BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1mL intradermal dose of BCG-Denmark (BCG group, n=1999) or saline (placebo group, n=1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12-months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6% to 24.5%) compared with the placebo group (19.6%; 95%CI 17.6% to 21.5%); adjusted difference +3.0 percentage points (95%CI 0.2% to 5.8%; p=0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95%CI 9.5% to 12.4%) compared with 9.6% in the placebo group (95%CI 8.3% to 11.1%); adjusted difference +1.3 percentage points (95%CI -0.7% to 3.3%, p=0.2). Breakthrough COVID-19 (post COVID-19 vaccination), and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95%CI 0.60 to 4.02, p=0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among health care workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Prevalence and Determinants of Food Allergy in the Era of Early Allergen Introduction: the EarlyNuts Population-Based Study.

BACKGROUND: Infant feeding guidelines in Australia changed in 2016 to recommend introducing common allergy-causing foods by age 1 year to prevent food allergy. Although most Australian infants now eat peanut and egg by age 6 months, some still develop food allergy despite the early introduction of allergens. OBJECTIVES: To describe the prevalence of food allergy in a cohort recruited after introducing the nationwide allergy prevention recommendations; identify characteristics of infants who developed allergy despite early introduction of allergens; and estimate the causal effect of modifiable exposures on food allergy prevalence and whether this differed between infants who were introduced to allergens before or after age 6 months. METHODS: We recruited a population-based sample of 12-month-old infants in Melbourne, Australia. Infants had skin prick tests to four foods and parents completed questionnaires. Infants with evidence of sensitization were offered oral food challenges. Prevalence estimates were adjusted using inverse probability weighting. RESULTS: In a cohort of infants (n = 1,420) in which nearly all infants had been introduced to common allergens such as egg, milk, and peanut by age 1 year, the prevalence of food allergy remained high at 11.3% (95% CI, 9.6-13.4). Infants who developed food allergy despite introduction of the allergen by age 6 months were more likely to have Asian-born parents. Early-onset moderate or severe eczema was associated with an increased odds of food allergy irrespective of whether allergens were introduced before or after age 6 months. Among infants who were introduced to peanut at age 6 months or earlier, antibiotic use by age 6 months was associated with an increased odds of peanut allergy (adjusted odds ratio = 6.03; 95% CI, 1.15-31.60). CONCLUSIONS: In a cohort in which early allergen introduction was common, the prevalence of food allergy remained high. Infants who developed food allergy despite introduction of the respective allergen by age 6 months were more likely to have had Asian parents and early-onset eczema. New interventions are needed for infants with a phenotype of food allergy that is not amenable to early allergen introduction.

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Longitudinal peanut and Ara h 2 specific-IgE, -IgG4, and -IgG4/-IgE ratios are associated with the natural resolution of peanut allergy in childhood.

BACKGROUND: There are no studies of longitudinal immunoglobulin measurements in a population-based cohort alongside challenge-confirmed peanut allergy outcomes. Little is known about biomarkers for identifying naturally resolving peanut allergy during childhood. OBJECTIVES: To measure longitudinal trends in whole peanut and component Ara h 2 sIgE and sIgG4 in the first 10 years of life, in a population cohort of children with challenge-confirmed peanut allergy, and to determine whether peanut-specific immunoglobulin levels or trends are associated with peanut allergy persistence or resolution by 10 years of age. METHODS: One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the HealthNuts study (n = 5276) were prospectively followed at ages 4, 6, and 10 years with questionnaires, skin prick tests, oral food challenges, and plasma total-IgE, sIgE and sIgG4 to peanut and Ara h 2. RESULTS: Peanut allergy resolved in 33.9% (95% CI = 25.3%, 43.3%) of children by 10 years old with most resolving (97.4%, 95% CI = 86.5%, 99.9%) by 6 years old. Decreasing Ara h 2 sIgE (p = .01) and increasing peanut sIgG4 (p < .001), Ara h 2 sIgG4 (p = .01), peanut sIgG4/sIgE (p < .001) and Ara h 2 sIgG4/sIgE (p < .001) from 1 to 10 years of age were associated with peanut allergy resolution. Peanut sIgE measured at 1 year old had the greatest prognostic value (AUC = 0.75 [95% CI = 0.66, 0.82]); however, no single threshold produced both high sensitivity and specificity. CONCLUSION: One third of infant peanut allergy resolved by 10 years of age. Decreasing sIgE and sIgG4 to peanut and Ara h 2 over time were associated with natural resolution of peanut allergy. However, biomarker levels at diagnosis were not strongly associated with the natural history of peanut allergy.

