SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition.

T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.

A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity.

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18-80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.

Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

Rationale: Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.

Executive functions and problem-solving-The contribution of inhibition, working memory, and cognitive flexibility to science problem-solving performance in elementary school students.

Previous research has shown that executive functions can contribute to successful problem-solving in preschool and elementary school children. However, most studies did not simultaneously assess the role of different specific aspects of executive functions. Therefore, the aim of our study was to investigate the individual contribution of inhibition, working memory, and cognitive flexibility to science problem-solving performance in elementary school children. A total of 478 children from first and second grades (Mage = 7.44 years) participated in our study. They performed a Go/No-go task (inhibition), a Corsi blocks backward task (working memory), a flexible item selection task (cognitive flexibility), and three science problem-solving tasks, including two gear turning tasks and one stabilization task. Structural equation modeling showed that working memory and cognitive flexibility individually contributed to problem-solving performance, whereas inhibition did not. We conclude that maintaining task requirements and dynamic object relations (working memory) and switching between different problem-solving phases (cognitive flexibility) are essential components of successful science problem-solving in elementary school children. Inhibitory processes may be more relevant in tasks involving a higher degree of interference at the task or response level.

The factorial structure of executive functions in preschool and elementary school children and relations with intelligence.

The timing of structural changes in executive functions (EFs) across development is a matter of controversy; whereas some studies suggest a uniform structure of EFs in early childhood, findings in middle and late childhood are mixed. There are results indicating uniformity of EFs as well as several studies suggesting multidimensionality of the construct. In addition, studies demonstrate an age-related differentiation of the relation between EFs and intelligence. We conducted a comparative analysis of the EF structure and relations with fluid intelligence in two distinct age groups. A sample of n = 145 preschool children (5.2-6.7 years of age) and n = 109 elementary school children (8.8-11.8 years) completed measures of working memory, inhibition, cognitive flexibility, and fluid intelligence. Confirmatory factor analysis (CFA) revealed that a single-factor model best represented performance on EF tasks in both preschool and elementary school children. Multi-group CFA indicated equivalent and strong relations between EFs and intelligence across both age groups (r = .64 in preschool and elementary school children). Our results confirm that EFs are significantly related to fluid intelligence but might not underlie a uniform pattern of successive differentiation into multiple EF components in childhood. We discuss how methodological artifacts such as simultaneous interference might have contributed to previous findings on differentiation in middle and late childhood.

Feeling lonely during the pandemic: Towards personality-tailored risk profiles.

This is the first study to disentangle associations of within- and between-person fluctuations in loneliness and their effect on evening mood during a nationwide lockdown due to COVID-19. To contribute to the development of personality-tailored risk profiles, we additionally explored the moderating role of trait neuroticism and extraversion on the association of within- and between-person loneliness and mood. We employed an ambulatory assessment design during 21 days of nationwide lockdown in Germany (13/04/2020-03/05/2020) with two interval-based assessments. The final sample comprised 322 participants (74.5% women) aged between 15 and 82 years (M = 30.7, SD = 14.9) providing 6,084 evening assessments. Linear mixed models were used to evaluate the effects of within- and between-person fluctuations in loneliness on evening mood while controlling for unspecific effects of time, sex, and age. Moderation analysis was used to investigate the influence of neuroticism and extraversion on the relation between loneliness and mood, respectively. Results indicate that especially higher between-person loneliness (i.e. participants felt lonelier compared to the average participant) but also higher within-person loneliness (i.e. participants felt lonelier compared to their individual mean) were associated with a more unpleasant mood. Neuroticism augmented the effect of within-person loneliness, while extraversion seemed to buffer the effect of between-person loneliness on mood. Our findings underline the importance of carefully monitoring loneliness during COVID-19. The findings contribute towards the development of personality-tailored risk profiles (e.g. among newly arising risk groups for loneliness due to COVID-19). We discuss how the differential consideration of within- and between-psychological processes might help to elucidate currently mixed findings on psychological coping during the COVID-19 pandemic.

Validation of a digital, tablet-based version of the Trail Making Test in the ∆elta platform.

