Recent development of oral vaccines (Review).

Oral immunization can elicit an effective immune response and immune tolerance to specific antigens. When compared with the traditional injection route, delivering antigens via the gastrointestinal mucosa offers superior immune effects and compliance, as well as simplicity and convenience, making it a more optimal route for immunization. At present, various oral vaccine delivery systems exist. Certain modified bacteria, such as Salmonella, Escherichia coli and particularly Lactobacillus, are considered promising carriers for oral vaccines. These carriers can significantly enhance immunization efficiency by actively replicating in the intestinal tract following oral administration. The present review provided a discussion of the main mechanisms of oral immunity and the research progress made in the field of oral vaccines. Additionally, it introduced the advantages and disadvantages of the currently more commonly administered injectable COVID-19 vaccines, alongside the latest advancements in this area. Furthermore, recent developments in oral vaccines are summarized, and their potential benefits and side effects are discussed.

Oral Vaccines: A Better Future of Immunization.

Oral vaccines are gaining more attention due to their ease of administration, lower invasiveness, generally greater safety, and lower cost than injectable vaccines. This review introduces certified oral vaccines for adenovirus, recombinant protein-based, and transgenic plant-based oral vaccines, and their mechanisms for inducing an immune response. Procedures for regulatory approval and clinical trials of injectable and oral vaccines are also covered. Challenges such as instability and reduced efficacy in low-income countries associated with oral vaccines are discussed, as well as recent developments, such as Bacillus-subtilis-based and nanoparticle-based delivery systems that have the potential to improve the effectiveness of oral vaccines.

Retraction: Sung et al. Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate. Vaccines 2022, 10, 2.

The journal retracts the article "Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate"[...].

Safety and Immunogenicity of Inactivated Bacillus subtilis Spores as a Heterologous Antibody Booster for COVID-19 Vaccines.

The coronavirus diseases 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have threatened the world for more than 2 years. Multiple vaccine candidates have been developed and approved for emergency use by specific markets, but multiple doses are required to maintain the antibody level. Preliminary safety and immunogenicity data about an oral dose vaccine candidate using recombinant Bacillus subtilis in healthy adults were reported previously from an investigator-initiated trial in Hong Kong. Additional data are required in order to demonstrate the safety and efficacy of the candidate as a heterologous booster in vaccinated recipients. In an ongoing, placebo-controlled, observer-blinded, fixed dose, investigator-initiated trial conducted in the Macau, we randomly assigned healthy adults, 21 to 62 years of age to receive either placebo or a Bacillus subtilis oral dose vaccine candidate, which expressed the spike protein receptor binding domain of SARS-CoV-2 on the spore surface. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. For both the active vaccine and placebo, participants received three courses in three consecutive days. A total of 16 participants underwent randomization: 9 participants received vaccine and 7 received placebo. No observable local or systemic side-effect was reported. In both younger and older adults receiving placebo, the neutralizing antibody levels were gradually declining, whereas the participants receiving the antibody booster showed an increase in neutralizing antibody level.

Investigation into activation of dysfunctional schemas in euthymic bipolar disorder following positive mood induction.

OBJECTIVES. There are dysfunctional cognitions that may be characteristic of bipolar disorder (BD), and which may be mood-state dependent. However, it has been found that such cognitions may be resilient to minor positive mood increase. The aim of this study is to investigate whether positive mood-induction procedure has the effect of altering the availability of dysfunctional schemas in a group of individuals with BD. DESIGN. The sentence completion task was designed to assess the content of dysfunctional schemas: it was modified for use with positive mood-induction procedure in the current study so that more dysfunctional schematic models would lead to completion of sentence stems by negative constructs, whereas functional schematic models led to completion of sentence stems by positive constructs. METHODS. Using the modified sentence completion task, 30 participants with remitted bipolar I disorder were compared with 30 individuals with no history of affective disorder. Results. At baseline the bipolar group inserted significantly more dysfunctional completions than the control group. Following mood induction, the number of dysfunctional completions was reduced for both groups. The bipolar group still inserted significantly more dysfunctional completions relating to autonomy than the control group following mood induction. However, no significant group by time interactions were identified. CONCLUSIONS. As predicted, participants' reports of dysfunctional attitudes reduced following the mood-induction procedure, although no difference was identified between the groups in terms of the size of this reduction. The bipolar group continued to insert significantly more dysfunctional completions for the factor of autonomy, suggesting that this group has more access to autonomy schemas, regardless of change in mood. This finding may have implications in terms of focus of therapy and relapse prevention work.

A comparison of mood-dependent memory in bipolar disorder and normal controls.

Mood-dependent memory was investigated in a sample of 28 individuals, with a diagnosis of bipolar disorder I but not during acute episodes, and 30 non-clinical controls by using the word lists from Wechsler Memory Scale--Third Edition and abstract inkblot recognition. Positive or negative mood induction procedures were used prior to and after the stimuli were presented. After either the same or contrasting high or low mood inductions, participants attempted to recall the word list and performed an inkblot recognition task. Bipolar patients were significantly better at the inkblot recognition in the same mood state, showing mood-dependent memory. No differences were found in the verbal recall task. This study paves the way for further investigation into memory differences of this sort in mood disorders.

Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate.

Various types of vaccines, such as mRNA, adenovirus, and inactivated virus by injection, have been developed to prevent SARS-CoV-2 infection. Although some of them have already been approved under the COVID-19 pandemic, various drawbacks, including severe side effects and the requirement for sub-zero temperature storage, may hinder their applications. Bacillus subtilis (B. subtilis) is generally recognized as a safe and endotoxin-free Gram-positive bacterium that has been extensively employed as a host for the expression of recombinant proteins. Its dormant spores are extraordinarily resistant to the harsh environment in the gastrointestinal tract. This feature makes it an ideal carrier for oral administration in resisting this acidic environment and for release in the intestine. In this study, an engineered B. subtilis spore expressing the SARS-CoV-2 spike protein receptor binding domain (sRBD) on the spore surface was developed. In a pilot test, no adverse health event was observed in either mice or healthy human volunteers after three oral courses of B. subtilis spores. Significant increases in neutralizing antibody against sRBD, in both mice and human volunteers, after oral administration were also found. These findings may enable the further clinical developments of B. subtilis spores as an oral vaccine candidate against COVID-19 in the future.

Profiling microRNAs differentially expressed in rabbit retina.

MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression at the post-transcriptional level. Recent studies indicate that miRNAs may constitute a major mechanism underlying mammal's retinal development. The overall objective of this study is to compare and contrast retinal miRNAs expression between newborn and adult rabbits, and to identify some of the genes possibly associated with retinal development. Retinas were isolated from 3-day-old and 2-month-old rabbits. A miRNA microarray designed to detect 924 miRNAs was used to determine the expression profile of miRNAs from newborn and adult rabbits. The expression of twenty-eight miRNAs was found to differ significantly between newborn and adult rabbit retina. Among these, 17 appear to be up-regulated and the other 11 miRNAs down-regulated, suggesting a role of differential miRNA expression in retinal development. Computer prediction tools indicate that some of the target genes might be directly associated with signal pathways relevant to visual development.

Psychological therapies in bipolar disorder: the effect of illness history on relapse prevention - a systematic review.

OBJECTIVES: Despite some encouraging outcomes and shared components of psychological therapies specific to bipolar disorders, not all studies found conclusively that the addition of a psychosocial intervention to pharmacological interventions improves outcomes. There was some tentative evidence from post hoc analyses that patients with more than 12 previous episodes did not benefit from psychoeducation or cognitive therapy. This paper presents a systematic review and meta-analysis which examines the overall efficacy of bipolar disorder-specific psychological therapies and the impact of the number of previous episodes on the efficacy of psychological therapies in relapse prevention. METHODS: Systematic literature searches of electronic databases and reference lists of existing reviews were carried out. The number of participants experiencing relapse in randomized, controlled studies was combined in a meta-analysis to determine the overall treatment effect in relapse prevention. Metaregression modeling was used to examine whether the number of previous episodes confounded the number of relapses experienced by participants by the end of treatment. RESULTS: Meta-analysis of relapse calculated an overall relative risk of 0.74 [95% confidence interval (CI): 0.64-0.85] with some heterogeneity present (I(2) = 43.3%). Metaregression of six studies showed no relationship between number of episodes and number of relapses by endpoint. CONCLUSION: Psychological therapy specifically designed for bipolar disorder is effective in preventing or delaying relapses in bipolar disorders, and there is no clear evidence that the number of previous episodes moderated the effect.

Dysregulation of the behavioral activation system in remitted bipolar I disorder.

The current study tests a prediction of the behavioral activation system (BAS) dysregulation theory of bipolar disorder, namely that following high levels of reward or frustration, individuals with bipolar disorder will take longer than will healthy controls to recover to baseline levels of BAS activity. Eighty individuals (40 with bipolar I disorder, currently euthymic; 40 with no history of affective disorder) completed a daily diary over a 28 day period. No differences were found between the 2 groups in terms of the relation among levels of reward or frustration experienced, magnitude of initial response, or time taken to recover. However, examination of the relation between number of previous episodes and time to recover revealed that history of mania was associated with prolonged activation following reward, whereas history of both mania and depression were associated with prolonged recovery following frustration. The findings do not support an association between lifetime diagnosis of bipolar disorder and slow recovery of BAS activity. Nevertheless, they offer tentative support for an association between number of previous episodes and slow recovery of BAS activity.

