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Reverse Vaccinology

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Basics and Applications
  Volume 4 ã Issue 6 ã 1000194J Vaccines VaccinISSN:2157-7560 JVV an open access journal Review ArticleOpen Access Vaccines & Vaccination Kanampalliwar et al., J Vaccines Vaccin 2013, 4:6http://dx.doi.org/10.4172/2157-7560.1000194 Keywords: Conventional vaccinology; Reverse vaccinology; Epitope prediction Introduction Disease prevention is the most effective approach or health and can easily be achieved by administration o the biological preparation called vaccines [1]. Development o vaccines has proved a milestone in prevention o diseases or which the cure is not available. In many countries mortality rate or various diseases like small pox, polio, measles, diphtheria etc [2] was very high but due to invention o  vaccines against these diseases, it has allen to negligible. In many developing countries vaccines have played an important role in decreasing the mortality rate due some major killer diseases. Vaccines are biological preparations that are helpul in improving the immunity o a person against a particular disease [3]. Vaccines can be prepared by  various means depending on the pathogenecity o microbes.Te concept o vaccination was given by Edward Jenner in 1796 by developing vaccine against smallpox and averting the inection by isolating the materials rom cow. He also introduced the term vaccine. Te widespread progressive use o vaccines or many inectious pathogens has been the milestone in medical sciences. When it was ound that micro organisms are the cause o inectious diseases, Louis Pasteur gave the rules o vaccinology. Te rules given by Pasteur were ollowed by Salk and Sabin. Tey prepared the vaccine against polio that is killed and attenuated live polio virus as a vaccine respectively. Measles is a severely communicable disease that mainly inects the children. Rubella is another serious disorder that causes severe child birth deects. Hilleman developed vaccine against measles, mumps and rubella [4] with the help o attenuated viruses and ocused light on development o vaccine against diphtheria, tetanus, N. meningitides , S. pneumonia and so on. In case o hepatitis the vaccine was prepared using inactivated viral antigen. So, development o vaccines with the use o rules o Pasteur has indeed been the most powerul tool in the history o medicine (Figure 1) [5].Te chart shows that how the vaccine can be prepared by various means and each one o them has their own importance or preventing the disease. Vaccine may be prophylactics [6] that are used or decreasing the effect o the disease occurring in the uture while some may be curative. ill 20 th  century vaccines were prepared by using traditional means but now a days various other techniques are available those are being used or the development o recombinant DNA vaccine, conjugated proteins and advances in novel adjuvant. Tere have been many innovations in the field o vaccines, the first being against hepatitis B [7] and Bordetella pertusis with the introduction o the molecular biology and genetic engineering [8].With the start o genomic era new revolutions have been taking place in the field o vaccines [9]. Te application o shotgun sequencing has been introduced in giving the whole genomic sequences o several pathogens. With the completion o the sequence o the first living organism, the genomic data was used or the preparation o the  vaccines against the organism. Te complete genomic sequence o an organism is the reservoir o genes encoding the proteins that can act as potential antigens that can be used as vaccine candidates. Tis technique o identiying the proteins that are exposed on the surace by using genome instead o the microorganism, this novel approach is known as “reverse vaccinology” [10]. Te present review ocuses on the idea o the reverse vaccinology *Corresponding author:  Amol M Kanampalliwar, Master of Technology, School of Biotechnology, UTD, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Bhopal, India, E-mail: amol.kanampalliwar@gmail.com Received  May 01, 2013; Accepted  July 17, 2013; Published  July 20, 2013 Citation:  Kanampalliwar AM, Rajkumar S, Girdhar A, Archana T (2013) Reverse Vaccinology: Basics and Applications. J Vaccines Vaccin 4: 194. doi: 10.4172/2157-7560.1000194 Copyright: © 2013 Kanampalliwar AM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal author and source are credited. Reverse Vaccinology: Basics and Applications Amol M Kanampalliwar *, Rajkumar Soni, Amandeep Girdhar and Archana Tiwari School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Bhopal, Madhya Pradesh, India Abstract Vaccinomics is a new branch of bioinformatics that deals with designing a candidate vaccine against a pathogen that can be used for production of the vaccine in less time as that of conventional vaccinology. Reverse vaccinology is a part of vaccinomics which starts with the genome of pathogen and is used for the predicting the epitope. Epitope prediction is the heart of reverse vaccinology. Reverse vaccinology was used for designing vaccines against some diseases eg. Malaria, Anthrax, Endocarditis, Meningitidis etc. Some approaches against viruses have also been done by reverse vaccinology. Vaccines ConventionalvaccinesPurified antigenvaccinesRecombinantvaccinesLive vaccine eg. yellowfever, rubellaSubunitvaccinesInactivatedvaccineeg. cholera polio, plagueWhole proteinmoleculeeg. HPVDNA vaccineseg. bird fluDNA vaccine Polypeptdeeg. Hepatts B Figure 1: Classication of vaccines .  