Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells.

Background & Aims: Liver diseases resulting from chronic HBV infection are a significant cause of morbidity and mortality. Vaccines that elicit T-cell responses capable of controlling the virus represent a treatment strategy with potential for long-term effects. Here, we evaluated vaccines that induce the activity of type I natural killer T (NKT) cells to limit viral replication and license stimulation of conventional antiviral T-cells. Methods: Vaccines were prepared by conjugating peptide epitopes to an NKT-cell agonist to promote co-delivery to antigen-presenting cells, encouraging NKT-cell licensing and stimulation of T cells. Activity of the conjugate vaccines was assessed in transgenic mice expressing the complete HBV genome, administered intravenously to maximise access to NKT cell-rich tissues. Results: The vaccines induced only limited antiviral activity in unmanipulated transgenic hosts, likely attributable to NKT-cell activation as T-cell tolerance to viral antigens is strong. However, in a model of chronic hepatitis B involving transfer of naive HBcAg-specific CD8+ T cells into the transgenic mice, which typically results in specific T-cell dysfunction without virus control, vaccines containing the targeted HBcAg epitope induced prolonged antiviral activity because of qualitatively improved T-cell stimulation. In a step towards a clinical product, vaccines were prepared using synthetic long peptides covering clusters of known HLA-binding epitopes and shown to be immunogenic in HLA transgenic mice. Predictions based on HLA distribution suggest a product containing three selected SLP-based vaccines could give >90 % worldwide coverage, with an average of 3.38 epitopes targeted per individual. Conclusions: The novel vaccines described show promise for further clinical development as a treatment for chronic hepatitis B. Impact and Implications: Although there are effective prophylactic vaccines for HBV infection, it is estimated that 350-400 million people worldwide have chronic hepatitis B, putting these individuals at significant risk of life-threatening liver diseases. Therapeutic vaccination aimed at activating or boosting HBV-specific T-cell responses holds potential as a strategy for treating chronic infection, but has so far met with limited success. Here, we show that a glycolipid-peptide conjugate vaccine designed to coordinate activity of type I NKT cells alongside conventional antiviral T cells has antiviral activity in a mouse model of chronic infection. It is anticipated that a product based on a combination of three such conjugates, each prepared using long peptides covering clusters of known HLA-binding epitopes, could be developed further as a treatment for chronic hepatitis B with broad global HLA coverage.

Does socioeconomic status impact the relationship between school absence and outcomes?

Absence from school, especially frequent or prolonged absence, is acknowledged as a potential factor in school dropout and suboptimal academic achievement. The issue of absence from school took on added significance in 2020 with the onset of the COVID-19 crisis, which resulted in schooling interruptions in several jurisdictions. However, there is little agreement in the literature on the exact relationship between absence and school outcomes as a function of socioeconomic status (SES). Using nationally representative pre-COVID longitudinal data of young Australians aged 12-13 and 14-15, this paper examines the relationship between absence from school on the one hand and school belonging and academic achievement (numeracy and reading test scores) on the other. The paper also examines whether SES intersects this relationship. Controlling for gender, prior educational achievement, computer access, and time spent doing homework, the study finds that absence impacts belonging, but that SES does not significantly influence this relationship. The effect of absence on reading is not significant either. However, absence is associated with numeracy outcomes, with the strongest associations among low SES young people at age 14. Policy implications of these findings are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s13384-022-00535-2.

Glycolipid-peptide conjugate vaccines elicit CD8+ T-cell responses and prevent breast cancer metastasis.

