Maternal supplementation with LGG reduces vaccine-specific immune responses in infants at high-risk of developing allergic disease

Probiotics are defined as live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Among their pleiotropic effects, inhibition of pathogen colonization at the mucosal surface as well as modulation of immune responses are widely recognized as the principal biological activities of probiotic bacteria. In recent times, the immune effects of probiotics have led to their application as vaccine adjuvants, offering a novel strategy for enhancing the efficacy of current vaccines. Such an approach is particularly relevant in regions where infectious disease burden is greatest and where access to complete vaccination programs is limited. In this study, we report the effects of the probiotic, Lactobacillus rhamnosus GG (LGG) on immune responses to tetanus, Haemophilus influenzae type b (Hib) and pneumococcal conjugate (PCV7) vaccines in infants. This study was conducted as part of a larger clinical trial assessing the impact of maternal LGG supplementation in preventing the development of atopic eczema in infants at high-risk for developing allergic disease. Maternal LGG supplementation was associated with reduced antibody responses against tetanus, Hib, and pneumococcal serotypes contained in PCV7 (N = 31) compared to placebo treatment (N = 30) but not total IgG levels. Maternal LGG supplementation was also associated with a trend to increased number of tetanus toxoid-specific T regulatory in the peripheral blood compared to placebo-treated infants. These findings suggest that maternal LGG supplementation may not be beneficial in terms of improving vaccine-specific immunity in infants. Further clinical studies are needed to confirm these findings. As probiotic immune effects can be species/strain specific, our findings do not exclude the potential use of other probiotic bacteria to modulate infant immune responses to vaccines

Epigenome targeting by probiotic metabolites

BACKGROUND: The intestinal microbiota plays an important role in immune development and homeostasis. A disturbed microbiota during early infancy is associated with an increased risk of developing inflammatory and allergic diseases later in life. The mechanisms underlying these effects are poorly understood but are likely to involve alterations in microbial production of fermentation-derived metabolites, which have potent immune modulating properties and are required for maintenance of healthy mucosal immune responses. Probiotics are beneficial bacteria that have the capacity to alter the composition of bacterial species in the intestine that can in turn influence the production of fermentation-derived metabolites. Principal among these metabolites are the short-chain fatty acids butyrate and acetate that have potent anti-inflammatory activities important in regulating immune function at the intestinal mucosal surface. Therefore strategies aimed at restoring the microbiota profile may be effective in the prevention or treatment of allergic and inflammatory diseases. PRESENTATION OF THE HYPOTHESIS: Probiotic bacteria have diverse effects including altering microbiota composition, regulating epithelial cell barrier function and modulating of immune responses. The precise molecular mechanisms mediating these probiotic effects are not well understood. Short-chain fatty acids such as butyrate are a class of histone deacetylase inhibitors important in the epigenetic control of host cell responses. It is hypothesized that the biological function of probiotics may be a result of epigenetic modifications that may explain the wide range of effects observed. Studies delineating the effects of probiotics on short-chain fatty acid production and the epigenetic actions of short-chain fatty acids will assist in understanding the association between microbiota and allergic or autoimmune disorders. TESTING THE HYPOTHESIS: We propose that treatment with specific probiotic bacteria under in vivo conditions would offer the ideal conditions to examine the microbiological, immunological and epigenetic mechanisms of action. Advances in epigenetic technology now allow investigators to better understand the complex biological properties of probiotics and their metabolites. IMPLICATIONS OF THE HYPOTHESIS: Determining the precise mechanisms of probiotic action will lead to more specific and efficacious therapeutic strategies in the prevention or treatment of chronic inflammatory conditions

Repeat pneumococcal polysaccharide vaccine in Indigenous Australian adults is associated with decreased immune responsiveness.

