Browsing by Author "Chaudhury, Sidhartha"
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- ItemIdentification of Immune Signatures of Novel Adjuvant Formulations Using Machine Learning.(0000-00-00) Chaudhury, Sidhartha; Duncan, Elizabeth H; Atre, Tanmaya; Storme, Casey K; Beck, Kevin; Kaba, Stephen A; Lanar, David E; Bergmann-Leitner, Elke SAdjuvants have long been critical components of vaccines but the exact mechanisms of their action and precisely how they alter or enhance vaccine induced immune responses are often unclear In this study we used broad immunoprofiling of antibody cellular and cytokine responses combined with data integration and machine learning to gain insight into the impact of different adjuvant formulations on vaccine induced immune responses A Self Assembling Protein Nanoparticles SAPN presenting the malarial circumsporozoite protein CSP was used as a model vaccine adjuvanted with three different liposomal formulations liposome plus Alum ALFA liposome plus QS21 ALFQ and both ALFQA Using a computational approach to integrate the immunoprofiling data we identified distinct vaccine induced immune responses and developed a multivariate model that could predict the adjuvant condition from immune response data alone with 92 accuracy p 0 003 The data integration also revealed that commonly used readouts i e serology frequency of T cells producing IFN IL2 TNF missed important differences between adjuvants In summary broad immune profiling in combination with machine learning methods enabled the reliable and clear definition of immune signatures for different adjuvant formulations providing a means for quantitatively characterizing the complex roles that adjuvants can play in vaccine induced immunity The approach described here provides a powerful tool for identifying potential immune correlates of protection a prerequisite for the rational pairing of vaccines candidates and adjuvants
- ItemSimulation of B cell affinity maturation explains enhanced antibody cross-reactivity induced by the polyvalent malaria vaccine AMA1.(2014-08-16) Chaudhury, Sidhartha; Reifman, Jaques; Wallqvist, AndersPolyvalent vaccines use a mixture of Ags representing distinct pathogen strains to induce an immune response that is cross reactive and protective However such approaches often have mixed results and it is unclear how polyvalency alters the fine specificity of the Ab response and what those consequences might be for protection In this article we present a coarse grain theoretical model of B cell affinity maturation during monovalent and polyvalent vaccinations that predicts the fine specificity and cross reactivity of the Ab response We stochastically simulate affinity maturation using a population dynamics approach in which the host B cell repertoire is represented explicitly and individual B cell subpopulations undergo rounds of stimulation mutation and differentiation Ags contain multiple epitopes and are present in subpopulations of distinct pathogen strains each with varying degrees of cross reactivity at the epitope level This epitope and strain specific model of affinity maturation enables us to study the composition of the polyclonal response in granular detail and identify the mechanisms driving serum specificity and cross reactivity We applied this approach to predict the Ab response to a polyvalent vaccine based on the highly polymorphic malaria Ag apical membrane antigen 1 Our simulations show how polyvalent apical membrane Ag 1 vaccination alters the selection pressure during affinity maturation to favor cross reactive B cells to both conserved and strain specific epitopes and demonstrate how a polyvalent vaccine with a small number of strains and only moderate allelic coverage may be broadly neutralizing Our findings suggest that altered fine specificity and enhanced cross reactivity may be a universal feature of polyvalent vaccines
- ItemSynthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication.(2014-01-24) Munagala, Surendrachary; Sirasani, Gopal; Kokkonda, Praveen; Phadke, Manali; Krynetskaia, Natalia; Lu, Peihua; Sharom, Frances J; Chaudhury, Sidhartha; AbdulHameed, Mohamed Diwan M; Tawa, Gregory; Wallqvist, Anders; Martinez, Rogelio; Childers, Wayne; Abou-Gharbia, Magid; Krynetskiy, Evgeny; Andrade, Rodrigo BNatural products represent the fourth generation of multidrug resistance MDR reversal agents that resensitize MDR cancer cells overexpressing P glycoprotein Pgp to cytotoxic agents We have developed an effective synthetic route to prepare various Strychnos alkaloids and their derivatives Molecular modeling of these alkaloids docked to a homology model of Pgp was employed to optimize ligand protein interactions and design analogues with increased affinity to Pgp Moreover the compounds were evaluated for their 1 binding affinity to Pgp by fluorescence quenching and 2 MDR reversal activity using a panel of in vitro and cell based assays and compared to verapamil a known inhibitor of Pgp activity Compound 7 revealed the highest affinity to Pgp of all Strychnos congeners Kd 4 4 M the strongest inhibition of Pgp ATPase activity and the strongest MDR reversal effect in two Pgp expressing cell lines Altogether our findings suggest the clinical potential of these synthesized compounds as viable Pgp modulators justifies further investigation