Objectives: Metastasis is the principal cause of breast cancer mortality. Vaccines targeting breast cancer antigens have yet to demonstrate clinical efficacy, and there remains an unmet need for safe and effective treatment to reduce the risk of metastasis, particularly for people with triple-negative breast cancer (TNBC). Certain glycolipids can act as vaccine adjuvants by specifically stimulating natural killer T (NKT) cells to provide a universal form of T-cell help. Methods: We designed and made a series of conjugate vaccines comprising a prodrug of the NKT cell-activating glycolipid α-galactosylceramide covalently linked to tumor-expressed peptides, and assessed these using E0771- and 4T1-based breast cancer models in vivo. We employed peptides from the model antigen ovalbumin and from clinically relevant breast cancer antigens HER2 and NY-ESO-1. Results: Glycolipid-peptide conjugate vaccines that activate NKT cells led to antigen-presenting cell activation, induced inflammatory cytokines, and, compared with peptide alone or admixed peptide and α-galactosylceramide, specifically enhanced CD8+ T-cell responses against tumor-associated peptides. Primary tumor growth was delayed by vaccination in all tumor models. Using 4T1-based cell lines expressing HER2 or NY-ESO-1, a single administration of the relevant conjugate vaccine prevented tumor colonisation of the lung following intravenous inoculation of tumor cells or spontaneous metastasis from breast, respectively. Conclusion: Glycolipid-peptide conjugate vaccines that activate NKT cells prevent lung metastasis in breast cancer models and warrant investigation as adjuvant therapies for high-risk breast cancer.

Potential Association Between Dietary Fibre and Humoral Response to the Seasonal Influenza Vaccine.

Influenza vaccination is an effective public health measure to reduce the risk of influenza illness, particularly when the vaccine is well matched to circulating strains. Notwithstanding, the efficacy of influenza vaccination varies greatly among vaccinees due to largely unknown immunological determinants, thereby dampening population-wide protection. Here, we report that dietary fibre may play a significant role in humoral vaccine responses. We found dietary fibre intake and the abundance of fibre-fermenting intestinal bacteria to be positively correlated with humoral influenza vaccine-specific immune responses in human vaccinees, albeit without reaching statistical significance. Importantly, this correlation was largely driven by first-time vaccinees; prior influenza vaccination negatively correlated with vaccine immunogenicity. In support of these observations, dietary fibre consumption significantly enhanced humoral influenza vaccine responses in mice, where the effect was mechanistically linked to short-chain fatty acids, the bacterial fermentation product of dietary fibre. Overall, these findings may bear significant importance for emerging infectious agents, such as COVID-19, and associated de novo vaccinations.

Practise till you drop: Trialing an online intervention for late-career medical practitioners to promote planning for retirement.

Many medical practitioners in Australia work beyond the traditional retirement age. Transitioning to retirement is important, however, because the likelihood of poorer clinical outcomes increases with practitioner age. The objective of the present study was to develop and trial an online educational intervention to promote planning for a smoother transition to retirement using a non-randomized control group pre- and post-test design. Medical practitioners aged 55 or over (N = 262, Mage = 61.9) and working 30 or more hours per week were recruited to complete four online modules that addressed a range of topics (physical, health, financial, social, cognitive, and emotional well-being) and encouraged planning for retirement resources. Outcome measures included work centrality, mastery, and goal perceptions across the aforementioned resource domains. Eighty-one doctors completed post-training measures; a control group who completed only the measures (n = 23) and a training group (n = 58). Pre-post comparisons showed no significant changes for the control group. However, the training group at Time 2 showed lower work centrality t(57) = 2.12, (p = .036), and changes to social t(57) = 2.35, (p = .022), emotional t(57) = 3.18, (p = .002) and health goal perceptions t(57) = -2.02, (p = .049). Controlling for baseline scores and self-selection bias determinants, Generalized Linear Model (GLM) analyses indicated a training group increase in mastery scores (ß = 0.87, p = .045) and decrease in negative perception of the consequence of not meeting emotional goals (ß = -0.37, p = .043). Although not significant, GLM results also showed an increase in resources, three of four health goal domains and financial goals, indicating the potential for positive training effects in future applications of the program. The online retirement planning resource showed promise in promoting a sense of mastery and a reassessment of retirement plans, taking into consideration resource accumulation and goal setting across five specific goal domains. We discuss the theoretical and practical implications of our findings.