The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic.

Gendicine (recombinant human p53 adenovirus), developed by Shenzhen SiBiono GeneTech Co. Ltd., was approved in 2003 by the China Food and Drug Administration (CFDA) as a first-in-class gene therapy product to treat head and neck cancer, and entered the commercial market in 2004. Gendicine is a biological therapy that is delivered via minimally invasive intratumoral injection, as well as by intracavity or intravascular infusion. The wild-type (wt) p53 protein expressed by Gendicine-transduced cells is a tumor suppressor that is activated by cellular stress, and mediates cell-cycle arrest and DNA repair, or induces apoptosis, senescence, and/or autophagy, depending upon cellular stress conditions. Based on 12 years of commercial use in >30,000 patients, and >30 published clinical studies, Gendicine has exhibited an exemplary safety record, and when combined with chemotherapy and radiotherapy has demonstrated significantly higher response rates than for standard therapies alone. In addition to head and neck cancer, Gendicine has been successfully applied to treat various other cancer types and different stages of disease. Thirteen published studies that include long-term survival data showed that Gendicine combination regimens yield progression-free survival times that are significantly longer than standard therapies alone. Although the p53 gene is mutated in >50% of all human cancers, p53 mutation status did not significantly influence efficacy outcomes and long-term survival rate for Ad-p53-treated patients. To date, Shenzhen SiBiono GeneTech has manufactured 41 batches of Gendicine in compliance with CFDA QC/QA requirements, and 169,571 vials (1.0 × 1012 vector particles per vial) have been used to treat patients. No serious adverse events have been reported, except for vector-associated transient fever, which occurred in 50-60% of patients and persisted for only a few hours. The manufacturing accomplishments and clinical experience with Gendicine, as well as the understanding of its cellular mechanisms of action and implications, could provide valuable insights for the international gene therapy community and add valuable data to promote further developments and advancements in the gene therapy field.

Rumination and attention in major depression.

Up until recently, it had been assumed that attentional biases for negative information do not exist in depression. However studies using post-conscious exposure durations have produced contradictory results. The limitations of common attentional tasks, suitability of stimulus materials and differences in stimulus duration times may have contributed to these inconsistencies. We aimed to address many of these issues and examine attentional responses in major depression at two post-conscious exposure times. We also investigated possible roles for rumination and distraction in increasing and lessening attentional biases for negative information. We used a fully controlled experimental design to test the effects of both induced and trait rumination and distraction on attention in patients with major depression and healthy controls. Attention was assessed using the dot-probe task. The findings revealed an attentional bias for negative information in depressed patients only at the longer post-conscious exposure duration. Furthermore although this bias was not influenced by either induced or trait distraction, it was related to trait rumination. Overall, the results showed that depression is associated with a strategic attentional bias towards negative information and that this bias is stronger in individuals who habitually ruminate.

"I won't do what you tell me!": elevated mood and the assessment of advice-taking in euthymic bipolar I disorder.

We hypothesized that when individuals with bipolar disorder are engaged in goal-directed behaviour and experience elevated mood, their decision-making becomes less constrained by advice from other people. This process may allow their goal-directed behaviour to persist, contributing to manic symptoms. Three groups of 32 participants: euthymic-bipolar-I, remitted-unipolar and never-depressed healthy controls were allocated to either a high or low mood induction. Advice-taking was assessed before and after the induction by a computerized task incorporating facial images. The bipolar group significantly opposed the advice given in the task after the high mood induction. The effect was specific to bipolar disorder and remained when controlling for possible confounds. Future work could investigate the effects of this process on manic symptoms, its origins, and the wider theoretical and clinical implications.

Relapse prevention in patients with bipolar disorder: cognitive therapy outcome after 2 years.