Citation:  Kanampalliwar AM, Rajkumar S, Girdhar A, Archana T (2013) Reverse Vaccinology: Basics and Applications. J Vaccines Vaccin 4: 194. doi: 10.4172/2157-7560.1000194 Page 2 of 5 Volume 4 ã Issue 6 ã 1000194J Vaccines VaccinISSN:2157-7560 JVV an open access journal how it is important or the preparation o vaccines against pathogens which are difficult to culture in laboratory. Until now vaccines against some diseases like AIDS, hepatitis C are not present. Reverse  vaccinology can make a breakthrough or this. Is reverse vaccinology a hope or preparation o the vaccine against such pathogens or a myth?? Evidently, vaccines against some disease have been provoked due to inection and death o the individuals afer the vaccination; these vaccines were prepared by using the conventional approach that contained the inactivated pathogens. So to prepare a successul vaccine reverse vaccinology can be a much better approach. Reverse Vaccinology vs. Conventional Vaccinology  Te use o genomic inormation with aid o computer or the preparation o vaccines without culturing microorganism is known as reverse vaccinology. Te first revolution in field o vaccination is the use o genetic engineering to produce vaccines. In this approach the pathogenic components o organisms were identified by culturing in laboratory. But it was not a very successul approach or vaccine preparation (Figure 2) [11].Te 2 nd  revolution took place in 20 th  century with the aid o genomic technology [4]. Now a days various technologies are available which can be helpul in determining the whole genome sequence o the organism which can be used to explore the protein coding sequences that can be used as a potential target or vaccine preparation (Figure 3) [11].Te genome sequences provide at once all protein antigens that the pathogen can express at any time. Tis approach contains1. Genome sequences2. Computer analysis3. Prediction o epitope/ antigen 4. Candidate vaccineBut the question arises whether any o the potential antigen candidate acts to provide the properties o immunity without prior knowledge o that antigen present in sufficient amount and could it develop a potential immunity afer inection or expressed in vitro . By this approach one may discover a new antigen that can work on a different pattern. High throughput screening is required or the production o easible candidate vaccine. For achieving this, all genes o pathogens are studied that can efficiently act as candidate vaccine but there are some limitations that it can’t predict polysaccharides, lipids which are some active compounds o vaccine. Modification in Reverse Vaccinology  Pan genomic reverse vaccinology   In this approach the genome o the different isolates o same organism is compared with each other by using computer analysis. Te first pan genome approach was done against Streptococcus agalactica . (Figure 4) [12,13]. Comparative reverse vaccinology  In this approach the pathogenic and non pathogenic strains o one species are compared at their genetic level. It deals with the differences in structure o proteins o different organisms. Role of Epitope Prediction in Reverse Vaccinology  When the conventional ways ail to develop a vaccine, then one has to ollow the non conventional ways or the preparation o vaccine. Until now the genomic sequences o more than 500 pathogens including bacteria and viruses are available on NIH list. As the techniques are available or studying host- pathogen interactions, whole genome study and every unique gene, the work is now ocused on the development o epitope driven vaccines that are target specific.An epitope is an antigenic determinant that plays an important role in immunity o an organism. Tese are present on the surace o organisms that can be detected by the antibody [14]. Reverse  vaccinology deals with computational analysis o genome that can be used or the prediction o the epitopes that are surace proteins. So the epitopes play an important role in development o a candidate vaccine. Te major role played in immune system is by B and  lymphocyte. B cells are important in recognizing the epitopes o the antigens that can be identified by the paratopes o antibody. In some cases,  cells play a role in cell mediated immunity as the processed antigenic peptides interact with the  cell when they are presented in context o  cell. So Micro organismcultivationSelection of antigenIdentification,testing of immunogenecity,component purificationVaccineDevelopment of vaccineTesting inAnimalsCloning of genes Figure 2: Pipeline for the development of the vaccines by conventional means. Genome sequenceanalysisImmunogenecitytesting in animalmodelDevelopment of vaccine VaccinesPrediction of novelantigensRecombinant proteinexpression Figure 3: Pipeline for the development of the vaccines by reverse vaccinology. Prediction of ORFs, function and localisation of proteinsORFs clustered in Orthologus genes clusterExperimental validationStudy of selected antigens within population Figure 4: Flow chart of the process of Pan Genomic Reverse Vaccinology.  