Virus-like particle-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice.

BACKGROUND: Neoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in-silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. Moreover, the therapeutic potential of neoantigen-based vaccines may be enhanced using an optimal delivery platform that elicits robust de novo immune responses. METHODS: We developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction, as well as the interaction between the peptide/MHC-I complex and the TCR, in its prediction strategy. Moreover, to maximize neoantigens' therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance. RESULTS: We generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments. CONCLUSIONS: Our results indicate the relevance of incorporating other immunogenic determinants beyond the binding of neoantigens to MHC-I. Thus, neoVLPs loaded with neoantigens enhancing the interaction with the TCR can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy.

Neuropsychological profiles in first-episodes psychosis and their relationship with clinical, metacognition and social cognition variables.

An increasing interest in the assessment of neuropsychological performance variability in people with first-episode psychosis (FEP) has emerged. However, its association with clinical and functional outcomes requires further study. Furthermore, FEP neuropsychological subgroups have not been characterized by clinical insight or metacognition and social cognition domains. The aim of this exploratory study was to identify specific groups of patients with FEP based on neuropsychological variables and to compare their sociodemographic, clinical, metacognition and social cognition profiles. A sample of 149 FEP was recruited from adult mental health services. Neuropsychological performance was assessed by a neuropsychological battery (WAIS-III; TMT; WSCT; Stroop Test; TAVEC). The assessment also included sociodemographic characteristics, clinical, functional, metacognition and social cognition variables. Two distinct neuropsychological profiles emerged: one neuropsychological impaired cluster (N = 56) and one relatively intact cluster (N = 93). Significant differences were found between both profiles in terms of sociodemographic characteristics (age and level of education) (p = 0.001), clinical symptoms (negative, positive, disorganized, excitement and anxiety) (p = 0.041-0.001), clinical insight (p = 0.038-0.017), global functioning (p = 0.014), as well as in social cognition domains (emotional processing and theory of mind) (p = 0.001; p = 0.002). No significant differences were found in metacognitive variables (cognitive insight and 'jumping to conclusions' bias). Relationship between neurocognitive impairment, social cognition and metacognition deficits are discussed. Early identifying of neuropsychological profiles in FEP, characterized by significant differences in clinical and social cognition variables, could provide insight into the prognosis and guide the implementation of tailored early-intervention.

The influence of gender in cognitive insight and cognitive bias in people with first-episode psychosis: an uncontrolled exploratory analysis.

PURPOSE: Previous studies have investigated the role of gender in clinical symptoms, social functioning, and neuropsychological performance in people with first-episode psychosis (FEP). However, the evidence of gender differences for metacognition in subjects with FEP is still limited and controversial. The aim of the present study was to explore gender differences in cognitive insight and cognitive biases in this population. METHODS: Cross-sectional study was carried out in a sample of 104 patients with FEP (35 females and 69 males) recruited from mental health services. Symptoms were assessed with the Positive and Negative Syndrome Scale, cognitive insight with the Beck Cognitive Insight Scale, and cognitive bias by the Cognitive Biases Questionnaire for Psychosis. The assessment also included clinical and sociodemographic characteristics. RESULTS: After controlling for potential confounders (level of education, marital status, and duration of psychotic illness) analysis of covariance revealed that males presented greater self-reflectiveness (p = 0.004) when compared to females. However, no significant differences were found in self-certainty and composite index of the cognitive insight scale, as in the cognitive biases assessed. CONCLUSIONS: Gender was an independent influence factor for self-reflectiveness, being better for males. Self-reflectiveness, if shown to be relatively lacking in women, could contribute to the design of more gender-sensitive and effective psychotherapeutic treatments, as being able to self-reflect predicts to better treatment response in psychosis.

Alanine-based spacers promote an efficient antigen processing and presentation in neoantigen polypeptide vaccines.

