Le dauphin bleu et blanc (Stenella coeruleoalba) en Méditerranée : de la vicariance à l'épisode à Morbillivirus

Le Dauphin bleu et blanc est l'espèce de Cétacé majoritaire en Méditerranée. L'espèce a subi une épizootie sévère à Morbillivirus en 1990-91 en Méditerranée uniquement. L'objectif de ce travail était d'étudier l'histoire évolutive de cette espèce en Méditerranée et d'essayer de la lier à cet épisode infectieux. Pour cela, des marqueurs mitochondriaux (séquence de la région de contrôle), microsatellites, du chromosome Y (amélogénine) et du Complexe Majeur d'Histocompatbilité (DRB) ont été étudiés. Dans un premier temps, l'analyse phylogénique de l'amélogénine comparée au sein des Cétartiodactyla a permis de montrer l'existence d'une synapomorphie (insertion) pouvant être utilisée à la fois en biologie évolutive et pour le sexage. Dans un deuxième temps, la variabilité et de la région de contrôle et des microsatellites a été étudiée par statistique fréquentiste (F-statistiques) et bayésienne :coefficients individuels de mélange - admixture coefficients, flux de gènes entre groupes, estimation des temps de coalescence des divers clades avec et sans horloge moléculaire. Il en ressort en particulier que deux groupes fortement différenciés coexistent en Méditerranée. La divergence de ces groupes est ancienne (Miocène) et pourrait être due à une divergence allopatrique dont l'événement vicariant serait l'isolement de la Méditerranée lors de la Crise de Salinité du Messinien. Finalement, le DRB a été étudié ce qui constitue une première dans cette espèce sachant que cette molécule a fait l'objet de peu de travaux chez les Cétacés. Cette étude apporte des éléments descriptifs en termes de diversité et de profils de sélection. Le DRB s'avère finalement plus variable qu'initialement décrit dans diverses espèces de Mammifères marins. Ce travail ouvre à la fois des perspectives quant aux mécanismes endogènes et exogènes permettant la coexistence sympatrique de populations/sous-espèces et en termes de médecine évolutive (susceptibilité accrue à des pathogènes). Le Dauphin bleu et blanc pourrait en conséquence s'avérer un bon modèle pour étudier les rapports entre évolution et pathologie.The Striped dolphin is the most prominent Cetacean species in the Mediterranean. This species undertook a severe Morbillivirus episode in 1990-1991 and which occured in the mediterranean only. The objective of this work was to study evolutionary history of this species in the Mediterranean and to assess whether it could correlate with the infectious episode. For that purpose, mitochondrial, microsatellites, Y chromosome (amelogenin) and MHC (DRB) markers have been studies. It a first step, phylogenetic analysis of amelogenin as considered from within Cetardiodactyla showed the existence of a synapomorphy (insertion event) that may be used for evolutionary studies and sexing purposes. In a second step, variability of mitochondrial control region sequence and some microsatellites has been assessed using frequentist and bayesian methods (F-statitics, admixture coefficients, gene flow estimations and time of coalescence). We could particularly delineate two well-defined groups coexisting within the Mediterranean. The divergence of these two groups seems old (Miocen) and could be the result of an allopatric divergence provoked by a vicariant event : the Messinian Salinity Crisis. Finally, DRB has been studied for the first time in this species. This study brings descriptive elements in terms of diversity and selection profiles. DRB seems more variable than initially described in other marine mammals species. This work opens perspectives regarding both endogenous and exogenous mechanisms allowing sympatric coexistence of populations/subspecies and in terms of evolutionary medicine (increased susceptibility to pathogens). The stripes dolphin could therefore prove to be a good model for studying interplays between, evolution and disease

Evolutionary history of a Scottish harbour seal population

ACKNOWLEDGEMENTS The authors wish to thank Shaneve Tripp (NYU School of Law) and Wendy West (DAFF) for their english corrections. Ludovic Hoarau (IFREMER) for his help on ArcGis. Katia Feve (INRAE) for her help with the DNA extraction protocol. DNA samples were extracted at INRAE and genotyped at the Toulouse Genopole Platform (http://www.genotoul.fr/). Anonymous reviewers provided many helpful comments on an earlier version of the manuscript. Funding This work was supported by INRAE (FRANCE), Genotoul platform (FRANCE), and University of Aberdeen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability The following information was supplied regarding data availability: Data is available at INRAE: Nikolic, Natacha; Thompson, Paul; De Bruyn, Mark; Macé, Matthias; Chevalet, Claude, 2020, ‘‘Microsatellite data from: Evolutionary history of a Scottish harbour seal population’’, https://doi.org/10.15454/AOZ7JI, Portail Data INRAE, V2.Peer reviewedPublisher PD

Comparative study of statistical methods for detecting association with rare variants in exome-resequencing data

Genome-wide association studies for complex traits are based on the common disease/common variant (CDCV) and common disease/rare variant (CDRV) assumptions. Under the CDCV hypothesis, classical genome-wide association studies using single-marker tests are powerful in detecting common susceptibility variants, but under the CDRV hypothesis they are not as powerful. Several methods have been recently proposed to detect association with multiple rare variants collectively in a functional unit such as a gene. In this paper, we compare the relative performance of several of these methods on the Genetic Analysis Workshop 17 data. We evaluate these methods using the unrelated individual and family data sets. Association was tested using 200 replicates for the quantitative trait Q1. Although in these data the power to detect association is often low, our results show that collapsing methods are promising tools. However, we faced the challenge of assessing the proper type I error to validate our power comparisons. We observed that the type I error rate was not well controlled; however, we did not find a general trend specific to each method. Each method can be conservative or nonconservative depending on the studied gene. Our results also suggest that collapsing and the single-locus association approaches may not be affected to the same extent by population stratification. This deserves further investigation