Citation:  Kanampalliwar AM, Rajkumar S, Girdhar A, Archana T (2013) Reverse Vaccinology: Basics and Applications. J Vaccines Vaccin 4: 194. doi: 10.4172/2157-7560.1000194 Page 3 of 5 Volume 4 ã Issue 6 ã 1000194J Vaccines VaccinISSN:2157-7560 JVV an open access journal the prediction o the epitopes o  and B cell plays an important role in determination o the candidate vaccine. Te epitope prediction plays an important role in designing o epitope based vaccine. T-Cell Epitope Mapping and Prediction A successul peptide-based vaccine must include immune dominant epitopes [15,16]. One o the problems acing traditional  vaccines is the lack o a broad cell-mediated immune response against  variable pathogens [17-19].Humoral immunity may help prevent inection, but to date only a limited number o antibodies with neutralizing capability have been identi󿬁ed or viruses such as HIV. Te induction o cell-mediated immune responses with a large repertoire o immune speci󿬁cities has emerged as an essential characteristic or the clearance or control o hypervariable viral inections such as HCV and HIV [19-21].  cell recognizes the antigenic peptides only when they are presented by MHC I or II, with the help o the CD4 and CD8 molecule. Given the importance o -cell responses in controlling viral inections, the larger number o -cell epitope mapping and prediction algorithms available today comes as no surprise [22,23].One o the more comprehensive programs seems to be EpiMatrix rom EpiVax Inc. Te EpiMatrix tool set is able to predict epitopes against over 100 different MHC class I and class II alleles. In a typical EpiMatrix analysis the target protein sequence is broken down into overlapping 9-mer rames in which each rame overlaps the last by eight amino acids. Each o the derived 9-mer rames is then screened or predicted affinity against a panel o MHC class I and/or class II alleles. Te resulting scores all on a common scale that can be directly compared across HLA alleles. Te ability to rate putative epitopes on a common scale is described as an exclusive eature o the EpiMatrix system [24]. Te EpiMatrix platorm is also closely tied with additional computational tools such as ClustiMer (scans EpiMatrix results or -cell epitope ‘clusters’), BlastiMer (automated BLAS search tool), OptiMatrix (involved in de-immunizing sequences), Conservatrix (involved in finding conserved epitopes) and Vaccine CAD ( an in silico  vaccine design algorithm) [25]. B-Cell Epitope Mapping and Prediction Te antigen antibody interaction plays an important role in immunity, binding takes place at antigenic determinant also known as B-cell epitopes. Te B-cell epitopes are de󿬁ned by a speci󿬁c surace region o an antigenic protein, and may be divided into two different types o epitopes: linear epitopes and conormational epitopes [26].Te linear epitopes are short peptides while conormational epitopes composed o amino acid olded in 3- dimensional protein structure [27]. Te mapping o the B cell epitopes can be done by various techniques. Te ocus o the scientist is only on the determination o linear B cell epitope [28]. Te propensity value o amino acid plays an important role in determination o its position in B cell epitopes. It was introduced by Hopp and Woods. Tey utilized the Levitt hydrophobicity scale or the determination o the propensity value or each amino acid [27]. oday, several tools are available or the prediction o linear B cell epitopes such as PREDIOPE [29], PEOPLE [30], BEPIOPE [29] and BcePred [31] with the determination o the propensity value. ABC pred [31] uses the machine learning based method or the prediction o the linear B cell epitopes. Te conormational B cell epitope prediction can be done by ollowing: Sequence based prediction method It does not require the target antigen structure to be known [27]. Structure based prediction method: - It depends on the determination o the antigen antibody complexes using X- ray crystallography. Discoope is used or the determination o the conormational B cell epitope prediction. PEPIOPE uses combination o propensity value and hal sphere exposure value o amino acid residues [27]. Mimotpoe analysis based prediction method It combines both computational and experimental techniques or B cell epitope mapping. It determines the organization o the genuine epitopes [27].Examples o B-cell epitope-mapping algorithms include 3DEX (3D-Epitope-Explorer) [32] ,CEP (conormational epitope predictor) [33] and Discoope [34]. 3DEX sofware is designed to allow the localization o linear peptide sequences within the three-dimensional structure o a protein. CEP predicts epitopes o proteins with known structures using accessibility o residues and spatial distance cutoffs to predict antigenic determinants, conormational epitopes and sequential epitopes [33,34]. Discoope was designed speci󿬁cally or the prediction o conormational B-cell epitopes [14]. Developments in B cell epitope prediction Prediction o the protective linear B cell epitopes [6], hybrid and consensus prediction o B cell epitopes [27] , improved conormational B cell epitope prediction [27] , critical assessment o B cell epitope prediction [27], immune epitope database and analysis resources [35]. With the help o these databases one can easily identiy and predict