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Background: The Vaxxas high-density microarray patch (HD-MAP) consists of a high density of microprojections coated with vaccine for delivery into the skin. Microarray patches (MAPs) offer the possibility of improved vaccine thermostability as well as the potential to be safer, more acceptable, easier to use, and more cost-effective for the administration of vaccines than injection by needle and syringe (N&S). Here, we report a phase I trial using the Vaxxas HD-MAP to deliver a monovalent influenza vaccine that was to the best of our knowledge the first clinical trial to evaluate the safety, tolerability, and immunogenicity of lower doses of influenza vaccine delivered by MAPs., Methods and Findings: HD-MAPs were coated with a monovalent, split inactivated influenza virus vaccine containing A/Singapore/GP1908/2015 H1N1 haemagglutinin (HA). Between February 2018 and March 2018, 60 healthy adults (age 18-35 years) in Melbourne, Australia were enrolled into part A of the study and vaccinated with either: HD-MAPs delivering 15 μg of A/Singapore/GP1908/2015 H1N1 HA antigen (A-Sing) to the volar forearm (FA); uncoated HD-MAPs; intramuscular (IM) injection of commercially available quadrivalent influenza vaccine (QIV) containing A/Singapore/GP1908/2015 H1N1 HA (15 μg/dose); or IM injection of H1N1 HA antigen (15 μg/dose). After 22 days' follow-up and assessment of the safety data, a further 150 healthy adults were enrolled and randomly assigned to 1 of 9 treatment groups. Participants (20 per group) were vaccinated with HD-MAPs delivering doses of 15, 10, 5, 2.5, or 0 μg of HA to the FA or 15 μg HA to the upper arm (UA), or IM injection of QIV. The primary objectives of the study were safety and tolerability. Secondary objectives were to assess the immunogenicity of the influenza vaccine delivered by HD-MAP. Primary and secondary objectives were assessed for up to 60 days post-vaccination. Clinical staff and participants were blind as to which HD-MAP treatment was administered and to administration of IM-QIV-15 or IM-A/Sing-15. All laboratory investigators were blind to treatment and participant allocation. Two further groups in part B (5 participants per group), not included in the main safety and immunological analysis, received HD-MAPs delivering 15 μg HA or uncoated HD-MAPs applied to the forearm. Biopsies were taken on days 1 and 4 for analysis of the cellular composition from the HD-MAP application sites. The vaccine coated onto HD-MAPs was antigenically stable when stored at 40°C for at least 12 months. HD-MAP vaccination was safe and well tolerated; any systemic or local adverse events (AEs) were mild or moderate. Observed systemic AEs were mostly headache or myalgia, and local AEs were application-site reactions, usually erythema. HD-MAP administration of 2.5 μg HA induced haemagglutination inhibition (HAI) and microneutralisation (MN) titres that were not significantly different to those induced by 15 μg HA injected IM (IM-QIV-15). HD-MAP delivery resulted in enhanced humoral responses compared with IM injection with higher HAI geometric mean titres (GMTs) at day 8 in the MAP-UA-15 (GMT 242.5, 95% CI 133.2-441.5), MAP-FA-15 (GMT 218.6, 95% CI 111.9-427.0), and MAP-FA-10 (GMT 437.1, 95% CI 254.3-751.3) groups compared with IM-QIV-15 (GMT 82.8, 95% CI 42.4-161.8), p = 0.02, p = 0.04, p < 0.001 for MAP-UA-15, MAP-FA-15, and MAP-FA-10, respectively. Higher titres were also observed at day 22 in the MAP-FA-10 (GMT 485.0, 95% CI 301.5-780.2, p = 0.001) and MAP-UA-15 (367.6, 95% CI 197.9-682.7, p = 0.02) groups compared with the IM-QIV-15 group (GMT 139.3, 95% CI 79.3-244.5). Results from a panel of exploratory immunoassays (antibody-dependent cellular cytotoxicity, CD4+ T-cell cytokine production, memory B cell (MBC) activation, and recognition of non-vaccine strains) indicated that, overall, Vaxxas HD-MAP delivery induced immune responses that were similar to, or higher than, those induced by IM injection of QIV. The small group sizes and use of a monovalent influenza vaccine were limitations of the study., Conclusions: Influenza vaccine coated onto the HD-MAP was stable stored at temperatures up to 40°C. Vaccination using the HD-MAP was safe and well tolerated and resulted in immune responses that were similar to or significantly enhanced compared with IM injection. Using the HD-MAP, a 2.5 μg dose (1/6 of the standard dose) induced HAI and MN titres similar to those induced by 15 μg HA injected IM., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR.org.au), trial ID 108 ACTRN12618000112268/U1111-1207-3550., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: AHF, KW, ACID are paid employees of Vaxxas Pty Ltd. JWW, PT, GJPF and JH received consulting fees from Vaxxas Pty Ltd. JWW and MV are employees of the University of Queensland which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. MP is an employee of 360Biolabs Pty Ltd which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. JDL is an employee of Nucleus Network which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. BF is an employee of Avance Clinical (formerly CPR Pharma Services) which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. AW is an employee of Melbourne University which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. AW has received travel expenses from Vaxxas Pty Ltd to attend data-review meetings.

