Long term follow up of persistence of immunity following quadrivalent Human Papillomavirus (HPV) vaccine in immunocompromised children

Background: Human Papillomavirus (HPV) causes significant burden of HPV-related diseases, which are more prevalent in immunosuppressed compared to immunocompetent people. We conducted a multi-centre clinical trial to determine the immunogenicity and reactogenicity of HPV vaccine in immunocompromised children. Here we present the immunogenicity results 5 years post vaccination. Methods: We followed up immunocompromised children (5-18 years) with a range of specified underlying conditions who were previously recruited from three Australian paediatric hospitals. Participants received three doses of quadrivalent HPV vaccine (Gardasil Quadrivalent HPV Types 6, 11, 16, 18) and were followed up between 2007 and 2016 (60 months post-vaccination). The immunogenicity primary outcome was seroconversion and geometric mean titres (GMT) of the quadrivalent HPV vaccine serotypes in the study. Results: Of the 59 original participants, 37 were followed up at 60 months. The proportion of participants who seroconverted were: 86.5%, 89.2%, 89.2%, 91.9% by competitive Luminex immunoassay (cLIA) and 83.8%, 83.8%, 94.6%, 78.4% by total immunoglobulin G assays (IgG) for serotypes 6, 11, 16 and 18 respectively. GMT values ranged from 118 (95%CI: 79-177) for serotype 11, to 373 (95%CI: 215-649) for serotype 16 by cLIA. For IgG, serotype 16 had the highest GMT of 261 (95%CI: 143-477) and serotype 18 had the lowest value of 37 (95%CI: 21-68). All antibody titres were lower in females compared to males but the difference was not statistically significant except for serotype 16. No serious adverse event was reported during this follow-up period. Conclusion: Our evidence, although limited by small numbers, is reassuring that a three dose schedule of HPV vaccine remains immunogenic in immunocompromised children to five years post vaccination. Large scale studies are required to determine long term protection in immunocompromised children.C. Raina MacIntyre, Peter J. Shaw, Fiona E. Mackie, Christina Boros, Helen Marshall, Holly Seale, Sean E. Kennedy, Aye Moa, Abrar Ahmad Chughtai, Mallory Trent, Edward V O’Loughlin, Michael Stormo

Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome:Results from The GALA Study

BACKGROUND: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (&gt;6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and &lt;10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those &lt;5.0 mg/dL. Median TB levels between ≥5.0 and &lt;10.0 mg/dL and &gt;10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to &lt;5.0 mg/dL. Median TB &lt;5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p&lt;0.001).CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB &lt;5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.</p

Regulation of human CD4+ T cell differentiation

Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation

Oral health: epidemiology and concordance in Australian children and parents

First published: 28 May 2021Introduction: Studying parent-child pair health provides the opportunity to identify risk factors and opportunities for oral health prevention and intervention focusing on the family context. The aim of this study was to describe the oral health of children aged 11-12 years and their parents in a national sample of parent-child dyads in Australia. Methods: The Child Health CheckPoint is a study of 11 to 12-year-old children and one parent nested within the Longitudinal Study of Australian Children, a nationally representative cohort study. In 2015-16, the study collected two-dimensional photographic intra-oral images and was scored using visual assessments of the teeth, oral hygiene and malocclusion. Results: Of the 1874 CheckPoint families, 1396 biological parent-child pairs had at least one oral health measure recorded. Over two-thirds of children had moderate to severe gingival inflammation (69.7%, 95%CI 64.7-74.9). Parents had a lower proportion of poor oral hygiene (2.1%, 95% CI 1.4-3.0) than children (13.0%, 95% CI 11.3-14.9). High concordance was seen in the Modified Gingival Index correlation coefficient 0.49 (95%CI 0.44-0.53). Conclusion: The high concordance in gingival health between child-parent pairs supports the familial and behavioural links established in previous studies. Children had poorer oral hygiene but fewer visible dental caries lesions than their parents. As dental caries is a chronic and cumulative disease, preventive interventions targeting children's oral hygiene are needed.Nicole Stormon, Susan Clifford, Katherine Lange, Clare Mangoyana, Pauline Ford, Melissa Wake, Ratilal Lallo

Evidence of a Generalized Defect of Acinar Cell Function in Shwachman-Diamond Syndrome

: Because the acinar cells of the exocrine pancreas in patients with Shwachman-Diamond syndrome (SDS) are severely depleted, we hypothesized that a similar deficiency may be present in acinar cells of the parotid gland

Immunogenicity and persistence of immunity of a quadrivalent Human Papillomavirus (HPV) vaccine in immunocompromised children

Abstract not availableC. Raina MacIntyre, Peter Shaw, Fiona E. Mackie, Christina Boros, Helen Marshall, Michelle Barnes, Holly Seale, Sean E. Kennedy Aye Moaa, Andrew Hayen, Abrar Ahmad Chughtai, Edward V. O, Loughlin, Michael Stormo