the B cell epitope very correctly. Applications of Reverse Vaccinology  Meningitides Te first pathogen against which the vaccine was prepared with the aid o reverse vaccinology was or serogroup B Niserria meningitidis. Te in silico approach or designing the vaccine by reverse vaccinology came into play due to high rate o mortality due to cause o meningitides by bacteria and N. menintidis . Te process o preparation o vaccine against meningitides was a difficult task during the impact o disease. Meningitis is the swelling o the membranes around the spinal cord and brain showing the symptoms like ever, stiff neck and back, conusion, coma; caused by bacteria, viruses, or other microorganisms [36,37].Te classical way or the production o the vaccine against meningitis ailed due to similarity o the proteins to humans and also because o the hypervariable nature o the pathogen. Te whole genome o N.meningitidis was analyzed and with computer aid, the specific sequences were selected that are surace protein and can act as a vaccine candidate. Te expression o protein was expressed in E.coli . Te proteins which are successully expressed in E.coli  were confirmed by using ELISA, FACS etc. Tese proteins are outer membrane protein, surace proteins, and surace associated lipoproteins. Tese proteins act as potential source or development o vaccine against Men B. Te analysis o many protein sequences were done to check its antigencity but only the ew could act as good vaccine candidate which has bactericidal activity that can induce the protective immunity against Men B strains. Te successul vaccine was then introduced in human  Citation:  Kanampalliwar AM, Rajkumar S, Girdhar A, Archana T (2013) Reverse Vaccinology: Basics and Applications. J Vaccines Vaccin 4: 194. doi: 10.4172/2157-7560.1000194 Page 4 of 5 Volume 4 ã Issue 6 ã 1000194J Vaccines VaccinISSN:2157-7560 JVV an open access journal  volunteers under phase III trials [38]. Te vaccine was also prepared with the combination o the other proteins o streptococcus. Listerosis Listerosis is inectious ood borne disease caused by Listeria monocytogenes  in animals and human. It leads to septicemia, encephalitis, pneumonia in humans. L. monocytogenes  classified under gram positive bacillus belongs to Firmicutes which is named by Joseph Lister. It was recognized as the threat to ood industry. Te DNA  vaccine or the disease is under progress which uses the MHC- I peptide chain. Reverse vaccinology approach is used or the development o the  vaccine against listeriosis [39]. Te whole genome sequence o the L. monocytogenes  is available which is now used or the development o the vaccine by the reverse vaccinology approach. Te signal peptides, LPXG motis, transmembrane helices and many surace proteins can be easily identified with the help o the various web based tools [40]. Various tools are used that have their own specific role. SignalP 3.0: Te tool was used or checking the position and the presence o the signal peptide cleavage positions in protein with the reerences o Gram positive bacteria [40]. TMHMM: Te tool was used or determining the number o the transmembrane helices in proteins with the help o the hydrophobic amino acid [40]. LipoP: Te tool was used or the determining the no. o the lipoproteins and it distinguishes between the lipoprotein signal peptides, other signal peptides and n terminal membrane helices in accordance with the gram positive bacteria [40]. PSORTb: Te sub cellular localization o the proteins can be done by PSORb, a valuable tool or the genome analysis [40].By the above tools, one can easily identiy the surace proteins which can be easily used as antigenic epitopes against which the vaccine was produced. Malaria Malaria is one o the most dangerous diseases that cause large number o deaths. Te spread o malaria is due to bite o the mosquitoes that transer the plasmodium into blood stream. Te cause and spread o the disease is due to resistance o pathogens against various drugs. In 2010, near about 1.2 million people died due to malaria [41]. Tere are several drugs available that act primarily against Plasmodium falciparum . It has become resistant to these drugs, so  vaccination could be the good approach or prevention o malaria. Vaccination is an efficient way or controlling spread o malaria. Te reverse vaccinology approach is in progress or development o vaccine [42]. Te sequences o 2 chromosomes o Plasmodium falciparum  out o 14 are now available. Te genome sequences were analyzed using computer approach and the ORFs were selected that can be translated in proteins. By studying the properties o these proteins and localization they can be used or the preparation o a successul vaccine candidate. Endocarditis It is the inflammation o the valves o the heart due to bacterial inection; characterized by scant inflammatory cells, vegetation. Te causative organism is Streptococus mutans . It is classified under gram positive bacteria and is a normal flora o the human oral cavity. So the reverse vaccinology approach is under progress or the preparation o a successul vaccine candidate. Te evolutionary conserved sequences o the surace proteins are selected that are used or vaccine preparation [43]. Anthrax  Bacillus anthracis is the causative agent o anthrax which inects animals and humans. