Stepwise Conformational Stabilization of a HIV-1 Clade C Consensus Envelope Trimer Immunogen Impacts the Profile of Vaccine-Induced Antibody Responses.

Stabilization of the HIV-1 Envelope glycoprotein trimer (Env) in its native pre-fusion closed conformation is regarded as one of several requirements for the induction of neutralizing antibody (nAb) responses, which, in turn, will most likely be a prerequisite for the development of an efficacious preventive vaccine. Here, we systematically analyzed how the stepwise stabilization of a clade C consensus (ConC) Env immunogen impacts biochemical and biophysical protein traits such as antigenicity, thermal stability, structural integrity, and particle size distribution. The increasing degree of conformational rigidification positively correlates with favorable protein characteristics, leading to optimized homogeneity of the protein preparations, increased thermal stability, and an overall favorable binding profile of structure-dependent broadly neutralizing antibodies (bnAbs) and non-neutralizing antibodies (non-nAbs). We confirmed that increasing the structural integrity and stability of the Env trimers positively correlates with the quality of induced antibody responses by the immunogens. These and other data contribute to the selection of ConCv5 KIKO as novel Env immunogens for use within the European Union's H2020 Research Consortium EHVA (European HIV Alliance) for further preclinical analysis and phase 1 clinical development

A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 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,  = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced 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

Preferential infection and depletion of Mycobacterium tuberculosis–specific CD4 T cells after HIV-1 infection

HIV-1 preferentially infects M. tuberculosis-specific CD4+ T cells due to their increased production of IL-2

Louisville Seamount Trail: implications for geodynamic mantle flow models and the geochemical evolution of primary hotspots

The Louisville Seamount Trail is a 4300 km long volcanic chain that has been built in the past 80 m.y. as the Pacific plate moved over a persistent mantle melting anomaly or hotspot. Because of its linear morphology and its long-lived age-progressive volcanism, Louisville is the South Pacific counterpart of the much better studied Hawaiian-Emperor Seamount Trail. Together, Louisville and Hawaii are textbook examples of two primary hotspots that have been keystones in deciphering the motion of the Pacific plate relative to a set of "fixed" deep-mantle plumes. However, drilling during Ocean Drilling Program (ODP) Leg 197 in the Emperor Seamounts documented a large ~15° southward motion of the Hawaiian hotspot prior to 50 Ma. Is it possible that the Hawaiian and Louisville hotspots moved in concert and thus constitute a moving reference frame for modeling plate motion in the Pacific? Alternatively, could they have moved independently, as predicted by mantle flow models that reproduce the observed latitudinal motion for Hawaii but that predict a largely longitudinal shift for the Louisville hotspot? These two end-member geodynamic models were tested during Integrated Ocean Drilling Program (IODP) Expedition 330 to the Louisville Seamount Trail. In addition, existing data from dredged lavas suggest that the mantle plume source of the Louisville hotspot has been remarkably homogeneous for as long as 80 m.y. These lavas are predominantly alkali basalts and likely represent a mostly alkalic shield-building stage, which is in sharp contrast to the massive tholeiitic shield-building stage of Hawaiian volcanoes. Geochemical and isotopic data for the recovered lavas during Expedition 330 will provide insights into the magmatic evolution and melting processes of individual Louisville volcanoes, their progression from shield-building to postshield and (maybe) posterosional stages, the temperature and depth of partial melting of their mantle plume source, and the enigmatic long-lived and apparent geochemical homogeneity of the Louisville mantle source. Collectively, this will enable us to characterize the Louisville Seamount Trail as a product of one of the few global primary hotspots, to better constrain its plume-lithosphere interactions, and to further test the hypothesis that the Ontong Java Plateau formed from the plume head of the Louisville mantle plume around 120 Ma. During Expedition 330 we replicated the drilling strategy of Leg 197, the first expedition to provide compelling evidence for the motion of the Hawaiian mantle plume between 80 and 50 Ma. For that reason we targeted Louisville seamounts that have ages similar to Detroit, Suiko, Nintoku, and Koko Seamounts in the Emperor Seamount Trail. In total, five seamounts were drilled in the Louisville Seamount Trail: Canopus, Rigil, Burton, Achernar, and Hadar Guyots (old to young). By analyzing a large number of time-independent in situ lava flows (and other volcanic eruptive products) from these seamounts using modern paleomagnetic, 40Ar/39Ar geochronological, and geochemical techniques, we will be able to directly compare the paleolatitude estimates and geochemical signatures between the two longest-lived hotspot systems in the Pacific Ocean. We drilled into the summits of the five Louisville guyots and reached volcanic basement at four of these drilling targets. In two cases we targeted larger seamount structures and drilled near the flanks of these ancient volcanoes, and in the other three cases we selected smaller edifices that we drilled closer to their centers. Drilling and logging plans for each of these sites were similar, with coring reaching 522.0 meters below seafloor (mbsf) for Site U1374 and 232.9, 65.7, 11.5, 182.8, and 53.3 mbsf for Sites U1372, U1373, U1375, U1376, and U1377, respectively. Some Expedition 330 drill sites were capped with only a thin layer of pelagic ooze between 6.6 and 13.5 m thick, and, if present, these were cored by using a low-rotation gravity-push technique with the rotary core barrel to maximize recovery. However, at Sites U1373 and U1376 no pelagic ooze was present, and the holes needed to be started directly into cobble-rich hardgrounds. In all cases, the bulk of the seamount sediment cover comprised sequences of volcanic sandstones and various kinds of basalt breccia or basalt conglomerate, which often were interspersed with basaltic lava flows, the spatter/tephra products of submarine eruptions, or other volcanic products, including auto-brecciated flows or peperites. Also several intervals of carbonate were cored, with the special occurrence of a ~15 m thick algal limestone reef at Site U1376 on Burton Guyot. In addition, some condensed pelagic limestone units were recovered on three of the other seamounts, but these did not exceed 30 cm in thickness. Despite their limited presence in the drilled sediment, these limestones provide valuable insights for the paleoclimate record at high ~50° southern latitudes since Mesozoic times. Several Louisville sites progressed from subaerial conditions in the top of volcanic basement into submarine eruptive environments, or drilling of the igneous basement immediately started in submarine volcanic sequences, as was the case for Sites U1376 and U1377 on Burton and Hadar Guyots. At three sites we cored >100 m into the igneous basement: 187.3 m at Site U1372, 505.3 m at Site U1374, and 140.9 m at Site U1376. At the other sites we did not core into basement (Site U1375) or we cored only 38.2 m (Site U1377) because of unstable hole conditions. Even so, drilling during Expedition 330 resulted in a large number of in situ lava flows, pillow basalts, or other types of volcanic products such as auto-brecciated lava flows, intrusive sheets or dikes, and peperites. In particular, the three holes on Canopus and Rigil Guyots (the two oldest seamounts drilled in the Louisville Seamount Trail), resulted in adequate numbers of in situ lava flows to average out paleosecular variation, with probable eruption ages estimated at ~78 and 73 Ma, respectively. Remarkably, at all drill sites large quantities of hyaloclastites, volcanic sandstones, and basaltic breccias were also recovered, which in many cases show consistent paleomagnetic inclinations compared to the lava flows bracketing these units. For Site U1374 on Rigil Guyot we also observed a magnetic polarity reversal in the cored sequence. Overall, this is very promising for determining a reliable paleolatitude record for the Louisville Seamounts following detailed postcruise examinations. The deeper penetrations of several hundred meters required bit changes and reentries using free-fall funnels. Basement penetration rates were 1.8–2.5 m/h depending on drill depth. In total, 1114 m of sediment and igneous basement at five seamounts was drilled, and 806 m was recovered (average recovery = 72.4%). At Site U1374 on Rigil Guyot, a total of 522 m was drilled, with a record-breaking 87.8% recovery. Most outstandingly, nearly all Expedition 330 core material is characterized by low degrees of alteration, providing us with a large quantity of samples of mostly well-preserved basalt, containing, for example, pristine olivine crystals with melt inclusions, fresh volcanic glass, unaltered plagioclase, carbonate, zeolite and celadonite alteration minerals, various micro- and macrofossils, and, in one case, mantle xenoliths and xenocrysts. The large quantity and excellent quality of the recovered sample material allow us to address all the scientific objectives of this expedition and beyond

