Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. METHODS AND FINDINGS: A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)-glycoprotein (GP)-specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%-100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264-908), 556 (95% CI: 280-1,101), 1,245 (95% CI: 899-1,724), and 1,503 (95% CI: 931-2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647-1,591), 1,887 (1,154-3,085), 1,445 (1,013-2,062), and 3,958 (2,249-6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025-1,989), and children, 1,620 (95% CI: 806-3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. CONCLUSIONS: Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000919191

Systematic review on antigens for serodiagnosis of visceral leishmaniasis, with a focus on East Africa.

BackgroundAccurate and accessible diagnosis is key for the control of visceral leishmaniasis (VL). Yet, current diagnostic tests for VL have severe limitations: they are invasive or not suitable as point of care (POC) test or their performance is suboptimal in East Africa. We analysed the antigens in the VL serodiagnostics development pipeline to identify shortcomings and to propose strategies in the development of an alternative POC test for VL in East Africa.ObjectivesThe objective of this study was to identify and to analyse all antigens for VL serodiagnosis that have been published before 2018 in order to identify candidates and gaps in the pipeline for a new POC test in East Africa.MethodsA systematic literature search was performed on PubMed for original research articles on Leishmania-specific antigens for antibody detection of VL in humans. From each article, the following information was extracted: the antigen name, test format and characteristics, its reported sensitivity and specificity and study cohort specifications.ResultsOne hundred and seven articles containing information about 96 tests based on 89 different antigens were included in this study. Eighty six of these tests, comprising 80 antigens, were evaluated in phase I and II studies only. Only 20 antigens, all of which are native, contain a carbohydrate and/or lipid moiety. Twenty-four antigens, of which 7 are non-native, are composed of antigen mixtures. Nineteen tests, comprising 18 antigens, have been evaluated on East African specimens, of which only 2 (rK28 based immunochromatographic test and intact promastigote based indirect fluorescent antibody technique) consistently showed sensitivities above 94 and specificities above 97% in a phase III study and one in a phase II study (dot blot with SLA). Only rK28 is a non-native mixture of antigens which we consider suitable for further evaluation and implementation.ConclusionsThe development pipeline for an alternative serodiagnostic test for VL is almost empty. Most antigens are not sufficiently evaluated. Non-protein antigens and antigen mixtures are being neglected. We propose to expand the evaluation of existing antigen candidates and to investigate the diagnostic potential of defined non-native carbohydrate and lipid antigens for VL serodiagnosis in East Africa

Behavioural and clinical predictors for Loiasis

Background: Loiasis is a vector-borne disease in Central and West Africa. While there is still uncertainty to what extent loiasis is responsible for population morbidity, individuals having both loiasis and onchocerciasis have a high risk of fatal encephalopathy when treatment (ie, ivermectin) for onchocerciasis is given. Therefore it is current policy that communities of high loiasis-burden are excluded from mass drug administration programmes of ivermectin. To address this treatment gap we present diagnostic scores, based on clinical and behavioural predictors that may help to rapidly identify sub-groups with loiasis within high-burden communities. Methods: A cross-sectional survey was performed in the province of la Ngounie, Gabon between December 2015 and Februrary 2016 and 947 participants of all ages were recruited. Clinical parameters and behavioural exposure factors were ascertained by questionnaire-based interviews. Parasitological analysis of blood samples was performed for L. loa detection. Diagnostic scores consisting of clinical and behavioural factors were modelled to predict loiasis in sub-groups residing in endemic regions. Results: Increasing sylvan exposure was identified as important risk factor for loiasis with adjusted odds ratios of 5.1 (95% confidence interval CI 2.6-9.9) for occasional forest exposure, 11.1 (95% CI 5.4-22.6) for frequent forest exposure and 25.7 (95% CI 12.5-52.9) for intensive forest exposure. Individuals with loiasis were 7.7 (95% CI 5.4-11.0) times more likely to report recurrent pruritus than those without loiasis. Reporting of regular daily exposure to the deep rain forest and recurrent pruritus was 9-fold (positive likelihood ratio 9.18; 95% CI: 6.39-13.18) more prevalent in individuals with loiasis than in controls. Concordantly, the absence of regular weekly forest exposure was associated with extremely low disease-likelihood (negative likelihood ratio 0.09; 95% CI 0.05-0.16). Conclusions: These composite scores may serve as a simple tool to rapidly identify both those most and those least at risk of disease and may simplify loiasis control activities as well as screening procedures for studies on loiasis. Further, they may aid policy-makers to tailor the delivery of ivermectin mass drug administration for onchocerciasis control programmes more effectively and safely in regions of high loiasis-burden.(VLID)477414

Geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV PsVNA50 in adults.

<p>Geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV PsVNA50 in adults.</p

Geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV-GP ELISA in children.

<p>Geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV-GP ELISA in children.</p

Baseline characteristics of study participants.

<p>Baseline characteristics of study participants.</p

Endpoint geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV-GP ELISA in adults.

<p>Endpoint geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV-GP ELISA in adults.</p

Participant flow diagram.

<p>Randomisation and flow of participants over a period of 6 months for adults (cohorts 1 to 5), adolescents (cohort 6; 13–17 years), and children (cohort 7; 6–12 years). Similar dose groups are matched with shading (light grey, 3 × 10⁶ PFU; dark grey, 2 × 10⁷ PFU). GP, glycoprotein; ELISA, enzyme-linked immunosorbent assay; PFU, plaque-forming units; rVSV, recombinant vesicular stomatitis virus.</p

Glycoprotein antibody distribution by age group: Comparison of distribution of ZEBOV-GP IgG antibodies (AEU/ml) measured by USAMRIID ZEBOV-GP ELISA for dose 2 × 10⁷ PFU administered to children, adolescents, and adults from day 0, 28, 56, 84, and 180.

<p>Data were not available for children and adolescents at D84. P < 0.05 indicates a statistical difference in ZEBOV-GP IgG between children, adolescents, and adults. AEU, arbitrary enzyme-linked immunosorbent assay units; ELISA, enzyme-linked immunosorbent assay; GP, glycoprotein; PFU, plaque-forming units; USAMRIID, US Army Medical Research Institute of Infectious Diseases; ZEBOV, Zaire Ebola virus.</p

Endpoint geometric mean titres measured by USAMRIID ZEBOV-GP ELISA in adults with and without baseline specific antibodies.

<p>Endpoint geometric mean titres measured by USAMRIID ZEBOV-GP ELISA in adults with and without baseline specific antibodies.</p