BACKGROUND: Indigenous adults residing in the Northern Territory of Australia experience elevated rates of invasive pneumococcal disease despite the routine use of 23-valent pneumococcal polysaccharide vaccine (23vPPV). We hypothesised that the limited protection from 23vPPV may be due to hyporesponsiveness as a result of vaccine failure from repeated vaccination. To explore this possibility, we evaluated the immune response to a first and second dose of 23vPPV in Indigenous adults and a first dose of 23vPPV in non-Indigenous adults. METHODS: Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline and at one month post-vaccination. Individuals were considered to have an adequate immune response if paired sera demonstrated either: a four-fold rise in antibody concentration; a two-fold rise if the post vaccination antibody was >1.3μg/ml but 4.0μg/ml for at least half of the serotypes tested (12/23). Our per-protocol analysis included the comparison of outcomes for three groups: Indigenous adults receiving a second 23vPPV dose (N=20) and Indigenous (N=60) and non-Indigenous adults (N=25) receiving their first 23vPPV dose. RESULTS: All non-Indigenous adults receiving a first dose of 23vPPV mounted an adequate immune response (25/25). There was no significant difference in the proportion of individuals with an adequate response using our definition (primary endpoint), with 88% of Indigenous adults mounted an adequate response following first dose 23vPPV (53/60) compared to 70% having an adequate response following a second dose of 23vPPV (14/20; p=0.05). The risk difference between Indigenous participants receiving first dose compared to non-Indigenous participants receiving first dose was significant when comparing a response threshold of at least 70% (-27%, 95% CI: -43% to -11%; p=0.01) and 90% (-38%, 95% CI: -60% to -16%; p=0.006) of serotypes with a positive response. CONCLUSION: Indigenous participants demonstrated a poorer response to a first dose 23vPPV compared to their non-Indigenous counterparts, with lower IgG following a second 23vPPV dose. These findings highlight the critical need to evaluate the efficacy of future pneumococcal vaccine programs in the Australian Indigenous populations that recommend repeated doses of 23vPPV

A systematic review of quality and consistency of clinical practice guidelines on the primary prevention of food allergy and atopic dermatitis

Background and aims: With an increasing number of Clinical Practice Guidelines (CPGs) addressing primary prevention of food allergy and atopic dermatitis, it is timely to undertake a comprehensive assessment of the quality and consistency of recommendations and evaluation of their implementability in different geographical settings. Methods: We systematically reviewed CPGs from 8 international databases and extensive website searches. Seven reviewers screened records in any language and then used the AGREE II and AGREE REX instruments to critically appraise CPGs published between January 2011 and April 2022. Results: Our search identified 2138 relevant articles, of which 30 CPGs were eventually included. Eight (27%) CPGs were shortlisted based on our predefined quality criteria of achieving scores \u3e70% in the “Scope and Purpose” and “Rigour of Development” domains of the AGREE II instrument. Among the shortlisted CPGs, scores on the “Applicability” domain were generally low, and only 3 CPGs rated highly in the “Implementability” domain of AGREE-REX, suggesting that the majority of CPGs fared poorly on global applicability. Recommendations on maternal diet and complementary feeding in infants were mostly consistent, but recommendations on use of hydrolysed formula and supplements varied considerably. Conclusion: The overall quality of a CPG for Food Allergy and Atopic Dermatitis prevention did not correlate well with its global applicability. It is imperative that CPG developers consider stakeholders’ preferences, local applicability, and adapt existing recommendations to each individual population and healthcare system to ensure successful implementation. There is a need for development of high-quality CPGs for allergy prevention outside of North America and Europe. PROSPERO registration number: CRD42021265689

Advance Access published March 30

Summary The modern environment is associated with an increasing burden of non-communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n ¼ 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early-life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2-and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [[email protected]]

A phase i study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates

<p>Abstract</p> <p>Background</p> <p>Defects in skin barrier function are associated with an increase risk of eczema and atopic sensitisation. Ceramide-dominant triple lipid mixture may improve and maintain the infant skin barrier function, and if shown to be safe and feasible, may therefore offer an effective approach to reduce the incidence of eczema and subsequent atopic sensitisation. We sort to assess the safety and compliance with daily application of a ceramide-dominant triple lipid formula (EpiCeram™) commencing in the neonatal period for the prevention of eczema.</p> <p>Methods</p> <p>Ten infants (0-4 weeks of age) with a family history of allergic disease were recruited into an open-label, phase one trial of daily application of EpiCeram™ for six weeks. The primary outcomes were rate of compliance and adverse events. Data on development of eczema, and physiological properties of the skin (transepidermal water loss, hydration, and surface pH) were also measured.</p> <p>Results</p> <p>Eighty percent (8/10) of mothers applied the study cream on 80% or more of days during the six week intervention period. Though a number of adverse events unrelated to study product were reported, there were no adverse skin reactions to the study cream.</p> <p>Conclusions</p> <p>These preliminary results support the safety and parental compliance with daily applications of a ceramide-dominant formula for the prevention of eczema, providing the necessary ground work for a randomised clinical trial to evaluate EpiCeram™ for the prevention of eczema.</p> <p>Trial registration</p> <p>The study was listed at the Australian/New Zealand Clinical Trial Registry (ANZCTR): reg. no. <a href="http://www.anzctr.org.au/ACTRN12609000727246.aspx">ACTRN12609000727246</a>.</p

