The objective of developing "Jenner-Predict" server is to provide credible vaccine candidates and information related to their immunogenic potential, conservation and autoimmunity in host. The server is based on the principle that non-cytosolic proteins having functions important in host-pathogen interactions and disease establishment could be potential vaccine candidates (Figure 1). Since the server prioritizes few numbers (3-5% proteins of a proteome) of protein as vaccine candidates (PVCs), user may express these few proteins and evaluate their immune response for subunit vaccine development.
Figure1: Flow Diagram of server
The server has two components: the PVCs prediction and analysis of their vaccine potentials. The PVCs prediction is performed in three steps: prediction of non-cytosolic subcellular localization, expressibility in laboratory and having domains critical in host-pathogenic interactions and disease establishment (Figure 1). The software PSORTb 3.0 is used for subcellular localization prediction (1) and cytosolic proteins are discarded. Since experiments have shown that a protein with more than two trans-membrane helices have high probability of failure to express (2), proteins with more than two trans-membrane helices, determined by using HMMTOP (3) software, are discarded. Domains involved in host-microbe interactions and disease establishment, the important component of server, was selected from functional classes of proteins belong to adhesin, invasin, toxin, porins, colonization, penicillin-binding and choline-binding(Table 1)/a>. Standalone Pfam sequence search is used for prediction of domains. The vaccine potential of predicted PVCs is determined on the basis of their immunogenicity, conservation across different pathogenic and nonpathogenic strains of same bacteria and autoimmunity information. Presence of antigenic determinant (epitope) is determined by mapping known B-cell epitopes (BCEs) and T-cell Epitopes (TCEs) reported in immune epitope database (IEDB) (4) to PVCs which enables us to know their possible immunogenic site and potential. Vaccine candidates specific to pathogenic strains are more attractive vaccine candidates as they are expected to be involved in virulence (5). Therefore, PVCs' are compared against pathogenic and nonpathogenic strains of that species separately to determine their conservation. The PVCs having homolog(s) in host (human) proteins may be discontinued from further vaccine development process since these PVCs may produce autoimmunity leading to lesser immune responses and could result in failure as vaccine candidates. These analyses were implemented for prioritization of predicted PVCs more effectively.      More....
The performance of server was evaluated against reported vaccine candidates in S. pneumoniae (gram positive) and E. coli (gram negative), diverse and broad classes bacterial datasets (both positive and negative) used for development of VaxiJen server and protective antigens reported in Protegen database. Our server's PVCs prediction accuracy (sensitivity) is better than existing software and servers such as new enhanced reverse vaccinology environment (NERVE) (6), Vaxign (7) and VaxiJen (8) for all levels data taken for evaluation (Table 2). Lack of negative dataset has deprived us to calculate specificity for all the cases. Our server has achieved sensitivity of 0.774 and 0.711 for dataset of protegen and VaxiJen while specificity of 0.941 is attained for the VaxiJen data.
UNIQUE FEATURE OF JENNER-PREDICT:
> Developed from biological findings that non-cytosolic proteins involved in host-pathogen interactions and disease establishment are better subunit vaccine candidates.
> Predicted few proteins as PVCs and prioritize them on the basis of their vaccine potential so that researcher may take few promising proteins for further subunit vaccine development.
> Since PVCs are predicted based on their functions, biologists can also access significance of those domains' function in pathogenesis and disease establishment in a given organism to prioritize predicted vaccine candidates for that organism.
> This server is expected to replace well-known sero-specific vaccine candidates by more conserved/sero-independent one so subunit vaccine with broad-specificity could be developed.
> In contrast to earlier software and servers, the performance of the server is validated on diverse datasets (Protegen database and data used in VaxiJen server development) from different bacteria.
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