Antibody Response in Immunocompromised Patients After the Administration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine BNT162b2 or mRNA-1273: A Randomized Controlled Trial

BACKGROUND BNT162b2 by Pfizer-BioNTech and mRNA-1273 by Moderna are the most commonly used vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Head-to-head comparison of the efficacy of these vaccines in immunocompromised patients is lacking. METHODS Parallel, 2-arm (allocation 1:1), open-label, noninferiority randomized clinical trial nested into the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. People living with human immunodeficiency virus (PLWH) or solid organ transplant recipients (SOTR; ie, lung and kidney) from these cohorts were randomized to mRNA-1273 or BNT162b2. The primary endpoint was antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain (Elecsys Anti-SARS-CoV-2 immunoassay, Roche; cutoff ≥0.8 units/mL) 12 weeks after first vaccination (ie, 8 weeks after second vaccination). In addition, antibody response was measured with the Antibody Coronavirus Assay 2 (ABCORA 2). RESULTS A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 PLWH and 71 SOTR). The percentage of patients showing an immune response was 92.1% (95% confidence interval [CI]: 88.4-95.8; 186/202) for mRNA-1273 and 94.3% (95% CI: 91.2-97.4; 198/210) for BNT162b2 (difference: -2.2%; 95% CI: -7.1 to 2.7), fulfilling noninferiority of mRNA-1273. With the ABCORA 2 test, 89.1% had an immune response to mRNA-1273 (95% CI: 84.8-93.4; 180/202) and 89.5% to BNT162b2 (95% CI: 85.4-93.7; 188/210). Based on the Elecsys test, all PLWH had an antibody response (100.0%; 341/341), whereas for SOTR, only 60.6% (95% CI: 49.2-71.9; 43/71) had titers above the cutoff level. CONCLUSIONS In immunocompromised patients, the antibody response of mRNA-1273 was noninferior to BNT162b2. PLWH had in general an antibody response, whereas a high proportion of SOTR had no antibody response

Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in people with HIV.

We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60 years, with CD4+ cell count superior to 350 cells/μl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations

Antibody response in immunocompromised patients after the administration of SARS-CoV-2 vaccine BNT162b2 or mRNA-1273: A randomised controlled trial.

BACKGROUND BNT162b2 by Pfizer-BioNTech and mRNA-1273 by Moderna are the most commonly used vaccines to prevent SARS-CoV-2 infections. Head-to-head comparison of the efficacy of these vaccines in immunocompromised patients is lacking. METHODS Parallel, two-arm (allocation 1:1), open-label, non-inferiority randomised clinical trial nested into the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. Patients living with HIV (PLWH) or solid organ transplant recipients (SOTR; i.e. lung and kidney) from these cohorts were randomised to mRNA-1273 or BNT162b2. The primary endpoint was antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain (Elecsys Anti-SARS-CoV-2 immunoassay, Roche; cut-off ≥0.8 units/ml) 8 weeks after second vaccination. In addition, antibody response was measured with the Antibody CORonavirus Assay 2 (ABCORA 2). RESULTS 430 patients were randomised and 412 were included in the intention-to-treat analysis (341 PLWH and 71 SOTR). The percentage of patients showing an immune response was 92.1% (95% confidence interval [CI] 88.4-95.8%; 186/202) for mRNA-1273 and 94.3% (95% CI 91.2-97.4; 198/210) for BNT162b2 (difference: 2.2%; 95% CI -7.1 to 2.7), fulfilling non-inferiority of mRNA-1273. With the ABCORA 2 test 89.1% had an immune response to mRNA-1273 (95% CI 84.8-93.4%; 180/202) and 89.5% to BNT162b2 (95% CI 85.4-93.7%; 188/210). Based on the Elecsys test, all PLWH had an antibody response (100.0%; 341/341), while for SOTR only 60.6% (95% CI 49.2-71.9%; 43/71) had titres above the cut-off. CONCLUSIONS In immunocompromised patients the antibody response of mRNA-1273 was non-inferior to BNT162b2. PLWH had in general an antibody response, while a high proportion of SOTR had no antibody response

Antibody Response After Third Vaccination With mRNA-1273 or BNT162b2: Extension of a Randomized Controlled SARS-CoV-2 Noninferiority Vaccine Trial in Patients With Different Levels of Immunosuppression (COVERALL-2).

Extension of the COVERALL (COrona VaccinE tRiAL pLatform) randomized trial showed noninferiority in antibody response of the third dose of Moderna mRNA-1273 vaccine (95.3% [95% confidence interval {CI}, 91.9%-98.7%]) compared to Pfizer-BioNTech BNT162b2 vaccine (98.1% [95% CI, 95.9%-100.0%]) in individuals with different levels of immunosuppression (difference, -2.8% [95% CI, -6.8% to 1.3%])

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2).

BACKGROUND After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. METHODS In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. RESULTS Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). CONCLUSIONS People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov)

Antibody Response After Third Vaccination With mRNA-1273 or BNT162b2: Extension of a Randomized Controlled SARS-CoV-2 Noninferiority Vaccine Trial in Patients With Different Levels of Immunosuppression (COVERALL-2)

Extension of the COVERALL (COrona VaccinE tRiAL pLatform) randomized trial showed noninferiority in antibody response of the third dose of Moderna mRNA-1273 vaccine (95.3% [95% confidence interval {CI}, 91.9%-98.7%]) compared to Pfizer-BioNTech BNT162b2 vaccine (98.1% [95% CI, 95.9%-100.0%]) in individuals with different levels of immunosuppression (difference, -2.8% [95% CI, -6.8% to 1.3%])

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2)

BACKGROUND After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. METHODS In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. RESULTS Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). CONCLUSIONS People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov)