Functional Profiling of Antibody Immune Repertoires in Convalescent Zika Virus Disease Patients

The re-emergence of Zika virus (ZIKV) caused widespread infections that were linked to Guillain-Barré syndrome in adults and congenital malformation in fetuses, and epidemiological data suggest that ZIKV infection can induce protective antibody responses. A more detailed understanding of anti-ZIKV antibody responses may lead to enhanced antibody discovery and improved vaccine designs against ZIKV and related flaviviruses. Here, we applied recently-invented library-scale antibody screening technologies to determine comprehensive functional molecular and genetic profiles of naturally elicited human anti-ZIKV antibodies in three convalescent individuals. We leveraged natively paired antibody yeast display and NGS to predict antibody cross-reactivities and coarse-grain antibody affinities, to perform in-depth immune profiling of IgM, IgG, and IgA antibody repertoires in peripheral blood, and to reveal virus maturation state-dependent antibody interactions. Repertoire-scale comparison of ZIKV VLP-specific and non-specific antibodies in the same individuals also showed that mean antibody somatic hypermutation levels were substantially influenced by donor-intrinsic characteristics. These data provide insights into antiviral antibody responses to ZIKV disease and outline systems-level strategies to track human antibody immune responses to emergent viral infections

Delayed boosting improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine

Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) — using AS01B-adjuvanted RH5.1 malaria antigen — substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells

Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per millilite

Optimisation de la vérification de l'équation vibroacoustique des plaques sur un échantillonnage spatial: application au bruit intérieur des avions

This PhD thesis deals with the use of damping patches on aircraft skins to reduce interior noise. Induced mass penalties are considered high today, hence the interest of damping size and placement optimizations. Three excitations are used by Airbus to assess a damping technology: mechanical (laboratory or ground tests), acoustic (laboratory or ground tests) and aerodynamic (flight tests) excitations. The strategy adopted to study the acoustic benefit of such treatments is chosen analytical so as to cover the large frequency band associated with low computation time. An original approach is first of all proposed to compute sound radiation from locally damped plates. The advantages of this method are twofold: first avoid difficulties of radiation impedances calculation and then handle complex aircraft structures. The scientific outcome in term of modelisation lies in the two following points. First an approach based on the minimization of error on a sample of observation points has been developed to solve vibroacoustic equations. A method handling Dirac delta functions to model heterogeneities at localized damping patch boundaries is then proposed. The analytical model developed is applied to unstiffened finite flat plates where a localized damping treatment, a multilayer plate or a varying thickness can be considered. The principle of the method remains valid for curved or stiffened plates, only the equation of motion must be adapted. All studies presented in this manuscript are led at ambient temperature. Numerical validations for mechanical, acoustic and aerodynamic excitations and an experimental validation for acoustic excitation are led. Results prove a very good accuracy of the method developed: fluid-structure interaction and localized damping are well modeled. The focus is also put on the choice of the aerodynamic excitation model. It is pointed out a strong influence of the model for absolute levels and a low influence for relative levels, in-flight validation appear to be necessary even if such flight tests are challenging. An experimental study led on localized damping patches under acoustic excitation has pointed out some tendencies for damping patch size optimization. Using the method developed, a numerical study has then detailed this analysis and extended it to excitation and damping patch placement influences. Acoustic and aerodynamic excitations play clearly different roles in damping impact assessment. Damping patch size and placement effects are finally analyzed under aerodynamic excitation in realistic conditions. A non-linear behavior of the size versus the added mass is observed allowing definition of an optimum. The placement of the damping treatment is presented to be critical only at low frequencies where modal phenomena dominate. This PhD work gives an accurate prediction tool adapted to the industrial needs of aircraft interior noise control. Extensions are of course necessary to consider more realistic structures but the present method allows already the optimization of damping treatments with regard to mass constraints.Dans le contexte du bruit intérieur des avions, ce travail de thèse étudie l'intérêt acoustique de l'utilisation de patchs viscoélastiques. La masse de ces traitements est aujourd'hui considérée comme pénalisante. Une optimisation en termes de taille et de placement est donc envisagée. La stratégie adoptée est choisie analytique pour couvrir une large gamme de fréquences avec des temps de calcul performants. Ce mémoire de thèse propose une approche originale calculant le rayonnement acoustique de plaques amorties localement. Cette approche présente les intérêts suivants : s'absoudre des difficultés de calcul des impédances de rayonnement et être particulièrement adaptée aux structures complexes de l'avion. L'apport scientifique de cette thèse en terme de modélisation réside d'une part dans une approche de calcul vibroacoustique basée sur la minimisation de l'erreur de vérification de l'équation de mouvement sur un échantillonnage spatial et, d'autre part, dans un formalisme par fonctions Dirac mis en œuvre pour simuler les hétérogénéités aux limites d'un patch amortissant localisé. Ce modèle analytique est appliqué à des plaques planes finies non raidies où un traitement amortissant localisé, une plaque multicouche ou une plaque à épaisseur variable peuvent être considérés. Une validation numérique pour les excitations mécanique, acoustique et aérodynamique ainsi qu'une validation expérimentale sous excitation champ diffus démontrent une très bonne précision du modèle développé : le couplage fluide-structure et l'amortissement localisé sont correctement modélisés. Les effets de taille et de placement du patch sont finalement étudiés sur un cas particulier sous excitation aérodynamique en conditions réalistes. Le comportement non linéaire observé de l'effet de taille par rapport à la masse ajoutée permet de définir un optimum. L'apport scientifique de cette thèse offre un outil prédictif performant et adapté à la problématique du bruit interne des avions