Neoantigens are tumor-specific antigens that are mostly particular for each patient. Since the immune system is able to mount a specific immune response against these neoantigens, they are a promising tool for the development of therapeutic personalized cancer vaccines. Neoantigens must be presented to T cells by antigen presenting cells (APC) in the context of MHC-I or MHC-II molecules. Therefore, the strategy of vaccine delivery may have a major impact on the magnitude and quality of T cell responses. Neoantigen-based vaccines are frequently administered as a pool of individual synthetic peptides that induce mainly CD4+ T cell responses. MHC-I-mediated presentation and the elicitation of CD8+ T cell responses may be improved using DNA or RNA sequences that code for a unique long polypeptide that concatenates the different neoantigens spaced by linker sequences. When administered this way, the selection of the spacer between neoantigens is of special interest, as it might influence the processing and presentation of the right peptides by APCs. Here, we evaluate the impact of such linker regions on the MHC-I-dependent antigen presentation using an in vitro assay that assesses the MHC-I presentation of SIINFEKL, a H-2 Kb-restricted OVA peptide. Our results show that spacers used to generate epitope concatenates have a large impact on the efficiency of neoantigen processing and presentation by MHC-I molecules; in contrast, the peptide position and the flanking regions have a minimal impact. Moreover, linkers based on alanine residues promote a more efficient peptide presentation than the commonly used GGGS linker.

Exploring FeLV-Gag-Based VLPs as a New Vaccine Platform-Analysis of Production and Immunogenicity.

Feline leukemia virus (FeLV) is one of the most prevalent infectious diseases in domestic cats. Although different commercial vaccines are available, none of them provides full protection. Thus, efforts to design a more efficient vaccine are needed. Our group has successfully engineered HIV-1 Gag-based VLPs that induce a potent and functional immune response against the HIV-1 transmembrane protein gp41. Here, we propose to use this concept to generate FeLV-Gag-based VLPs as a novel vaccine strategy against this retrovirus. By analogy to our HIV-1 platform, a fragment of the FeLV transmembrane p15E protein was exposed on FeLV-Gag-based VLPs. After optimization of Gag sequences, the immunogenicity of the selected candidates was evaluated in C57BL/6 and BALB/c mice, showing strong cellular and humoral responses to Gag but failing to generate anti-p15E antibodies. Altogether, this study not only tests the versatility of the enveloped VLP-based vaccine platform but also sheds light on FeLV vaccine research.

Development and validation of a short version of the questionnaire of stressful life events (QSLE).

Stressful life events (SLE) tend to occur before the onset of psychosis, this highlights the importance of its detection and evaluation in these patients. The need to have instruments that assess SLE easily and quickly underpins the objective of this study, which is to validate a short version of the questionnaire of stressful life events (QSLE). 124 patients with first-episode psychosis and 218 healthy controls aged between 11 and 52 years were recruited. The QSLE scale underwent discrimination analysis, which revealed 18 items had good SLEs discriminability between the two samples. These 18 items were then used to create the shorter QSLE-SV. The QSLE-SV showed good internal consistency (Cronbach's alpha = 0.749). An AUC of 0.830 was observed, suggesting that the predictor was good. Using 2 as the cut-off score to predict an individual as a patient would yield a sensitivity of 91.1% and a specificity of 51.6%, and using a cut-off point of 3, the sensitivity was 77.4% and the specificity was 72.5%. QSLE-SV displayed satisfactory psychometric properties in a Spanish population. The QSLE-SV allows for investigating childhood, adolescent and adult life events by measuring current stress and age on a continuous scale in a quick and easy way.

Depressive symptoms and their relationship with negative and other psychotic symptoms in early onset psychosis.

The importance of depression in adult people with first-episode psychosis (FEP) has been demonstrated. However, it has hardly been studied in children and adolescents. There is a need to broaden knowledge of the relationship between psychotic symptoms and specific depression symptomatology. The aims of study were (a) to examine the frequency of presence and type of depressive symptoms in early onset FEP, and (b) to assess the relationship between depressive symptoms and psychotic symptomatology, and specifically negative symptoms. An observational cross-sectional study was performed in 62 FEP cases. Inclusion criteria were two or more psychotic symptoms, age 7-17 years old, first mental health service consultation, and fewer than 6 months from the first contact with the service. Participants were assessed with clinical and socio-demographic questionnaires: the Positive and Negative Syndrome Scale (PANSS) and the Children Depression Inventory (CDI). A Student t test was performed to compare psychotic symptoms in both groups: presence of depression and the absence of depression. A Pearson correlation was performed in order to relate subscales of the PANSS and each of the depression subscales and factors, as well the relation between negative and depressive symptoms. Our results show that a high percentage of people with an early onset of a FEP scored positively for depression. The most prevalent depressive symptoms were associated with schooling. The presence of depression was associated with negative, affective, and excited symptoms. Self-esteem, school problems, negative affect, and biological dysregulation were associated with psychotic symptoms. Finally, depressive items related to social functioning were more closely associated with negative symptoms of the PANSS. In conclusion, owing to the high incidence of depression in FEP in those suffering early onset of psychosis, there is a need for instruments to measure the depression more specifically in children and adolescent, and to uncover the clinical characteristics of depression in this population.

