Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial.

BACKGROUND: Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers. METHODS: We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 × 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 × 10(4) CFU MTBVAC, and those in the third cohort received 5 × 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 × 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0·1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon γ release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. FINDINGS: Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5×10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells. INTERPRETATION: To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries. FUNDING: Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI)

Carbon on the Northwest European Shelf: Contemporary Budget and Future Influences

© Copyright © 2020 Legge, Johnson, Hicks, Jickells, Diesing, Aldridge, Andrews, Artioli, Bakker, Burrows, Carr, Cripps, Felgate, Fernand, Greenwood, Hartman, Kröger, Lessin, Mahaffey, Mayor, Parker, Queirós, Shutler, Silva, Stahl, Tinker, Underwood, Van Der Molen, Wakelin, Weston and Williamson. A carbon budget for the northwest European continental shelf seas (NWES) was synthesized using available estimates for coastal, pelagic and benthic carbon stocks and flows. Key uncertainties were identified and the effect of future impacts on the carbon budget were assessed. The water of the shelf seas contains between 210 and 230 Tmol of carbon and absorbs between 1.3 and 3.3 Tmol from the atmosphere annually. Off-shelf transport and burial in the sediments account for 60–100 and 0–40% of carbon outputs from the NWES, respectively. Both of these fluxes remain poorly constrained by observations and resolving their magnitudes and relative importance is a key research priority. Pelagic and benthic carbon stocks are dominated by inorganic carbon. Shelf sediments contain the largest stock of carbon, with between 520 and 1600 Tmol stored in the top 0.1 m of the sea bed. Coastal habitats such as salt marshes and mud flats contain large amounts of carbon per unit area but their total carbon stocks are small compared to pelagic and benthic stocks due to their smaller spatial extent. The large pelagic stock of carbon will continue to increase due to the rising concentration of atmospheric CO2, with associated pH decrease. Pelagic carbon stocks and flows are also likely to be significantly affected by increasing acidity and temperature, and circulation changes but the net impact is uncertain. Benthic carbon stocks will be affected by increasing temperature and acidity, and decreasing oxygen concentrations, although the net impact of these interrelated changes on carbon stocks is uncertain and a major knowledge gap. The impact of bottom trawling on benthic carbon stocks is unique amongst the impacts we consider in that it is widespread and also directly manageable, although its net effect on the carbon budget is uncertain. Coastal habitats are vulnerable to sea level rise and are strongly impacted by management decisions. Local, national and regional actions have the potential to protect or enhance carbon storage, but ultimately global governance, via controls on emissions, has the greatest potential to influence the long-term fate of carbon stocks in the northwestern European continental shelf

Growth and mortality of coccolithophores during spring in a temperate Shelf Sea (Celtic Sea, April 2015)

Coccolithophores are key components of phytoplankton communities, exerting a critical impact on the global carbon cycle and the Earth’s climate through the production of coccoliths made of calcium carbonate (calcite) and bioactive gases. Microzooplankton grazing is an important mortality factor in coccolithophore blooms, however little is currently known regarding the mortality (or growth) rates within non-bloom populations. Measurements of coccolithophore calcite production (CP) and dilution experiments to determine microzooplankton (≤63 µm) grazing rates were made during a spring cruise (April 2015) at the Central Celtic Sea (CCS), shelf edge (CS2), and within an adjacent April bloom of the coccolithophore Emiliania huxleyi at station J2. CP at CCS ranged from 10.4 to 40.4 µmol C m−3 d−1 and peaked at the height of the spring phytoplankton bloom (peak chlorophyll-a concentrations ∼6 mg m−3). Cell normalised calcification rates declined from ∼1.7 to ∼0.2 pmol C cell−1 d−1, accompanied by a shift from a mixed coccolithophore species community to one dominated by the more lightly calcified species E. huxleyi and Calciopappus caudatus. At the CCS, coccolithophore abundance increased from 6 to 94 cells mL−1, with net growth rates ranging from 0.06 to 0.21 d−1 from the 4th to the 28th April. Estimates of intrinsic growth and grazing rates from dilution experiments, at the CCS ranged from 0.01 to 0.86 d−1 and from 0.01 to 1.32 d−1, respectively, which resulted in variable net growth rates during April. Microzooplankton grazers consumed 59 to >100% of daily calcite production at the CCS. Within the E. huxleyi bloom a maximum density of 1986 cells mL−1 was recorded, along with CP rates of 6000 µmol C m−3 d−1 and an intrinsic growth rate of 0.29 d−1, with ∼80% of daily calcite production being consumed. Our results show that microzooplankton can exert strong top-down control on both bloom and non-bloom coccolithophore populations, grazing over 60% of daily growth (and calcite production). The fate of consumed calcite is unclear, but may be lost either through dissolution in acidic food vacuoles, and subsequent release as CO2, or export to the seabed after incorporation into small faecal pellets. With such high microzooplankton-mediated mortality losses, the fate of grazed calcite is clearly a high priority research direction