The ProPrems trial: investigating the effects of probiotics on late onset sepsis in very preterm infants

BACKGROUND: Late onset sepsis is a frequent complication of prematurity associated with increased mortality and morbidity. The commensal bacteria of the gastrointestinal tract play a key role in the development of healthy immune responses. Healthy term infants acquire these commensal organisms rapidly after birth. However, colonisation in preterm infants is adversely affected by delivery mode, antibiotic treatment and the intensive care environment. Altered microbiota composition may lead to increased colonisation with pathogenic bacteria, poor immune development and susceptibility to sepsis in the preterm infant.Probiotics are live microorganisms, which when administered in adequate amounts confer health benefits on the host. Amongst numerous bacteriocidal and nutritional roles, they may also favourably modulate host immune responses in local and remote tissues. Meta-analyses of probiotic supplementation in preterm infants report a reduction in mortality and necrotising enterocolitis. Studies with sepsis as an outcome have reported mixed results to date.Allergic diseases are increasing in incidence in "westernised" countries. There is evidence that probiotics may reduce the incidence of these diseases by altering the intestinal microbiota to influence immune function. METHODS/DESIGN: This is a multi-centre, randomised, double blinded, placebo controlled trial investigating supplementing preterm infants born at < 32 weeks' gestation weighing < 1500 g, with a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis). A total of 1,100 subjects are being recruited in Australia and New Zealand. Infants commence the allocated intervention from soon after the start of feeds until discharge home or term corrected age. The primary outcome is the incidence of at least one episode of definite (blood culture positive) late onset sepsis before 40 weeks corrected age or discharge home. Secondary outcomes include: Necrotising enterocolitis, mortality, antibiotic usage, time to establish full enteral feeds, duration of hospital stay, growth measurements at 6 and 12 months' corrected age and evidence of atopic conditions at 12 months' corrected age. DISCUSSION: Results from previous studies on the use of probiotics to prevent diseases in preterm infants are promising. However, a large clinical trial is required to address outstanding issues regarding safety and efficacy in this vulnerable population. This study will address these important issues. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN012607000144415The product "ABC Dophilus Probiotic Powder for Infants®", Solgar, USA has its 3 probiotics strains registered with the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ--German Collection of Microorganisms and Cell Cultures) as BB-12 15954, B-02 96579, Th-4 15957

Updated Guidance Regarding The Risk ofAllergic Reactions to COVID-19 Vaccines and Recommended Evaluation and Management: A GRADE Assessment, and International Consensus Approach

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against \u3e 15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history

The maternal microbiome during pregnancy and allergic disease in the offspring

There is substantial epidemiological and mechanistic evidence that the increase in allergic disease and asthma in many parts of the world in part relates to changes in microbial exposures and diet acting via the composition and metabolic products of the intestinal microbiome. The majority of research in this field has focused on the gut microbiome during infancy, but it is increasingly clear that the maternal microbiome during pregnancy also has a key role in preventing an allergy-prone immune phenotype in the offspring. The mechanisms by which the maternal microbiome influences the developing fetal immune system include alignment between the maternal and infant regulatory immune status and transplacental passage of microbial metabolites and IgG. Interplay between microbial stimulatory factors such as lipopolysaccharides and regulatory factors such as short-chain fatty acids may also influence on fetal immune development. However, our understanding of these pathways is at an early stage and further mechanistic studies are needed. There are also no data from human studies relating the composition and metabolic activity of the maternal microbiome during pregnancy to the offspring's immune status at birth and risk of allergic disease. Improved knowledge of these pathways may inform novel strategies for tackling the increase in allergic disorders in the modern world