Differential effects of sex on substance use between first episode psychosis patients and healthy people.

BACKGROUND: Substance use in psychosis is an important field of study given that it can be a risk factor for the development of psychosis and can give rise to psychotic symptoms. Studies of substance use in first episode psychosis patients do not frequently assess non-pathological substance consumption among patients, but rather the prevalence of substance abuse or dependence disorders. Moreover, most of these studies do not address the effects of sex in sufficient depth, and the consumption of caffeine or tobacco, which are two of the most frequently used substances, is often not assessed. OBJECTIVES: The aim of this study was to compare patterns and quantities of substance use between first episode psychosis patients and healthy controls and between men and women, and explore the potential interactive effects between group (patients or controls) and sex. METHODS: A total of 158 participants (82 first episode psychosis patients and 76 healthy controls) were included in the study. Both adults and adolescents were included in the study. Frequency and amount of use of caffeine, tobacco, alcohol, cannabis, cocaine, hallucinogens, stimulants, and opiates were gathered. RESULTS: A significant main effect of sex was found for the frequency of use of tobacco (p=.050). Main effects of group were found for the quantity of tobacco (p<.001) and cannabis (p<.001) consumed, as well as main effects of sex for the quantity of alcohol (p=.003) and cannabis (p=.017) consumed. There were also interaction effects between group and sex for the frequency of use of tobacco (p=.005) and cannabis (p=.009), and for the amount of cannabis consumed (p=.049). Qualitative differences between males and females regarding combined substance use are also reported. CONCLUSIONS: Among patients, men used tobacco more frequently than women, but this sex difference was not the same for the control group, in which women smoked more often than men. Regarding cannabis, men smoked cannabis more frequently and in larger amounts than women, but only in the patients group, whereas no sex differences for cannabis were found for the controls. Main effects of group and sex for tobacco and alcohol, as well as the lack of differences for the frequency and amount of use of caffeine, are also commented. This is the first study to assess the different effects of sex on substance use in first episode psychosis patients and healthy controls.

Measuring stages of recovery from psychosis.

BACKGROUND: Mental health consumers invite us to abandon the pathology model, which is tied to pessimism, and instead to embrace a model of personal recovery that goes beyond being free from symptoms, and involves self-management of the illness. The Stages of Recovery Instrument (STORI) is a measure developed from the perspective of consumers according to a conceptual five-stage model of recovery. AIMS: The main aim of this work was to study the psychometric properties of the STORI, but we also set out to compare the stages of recovery in our sample with the five-stage model in the sample with which the scale was developed. METHODS: Our sample consisted of 95 people diagnosed with schizophrenia-spectrum psychoses, with a mean age of 34.74 (SD=9.25). RESULTS: The STORI scores showed adequate psychometric properties in this sample. Cluster analysis indicated that the three-cluster model fitted the data better than the five-cluster model. Internal consistency of the STORI scores ranged between .83 and .87. STORI stages were associated with Recovery Styles Questionnaire scores. DISCUSSION: The results provide empirical validation of the STORI in other countries. Empirical evidence revealed that the stages of recovery found in our own and other clinical samples differ from those found in the samples with which the scale was developed.

Gender differences in individuals at high-risk of psychosis: a comprehensive literature review.

INTRODUCTION: To date, few studies have focused on the characterization of clinical phenomenology regarding gender in population at high-risk of psychosis. This paper is an attempt to summarize the findings found in the scientific literature regarding gender differences in high-risk populations, taking into account parameters studied in populations with schizophrenia and other psychotic disorders, such as incidence, clinical expression, duration of untreated illness (DUI), social functioning, and cognitive impairment prior to full-blown psychosis development. METHOD: Studies were systematically searched in PubMed. Studies using gender variable as a control variable were excluded. 12 studies met inclusion criteria. RESULTS: Most of the studies found a differential pattern between women and men as regards clinical, social, and cognitive variables in the prodromal phase, with worse performance in men except in cognitive functioning (more severe negative symptoms, worse social functioning, and longer DUI in men). Similar conversion rates over time were found between men and women. CONCLUSIONS: Many of the studies analyzed suggest that differences between men and women in the expression of psychosis extend across a continuum, from the subclinical forms of illness to the debut of psychosis. However, the small number of studies and their significant methodological and clinical limitations do not allow for firm conclusions.

Predictors of clinical insight in first-episode psychosis: Different patterns in men and women.

BACKGROUND: We aimed to explore gender-related differences in the associations of insight impairment with clinical symptoms, metacognition, and social cognition in psychosis. METHODS: Regression analysis of several clinical insight dimensions was conducted on the data from 116 men and 56 women with first-episode psychosis. Various clinical symptoms and measures of metacognition and social cognition were entered as predictors. RESULTS: In both men and women, delusions emerged as a strong predictor of all insight dimensions, and verbal hallucinations as a strong predictor of symptom relabelling. In men, certain negative symptoms as well as self-certainty, lack of self-reflectiveness, impaired theory of mind, attributional biases, and a jumping-to-conclusions bias were additional predictors of poor insight, while good insight was associated with depression, anxiety, avolition, blunted affect, and impaired emotional recognition. In women, poor insight was associated with a self-serving/externalising bias, impaired emotional recognition, and attention disorders. CONCLUSIONS: Poor insight in first-episode psychosis is strongly linked to deficits in metacognition and social cognition, with marked differences between men and women with respect to the specific skills involved in the impairment. Meanwhile, good insight is linked to a variety of affective manifestations in men. These findings suggest new avenues for more targeted cognitive interventions to improve clinical insight in psychosis.

Production and Immunogenicity of FeLV Gag-Based VLPs Exposing a Stabilized FeLV Envelope Glycoprotein.

The envelope glycoprotein (Env) of retroviruses, such as the Feline leukemia virus (FeLV), is the main target of neutralizing humoral response, and therefore, a promising vaccine candidate, despite its reported poor immunogenicity. The incorporation of mutations that stabilize analogous proteins from other viruses in their prefusion conformation (e.g., HIV Env, SARS-CoV-2 S, or RSV F glycoproteins) has improved their capability to induce neutralizing protective immune responses. Therefore, we have stabilized the FeLV Env protein following a strategy based on the incorporation of a disulfide bond and an Ile/Pro mutation (SOSIP) previously used to generate soluble HIV Env trimers. We have characterized this SOSIP-FeLV Env in its soluble form and as a transmembrane protein present at high density on the surface of FeLV Gag-based VLPs. Furthermore, we have tested its immunogenicity in DNA-immunization assays in C57BL/6 mice. Low anti-FeLV Env responses were detected in SOSIP-FeLV soluble protein-immunized animals; however, unexpectedly no responses were detected in the animals immunized with SOSIP-FeLV Gag-based VLPs. In contrast, high humoral response against FeLV Gag was observed in the animals immunized with control Gag VLPs lacking SOSIP-FeLV Env, while this response was significantly impaired when the VLPs incorporated SOSIP-FeLV Env. Our data suggest that FeLV Env can be stabilized as a soluble protein and can be expressed in high-density VLPs. However, when formulated as a DNA vaccine, SOSIP-FeLV Env remains poorly immunogenic, a limitation that must be overcome to develop an effective FeLV vaccine.

Cognitive insight in first-episode psychosis: Exploring the complex relationship between executive functions and social cognition.

Social cognition (SC) and executive function (EF) have been described as important variables for social functioning and recovery of patients with psychosis. However, the relationship between SC and EF in first-episode psychosis (FEP) deserves further investigation, especially focusing on gender differences. AIMS: To investigate the relationship between EF and different domains of SC in FEP patients and to explore gender differences in the relationship between these domains. METHODS: A cross-sectional study of 191 patients with new-onset psychosis recruited from two multicenter clinical trials. A comprehensive cognitive battery was used to assess SC (Hinting Task, Face Test and IPSAQ) and EF (TMT, WSCT, Stroop Test and digit span - WAIS-III). Pearson correlations and linear regression models were performed. RESULTS: A correlation between Theory of Mind (ToM), Emotional Recognition (ER) and EF was found using the complete sample. Separating the sample by gender showed different association profiles between these variables in women and men. CONCLUSIONS: A relationship between different domains of SC and EF is found. Moreover, women and men presented distinct association profiles between EF and SC. These results should be considered in order to improve the treatment of FEP patients and designing personalized interventions by gender.

Family Metacognitive Training (MCT-F): Adapting MCT to Mothers with Psychosis and Their Adolescent Children.