Hydrocarbon contamination affects deep-sea benthic oxygen uptake and microbial community composition

Accidental oil well blowouts have the potential to introduce large quantities of hydrocarbons into the deep sea and disperse toxic contaminants to midwater and seafloor areas over ocean-basin scales. Our ability to assess the environmental impacts of these events is currently impaired by our limited understanding of how resident communities are affected. This study examined how two treatment levels of a water accommodated fraction of crude oil affected the oxygen consumption rate of a natural, deep-sea benthic community. We also investigated the resident microbial community’s response to hydrocarbon contamination through quantification of phospholipid fatty acids (PLFAs) and their stable carbon isotope (?13C) values. Sediment community oxygen consumption rates increased significantly in response to increasing levels of contamination in the overlying water of oil-treated microcosms, and bacterial biomass decreased significantly in the presence of oil. Multivariate ordination of PLFA compositional (mol%) data showed that the structure of the microbial community changed in response to hydrocarbon contamination. However, treatment effects on the ?13C values of individual PLFAs were not statistically significant. Our data demonstrate that deep-sea benthic microbes respond to hydrocarbon exposure within 36 h

Growth and mortality of coccolithophores during spring in a temperate Shelf Sea (Celtic Sea, April 2015)

Coccolithophores are key components of phytoplankton communities, exerting a critical impact on the global carbon cycle and the Earth's climate through the production of coccoliths made of calcium carbonate (calcite) and bioactive gases. Microzooplankton grazing is an important mortality factor in coccolithophore blooms, however little is currently known regarding the mortality (or growth) rates within non-bloom populations. Measurements of coccolithophore calcite production (CP) and dilution experiments to determine microzooplankton (≤63 µm) grazing rates were made during a spring cruise (April 2015) at the Central Celtic Sea (CCS), shelf edge (CS2), and within an adjacent April bloom of the coccolithophore Emiliania huxleyi at station J2. CP at CCS ranged from 10.4 to 40.4 µmol C m−3 d−1 and peaked at the height of the spring phytoplankton bloom (peak chlorophyll-a concentrations ∼6 mg m−3). Cell normalised calcification rates declined from ∼1.7 to ∼0.2 pmol C cell−1 d−1, accompanied by a shift from a mixed coccolithophore species community to one dominated by the more lightly calcified species E. huxleyi and Calciopappus caudatus. At the CCS, coccolithophore abundance increased from 6 to 94 cells mL−1, with net growth rates ranging from 0.06 to 0.21 d−1 from the 4th to the 28th April. Estimates of intrinsic growth and grazing rates from dilution experiments, at the CCS ranged from 0.01 to 0.86 d−1 and from 0.01 to 1.32 d−1, respectively, which resulted in variable net growth rates during April. Microzooplankton grazers consumed 59 to &gt;100% of daily calcite production at the CCS. Within the E. huxleyi bloom a maximum density of 1986 cells mL−1 was recorded, along with CP rates of 6000 µmol C m−3 d−1 and an intrinsic growth rate of 0.29 d−1, with ∼80% of daily calcite production being consumed. Our results show that microzooplankton can exert strong top-down control on both bloom and non-bloom coccolithophore populations, grazing over 60% of daily growth (and calcite production). The fate of consumed calcite is unclear, but may be lost either through dissolution in acidic food vacuoles, and subsequent release as CO2, or export to the seabed after incorporation into small faecal pellets. With such high microzooplankton-mediated mortality losses, the fate of grazed calcite is clearly a high priority research direction.</p

Immunomodulation profile of the biosimilar trastuzumab MYL-1401O in a bioequivalence phase I study.

The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab biosimilar (MYL-1401O) compared to the reference Herceptin &lt;sup&gt;®&lt;/sup&gt; . Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin &lt;sup&gt;®&lt;/sup&gt; and MYL-1401O. In CRA, PBMC stimulated with MYL-1401O or Herceptin &lt;sup&gt;®&lt;/sup&gt; similarly secreted IL-6, TNF-α, IL-1β, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin &lt;sup&gt;®&lt;/sup&gt; , strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals