Effect of Third and Fourth mRNA-Based Booster Vaccinations on SARS-CoV-2 Neutralizing Antibody Titer Formation, Risk Factors for Non-Response, and Outcome after SARS-CoV-2 Omicron Breakthrough Infections in Patients on Chronic Hemodialysis: A Prospective Multicenter Cohort Study.

The aim of this study is to determine the effect of repeated vaccinations on neutralizing SARS-CoV-2 IgG antibody titers, evaluate risk factors for immunological non-response, and to report breakthrough infections in chronic hemodialysis patients. METHODS: A prospective, multi-center cohort study in 163 chronic hemodialysis patients was conducted. Antibody titers were measured three months after second, third, and fourth (10 pts) booster vaccinations. SARS-CoV-2 neutralizing antibody titers in BAU/mL and % inhibition were divided into three categories (<216, 216-433, >433 and <33, 33-66, and >66%). Somers's test, paired t-test, and univariable and multivariable logistic regression analysis were applied to evaluate differences in antibody levels and search for risk factors for vaccination failure defined as neutralizing titers <50% and/or need for repeated booster vaccinations. Furthermore, we report on a case series to describe characteristics of patients after four vaccinations (n = 10) and breakthrough infections (n = 20). RESULTS: Third dose boosters resulted in higher proportions of patients with neutralizing antibody levels >66% as compared to after the second dose (64.7% after second dose vs. 88.9% after third dose, p = 0.003), as well as in a respective increase in neutralizing titer levels in % from 68 ± 33% to 89 ± 24 (p <0.001). The proportion of patients with IgG-titers below 216 BAU/mL decreased from 38.6 to 10.5% (p ≤ 0.001). Age (p = 0.004, OR 1.066, 95% CI 1.020-1.114) and presence of immunosuppressive medications (p = 0.002, OR 8.267, 95% CI 2.206-30.975) were identified as major risk factors for vaccination failure. Repeated booster vaccinations ≥4 times were effective in 8 out of 10 former low-responders (80%) without any side effects or safety concerns. Breakthrough infections showed a clinically mild course but were associated with prolonged viral shedding on PCR-testing ranging 7-29 (mean 13) days. CONCLUSIONS: Third and fourth mRNA-based booster vaccinations resulted in higher and longer lasting SARS-CoV-2 antibody levels as compared to after two dosages. The presence of immunosuppressive medication and repeat vaccinations are major potentially modifiable measures to increase antibody levels in non-or low-responders. Breakthrough infections with SARS-CoV-2 Omicron were associated with prolonged viral shedding but clinically mild disease courses.

Evolution of SARS-CoV-2-Neutralizing Antibodies after Two Standard Dose Vaccinations, Risk Factors for Non-Response and Effect of a Third Dose Booster Vaccination in Non-Responders on Hemodialysis: A Prospective Multi-Centre Cohort Study.

The aim of this investigation was to determine the effect of SARS-Cov-2 vaccination in hemodialysis patients, search for risk factors for non- or low-response, and to measure the effect of a third booster vaccination in non- or low-responders. Methods SARS-CoV-2 IgG antibodies and the virus-neutralizing capacity were measured 4-5 weeks after a full standard vaccination in 95 chronic hemodialysis patients and 60 controls. IgG titers > 30 AU/mL served to classify participants as responders. Multivariable binary logistic regression analysis was used to search for risk factors of reduced vaccination success. Patients with vaccination failure were offered a third booster dosage. Results 82.1% of the patient cohort as compared to 98.3% of the healthy control group were able to mount SARS-CoV-2 titers above 30 AU/mL after two standard vaccine doses. Mean IgG antibody titers were lower in hemodialysis patients than controls (78 ± 35 vs. 90 ± 20 AU/mL, p = 0.002). Multivariable binary logistic regression analysis showed age and immunosuppressive medication as major risk factors for vaccination failure with a decreased probability of successful vaccination of -6.1% (95% CI -1.2 to -10.9) per increase in age of one year and -87.4% (95% CI -98.0 to -21.5) in patients on immunosuppressive therapy (crude odds ratio for vaccination failure for immunosuppressive therapy 6.4). Ten out of 17 patients with non-response to vaccination were offered a third dose. Booster vaccination after the second dose induced an increase in effective antibody titers of >30 AU/mL in seven out of ten patients 4-5 weeks later (70%). Conclusion Standard SARS-CoV-2 vaccination schemes are highly effective in mounting protective neutralizing IgG antibodies in chronic hemodialysis patients. Nevertheless, response to vaccination is diminished as compared to a healthy control group. Major risk factors for vaccination failure are older age and immunosuppressive therapy. In non- or low-responders to standard vaccination a third booster vaccination was able to induce effective antibody titers in about 70% of patients, indicating that a third booster vaccination might be preferable to decreasing immunosuppressive therapy.

Marine temperatures underestimated for past greenhouse climate.

Understanding the Earth's climate system during past periods of high atmospheric CO2 is crucial for forecasting climate change under anthropogenically-elevated CO2. The Mesozoic Era is believed to have coincided with a long-term Greenhouse climate, and many of our temperature reconstructions come from stable isotopes of marine biotic calcite, in particular from belemnites, an extinct group of molluscs with carbonate hard-parts. Yet, temperatures reconstructed from the oxygen isotope composition of belemnites are consistently colder than those derived from other temperature proxies, leading to large uncertainties around Mesozoic sea temperatures. Here we apply clumped isotope palaeothermometry to two distinct carbonate phases from exceptionally well-preserved belemnites in order to constrain their living habitat, and improve temperature reconstructions based on stable oxygen isotopes. We show that belemnites precipitated both aragonite and calcite in warm, open ocean surface waters, and demonstrate how previous low estimates of belemnite calcification temperatures has led to widespread underestimation of Mesozoic sea temperatures by ca. 12 °C, raising estimates of some of the lowest temperature estimates for the Jurassic period to values which approach modern mid-latitude sea surface temperatures. Our findings enable accurate recalculation of global Mesozoic belemnite temperatures, and will thus improve our understanding of Greenhouse climate dynamics.

Cold spells in the Nordic Seas during the early Eocene Greenhouse.

The early Eocene (c. 56 - 48 million years ago) experienced some of the highest global temperatures in Earth's history since the Mesozoic, with no polar ice. Reports of contradictory ice-rafted erratics and cold water glendonites in the higher latitudes have been largely dismissed due to ambiguity of the significance of these purported cold-climate indicators. Here we apply clumped isotope paleothermometry to a traditionally qualitative abiotic proxy, glendonite calcite, to generate quantitative temperature estimates for northern mid-latitude bottom waters. Our data show that the glendonites of the Danish Basin formed in waters below 5 °C, at water depths of <300 m. Such near-freezing temperatures have not previously been reconstructed from proxy data for anywhere on the early Eocene Earth, and these data therefore suggest that regionalised cool episodes punctuated the background warmth of the early Eocene, likely linked to eruptive phases of the North Atlantic Igneous Province.

Eutrophication, microbial-sulfate reduction and mass extinctions.

In post-Cambrian time, life on Earth experienced 5 major extinction events, likely instigated by adverse environmental conditions. Biodiversity loss among marine taxa, for at least 3 of these mass extinction events (Late Devonian, end-Permian and end-Triassic), has been connected with widespread oxygen-depleted and sulfide-bearing marine water. Furthermore, geochemical and sedimentary evidence suggest that these events correlate with rather abrupt climate warming and possibly increased terrestrial weathering. This suggests that biodiversity loss may be triggered by mechanisms intrinsic to the Earth system, notably, the biogeochemical sulfur and carbon cycle. This climate warming feedback produces large-scale eutrophication on the continental shelf, which, in turn, expands oxygen minimum zones by increased respiration, which can turn to a sulfidic state by increased microbial-sulfate reduction due to increased availability of organic matter. A plankton community turnover from a high-diversity eukaryote to high-biomass bacterial dominated food web is the catalyst proposed in this anoxia-extinction scenario and stands in stark contrast to the postulated productivity collapse suggested for the end-Cretaceous mass extinction. This cascade of events is relevant for the future ocean under predicted greenhouse driven climate change. The exacerbation of anoxic "dead" zones is already progressing in modern oceanic environments, and this is likely to increase due to climate induced continental weathering and resulting eutrophication of the oceans.

Onset of main Phanerozoic marine radiation sparked by emerging Mid Ordovician icehouse.

The Great Ordovician Biodiversification Event (GOBE) was the most rapid and sustained increase in marine Phanerozoic biodiversity. What generated this biotic response across Palaeozoic seascapes is a matter of debate; several intrinsic and extrinsic drivers have been suggested. One is Ordovician climate, which in recent years has undergone a paradigm shift from a text-book example of an extended greenhouse to an interval with transient cooling intervals - at least during the Late Ordovician. Here, we show the first unambiguous evidence for a sudden Mid Ordovician icehouse, comparable in magnitude to the Quaternary glaciations. We further demonstrate the initiation of this icehouse to coincide with the onset of the GOBE. This finding is based on both abiotic and biotic proxies obtained from the most comprehensive geochemical and palaeobiological dataset yet collected through this interval. We argue that the icehouse conditions increased latitudinal and bathymetrical temperature and oxygen gradients initiating an Early Palaeozoic Great Ocean Conveyor Belt. This fuelled the GOBE, as upwelling zones created new ecospace for the primary producers. A subsequent rise in δ(13)C ratios known as the Middle Darriwilian Isotopic Carbon Excursion (MDICE) may reflect a global response to increased bioproductivity encouraged by the onset of the GOBE.

Jurassic climate mode governed by ocean gateway.

The Jurassic (∼201-145 Myr ago) was long considered a warm 'greenhouse' period; more recently cool, even 'icehouse' episodes have been postulated. However, the mechanisms governing transition between so-called Warm Modes and Cool Modes are poorly known. Here we present a new large high-quality oxygen-isotope dataset from an interval that includes previously suggested mode transitions. Our results show an especially abrupt earliest Middle Jurassic (∼174 Ma) mid-latitude cooling of seawater by as much as 10 °C in the north-south Laurasian Seaway, a marine passage that connected the equatorial Tethys Ocean to the Boreal Sea. Coincidence in timing with large-scale regional lithospheric updoming of the North Sea region is striking, and we hypothesize that northward oceanic heat transport was impeded by uplift, triggering Cool Mode conditions more widely. This extreme climate-mode transition provides a counter-example to other Mesozoic transitions linked to quantitative change in atmospheric greenhouse gas content.

Flourishing ocean drives the end-Permian marine mass extinction.

The end-Permian mass extinction, the most severe biotic crisis in the Phanerozoic, was accompanied by climate change and expansion of oceanic anoxic zones. The partitioning of sulfur among different exogenic reservoirs by biological and physical processes was of importance for this biodiversity crisis, but the exact role of bioessential sulfur in the mass extinction is still unclear. Here we show that globally increased production of organic matter affected the seawater sulfate sulfur and oxygen isotope signature that has been recorded in carbonate rock spanning the Permian-Triassic boundary. A bifurcating temporal trend is observed for the strata spanning the marine mass extinction with carbonate-associated sulfate sulfur and oxygen isotope excursions toward decreased and increased values, respectively. By coupling these results to a box model, we show that increased marine productivity and successive enhanced microbial sulfate reduction is the most likely scenario to explain these temporal trends. The new data demonstrate that worldwide expansion of euxinic and anoxic zones are symptoms of increased biological carbon recycling in the marine realm initiated by global warming. The spatial distribution of sulfidic water column conditions in shallow seafloor environments is dictated by the severity and geographic patterns of nutrient fluxes and serves as an adequate model to explain the scale of the marine biodiversity crisis. Our results provide evidence that the major biodiversity crises in Earth's history do not necessarily implicate an ocean stripped of (most) life but rather the demise of certain eukaryotic organisms, leading to a decline in species richness.

Effect of a Jurassic oceanic anoxic event on belemnite ecology and evolution.

The Toarcian oceanic anoxic event (T-OAE; ∼ 183 million y ago) is possibly the most extreme episode of widespread ocean oxygen deficiency in the Phanerozoic, coinciding with rapid atmospheric pCO2 increase and significant loss of biodiversity in marine faunas. The event is a unique past tipping point in the Earth system, where rapid and massive release of isotopically light carbon led to a major perturbation in the global carbon cycle as recorded in organic and inorganic C isotope records. Modern marine ecosystems are projected to experience major loss in biodiversity in response to enhanced ocean anoxia driven by anthropogenic release of greenhouse gases. Potential consequences of this anthropogenic forcing can be approximated by studying analog environmental perturbations in the past such as the T-OAE. Here we present to our knowledge the first organic carbon isotope record derived from the organic matrix in the calcite rostra of early Toarcian belemnites. We combine both organic and calcite carbon isotope analyses of individual specimens of these marine predators to obtain a refined reconstruction of the early Toarcian global exogenic carbon cycle perturbation and belemnite paleoecology. The organic carbon isotope data combined with measurements of oxygen isotope values from the same specimens allow for a more robust interpretation of the interplay between the global carbon cycle perturbation, environmental change, and biotic response during the T-OAE. We infer that belemnites adapted to environmental change by shifting their habitat from cold bottom waters to warm surface waters in response to expanded seafloor anoxia.