Immunogenicity of a universal HIV-1 vaccine vectored by DNA, MVA and CHADV-63 in a Phase I/IIA clinical trial

Background The major challenge facing both antibody and T cell-eliciting vaccines against HIV-1 is the extreme variability of the HIV-1 genome: a successful vaccine has to effectively target diverse HIV-1 strains circulating in the population and then must deal with ongoing virus escape in infected individuals. To address these issues, we assembled a vaccine immunogen HIVconsv from the functionally most conserved regions (not epitopes) of the HIV-1 proteome. Methods A gene coding for the HIVconsv immunogen was inserted into plasmid DNA (D), modified vaccinia virus Ankara (MVA; M) and non-replicating adenovirus of a chimpanzee origin ChAdV-63 (C). Currently, combined heterologous prime-boost regimens of these vaccines, namely CM, DDDCM and DDDMC, are being evaluated in a phase I/IIa trial HIV-CORE002 in healthy HIV-1/2-negative volunteers in Oxford. Results Preliminary data indicate that the vaccines are well tolerated and show high immunogenicity. Following the CM regimen, vaccine-induced T cell frequencies reached a median of 5150 (range 1475 to 16495) SFU/106 PMBC ex vivo one week post MVA vaccination. DNA priming increased subsequent T cell responses to ChAdV-63 vaccination (median: C 577 and DDDC 1328 SFU/106 PBMC) and ELISpot responses again peaked 1 week following MVA (median 4500; range 2260-7960 SFU/106 PBMC). Matrix analyses of the participants following CM vaccination showed that T cells responded to a range of peptides across the length of HIVconsv. The CM regimen elicited IFN-γ in both CD4+ and CD8+ T cell subsets and polyfunctional (IFN-γ & TNF-α) responses to HIVconsv peptides. Conclusion Presented data will be very much work in progress. Nevetheless, the HIVconsv vaccines have so far induced T cell responses superior to other HIV-1 vaccine candidates tested to date. ChAdV-63 is the first adenovirus of chimp origin delivering an HIV-1-derived immunogen that has reached the clinic. The work is supported by Medical Research Council UK

A Conformally Invariant Holographic Two-Point Function on the Berger Sphere

We apply our previous work on Green's functions for the four-dimensional quaternionic Taub-NUT manifold to obtain a scalar two-point function on the homogeneously squashed three-sphere (otherwise known as the Berger sphere), which lies at its conformal infinity. Using basic notions from conformal geometry and the theory of boundary value problems, in particular the Dirichlet-to-Robin operator, we establish that our two-point correlation function is conformally invariant and corresponds to a boundary operator of conformal dimension one. It is plausible that the methods we use could have more general applications in an AdS/CFT context.Comment: 1+49 pages, no figures. v2: Several typos correcte

The biology of micrometastases from uveal melanoma

Background The aim of this study was to investigate the possible causes of tumour latency in uveal melanoma primarily through the analysis of micrometastases in tissue obtained from donors postmortem. Various explanations have been proposed but there is no clear answer from animal studies and few human data. The main hypotheses may be divided into several areas-immunological control of metastatic cells, lack of angiogenesis within micrometastases and reduced cell turnover. Methods 196 patients were recruited to the study between 2003 and 2007. Patients were invited to take part and their relatives agreed to postmortem examination of their liver and lungs in the event of their death, including tissue sampling to assess the presence of micrometastases and their biology. Metastatic cells were detected by immunohistochemistry using a pan-melanoma antibody reagent, and by quantitative reverse transcriptase (qRT)-PCR for three melanoma-associated genes (tyrosinase Melan-A, and gp100) and a housekeeping gene (HMBS/PBGD) in samples stored in RNAlater or as formalin-fixed paraffin-embedded tissue. Results 22 deaths were investigated at autopsy as part of the study. Sixteen patients died with large deposits of metastatic melanoma, while six patients died of other causes. In addition, a liver resection for hepatic adenoma provided further tissue from a case without clinical evidence of metastasis. Metastatic melanoma cells were identified by immunohistochemistry of the liver samples in one case and by qRT-PCR in two further cases without macrometastases. There was no evidence of multicellular micrometastases sufficiently large to require angiogenesis and no associated inflammation was observed. Conclusion The most likely explanation for latency in this setting is the inability of uveal melanoma cells in metastatic sites to grow.Ophthalmic researc

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

Background Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. Methods In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Findings Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48). Interpretation ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca

X-ray crystal spectrometer upgrade for ITER-like wall experiments at JET

The high resolution X-Ray crystal spectrometer at the JET tokamak has been upgraded with the main goal of measuring the tungsten impurity concentration. This is important for understanding impurity accumulation in the plasma after installation of the JET ITER-like wall (main chamber: Be, divertor: W). This contribution provides details of the upgraded spectrometer with a focus on the aspects important for spectral analysis and plasma parameter calculation. In particular, we describe the determination of the spectrometer sensitivity: important for impurity concentration determination