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

The Prevalence of IgE-Mediated Food Allergy and Other Allergic Diseases in the First 10 Years: The Population-Based, Longitudinal HealthNuts Study.

BACKGROUND: There are limited longitudinal data on the population prevalence of allergic conditions during childhood, and few studies have incorporated the reference standard oral food challenge to confirm food allergy. OBJECTIVE: To describe the population prevalence of IgE-mediated food allergy, eczema, asthma, and rhinitis at ages 6 and 10 years in Melbourne, Australia. METHODS: The HealthNuts study recruited 5,276 1-year-old infants in Melbourne, Australia, with repeat assessments at ages 6 and 10 years. At ages 6 and 10 years, carers completed a questionnaire on symptoms and doctor diagnosis of allergic conditions (International Study of Asthma and Allergies in Children). Children were invited to attend a clinic assessment including skin prick test, lung function tests, and oral food challenges when indicated. To minimize the impact of attrition bias, prevalence estimates among participants at ages 6 and 10 years were weighted to reflect characteristics of the whole cohort at recruitment. RESULTS: In total, 4,455 and 4,065 families participated at ages 6 and 10 years, respectively (84% and 77% of the original cohort). Of those, 73% and 55% of participants ages 6 and 10 years, respectively, completed clinical assessments. Overall, 36.5% (95% CI, 34.8-38.2) and 38.2% (95% CI, 36.5-40.1%) of 6- and 10-year-olds had at least one current allergic disease, and around one third of those had two or more allergic diseases. Food allergy occurred in 6.4% (95% CI, 5.6-7.2) of 6-year olds and 6.3% (95% CI, 5.5-7.2) of 10-year-olds. Among infants with challenge-confirmed food allergy in infancy, 45% had persistent disease at age 10 years. The prevalence of current diagnosed asthma at ages 6 and 10 years were 12.1% (95% CI, 10.9-13.3) and 13.1% (95% CI, 11.9-14.4), respectively, current eczema decreased slightly from 15.3% (95% CI, 14.1-19.7) at age 6 years to 12.9% (95% CI, 11.7-14.2) at age 10 years, and current rhinitis increased from 15.1% (95% CI, 13.9-16.5) at age 6 years to 25.0% (95% CI, 23.4-26.7) at age 10 years. CONCLUSIONS: Allergic diseases affect 40% of primary school-age children; one third have multiple allergic diagnoses. Challenge-confirmed food allergy prevalence remains high, and 45% of infants with food allergy have persistent disease to age 10 years.

The Human Health Impacts of the Red Imported Fire Ant in the Western Pacific Region Context: A Narrative Review.

Background: The red imported fire ant (RIFA) is one of the world's most destructive invasive species. RIFA stings are painful and can lead to allergic reactions, including life-threatening anaphylaxis, yet health impacts remain inadequately defined. Methods: We searched MEDLINE (Ovid) and Google Scholar (grey literature) from inception until 20 September 2023 for articles in English using search terms related to red imported fire ants and allergies, including anaphylaxis. Results: Approximately a third of the population in RIFA-infested areas are stung each year. The most frequent reaction is a sterile 1-2 mm pseudo pustule on the skin. Approximately 20% of stings cause a large local reaction and between about 0.5% and 2% stings cause a systemic allergic reaction which can range from skin symptoms to life-threatening anaphylaxis. Local biodiversity is also significantly disrupted by invading RIFA and may lead to complex adverse effects on human health, from agriculture losses to expanded ranges for pathogen vectors. Conclusions: The potential for red imported fire ants to establish themselves as an invasive species in the Western Pacific presents a substantial and costly health issue. Successful eradication and surveillance programs, to identify and eradicate new incursions, would avoid substantial health impacts and costs.