Using digital technology for neuropsychological assessment is gaining popularity in both clinical and research settings. Digital neuropsychology offers many benefits over the traditional paper-pencil assessments; however, their comparability requires further validation. The aim of this study was to compare a digital, tablet-based Trail Making Test to the standard paper version. In a within-subject design, 108 healthy adults completed both digital and paper Trail Making Test in a counterbalanced order. Each participant also performed other tasks measuring core executive abilities (inhibition, working memory, and flexibility) on the tablet. Our findings indicated that the Trail Making Test performance on the two different modalities correlated significantly. Furthermore, correlations of Trail Making Test performance with other cognitive tasks revealed that digital Trail Making Test is comparable with the paper version. However, the modality had a significant effect on Trail Making Test performance; that is, participants were generally faster on the digital platform. Taken together, our findings suggest that with new normative data, traditional Trail Making Test can be adapted successfully to a digital platform.

Self-regulation in preschool: Are executive function and effortful control overlapping constructs?

The concepts of executive function (EF) and effortful control (EC) are strikingly similar. EF originate from neurocognitive research and are described as an accumulation of cognitive processes that serve the goal-oriented self-regulation (SR) of an individual. EC originates from temperament research and is defined as the efficiency of executive attention, including the ability to inhibit a dominant response, to activate a subdominant response, to proceed in a planned manner and to recognize conflicts or errors. The aim of this article was to examine the association between the constructs of EF and EC at the preschool-age. Eighty-eight children (49 female; M-age = 3.93 years, SD = .78) were tested with a computerized battery designed to assess EF at 3-6 years of age (EF Touch). Children's parents completed questionnaires assessing EF impairments (BRIEF-P) and EC (CBQ). Associations between the constructs and their conceptual overlap were analyzed using correlations and confirmatory factor analyses. We found significant correlations between EF and EC measures. A one-factor confirmatory model fitted the data very well and indicated that EF and EC are indeed overlapping and highly similar constructs. Therefore, our results show that measures of EC and EF have substantial overlap in preschoolers and suggest an integrated model of self-regulation.

Age-differences in network models of self-regulation and executive control functions.

Self-regulation (SR) and executive control functions (EF) are broad theoretical concepts that subsume various cognitive abilities supporting the regulation of behavior, thoughts, and emotions. However, many of these concepts stem from different psychological disciplines relying on distinct methodologies, such as self-reports (common in SR research) and performance-based tasks (common in EF research). Despite the striking overlap between SR and EF on the theoretical level, recent evidence suggests that correlations between self-report measures and behavioral tasks can be difficult to observe. In our study, participants from a life-span sample (14-82 years) completed self-report measures and behavioral tasks, which were selected to include a variety of different facets of SR (e.g., sensation seeking, mindfulness, grit, or eating behavior) and EF (working memory, inhibition, shifting). Using this broad approach, we systematically investigated connections and overlap of different aspects of SR and EF to improve their conceptual understanding. By comparing network models of a youth, middle-aged, and older-aged group, we identified key variables that are well connected in the SR and EF construct space. In general, we found connections to be stronger within the clusters of SR and EF than between them. However, older adults demonstrated more connections between SR and EF than younger individuals, likely because of declining cognitive resources.

Detecting subtle signs of depression with automated speech analysis in a non-clinical sample.

BACKGROUND: Automated speech analysis has gained increasing attention to help diagnosing depression. Most previous studies, however, focused on comparing speech in patients with major depressive disorder to that in healthy volunteers. An alternative may be to associate speech with depressive symptoms in a non-clinical sample as this may help to find early and sensitive markers in those at risk of depression. METHODS: We included n = 118 healthy young adults (mean age: 23.5 ± 3.7 years; 77% women) and asked them to talk about a positive and a negative event in their life. Then, we assessed the level of depressive symptoms with a self-report questionnaire, with scores ranging from 0-60. We transcribed speech data and extracted acoustic as well as linguistic features. Then, we tested whether individuals below or above the cut-off of clinically relevant depressive symptoms differed in speech features. Next, we predicted whether someone would be below or above that cut-off as well as the individual scores on the depression questionnaire. Since depression is associated with cognitive slowing or attentional deficits, we finally correlated depression scores with performance in the Trail Making Test. RESULTS: In our sample, n = 93 individuals scored below and n = 25 scored above cut-off for clinically relevant depressive symptoms. Most speech features did not differ significantly between both groups, but individuals above cut-off spoke more than those below that cut-off in the positive and the negative story. In addition, higher depression scores in that group were associated with slower completion time of the Trail Making Test. We were able to predict with 93% accuracy who would be below or above cut-off. In addition, we were able to predict the individual depression scores with low mean absolute error (3.90), with best performance achieved by a support vector machine. CONCLUSIONS: Our results indicate that even in a sample without a clinical diagnosis of depression, changes in speech relate to higher depression scores. This should be investigated in more detail in the future. In a longitudinal study, it may be tested whether speech features found in our study represent early and sensitive markers for subsequent depression in individuals at risk.

