4 research outputs found
NikR mediates nickel-responsive transcriptional induction of urease expression in Helicobacter pylori
The important human pathogen Helicobacter pylori requires the abundant
expression and activity of its urease enzyme for colonization of the
gastric mucosa. The transcription, expression, and activity of H. pylori
urease were previously demonstrated to be induced by nickel
supplementation of growth media. Here it is demonstrated that the HP1338
protein, an ortholog of the Escherichia coli nickel regulatory protein
NikR, mediates nickel-responsive induction of urease expression in H.
pylori. Mutation of the HP1338 gene (nikR) of H. pylori strain 26695
resulted in significant growth inhibition of the nikR mutant in the
presence of supplementation with NiCl(2) at > or =100 microM, whereas the
wild-type strain tolerated more than 10-fold-higher levels of NiCl(2).
Mutation of nikR did not affect urease subunit expression or urease enzyme
activity in unsupplemented growth media. However, the nickel-induced
increase in urease subunit expression and urease enzyme activity observed
in wild-type H. pylori was absent in the H. pylori nikR mutant. A similar
lack of nickel responsiveness was observed upon removal of a 19-bp
palindromic sequence in the ureA promoter, as demonstrated by using a
genomic ureA::lacZ reporter gene fusion. In conclusion, the H. pylori NikR
protein and a 19-bp operator sequence in the ureA promoter are both
essential for nickel-responsive induction of urease expression in H.
pylori
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 â„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 18â55 years, 56â69 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 â„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 (2·2âĂâ1010 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 18â55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56â69 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 (3·5â6·5âĂâ1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18â55 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-Îł 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 18â55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56â69 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 â„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 18â55 years group, 22 (73%) of 30 in the 56â69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18â55 years group, 23 (77%) in the 56â69 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: 18â55 years, 20â713 arbitrary units [AU]/mL [IQR 13â898â33â550], n=39; 56â69 years, 16â170 AU/mL [10â233â40â353], n=26; and â„70 years 17â561 AU/mL [9705â37â796], 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: 18â55 years, 193 [IQR 113â238], n=39; 56â69 years, 144 [119â347], n=20; and â„70 years, 161 [73â323], 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 (18â55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841â2428], n=24; 56â69 years: 797 SFCs [383â1817], n=29; and â„70 years: 977 SFCs [458â1914], 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
First joint oscillation analysis of Super-Kamiokande atmospheric and T2K accelerator neutrino data
The Super-Kamiokande and T2K collaborations present a joint measurement of neutrino oscillation parameters from their atmospheric and beam neutrino data. It uses a common interaction model for events overlapping in neutrino energy and correlated detector systematic uncertainties between the two datasets, which are found to be compatible. Using 3244.4 days of atmospheric data and a beam exposure of protons on target in (anti)neutrino mode, the analysis finds a 1.9 exclusion of CP-conservation (defined as ) and a preference for the normal mass ordering
First joint oscillation analysis of Super-Kamiokande atmospheric and T2K accelerator neutrino data
International audienceThe Super-Kamiokande and T2K collaborations present a joint measurement of neutrino oscillation parameters from their atmospheric and beam neutrino data. It uses a common interaction model for events overlapping in neutrino energy and correlated detector systematic uncertainties between the two datasets, which are found to be compatible. Using 3244.4 days of atmospheric data and a beam exposure of protons on target in (anti)neutrino mode, the analysis finds a 1.9 exclusion of CP-conservation (defined as ) and a preference for the normal mass ordering