A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, and Env gp 140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p =  0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccineinduced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen

Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults

Background: T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. Methods: We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months. Findings: Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The foldincrease and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1. Interpretation: A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly crossreactive protection against influenza

Identification of carbon dioxide in an exoplanet atmosphere

Carbon dioxide (CO2) is a key chemical species that is found in a wide range of planetary atmospheres. In the context of exoplanets, CO2 is an indicator of the metal enrichment (that is, elements heavier than helium, also called ‘metallicity’)1–3, and thus the formation processes of the primary atmospheres of hot gas giants4–6. It is also one of the most promising species to detect in the secondary atmospheres of terrestrial exoplanets7–9. Previous photometric measurements of transiting planets with the Spitzer Space Telescope have given hints of the presence of CO2, but have not yielded definitive detections owing to the lack of unambiguous spectroscopic identification10–12. Here we present the detection of CO2 in the atmosphere of the gas giant exoplanet WASP-39b from transmission spectroscopy observations obtained with JWST as part of the Early Release Science programme13,14. The data used in this study span 3.0–5.5 micrometres in wavelength and show a prominent CO2 absorption feature at 4.3 micrometres (26-sigma significance). The overall spectrum is well matched by one-dimensional, ten-times solar metallicity models that assume radiative–convective–thermochemical equilibrium and have moderate cloud opacity. These models predict that the atmosphere should have water, carbon monoxide and hydrogen sulfide in addition to CO2, but little methane. Furthermore, we also tentatively detect a small absorption feature near 4.0 micrometres that is not reproduced by these models

Identification of carbon dioxide in an exoplanet atmosphere

Carbon dioxide (CO2) is a key chemical species that is found in a wide range of planetary atmospheres. In the context of exoplanets, CO2 is an indicator of the metal enrichment (that is, elements heavier than helium, also called ‘metallicity’), and thus the formation processes of the primary atmospheres of hot gas giants. It is also one of the most promising species to detect in the secondary atmospheres of terrestrial exoplanets. Previous photometric measurements of transiting planets with the Spitzer Space Telescope have given hints of the presence of CO2, but have not yielded definitive detections owing to the lack of unambiguous spectroscopic identification. Here we present the detection of CO2 in the atmosphere of the gas giant exoplanet WASP-39b from transmission spectroscopy observations obtained with JWST as part of the Early Release Science programme. The data used in this study span 3.0–5.5 micrometres in wavelength and show a prominent CO2 absorption feature at 4.3 micrometres (26-sigma significance). The overall spectrum is well matched by one-dimensional, ten-times solar metallicity models that assume radiative–convective–thermochemical equilibrium and have moderate cloud opacity. These models predict that the atmosphere should have water, carbon monoxide and hydrogen sulfide in addition to CO2, but little methane. Furthermore, we also tentatively detect a small absorption feature near 4.0 micrometres that is not reproduced by these models

Application of "Systems Vaccinology" to evaluate inflammation and reactogenicity of adjuvanted preventative vaccines

Advances in “omics” technology (transcriptomics, proteomics, metabolomics, genomics/epigenomics, etc.) allied with statistical and bioinformatics tools are providing insights into basic mechanisms of vaccine and adjuvant efficacy or inflammation/reactogenicity. Predictive biomarkers of relatively frequent inflammatory reactogenicity may be identified in systems vaccinology studies involving tens or hundreds of participants and used to screen new vaccines and adjuvants in in vitro, ex vivo, animal, or human models. The identification of rare events (such as those observed with initial rotavirus vaccine or suspected autoimmune complications) will require interrogation of large data sets and population-based research before application of systems vaccinology. The Innovative Medicine Initiative funded public-private project BIOVACSAFE is an initial attempt to systematically identify biomarkers of relatively common inflammatory events after adjuvanted immunization using human, animal, and population-based models. Discriminatory profiles or biomarkers are being identified, which require validation in large trials involving thousands of participants before they can be generalized. Ultimately, it is to be hoped that the knowledge gained from such initiatives will provide tools to the industry, academia, and regulators to select optimal noninflammatory but immunogenic and effective vaccine adjuvant combinations, thereby shortening product development cycles and identifying unsuitable vaccine candidates that would fail in expensive late stage development or postmarketing