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines-an exploratory sub-study of the BRACE trial.

BACKGROUND: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. METHODS: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. FINDINGS: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. INTERPRETATION: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

A genome catalog of the early-life human skin microbiome.

BACKGROUND: Metagenome-assembled genomes have greatly expanded the reference genomes for skin microbiome. However, the current reference genomes are largely based on samples from adults in North America and lack representation from infants and individuals from other continents. RESULTS: Here we use deep shotgun metagenomic sequencing to profile the skin microbiota of 215 infants at age 2-3 months and 12 months who are part of the VITALITY trial in Australia as well as 67 maternally matched samples. Based on the infant samples, we present the Early-Life Skin Genomes (ELSG) catalog, comprising 9483 prokaryotic genomes from 1056 species, 206 fungal genomes from 13 species, and 39 eukaryotic viral sequences. This genome catalog substantially expands the diversity of species previously known to comprise human skin microbiome and improves the classification rate of sequenced data by 21%. The protein catalog derived from these genomes provides insights into the functional elements such as defense mechanisms that distinguish early-life skin microbiome. We also find evidence for microbial sharing at the community, bacterial species, and strain levels between mothers and infants. CONCLUSIONS: Overall, the ELSG catalog uncovers the skin microbiome of a previously underrepresented age group and population and provides a comprehensive view of human skin microbiome diversity, function, and development in early life.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists.

Background: Vaccines can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections. The heterologous effects of COVID-19 vaccines have not been investigated in children. Aim: To investigate heterologous and specific immunological effects of BNT162b2 COVID-19 vaccination in children. Methods: A whole blood stimulation assay was used to investigate in vitro cytokine responses to heterologous stimulants (killed pathogens, Toll-like receptor ligands) and SARS-CoV-2 antigens. Samples from 29 children, aged 5-11 years, before and 28 days after a second BNT162b2 vaccination were analysed (V2 + 28). Samples from eight children were analysed six months after BNT162b2 vaccination. Results: At V2 + 28, interferon-γ and monocyte chemoattractant protein-1 responses to S. aureus, E. coli, L. monocytogenes, BCG vaccine, H. influenzae, hepatitis B antigen, poly(I:C) and R848 stimulations were decreased compared to pre-vaccination. For most of these heterologous stimulants, IL-6, IL-15 and IL-17 responses were also decreased. There were sustained decreases in cytokine responses to viral, but not bacterial, stimulants six months after BNT162b2 vaccination. Cytokine responses to irradiated SARS-CoV-2, and spike glycoprotein subunits (S1 and S2) were increased at V2 + 28 for most cytokines and remained higher than pre-vaccination responses 6 months after BNT162b2 vaccination for irradiated SARS-CoV-2 and S1. There was no correlation between BNT162b2 vaccination-induced anti-SARS-CoV2-receptor binding domain IgG antibody titre at V2 + 28 and cytokine responses. Conclusions: BNT162b2 vaccination in children alters cytokine responses to heterologous stimulants, particularly one month after vaccination. This study is the first to report the immunological heterologous effects of COVID-19 vaccination in children.

A genome catalog of the early-life human skin microbiome.

Metagenome-assembled genomes have greatly expanded the reference genomes for skin microbiome. However, the current reference genomes are largely based on samples from adults in North America and lack representation from infants and individuals from other continents. Here we used ultra-deep shotgun metagenomic sequencing to profile the skin microbiota of 215 infants at age 2-3 months and 12 months who were part of the VITALITY trial in Australia as well as 67 maternally-matched samples. Based on the infant samples, we present the Early-Life Skin Genomes (ELSG) catalog, comprising 9,194 bacterial genomes from 1,029 species, 206 fungal genomes from 13 species, and 39 eukaryotic viral sequences. This genome catalog substantially expands the diversity of species previously known to comprise human skin microbiome and improves the classification rate of sequenced data by 25%. The protein catalog derived from these genomes provides insights into the functional elements such as defense mechanisms that distinguish early-life skin microbiome. We also found evidence for vertical transmission at the microbial community, individual skin bacterial species and strain levels between mothers and infants. Overall, the ELSG catalog uncovers the skin microbiome of a previously underrepresented age group and population and provides a comprehensive view of human skin microbiome diversity, function, and transmission in early life.

Australian Infant Food Allergy Emergency Presentations Following Updated Early Food Introduction Guidelines.

BACKGROUND: The Australasian Society of Clinical Immunology and Allergy food allergy prevention guidelines were updated in 2016 to recommend home introduction of allergenic foods actively in the first year of life, including to infants at high risk of allergy. An important consideration for parents and providers is whether this practice increases food allergy reactions or anaphylaxis. OBJECTIVE: We aimed to determine whether the 2016 update of food allergy prevention guidelines was associated with an increase in food allergy or anaphylaxis emergency department (ED) presentations. METHODS: We obtained hospital electronic medical records for infants aged 4 to 12 months who attended the Royal Children's Hospital Melbourne ED in 2015 or in 2018 with a presenting problem or an encounter diagnosis of food allergy or anaphylaxis. RESULTS: Emergency department presentations owing to food allergy increased from 1.0% (95% CI, 0.85-1.23) in 2015 to 1.4% (95% CI, 1.22-1.67) in 2018 (P = .006). There was no increase in the number of anaphylaxis presentations (28 in 2015 and 22 in 2018) or peanut anaphylaxis presentations (three in 2015 and three in 2018). Overall, the proportion of food allergy presentations attributed to IgE-mediated food allergy was similar (82.1% in 2015 and 84.1% in 2018), whereas peanut allergy presentations increased slightly, although not statically significantly, from 14.6% to 21.2% (P = .09). Food protein-induced enterocolitis syndrome ED presentations were five in 2015 (4.3%) and 12 in 2018(7.6%), although not statistically significant (P = .25). CONCLUSIONS: Changes to food allergy prevention guidelines recommending the earlier introduction of allergenic food may have led to a small increase in ED presentations for food allergy but not anaphylaxis.

Efficacy and safety of oral immunotherapy for peanut, cow's milk, and hen's egg allergy: A systematic review of randomized controlled trials.

BACKGROUND: Oral immunotherapy (OIT) is a promising treatment for food allergies; however, safety is a concern. We synthesized evidence from the best randomized controlled trials (RCTs) on efficacy/safety of OIT for desensitization (DS) and remission (sustained unresponsiveness (SU)) in IgE mediated allergy to peanut, hen's eggs, and cow's milk. BODY: We searched Pubmed, EMBASE, and Cochrane databases (Until Oct 22) identifying 16 eligible RCTs published in English measuring food allergy by food challenge at the beginning and at the end of the study. The Cochrane Risk of Bias tool was used to assess study quality. We found 18 eligible studies. There was evidence of efficacy for DS for all allergens: peanut (RR 11.32; 95% CI 5.93, 21.60, I2 49%, 8 studies); hen's egg (RR 4.67; 2.66, 8.21, I2 0%, 5 studies); cow's milk (RR 13.98; 3.51, 55.65, I2 0%, 4 studies) and evidence for SU for peanut (RR 7.74; 2.90, 20.69, I2 0%, 3 studies) and hen's egg (RR 6.91; 1.67, 28.57, I2 0%, 2 studies). Allergic events were increased with intervention, and risk of adrenaline use increased for peanut RR 2.96; 1.63, 5.35, I2 0%, 8 studies; egg RR 1.71; 0.42, 6.92, I2 0%, 6 studies; and milk RR 8.45; 2.02, 35.27, I2 0%, 4 studies. CONCLUSION: We found strong evidence that peanut, hen's egg, and cow's milk OIT can induce DS and some evidence for remission. There was a high risk of allergic reactions. Generalizability to the entire food allergic population is not known.

Infant food allergy phenotypes and association with lung function deficits and asthma at age 6 years: a population-based, prospective cohort study in Australia.