Purpose: To examine the response or pre- and postmatch salivary immunoglobulin A concentration ([s-IgA]) to Australian Football League (AFL) match play and investigate the acute and cumulative influence of player workload and postmatch [s-IgA] after repeated participation in AFL match play., Methods: Eleven elite AFL athletes (21.8±2.4 y, 186.9±7.9 cm, 87.4±7.5 kg) were monitored throughout 3 matches during the preseason that were separated by 7 d. Saliva samples were collected across each AFL match at 24 h and 1 h prematch and 1, 12, 36, and 60 h postmatch to determine [s-IgA]. Global positioning systems (GPS) with integrated triaxial accelerometers were used to determine total player workload during match play. Hypothesis testing was conducted for time-dependent changes in [s-IgA] and player load using a repeated-measures ANOVA., Results: Player load during match 3 (1266±124.6 AU) was significantly (P<.01) greater than in match 1 (1096±115.1 AU) and match 2 (1082±90.4 AU). Across match 3, [s-IgA] was significantly (P<.01) suppressed at 2 postmatch measures (12 and 36 h) compared with prematch measures (24 and 1 h), which coincided with significantly (P<.01) elevated player load., Conclusion: The findings indicate that an increase in player load during AFL preseason match play resulted in compromised postmatch mucosal immunological function. Longitudinal assessment of AFL-match player load and mucosal immunological function across the first 60 h of recovery may augment monitoring and preparedness strategies for athletes.

We studied serum IgA as antibodies to dietary antigens (Ag), as lectin-binding molecules, and as conglutinin-binding immune complexes (IgAIC) in people from geographical areas in which IgA nephropathy (IgAGN) is particularly frequent. Sera from 63 Italian, 21 Australian, and 25 Japanese patients affected by IgAGN and 24 Italian, 20 Australian, and 40 Japanese healthy controls were studied. Increased values of IgAIC were detected in 42.8% of Italian patients, while only in 23.8% and 8% of Australian and Japanese patients, respectively. Mean values were significantly increased only in Italian patients (P less than 0.0001). Positive values of IgA antibodies against dietary Ag had variable prevalences, but again Italian patients showed the highest frequency, from 19% to 28.5% versus 0 to 38% in Australians and 0 to 16% in Japanese. Mean values of these antibodies were not significantly increased in any patient groups in comparison to the corresponding healthy populations. However, patients with elevated values of IgAIC had significantly higher serum concentrations of antibodies to alimentary components and a linear correlation was found between IgAIC and some IgA antibodies to food components. The relationship between these two series of data was particularly evident for Italian and Australian IgAGN patients. Moreover, the patients with positive data tended to have a cluster of increased levels of IgA antibodies against several alimentary Ag at the same time. A linear correlation was evident between values of IgA antibodies to gluten fractions and to heterologous albumins. None of these correlations was evident among healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Intestinal immunoglobulin levels were quantitated in undernourished Indonesian children with enteric infections and normally nourished Indonesians with and without enteric infections. These were compared to the same parameters in Australian Aboriginal children (also suffering undernutrition) and normal Caucasian children. Children with enteric infections displayed equally elevated levels of intestinal immunoglobulin irrespective of their nutritional status. Intestinal infections appeared to elevate IgG levels more than secretory IgA levels in the age group examined. However, it appeared likely that some of the EgG was serum-derived whereas the IgA appeared to be locally produced. There was no apparent deficiency in the capacity of undernourished children to manufacture and secrete immunoglobulin in the gut.