Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Surface-functionalized and surface-functionalizable poly(vinylidene fluoride) graft copolymer membranes via click chemistry and atom transfer radical polymerization.

Poly(vinylidene fluoride) (PVDF) with azide-functionalized poly(glycidyl methacrylate) (PGMA) side chains (PVDF-g-P[GMA-(N3)(OH)]) were synthesized via free radical-initiated graft copolymerization of glycidyl methacrylate (GMA) from ozone-pretreated PVDF backbone (PVDF-g-PGMA), followed by reaction of the oxirane rings in the GMA side chains with sodium azide. Alkyne-functionalized poly(N-isopropylacrylamide) (alkynyl-PNIPAM), prepared a priori by atom transfer radical polymerization (ATRP), was used for the click reaction with the azido-containing PGMA side chains of the PVDF-g-P[GMA-(N3)(OH)] copolymer to give rise to the thermoresponsive PVDF-g-P[GMA-click-PNIPAM] copolymer. Both the PVDF-g-P[GMA-(N3)(OH)] and PVDF-g-P[GMA-click-PNIPAM] copolymers can be readily cast into microporous membranes by phase inversion in an aqueous medium. The PVDF-g-P[GMA-(N3)(OH)] microporous membranes with azido-containing surfaces could be further functionalized via surface click reaction with alkyne-terminated PNIPAM of controlled chain lengths to obtain the PVDF-g-P[GMA-click-PNIPAM]surface microporous membranes. The surface composition and morphology of the PVDF-g-P[GMA-click-PNIPAM] membranes can be adjusted by the temperature of casting medium, while the flux through both types of membranes exhibits thermoresponsive behavior.

Influence of fouling on the efficiency of sacrificial anodes in providing cathodic protection in Southeast Asian tropical seawater.

Aluminum and zinc based sacrificial anodes are routinely used to provide corrosion protection to metals (typically steel) exposed to seawater, for example in steel pipelines and storage tanks. However, the high fouling rates experienced in South East Asia means that both the anodes and the metals to be protected rapidly become coated with macrofoulers, which could potentially prevent the anodes from being effective. The present study, involving exposure tests of up to 18 months, indicates that both aluminum and zinc sacrificial anodes remain effective even after being completely coated with biofouling. Furthermore, it was easier to remove the biofouling on the cathodically protected samples than on their unprotected counterparts, possibly due to the higher local pH produced by cathodic protection at the metal and seawater interface.

Migratory movements, depth preferences, and thermal biology of Atlantic bluefin tuna.

The deployment of electronic data storage tags that are surgically implanted or satellite-linked provides marine researchers with new ways to examine the movements, environmental preferences, and physiology of pelagic vertebrates. We report the results obtained from tagging of Atlantic bluefin tuna with implantable archival and pop-up satellite archival tags. The electronic tagging data provide insights into the seasonal movements and environmental preferences of this species. Bluefin tuna dive to depths of >1000 meters and maintain a warm body temperature. Western-tagged bluefin tuna make trans-Atlantic migrations and they frequent spawning grounds in the Gulf of Mexico and eastern Mediterranean. These data are critical for the future management and conservation of bluefin tuna in the Atlantic.

Habitat and behaviour of yellowfin tuna Thunnus albacares in the Gulf of Mexico determined using pop-up satellite archival tags.

This study presents the first data on movement, habitat use and behaviour for yellowfin tuna Thunnus albacares in the Atlantic Basin. Six individuals were tracked in the Gulf of Mexico using pop-up satellite archival tags. Records up to 80 days in length were obtained, providing information on depth and temperature preferences as well as horizontal movements. Thunnus albacares in the Gulf of Mexico showed a strong preference for the mixed layer and thermocline, consistent with findings for this species in other ocean basins. Fish showed a diel pattern in depth distribution, remaining in surface and mixed layer waters at night and diving to deeper waters during the day. The vertical extent of T. albacares habitat appeared to be temperature limited, with fish generally avoiding waters that were >6 degrees C cooler than surface waters. The vertical and thermal habitat usage of T. albacares differs from that of bigeye Thunnus obesus and bluefin Thunnus thynnus, Thunnus orientalis and Thunnus maccoyii tunas. These results are consistent with the results of earlier studies conducted on T. albacares in other oceans.

Detection of diarrhetic shellfish poisoning toxins from tropical shellfish using liquid chromatography-selected reaction monitoring mass spectrometry.

A negative mode liquid chromatography-selected reaction monitoring mass spectrometry (LC-SRM MS) method was developed to detect low concentrations of the diarrhetic shellfish poisoning (DSP) toxins okadaic acid and dinophysistoxin-1 (DTX-1). Detection relies upon monitoring the transition of negative precursor ions [M - H]- to a common fragment ion of m/z 255. Our limit of detection for okadaic acid with this method is 0.5 pg on column. LC-SRM MS has allowed us to detect persistent, low concentrations of DSP toxins from Singapore shellfish.

A new cytotoxic polyhydroxysterol from soft coral Sarcophyton trocheliophorum.

A new cytotoxic polyhydroxysterol, 23,24-dimethylcholest-16(17)-E-en-3beta,5alpha,6beta,2 0(S)-tetraol (2), together with nine known compounds was isolated from the soft coral Sarcophyton trocheliophorum. Their structures were determined by spectroscopic methods. Compound 2 showed potent growth inhibitory activity against human HL60 leukemia, M14 skin melanoma, and MCF7 breast carcinoma cells with EC50 values of 2.8, 4.3, and 4.9 microg/ml, respectively, and exhibited minimal toxicity to normal human peripheral blood lymphocytes.