-0.31]), and age (0.26 [0.12-0.39]) were positively associated with the kynurenine/tryptophan ratio. The phenylalanine/tyrosine ratio was lower in SARS-CoV-2-positive than uninfected participants (-0.38 [-0.68 to -0.08]). In the INCOV cohort, markers of inflammation were associated with lower serotonin (IL6: -0.22 [-0.38 to -0.053]) and dopamine 3-O-sulfate levels (interferon-gamma: -0.15 [-0.26 to -0.036]). Serotonin (0.76 [0.34-1.2]) and dopamine 3-O-sulfate levels (0.63 [0.28-0.99]) were higher during recovery than in acute SARS-CoV-2 infection. CONCLUSION: SARS-CoV-2 infection, inflammation, age and mental stress are key independent predictors of kynurenine pathway activity, which may influence serotonin availability. The catecholamine pathway was also affected in SARS-CoV-2 infection. Altered activity of these pathways may contribute to impaired mental health following COVID-19.

Immune response after two doses of the BNT162b2 COVID-19 vaccine and risk of SARS-CoV-2 breakthrough infection in Tyrol, Austria: an open-label, observational phase 4 trial.

BACKGROUND: Correlates of protection could help to assess the extent to which a person is protected from SARS-CoV-2 infection after vaccination (so-called breakthrough infection). We aimed to clarify associations of antibody and T-cell responses after vaccination against COVID-19 with risk of a SARS-CoV-2 breakthrough infection and whether measurement of these responses enhances risk prediction. METHODS: We did an open-label, phase 4 trial in two community centres in the Schwaz district of the Federal State of Tyrol, Austria, before the emergence of the omicron (B.1.1.529) variant of SARS-CoV-2. We included individuals (aged ≥16 years) a mean of 35 days (range 27-43) after they had received a second dose of the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. We quantified associations between immunological parameters and breakthrough infection and assessed whether information on these parameters improves risk discrimination. The study is registered with the European Union Drug Regulating Authorities Clinical Trials Database, 2021-002030-16. FINDINGS: 2760 individuals (1682 [60·9%] female, 1078 [39·1%] male, mean age 47·4 years [SD 14·5]) were enrolled into this study between May 15 and May 21, 2021, 712 (25·8%) of whom had a previous SARS-CoV-2 infection. Over a median follow-up of 5·9 months, 68 (2·5%) participants had a breakthrough infection. In models adjusted for age, sex, and previous infection, hazard ratios for breakthrough infection for having twice the immunological parameter level at baseline were 0·72 (95% CI 0·60-0·86) for anti-spike IgG, 0·80 (0·70-0·92) for neutralising antibodies in a surrogate virus neutralisation assay, 0·84 (0·58-1·21) for T-cell response after stimulation with a CD4 peptide pool, and 0·77 (0·54-1·08) for T-cell response after stimulation with a combined CD4 and CD8 peptide pool. For neutralising antibodies measured in a nested case-control sample using a pseudotyped virus neutralisation assay, the corresponding odds ratio was 0·78 (0·62-1·00). Among participants with previous infection, the corresponding hazard ratio was 0·73 (0·61-0·88) for anti-nucleocapsid Ig. Addition of anti-spike IgG information to a model containing information on age and sex improved the C-index by 0·085 (0·027-0·143). INTERPRETATION: In contrast to T-cell response, higher levels of binding and neutralising antibodies were associated with a reduced risk of breakthrough SARS-CoV-2 infection. The assessment of anti-spike IgG enhances the prediction of incident breakthrough SARS-CoV-2 infection and could therefore be a suitable correlate of protection in practice. Our phase 4 trial measured both humoral and cellular immunity and had a 6-month follow-up period; however, the longer-term protection against emerging variants of SARS-CoV-2 remains unclear. FUNDING: None.

Seroprevalence of SARS-CoV-2 infection in the Tyrolean district of Schwaz at the time of the rapid mass vaccination in March 2021 following B.1.351-variant outbreak.

In order to curb the rapid dissemination of the B.1.351 variant of SARS-CoV-2 in the district of Schwaz and beyond, the EU allocated additional vaccine doses at the beginning of March 2021 to implement a rapid mass vaccination of the population (16+). The aim of our study was to determine the seroprevalence of SARS-CoV-2 among the adult population in the district of Schwaz at the time of the implementation. Data on previous history of infections, symptoms and immunization status were collected using a structured questionnaire. Blood samples were used to determine SARS-CoV-2 specific anti-spike, anti-nucleocapsid and neutralizing antibodies. We recruited 2,474 individuals with a median age (IQR) of 42 (31-54) years. Using the official data on distribution of age and sex, we found a standardized prevalence of undocumented infections at 15.0% (95% CI: 13.2-16.7). Taken together with the officially documented infections, we estimated that 24.0% (95% CI: 22.5-25.6) of the adult population had prior SARS-CoV-2 infection. Hence, the proportion of undocumented infections identified by our study was 55.8% (95% CI: 52.7-58.5). With a vaccination coverage of 10% among the adults population at that time, we imply that a minimum of two-thirds of the target popuation was susceptible to the circulating threat when this unique campaign started.

Estimating seroprevalence of SARS-CoV-2 antibodies using three self-reported symptoms: development of a prediction model based on data from Ischgl, Austria.

We report the development of a regression model to predict the prevalence of severe acute respiratory syndrome coronavirus (SARS-CoV-2) antibodies on a population level based on self-reported symptoms. We assessed participant-reported symptoms in the past 12 weeks, as well as the presence of SARS-CoV-2 antibodies during a study conducted in April 2020 in Ischgl, Austria. We conducted multivariate binary logistic regression to predict seroprevalence in the sample. Participants (n = 451) were on average 47.4 years old (s.d. 16.8) and 52.5% female. SARS-CoV-2 antibodies were found in n = 197 (43.7%) participants. In the multivariate analysis, three significant predictors were included and the odds ratios (OR) for the most predictive categories were cough (OR 3.34, CI 1.70-6.58), gustatory/olfactory alterations (OR 13.78, CI 5.90-32.17) and limb pain (OR 2.55, CI 1.20-6.50). The area under the receiver operating characteristic curve was 0.773 (95% CI 0.727-0.820). Our regression model may be used to estimate the seroprevalence on a population level and a web application is being developed to facilitate the use of the model.