Over half of women with psychosis are mothers. Research suggests that mothers with psychosis face unique challenges affecting both their mental health prognosis and their relationship with their children. Moreover, those children have a higher risk of developing a mental disorder. Notwithstanding, interventions specifically tailored to these families remain largely uncovered. Metacognitive Training (MCT) has demonstrated its efficacy in improving cognitive insight, symptom management, and social cognition in people with psychosis. However, there is no evidence of the efficacy of MCT in a family setting (MCT-F). This study describes the first adaptation of MCT for mothers with psychosis and their adolescent children in an online group setting. The phases (assessment, decision, adaptation, production, topical experts' integration) of the ADAPT-ITT model were systematically applied through a participatory approach (n = 22), including a first-person perspective and involving qualitative (e.g., topical expert literature review and consensus groups, interviews, thematic analyses) and quantitative methods. While MCT's core components were retained, participants guided adaptations both in content and delivery. The findings suggest the importance of community engagement and sharing decision-making processes to demonstrate the acceptability and feasibility of the adapted intervention. Employing a structured approach such as the ADAPT-ITT model ensures readiness of the new training for efficacy trials.

Effectiveness of family metacognitive training in mothers with psychosis and their adolescent children: a multicenter study protocol.

Background: More than half of women with psychosis take care of their children despite the difficulties caused by the disease. Additionally, these kids have a higher risk of developing a mental health disorder. However, no interventions have been developed to meet these needs. Metacognitive Training (MCT) is a psychological intervention that has demonstrated its efficacy in improving cognitive insight, symptom management and social cognition in people with first-episode psychosis (FEP). Additionally, MCT has shown better results in women than men with FEP. This study aims to adapt and evaluate the efficacy of MCT-F in mothers and adolescent children in an online group context with the main purpose of improving family relationships, cognitive awareness and symptoms in women with psychosis and increase their children's knowledge of the disease and their functioning. As secondary objectives, it also aims to evaluate improvements in metacognition, social cognition, symptoms, protective factors and self-perception of stigma. Materials and methods: A quasi-experimental design with participants acting as their own control will be carried out. Forty-eight mothers with psychosis and their adolescent children (between 12 and 20 years old) recruited from a total of 11 adult mental health care centers will receive MCT-F. Participants will be evaluated 11 weeks before the intervention (T1), at baseline (T2), and post-intervention (T3) with a cognitive insight scale, as a primary outcome. Measures of metacognitive and social cognition, symptoms, cognitive functioning, family and social functioning, protective factors (self-esteem, resilience, and coping strategies) and self-perceived stigma will be addressed as secondary outcomes. Assessment will also address trauma and attachment in mothers and, lastly, the feasibility and acceptability of MCT-F in both participant groups. Discussion: This will be the first investigation of the efficacy, acceptability, and viability of the implementation of MCT-F. The results of this study may have clinical implications, contributing to improving mothers' with psychosis and adolescents' functioning and better understanding of the disease, in addition to the possible protective and preventive effect in adolescents, who are known to be at higher risk of developing severe mental disorders.Clinical trial registration:https://clinicaltrials.gov/, identifier [NCT05358457].

Immunization with V987H-stabilized Spike glycoprotein protects K18-hACE2 mice and golden Syrian hamsters upon SARS-CoV-2 infection.

Safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most vaccines are based on a mutated version of the Spike glycoprotein [K986P/V987P (S-2P)] with improved stability, yield and immunogenicity. However, S-2P is still produced at low levels. Here, we describe the V987H mutation that increases by two-fold the production of the recombinant Spike and the exposure of the receptor binding domain (RBD). S-V987H immunogenicity is similar to S-2P in mice and golden Syrian hamsters (GSH), and superior to a monomeric RBD. S-V987H immunization confer full protection against severe disease in K18-hACE2 mice and GSH upon SARS-CoV-2 challenge (D614G or B.1.351 variants). Furthermore, S-V987H immunized K18-hACE2 mice show a faster tissue viral clearance than RBD- or S-2P-vaccinated animals challenged with D614G, B.1.351 or Omicron BQ1.1 variants. Thus, S-V987H protein might be considered for future SARS-CoV-2 vaccines development.

Spanish validation of the Premorbid Adjustment Scale (PAS-S).

BACKGROUND: The Premorbid Adjustment Scale (PAS) has been the most widely used scale to quantify premorbid status in schizophrenia, coming to be regarded as the gold standard of retrospective assessment instruments. AIMS: To examine the psychometric properties of the Spanish version of the PAS (PAS-S). METHOD: Retrospective study of 140 individuals experiencing a first episode of psychosis (n=77) and individuals who have schizophrenia (n=63), both adult and adolescent patients. Data were collected through a socio-demographic questionnaire and a battery of instruments which includes the following scales: PAS-S, PANSS, LSP, GAF and DAS-sv. The Cronbach's alpha was performed to assess the internal consistency of PAS-S. Pearson's correlations were performed to assess the convergent and discriminant validity. RESULTS: The Cronbach's alpha of the PAS-S scale was 0.85. The correlation between social PAS-S and total PAS-S was 0.85 (p<0.001); while for academic PAS-S and total PAS-S it was 0.53 (p<0.001). Significant correlations were observed between all the scores of each age period evaluated across the PAS-S scale, with a significance value less than 0.001. There was a relationship between negative symptoms and social PAS-S (0.20, p<0.05) and total PAS-S (0.22, p<0.05), but not with academic PAS-S. However, there was a correlation between academic PAS-S and general subscale of the PANSS (0.19, p<0.05). Social PAS-S was related to disability measures (DAS-sv); and academic PAS-S showed discriminant validity with most of the variables of social functioning. PAS-S did not show association with the total LSP scale (discriminant validity). CONCLUSION: The Spanish version of the Premorbid Adjustment Scale showed appropriate psychometric properties in patients experiencing a first episode of psychosis and who have a chronic evolution of the illness. Moreover, each domain of the PAS-S (social and academic premorbid functioning) showed a differential relationship to other characteristics such as psychotic symptoms, disability or social functioning after onset of illness.

Relationship between cognition and suicidal behavior in recent-onset psychosis.

Suicidal behavior (SB) is common in first-episode psychosis (FEP), and cognitive impairment has also been described in psychosis. Despite well-established risk factors for SB in psychosis, the role of cognition and insight remains unclear. This study aimed to explore the relationship between history of SB and cognition in recent-onset FEP, distinguishing between neurocognition, social cognition, and metacognition, and including cognitive insight (CI) as a metacognitive variable. The sample consisted of 190 participants with recent-onset FEP recruited from two multicentric studies. Two groups were formed based on presence/absence of a history of SB. Demographic, clinical, and cognitive data were compared by group, including significance level adjustments and size effect calculation. No differences were found regarding demographic, clinical, neurocognitive, social cognition, and metacognitive variables except for CI (18.18 ± 4.87; t = -3.16; p = 0.0020; d = -0.635), which showed a medium effect size. Small to medium effect size were found for attributional style (externalizing bias) (1.15 ± 3.94; t = 2.07; d = 0.482), theory of mind (ToM) (1.73 ± 0.22; t = 2.04; d = -0.403), jumping to conclusions bias (JTC) (23.3 %; X2 = 0.94; V = 0.178). In recent-onset psychosis, neurocognitive functioning was not related to the history of SB. As novelty, individuals with previous SB showed higher CI. Also, regarding social cognition and metacognition, individuals with prior SB tended to present extremely low externalizing bias, better ToM, and presence of JTC.

An engineered HIV-1 Gag-based VLP displaying high antigen density induces strong antibody-dependent functional immune responses.

Antigen display on the surface of Virus-Like Particles (VLPs) improves immunogenicity compared to soluble proteins. We hypothesised that immune responses can be further improved by increasing the antigen density on the surface of VLPs. In this work, we report an HIV-1 Gag-based VLP platform engineered to maximise the presence of antigen on the VLP surface. An HIV-1 gp41-derived protein (Min), including the C-terminal part of gp41 and the transmembrane domain, was fused to HIV-1 Gag. This resulted in high-density MinGag-VLPs. These VLPs demonstrated to be highly immunogenic in animal models using either a homologous (VLP) or heterologous (DNA/VLP) vaccination regimen, with the latter yielding 10-fold higher anti-Gag and anti-Min antibody titres. Despite these strong humoral responses, immunisation with MinGag-VLPs did not induce neutralising antibodies. Nevertheless, antibodies were predominantly of an IgG2b/IgG2c profile and could efficiently bind CD16-2. Furthermore, we demonstrated that MinGag-VLP vaccination could mediate a functional effect and halt the progression of a Min-expressing tumour cell line in an in vivo mouse model.

Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant.

Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production and immunogenicity of the recombinant S trimer, suggesting that these two parameters are related. Nevertheless, S-2P still shows some molecular instability and it is produced with low yield. Here we described a novel set of mutations identified by molecular modeling and located in the S2 region of the S-2P that increase its production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S-29 mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.