Do schistosome vaccine trials in mice have an intrinsic flaw that generates spurious protection data?

The laboratory mouse has been widely used to test the efficacy of schistosome vaccines and a long list of candidates has emerged from this work, many of them abundant internal proteins. These antigens do not have an additive effect when co-administered, or delivered as SWAP homogenate, a quarter of which comprises multiple candidates; the observed protection has an apparent ceiling of 40–50 %. We contend that the low level of maturation of penetrating cercariae (~32 % for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes. The pulmonary capillary bed is the obstacle encountered by schistosomula en route to the portal system. The fragility of pulmonary capillaries and their susceptibility to a cytokine-induced vascular leak syndrome have been documented. During lung transit schistosomula burst into the alveolar spaces, and possess only a limited capacity to re-enter tissues. The acquired immunity elicited by the radiation attenuated (RA) cercarial vaccine relies on a pulmonary inflammatory response, involving cytokines such as IFNγ and TNFα, to deflect additional parasites into the alveoli. A principal difference between antigen vaccine protocols and the RA vaccine is the short interval between the last antigen boost and cercarial challenge of mice (often two weeks). Thus, after antigen vaccination, challenge parasites will reach the lungs when both activated T cells and cytokine levels are maximal in the circulation. We propose that “protection” in this situation is the result of physiological effects on the pulmonary blood vessels, increasing the proportion of parasites that enter the alveoli. This hypothesis will explain why internal antigens, which are unlikely to interact with the immune response in a living schistosomulum, plus a variety of heterologous proteins, can reduce the level of maturation in a non-antigen-specific way. These proteins are “successful” precisely because they have not been selected for immunological silence. The same arguments apply to vaccine experiments with S. japonicum in the mouse model; this schistosome species seems a more robust parasite, even harder to eliminate by acquired immune responses. We propose a number of ways in which our conclusions may be tested

Oxygen and hydrogen isotope evidence for meteoric water infiltration during mylonitization and uplift in the Ruby Mountains-East Humboldt Range core complex, Nevada

Stable isotope analyses of rocks and minerals associated with the detachment fault and underlying mylonite zone exposed at Secret Creek gorge and other localities in the Ruby-East Humboldt Range metamorphic core complex in northeastern Nevada provide convincing evidence for meteoric water infiltration during mylonitization. Whole-rock δ 18 O values of the lower plate quartzite mylonites (≥95% modal quartz) have been lowered by up to 10 per mil compared with structurally lower, compositionally similar, unmylonitized material. Biotite from these rocks has δD values ranging from -125 to -175, compared to values of -55 to-70 in biotite from unmylonitized rocks. Mylonitized leucogranites have large disequilibrium oxygen isotope fractionations ( Δ quartz-feldspar up to ∼8 per mil) relative to magmatic values ( Δ quartz-feldspar ∼1 to 2 per mil)). Meteoric water is the only major oxygen and hydrogen reservoir with an isotopic composition capable of generating the observed values. Fluid inclusion water from unstrained quartz in silicified breccia has a δD value of-119 which provides a plausible estimate of the δD of the infiltrating fluid, and is similar to the isotopic composition of present-day and Tertiary local meteoric water. The quartzite mylonite biotites would have been in equilibrium with such a fluid at temperatures of 480–620° C, similar to independent estimates of the temperature of mylonitization. The relatively high temperatures required for isotopic exchange between quartz and water, the occurrence of fluid inclusion trails and deformed veins in quartzite mylonites, and the spatial association of the low- 18 O, low-D rocks with the shear zone all constrain isotopic exchange to the mylonitic (plastic) deformation event. These observations suggest thata significant amount of meteoric water infiltrated the shear zone during mylonitization to depths of at least 5 to 10 km below the surface. The depth of penetration of meteoric fluids into the lower plate mylonites was at least 70 meters below the detachment fault. In contrast, the upper-plate unmylonitized fault slices are dominated by brittle fracture and are often intensely veined (carbonates) or silicified (volcanic rocks and breccias). The fluids associated with the veining and silicification were also meteoric as evidenced by low δ 18 O values of the veins, which are often 10 per mil lower than the adjacent carbonate matrix, and the exceptionally low δ 18 O values (down to-4.4) of the breccias. Several previous studies have documented the infiltration of meteoric fluids into the brittley deformed upper plate rocks of core complexes, but this study provides convincing evidence that surface fluids have penetrated lower plate rocks undergoing plastic deformation. It is proposed that infiltration took place as the shear zone began the transition from plastic flow to brittle fracture while the lower plate rocks were being uplifted. During this period, plastic flow and brittle fracture were operating simultaneously, perhaps allowing upper plate meteoric fluids to be seismically pumped down into the lower plate mylonites.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47299/1/410_2004_Article_BF00348952.pd