Early adolescent drinking and cannabis use predicts later sleep-quality problems.

A range of biopsychosocial changes occur during adolescence that contribute to changes in the sleep-wake system. Use of alcohol and cannabis also increases during early adolescence; however, limited studies have examined the associations between changes in the use of alcohol and cannabis and later sleep problems. Participants (n = 245) aged 12 years were recruited from schools and completed a baseline assessment, which included questions about their alcohol and cannabis use. Three subsequent follow-up assessments took place approximately 2.5 years (age 14 years), 4 years (age 16 years), and 6 years (age 18 years) after baseline, with sleep quality assessed at age 18 years. Earlier drug use was associated with poorer sleep quality at age 18 years, with different facets of alcohol and cannabis important in these associations. For alcohol, heavy episodic drinking across time was associated with poorer sleep; lifetime use at age 18 years (but not prior) was also associated with poorer sleep. For cannabis, recent use at age 18 years was associated with poor sleep quality. Our findings suggest that there are associations between specific facets of alcohol and cannabis use that are related to poor sleep in adolescents. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Genetic regulation of antibody responsiveness to immunization in substrains of BALB/c mice.

Antibody-mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen-specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B-cell intrinsic defect in the regulation of class-switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class-switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy.

A feasibility study: association between gut microbiota enterotype and antibody response to seasonal trivalent influenza vaccine in adults.

Objective: We investigated the potential feasibility of a randomized controlled trial of a nutritional intervention that may alter human gut microbiota and support immune defence against respiratory tract infection in adults (Proposed Study). Methods: In total, 125 healthy adults aged 18-64 participated in a 6-month study that measured antibody response to the seasonal trivalent influenza vaccine. We assessed completion rates, procedure adherence rates and the influence of possible exclusion criteria on potential recruitment into the Proposed Study. We examined whether the gut microbiota could be categorised into enterotypes, and whether there was an association between enterotypes and the antibody response to the influenza vaccine. Results: The participant completion rate was 97.6% (95% CI 93.1-99.5%). The proportions (95% CI) of participants who may be excluded for antibiotic or corticosteroid use in the 30 days prior to the study, or due to receiving the influenza vaccine in the previous two years were 9.6% (5.1-16.2), 8.0% (3.9-14.2) and 61.6% (52.5-70.2), respectively. All participants were stratified into four gut microbiota enterotypes. There was no association between these enterotypes and the antibody response to the influenza vaccine, although the study was not powered for this outcome. Conclusion: This study design is suitable for the Proposed Study. The completion rate is likely to be high, although exclusion criteria should be selected with care. Further analyses of gut microbiota composition or function in association with antibody and immune responses are warranted to explore the role of host-microbiota interactions on protective immunity.

Using Balanced Time Perspective to Explain Well-Being and Planning in Retirement.

The notion of whether people focus on the past, present or future, and how it shapes their behavior is known as Time Perspective. Fundamental to the work of two of its earliest proponents, Zimbardo and Boyd (2008), was the concept of balanced time perspective and its relationship to wellness. A person with balanced time perspective can be expected to have a flexible temporal focus of mostly positive orientations (past-positive, present-hedonistic, and future) and much less negative orientations (past-negative and present-fatalistic). This study measured deviation from balanced time perspective (DBTP: Zhang et al., 2013) in a sample of 243 mature adults aged 45 to 91 years and explored relationships to Retirement Planning, Depression, Anxiety, Stress, Positive Mood, and Negative Mood. Results indicate that DBTP accounts for unexplained variance in the outcome measures even after controlling for demographic variables. DBTP was negatively related to Retirement Planning and Positive Mood and positively related to Depression, Anxiety, Stress, and Negative Mood. Theoretical and practical implications regarding balanced time perspective are discussed.