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

Evaluation of toxicity of Acacia angustissima in a rat bioassay

Acacia angustissima has potential as a fodder tree, but was toxic to sheep when fed without adaptation at levels higher than 50 g per day in previous studies. In the present study it was determined that rats are sensitive to anti-nutritional factor(s) of A. angustissima and can therefore be used in bioassays to evaluate the toxicity of this legume. Weanling rats fed a diet supplemented with 7.5% A. angustissima had reduced intake and average daily gain (ADG) (4.5 and -0.8 g/d) when compared to rats fed a diet containing 7.5% Medicago sativa (6.8 and 2.4 g/d). When A. angustissima leaves were incubated in the rumen of steers for 24 h before feeding to the rats no toxicity symptoms were observed suggesting that the anti-nutritional factors were either transformed by rumen microbial activity, solubilized out of the plant leaves or reduced due to oven drying. Variable mild lymphocytic typhlitis was observed in cecal tissues in both groups fed 7.5% A. angustissima, either whole or after rumen incubation. No other significant histological or gross pathological changes were observed. In order to ascertain the nature of the anti nutritional factor(s) milled A. angustissima leaf material was extracted with a variety of solvents and extracts added to rat diets to determine their effect. Intake and ADG (6.0 and 0.5 g/d) were significantly reduced in rats fed a diet containing a 70% acetone extract compared to the rats fed the control diet (8.8 and 3.1 g/d). The rats fed the 70% acetone extract containing diet showed an increase in cecal wet weight and/or contents, salivary gland dry weight (% of live weight), fecal nitrogen excretion and increased concentrations of proline, glycine and glutamic acid in the feces. Further fractionation of a 70% acetone fraction was performed to yield ethyl acetate, acetone and watersoluble fractions. Again intake and ADG (6.7 and 0.2 g/d) were significantly reduced in rats fed a diet containing a 70% acetone extract compared to the rats fed the control diet (10.7 and 3.6 g/d). In vitro incubation of the 70% acetone fraction with rumen fluid did not result in significant microbial transformation of the anti-nutritional factors (7.4 and 0.1 g/d). Intake and ADG were significantly reduced when compared to the control diet in the diet containing the ethyl acetate soluble fraction (8.6 and 2.1 g/d), but no anti-nutritional effects were noted in the diets containing the acetone (11.3 and 3.8 g/d) or water-soluble fractions (11.1 and 3.8 g/d) of the 70% acetone extraction. The size increase in salivary glands, increased fecal nitrogen excretion and increased concentrations of proline, glycine and glutamic acid in the feces together with decreased intake and ADG when diets are fed containing phenolics indicate that phenolics were the major component involved in the antinutritional effects of A. angustissima used in these studies. Condensed tannins, but not gallotannins, were detected in phenolic-containing plant extracts. Inhibition of intake and weight gain of condensed tannin containing diets was reversed by polyethylene glycol, which complexes with tannins