BACKGROUND: Food allergy is considered a precursor to asthma in the context of the atopic march, but the relationship between infant food allergy phenotypes and lung function and asthma in childhood is unclear. We aimed to examine the association between food sensitisation and challenge-confirmed food allergy in infancy, as well as persistent and resolved food allergy up to age 6 years, and the risk of lung function deficits and asthma at age 6 years. METHODS: The longitudinal, population-based HealthNuts cohort study in Melbourne, VIC, Australia, recruited 5276 infants children aged 1 year who attended council-run immunisation sessions between Sept 28, 2007, and Aug 5, 2011. At age 1 year, all children completed skin prick testing to four food allergens (egg, peanut, sesame, and either shrimp or cow's milk) and an oral food challenge (egg, peanut, and sesame) at the Royal Children's Hospital in Melbourne. Parents completed questionnaires about their infant's allergy history, demographic characteristics, and environmental exposures. At age 6 years, children were invited for a health assessment that included skin prick testing for ten foods (milk, egg, peanut, wheat, sesame, soy, shrimp, cashew, almond, and hazelnut) and eight aeroallergens (alternaria, cladasporum, house dust mite, cat hair, dog hair, bermuda grass, rye grass, and birch mix), oral food challenges, and lung function testing by spirometry. Questionnaires completed by parents (different to those completed at age 1 year) captured the child's allergy and respiratory history and demographics. We investigated associations between food allergy phenotypes (food-sensitised tolerance or food allergy; and ever, transient, persistent, or late-onset food allergy), lung function spirometry measures (forced expiratory volume in 1 sec [FEV1] and forced vital capacity [FVC] z-scores, FEV1/FVC ratio, forced expiratory flow at 25% and 75% of the pulmonary volume [FEF25-75%], and bronchodilator responsiveness), and asthma using regression methods. Only children with complete data on the exposure, outcome, and confounders were included in models. Infants without food sensitisation or food allergy at age 1 year and 6 years served as the reference group. FINDINGS: Of 5276 participants, 3233 completed the health assessment at age 6 years and were included in this analysis. Food allergy, but not food-sensitised tolerance, at age 1 year was associated with reduced FEV1 and FVC (aß -0·19 [95% CI -0·32 to -0·06] and -0·17 [-0·31 to -0·04], respectively) at age 6 years. Transient egg allergy was associated with reduced FEV1 and FVC compared with never having egg allergy (-0·18 [95% CI -0·33 to -0·03] and -0·15 [-0·31 to 0·00], respectively), whereas persistent egg allergy was not (FEV1 -0·09 [-0·48 to 0·31]; FVC -0·20 [-0·62 to 0·21]). Transient peanut allergy was associated with reduced FEV1 and FVC (FEV1 aß -0·37 [-0·79 to 0·04] and FVC aß -0·55 [-0·98 to -0·12]), in addition to persistent peanut allergy (FEV1 aß -0·30 [-0·54 to -0·06] and FVC aß-0·30 [-0·55 to -0·05]), and late-onset peanut allergy (FEV1 aß -0·62 [-1·06 to -0·18] and FVC aß-0·49 [-0·96 to -0·03]). Estimates suggested that food-sensitised tolerance and food allergy were associated with reduced FEF25-75%, although some estimates were imprecise. Food allergy phenotypes were not associated with an FEV1/FVC ratio. Late-onset peanut allergy was the only allergy phenotype that was possibly associated with increased risk of bronchodilator responsiveness (2·95 [95% CI 0·77 to 11·38]). 430 (13·7%) of 3135 children were diagnosed with asthma before age 6 years (95% CI 12·5-15·0). Both food-sensitised tolerance and food allergy at age 1 year were associated with increased asthma risk at age 6 years (adjusted odds ratio 1·97 [95% CI 1·23 to 3·15] and 3·69 [2·81 to 4·85], respectively). Persistent and late-onset peanut allergy were associated with higher asthma risk (3·87 [2·39 to 6·26] and 5·06 [2·15 to 11·90], respectively). INTERPRETATION: Food allergy in infancy, whether it resolves or not, is associated with lung function deficits and asthma at age 6 years. Follow-up studies of interventions to prevent food allergy present an opportunity to examine whether preventing these food allergies improves respiratory health. FUNDING: National Health & Medical Research Council of Australia, Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government's Operational Infrastructure Support Program.

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).