OBJECTIVE: In a previous randomized controlled study, the authors reported significant beneficial effects of cognitive therapy for relapse prevention in bipolar disorder patients up to 1 year. This study reports additional 18-month follow-up data and presents an overview of the effect of therapy over 30 months. METHOD: Patients with DSM-IV bipolar I disorder (N=103) suffering from frequent relapses were randomly assigned into a cognitive therapy plus medication group or a control condition of medication only. Independent raters, who were blind to patient group status, assessed patients at 6-month intervals. RESULTS: Over 30 months, the cognitive therapy group had significantly better outcome in terms of time to relapse. However, the effect of relapse prevention was mainly in the first year. The cognitive therapy group also spent 110 fewer days (95% CI=32 to 189) in bipolar episodes out of a total of 900 for the whole 30 months and 54 fewer days (95% CI=3 to 105) in bipolar episodes out of a total of 450 for the last 18 months. Multivariate analyses of variance showed that over the last 18 months, the cognitive therapy group exhibited significantly better mood ratings, social functioning, coping with bipolar prodromes, and dysfunctional goal attainment cognition. CONCLUSIONS: Patients in the cognitive therapy group had significantly fewer days in bipolar episodes after the effect of medication compliance was controlled. However, the results showed that cognitive therapy had no significant effect in relapse reduction over the last 18 months of the study period. Further studies should explore the effect of booster sessions or maintenance therapy.

A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year.

BACKGROUND: Despite the use of mood stabilizers, a significant proportion of patients with bipolar affective disorder experience frequent relapses. A pilot study of cognitive therapy (CT) specifically designed to prevent relapses for bipolar affective disorder showed encouraging results when used in conjunction with mood stabilizers. This article reports the outcome of a randomized controlled study of CT to help prevent relapses and promote social functioning. METHODS: We randomized 103 patients with bipolar 1 disorder according to the DSM-IV, who experienced frequent relapses despite the prescription of commonly used mood stabilizers, into a CT group or control group. Both the control and CT groups received mood stabilizers and regular psychiatric follow-up. In addition, the CT group received an average of 14 sessions of CT during the first 6 months and 2 booster sessions in the second 6 months. RESULTS: During the 12-month period, the CT group had significantly fewer bipolar episodes, days in a bipolar episode, and number of admissions for this type of episode. The CT group also had significantly higher social functioning. During these 12 months, the CT group showed less mood symptoms on the monthly mood questionnaires. Furthermore, there was significantly less fluctuation in manic symptoms in the CT group. The CT group also coped better with manic prodromes at 12 months. CONCLUSION: Our findings support the conclusion that CT specifically designed for relapse prevention in bipolar affective disorder is a useful tool in conjunction with mood stabilizers.

Prodromes, coping strategies and psychological interventions in bipolar disorders.

Bipolar disorder is known to be highly recurrent and people with bipolar illnesses often experience high degrees of interpersonal and social impairment. The emergence of prodromal symptoms not only causes distress but may also predispose patients to greater risk of a full relapse. Studies have found that patients can report prodromes reliably. Common mania prodromes include decreased need for sleep, increased activities, being more sociable and racing thoughts while common depression prodromes are loss of interest, not being able to put worries aside and interrupted sleep. Furthermore, patients' coping with prodromal symptoms predicted relapses in bipolar disorder. These findings have led to a handful of randomized controlled studies which aimed at teaching patients relevant and adaptive coping strategies in dealing with bipolar prodromes as part of the intervention strategies and the results are very encouraging. The packages in these studies are of different complexity. The mode of intervention also varied from individual work, group work to family work. This paper also examines the differential effects of these interventions.

Induced mood change and dysfunctional attitudes in remitted bipolar I affective disorder.

This study investigated the possibility that, in remitted bipolar I affective disorder, dysfunctional attitudes are mood-state dependent. Participants were 120 individuals with remitted bipolar I disorder, remitted unipolar depression, or no history of affective disorder. The Dysfunctional Attitudes Scale (DAS; Weissman, 1979) was completed before and after positive or negative mood challenge. Following mood increase, the bipolar group changed significantly less in DAS total score than did the other 2 groups, and in goal-striving and achievement attitudes relative to the unipolar group. These findings did not provide clear support for the mood-state dependency theory in bipolar disorder, arguing instead for the presence in bipolar I disorder of dysfunctional cognitions that show characteristic resilience in the face of minor positive mood increase.

Psychoeducation: improving outcomes in bipolar disorder.

BACKGROUND: A relevant paradigm shift in the treatment of bipolar disorder started a few years ago; crucial findings on the usefulness of psychological interventions clearly support switching from an exclusively pharmacological therapeutic approach to a combined yet hierarchical model in which pharmacotherapy plays a central role, but psychological interventions may help cover the gap that exists between theoretical efficacy and "real world" effectiveness. Hereby we review the efficacy of several adjunctive psychotherapies in the maintenance treatment of bipolar patients. METHODS: A systematic review of the literature on the issue was performed, using MEDLINE and CURRENT CONTENTS databases. "Bipolar", "Psychotherapy", "Psychoeducation", "Cognitive-behavioral" and "Relapse prevention" were entered as keywords. RESULTS: Psychological treatments specifically designed for relapse prevention in bipolar affective disorder are useful tools in conjunction with mood stabilizers. Most of the psychotherapy studies recently published report positive results on maintenance as an add-on treatment, and efficacy on the treatment of depressive episodes. Interestingly, several groups from all over the world reported similar positive results and reached very similar conclusions; almost every intervention tested contains important psychoeducative elements including both compliance enhancement and early identification of prodromal signs - stressing the importance of life-style regularity - and exploring patients' health beliefs and illness-awareness. CONCLUSIONS: The usefulness of psychotherapy for improving treatment adherence and clinical outcome of bipolar patients is nowadays unquestionable, and future treatment guidelines should promote its regular use amongst clinicians. As clinicians, it is our major duty, to offer the best treatment available to our patients and this includes both evidence-based psychoeducation programs and newer pharmacological agents.

Dysfunctional assumptions in bipolar disorder.

BACKGROUND: Despite the initial encouraging outcome in developing CBT for bipolar affective disorder [Arch. Gen. Psychiatry 2002 (in press); Psychol. Med. 31 (2001) 459-467], very little is known about whether there are any differences in dysfunctional attitudes between unipolar and bipolar patients. Both the behavioural activation system theory [J. Pers. Soc. Psychol. 67 (1994) 488-498; Major Theories of Personality Disorder, Guilford Press, New York, 1996; Psychol. Bull. 117 (1995) 434-449] and the cognitive model for bipolar affective disorder [Cognitive Therapy for Bipolar Disorder: A Therapist's Guide to Concepts, Methods and Practise, Wiley, New York, 1999] postulate high goal striving as a risk factor for bipolar disorder. However, the existing subscales in the dysfunctional attitude scale (DAS) were derived from patients and relatives of patients suffering from unipolar depression, patients with a mixed psychiatric diagnosis or normal controls. None of the existing subscales reflects high goal striving beliefs. Using a sample of bipolar patients may yield different factors. METHODS: A total of 143 bipolar 1 patients filled in the short version of DAS 24. Principal component analysis was carried out to derive factors. The scores of these factors were compared with those of 109 unipolar patients to investigate if these factors distinguish bipolar patients from unipolar patients. RESULTS: Three factors were derived: factor 1 'Goal-attainment' accounted for 25.0% of the total variance. Factor 2 'Dependency' accounted for 11.0% of the total variance. Factor 3 'Achievement' accounted for 8.2% of the total variance. However, factor 1 appeared to consist of items that made a coherent theoretical construct. No significant differences were found when the validation sample was compared with 109 patients suffering from unipolar depression in any of the three factors. When subjects who were likely to be in a major depressive episode were excluded, the scores of bipolar patients (n=49) were significantly higher than euthymic unipolar patients (n=25) in factor 1 'Goal attainment'. Goal-attainment also correlated with the number of past hospitalisations due to manic episodes and to bipolar episodes as a whole. CONCLUSIONS: The Goal-attainment subscale captures the risky attitudes described by the behavioural activation system theory and the cognitive model for bipolar affective disorder. It is postulated that these beliefs may interact with the illness and predispose bipolar patients to have a more severe course of the illness.

Response style, interpersonal difficulties and social functioning in major depressive disorder.

BACKGROUND: It is postulated that depressed patients who engaged in self-focused rumination on their depressive symptoms may experience more hopelessness, more interpersonal distress and poorer social functioning while patients who distract themselves may experience less severe hopelessness and better social functioning. METHOD: One-hundred and nine outpatients suffering from DSM-IV (APA, 1994) major depressive disorders filled in questionnaires that mapped into their response style to depression, hopelessness and interpersonal style. They were also interviewed for their levels of social functioning. RESULTS: Rumination was associated with higher levels of depression and distraction was associated with lower levels of depression. Furthermore when levels of depression and gender were controlled for, rumination contributed to higher levels of hopelessness and distraction contributed to lower levels of hopelessness. Both rumination and levels of depression contributed significantly to higher levels of interpersonal distress when gender was controlled for. Ruminators were rated to have significantly more severe problems in intimate relationships while distractors were rated to have significantly higher social functioning. CONCLUSION: Our study suggests the importance of teaching patients techniques to distract themselves. This could prevent patients from getting into a vicious cycle of self-absorption and increased levels of hopelessness, finding it hard to interact with people in their social network and neglecting their intimate relationships.