Executive functions in mono- and bilingual children: Factor structure and relations with fluid intelligence.

The effects of bilingualism on executive functions (EFs) and intelligence are still controversially discussed. Most studies have focused on performance differences without considering the underlying structure of cognitive abilities. Thus, we examined whether the structure of EFs and the relations of EFs with intelligence differ between mono- and bilingual children. A total of 240 elementary school children (mean age = 8 years 6 months; 133 monolinguals and 95 bilinguals) performed two tasks measuring working memory, inhibition, cognitive flexibility, and fluid intelligence, respectively. Confirmatory factor analyses showed that one common EF factor provided the best fit to the data in both language groups, indicating that bilingualism is not associated with differences in the EF structure at this age. Moreover, there were no latent performance differences in either EFs or intelligence between mono- and bilingual children. However, we found a stronger relation between a common EF factor and fluid intelligence in bilingual children as compared with monolingual children, implying a closer coupling of EFs and intelligence abilities in bilingual children. This contributes to explaining the previous heterogeneous findings on the task level because more closely coupled cognitive functioning can be slightly beneficial for some tasks and irrelevant or even slightly obstructive for others.

Differences in cognitive processing? The role of verbal processes and mental effort in bilingual and monolingual children's planning performance.

Past research documents a bilingual advantage in the domain of executive functions (EFs). However, controversial debates have questioned the robustness of those behavioral differences. The current study aimed to better understand the underlying cognitive prerequisites in bilingual students as compared with monolingual students and focused on two processes: the role of verbal processes, on the one hand, and mental effort during task execution, on the other. The use of self-regulatory speech has been found to be related to performance in tasks requiring EFs. For bilinguals who have grown up with two language systems from an early age, those relations are not fully understood. Furthermore, results from neuroimaging studies have shown that bilinguals might exhibit less mental effort in EF tasks. We investigated both processes in German-speaking monolingual elementary school students (n = 33; Mage = 8.78 years) and German-Russian bilingual elementary school students (n = 34; Mage = 8.88 years) solving a planning task. Results showed that monolinguals were impaired by a verbal secondary task in comparison with a motor control condition, whereas bilinguals performed in both tasks at an equal level, indicating a differential role of self-regulatory speech in both language groups. Analyses of changes in pupil diameter revealed less mental effort during task execution for bilingual children as compared with monolingual children. The current study adds to the existing literature by supplying further evidence for cognitive differences between monolingual and bilingual children.

The relations between personality, components of executive functions, and intelligence in children and young adults.

Previous studies in adults showed heterogeneous results regarding the associations of personality with intelligence and executive functions (EF). In children, there is a lack of studies investigating the relations between personality and EF. Therefore, the aim of our study was to examine the relations between the Big Five personality traits, EF, and intelligence in a sample of children (Experiment 1) and young adults (Experiment 2). A total of 155 children (Experiment 1, mean age = 9.54 years) and 91 young adults (Experiment 2, mean age = 23.49 years) participated in the two studies. In both studies, participants performed tasks measuring working memory (WM), inhibitory control, cognitive flexibility, and fluid intelligence and completed a personality questionnaire. In Experiment 1, we found a negative relation between neuroticism and intelligence. In Experiment 2, we found a positive relation between conscientiousness and intelligence and a positive relation between conscientiousness and cognitive flexibility. Our results suggest a complex interplay between personality factors, EF, and intelligence both in children as well as in young adults.

Effects of game-based and standard executive control training on cognitive and academic abilities in elementary school children.