Low-volume intraplate volcanism in the Early/Middle Jurassic Pacific basin documented by accreted sequences in Costa Rica

Countless seamounts occur on Earth that can provide important constraints on intraplate volcanism and plate tectonics in the oceans, yet their nature and origin remain poorly known due to difficulties in investigating the deep ocean. We present here new lithostratigraphic, age and geochemical data from Lower/Middle Jurassic and Lower Cretaceous sequences in the Santa Rosa accretionary complex, Costa Rica, which offer a valuable opportunity to study a small-sized seamount from a subducted plate segment of the Pacific basin. The seamount is characterized by very unusual lithostratigraphic sequences with sills of potassic alkaline basalt emplaced within thick beds of radiolarite, basaltic breccia and hyaloclastite. An integration of new geochemical, biochronological and geochronological data with lithostratigraphic observations suggests that the seamount formed ~175 Ma ago on thick oceanic crust away from subduction zones and mid-ocean ridges. This seamount travelled ~65 Ma in the Pacific before accretion. It resembles lithologically and compositionally “petit-spot” volcanoes found off Japan, which form in response to plate flexure near subduction zones. Also, the composition of the sills and lava flows in the accreted seamount closely resembles that of potassic alkaline basalts produced by lithosphere cracking along the Line Islands chain. We hypothesize based on these observations, petrological constraints and formation of the accreted seamount coeval with the early stages of development of the Pacific plate that the seamount formed by extraction of small volumes of melt from the base of the lithosphere in response to propagating fractures at the scale of the Pacific basin

Collaborative research between academia and industry using a large clinical trial database: a case study in Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Large clinical trials databases, developed over the course of a comprehensive clinical trial programme, represent an invaluable resource for clinical researchers. Data mining projects sponsored by industry that use these databases, however, are often not viewed favourably in the academic medical community because of concerns that commercial, rather than scientific, goals are the primary purpose of such endeavours. Thus, there are few examples of sustained collaboration between leading academic clinical researchers and industry professionals in a large-scale data mining project. We present here a successful example of this type of collaboration in the field of dementia.</p> <p>Methods</p> <p>The Donepezil Data Repository comprised 18 randomised, controlled trials conducted between 1991 and 2005. The project team at Pfizer determined that the data mining process should be guided by a diverse group of leading Alzheimer's disease clinical researchers called the "Expert Working Group." After development of a list of potential faculty members, invitations were extended and a group of seven members was assembled. The Working Group met regularly with Eisai/Pfizer clinicians and statisticians to discuss the data, identify issues that were currently of interest in the academic and clinical communities that might lend themselves to investigation using these data, and note gaps in understanding or knowledge of Alzheimer's disease that these data could address. Leadership was provided by the Pfizer Clinical Development team leader; Working Group members rotated responsibility for being lead and co-lead for each investigation and resultant publication.</p> <p>Results</p> <p>Six manuscripts, each published in a leading subspecialty journal, resulted from the group's work. Another project resulted in poster presentations at international congresses and two were cancelled due to resource constraints.</p> <p>Conclusions</p> <p>The experience represents a particular approach to optimising the value of data mining of large clinical trial databases for the combined purpose of furthering clinical research and improving patient care. Fruitful collaboration between industry and academia was fostered while the donepezil data repository was used to advance clinical and scientific knowledge. The Expert Working Group approach warrants consideration as a blueprint for conducting similar research ventures in the future.</p

Morphological and geochemical variations along the eastern Galapagos Spreading Center

[1] As the eastern Galápagos Spreading Center (GSC) shallows westward toward the Galápagos Archipelago, axial morphology evolves from a low-relief, valley-and-ridge terrain to an increasingly prominent axial ridge, closely mirroring the western GSC. Between the Inca Transform (∼85.5°W) and its western termination near 91°W, the eastern GSC comprises seven morphological segments, separated by five morphological discontinuities and the eastward propagating 87°W overlapping spreading center. Combined morphologic and geochemical data divide the eastern GSC into two domains independent of the fine-scale morphologic segmentation. The western domain is defined by its axial ridge morphology and highly variable lava population. Elemental data define steep along-axis gradients, reflecting a complex source that includes one or more hot spot–related components in addition to a highly depleted component. The eastern domain is defined by transitional, valley-and-ridge morphologies and a surprisingly invariant lava population. This population is dominated by shallow crystal fractionation processes and displays significantly less variability attributable to multiple source components. The Galápagos hot spot has long been known to have a symmetrical, long-wavelength influence on crustal accretion along the GSC. Existing isotopic and new elemental data define twin “geochemical peaks” that we interpret as loci for transfer of distinct source components from the Galápagos plume to the GSC. Although Na8 and Fe8 values lie within the negatively correlated global array, Na8 increases with decreasing axial depth, contrary to global trends and consistent with emerging deep, hydrous melting models that predict decreasing overall extent of melting despite increasing melt production. Support for hydrous melting comes from decreasing heavy REE, increasing La/Sm and La/Yb, and the systematics of decreasing FeO and increasing CaO and Al2O3 with decreasing distance to the hot spot. Overall, an enriched, deep melt component appears to coexist in the shallow mantle with a ubiquitous, depleted primitive melt component, consistent with new models for channelized melt flow connecting a deep hydrous melt regime with the dry shallow mantle. Nevertheless, an absence of low-Fe lavas suggests that hydrous melting is strictly limited beneath the eastern GSC, becoming dominant only near the western geochemical peak where input from a hydrous “Northern” or “Wolf-Darwin” plume component is inferred

IODP Expedition 330: Drilling the Louisville Seamount Trail in the SW Pacific

Deep-Earth convection can be understood by studying hotspot volcanoes that form where mantle plumes rise up and intersect the lithosphere, the Earth's rigid outer layer. Hotspots characteristically leave age-progressive trails of volcanoes and seamounts on top of oceanic lithosphere, which in turn allow us to decipher the motion of these plates relative to "fixed" deep-mantle plumes, and their (isotope) geochemistry provides insights into the long-term evolution of mantle source regions. However, it is strongly suggested that the Hawaiian mantle plume moved ~15° south between 80 and 50 million years ago. This raises a fundamental question about other hotspot systems in the Pacific, whether or not their mantle plumes experienced a similar amount and direction of motion. Integrated Ocean Drilling Program (IODP) Expedition 330 to the Louisville Seamounts showed that the Louisville hotspot in the South Pacific behaved in a different manner, as its mantle plume remained more or less fixed around 48°S latitude during that same time period. Our findings demonstrate that the Pacific hotspots move independently and that their trajectories may be controlled by differences in subduction zone geometry. Additionally, shipboard geochemistry data shows that, in contrast to Hawaiian volcanoes, the construction of the Louisville Seamounts doesn’t involve a shield-building phase dominated by tholeiitic lavas, and trace elements confirm the rather homogenous nature of the Louisville mantle source. Both observations set Louisville apart from the Hawaiian-Emperor seamount trail, whereby the latter has been erupting abundant tholeiites (characteristically up to 95% in volume) and which exhibit a large variability in (isotope) geochemistry and their mantle source components