Several studies indicate that executive functions (EF), such as working memory (WM), inhibition or flexibility can be improved by training and that these training-related benefits in WM capacity generalize to reading and mathematical abilities. However, the results of these studies are inconsistent and most of them focused on WM training in children with learning difficulties. Evidence for typically developing children is rare and no study has investigated inhibition training or flexibility training. There is also a lack of studies taking motivational factors into account. Therefore, this study compared the effects of game-based and standard training regimens targeting WM, inhibition, or flexibility in children. One hundred and fifty-three typically developing elementary school students (mean age = 9.6 years, standard deviations  = 0.8) were investigated in an intervention design with a pretest, 21 sessions of training, a posttest and a follow-up after three months. They were randomized into one of six training groups or a control group. We found training gains in all training groups and higher self-reported motivation in the game-based as compared to the standard training groups. Furthermore, there was domain-specific transfer to untrained EF tasks across all training groups. We found greater performance improvements in reading ability (but not mathematics) in the game-based flexibility training group and the game-based inhibition training group as compared to the control group. Transfer effects were still significant at follow-up. In sum, our findings provide first evidence for a systematic comparison of training on different domains of EF and their differential effects on academic abilities.

Investigating dual-task interference in children versus young adults with the overlapping task paradigm.

Previous studies demonstrated that dual-task impairments (i.e., dual-task costs) are higher in children than in young adults. However, these studies did not specify the mechanisms explaining higher dual-task costs and did not assess the specific task processes that particularly impair simultaneous task performance in children. We assessed sources of higher dual-task costs in children (n = 32) as compared with young adults (n = 32) by combining auditory (Task 1) and visual (Task 2) sensorimotor tasks into dual tasks of the psychological refractory period (PRP) type. Both tasks are separated by a varying stimulus onset asynchrony (SOA). In Visual Task 2, we manipulated task difficulty at the perceptual stage (contrast manipulation) and response selection stage (mapping manipulation) in order to identify age-related changes in capacity limitations during dual-task performance. The results showed that the response selection manipulation and SOA yielded additive effects in children and young adults, providing evidence for interference at response selection processes in both age groups. In contrast, the perceptual stage manipulation and SOA resulted in underadditive effects in young adults and additive effects in children. This age-related difference is consistent with the assumption that limitations in central processing are present in both age groups, whereas perceptual interference between tasks seems to be larger in children than in young adults.

Age-related differentiation in verbal and visuospatial working memory processing in childhood.

Working memory (WM), a key feature of the cognitive system, allows for maintaining and processing information simultaneously and in a controlled manner. WM processing continuously develops across childhood, with significant increases both in verbal and visuospatial WM. Verbal and visuospatial WM may show different developmental trajectories, as verbal (but not visuospatial) WM relies on internal verbal rehearsal, which is less developed in younger children. We examined complex VWM and VSWM performance in 125 younger (age 4-6 years) and 101 older (age 8-10 years) children. Latent multi-group modeling showed that (1) older children performed better on both verbal and visuospatial WM span tasks than younger children, (2) both age groups performed better on verbal than visuospatial WM, and (3) a model with two factors representing verbal and visuospatial WM fit the data better than a one-factor model. Importantly, the correlation between the two factors was significantly higher in younger than in older children, suggesting an age-related differentiation of verbal and spatial WM processing in middle childhood. Age-related differentiation is an important characteristic of cognitive functioning and thus the findings contribute to our general understanding of WM processing.

Measuring Anxiety in Older Adults: Development, Diagnostic Accuracy, and Preliminary Validation of a Short-Form of the German Geriatric Anxiety Scale (GAS-G-SF).

Anxiety symptoms and anxiety disorders are highly prevalent among older adults, and are associated with considerable distress, functional impairment, and burden. Also, there is growing need for brief instruments to measure anxiety symptoms in primary care and geriatric medical settings. Therefore, the current study focuses on the development and psychometric evaluation of a short-form of the Geriatric Anxiety Scale (GAS-G), a well-established anxiety instrument for use with older adults. Study 1 draws on the original data from the GAS-G validation study (N = 242) to develop the short-form (GAS-G-SF) and determines whether the results replicate with the short-form. Study 2 extends the validation of the GAS-G-SF to a clinical sample (N = 156; 62 patients with heart disease, 94 patients with Parkinson's disease). Overall, the GAS-G-SF showed promising psychometric properties in terms of internal consistency and validity. Also, the GAS-G-SF showed good discriminatory power based on receiver operating characteristic curve analysis in both studies. These results support the utility of the GAS-G-SF as a brief assessment measure for anxiety.

In silico and cell-based analyses reveal strong divergence between prediction and observation of T-cell-recognized tumor antigen T-cell epitopes.

Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by in silico algorithms, but the predictive power of this approach is unclear. Here, we used the human tumor antigen NY-ESO-1 (ESO) and the human leukocyte antigen variant HLA-A*0201 (A2) as a model and predicted in silico the 41 highest-affinity, A2-binding 8-11-mer peptides and assessed their binding, kinetic complex stability, and immunogenicity in A2-transgenic mice and on peripheral blood mononuclear cells from ESO-vaccinated melanoma patients. We found that 19 of the peptides strongly bound to A2, 10 of which formed stable A2-peptide complexes and induced CD8+ T cells in A2-transgenic mice. However, only 5 of the peptides induced cognate T cells in humans; these peptides exhibited strong binding and complex stability and contained multiple large hydrophobic and aromatic amino acids. These results were not predicted by in silico algorithms and provide new clues to improving T-cell epitope identification. In conclusion, our findings indicate that only a small fraction of in silico-predicted A2-binding ESO peptides are immunogenic in humans, namely those that have high peptide-binding strength and complex stability. This observation highlights the need for improving in silico predictions of peptide immunogenicity.

NY-ESO-1- and survivin-specific T-cell responses in the peripheral blood from patients with glioma.

The prognosis for patients with glioblastoma is grim. Ex vivo expanded tumor-associated antigen (TAA)-reactive T-cells from patients with glioma may represent a viable source for anticancer-directed cellular therapies. Immunohistochemistry was used to test the survivin (n = 40 samples) and NY-ESO-1 (n = 38 samples) protein expression in tumor specimens. T-cells from peripheral blood were stimulated with TAAs (synthetic peptides) in IL-2 and IL-7, or using a combination of IL-2, IL-15 and IL-21. CD4+ and CD8+ T-cells were tested for antigen-specific proliferation by flow cytometry, and IFN-γ production was tested by ELISA. Twenty-eight out of 38 cancer specimens exhibited NY-ESO-1 protein expression, 2/38 showed a strong universal (4+) NY-ESO-1 staining, and 9/40 cancer lesions exhibited a strong (4+) staining for survivin. We could detect antigen-specific IFN-γ responses in 25% blood samples for NY-ESO-1 and 30% for survivin. NY-ESO-1-expanded T-cells recognized naturally processed and presented epitopes. NY-ESO-1 or survivin expression in glioma represents viable targets for anticancer-directed T-cells for the biological therapy of patients with glioma.

Validation of new online game-based executive function tasks for children.

Numerous tasks are available to measure executive functions (EFs; working memory, inhibition, and flexibility) in children. However, they differ massively in the way they are presented and framed. Some contain child-friendly stimuli, feedback, or game elements likely to increase motivation and interest to perform the tasks, whereas others do not. Yet, it is unclear whether these apparent differences affect task performance. Therefore, the aim of our study was to develop and validate new game-based tasks assessing EFs in children. We designed three tasks for each dimension of EF and implemented them in a game version (based on the motivational framework proposed by Ryan and Deci (2000) and a standard version. The game-based tasks included elements designed to improve perceived competence (appealing feedback), autonomy (choosing how the protagonists proceed), and relatedness (a child-friendly cover story). To investigate whether adding these game elements influenced the motivation to engage in these tasks and task performance, 60 children (third and fourth graders) performed the game-based version and the standard version in two sessions (counterbalanced across participants). Because both the game-based and standard versions of the tasks should tap the same cognitive processes, we also tested whether performances in both versions were correlated. We found higher self-reported motivation in terms of interest, perceived competence, and relatedness after performing the game-based version as compared with the standard version. Performance on the game-based and standard versions of most of the tasks was significantly correlated, and there were no performance differences between the game-based and standard versions.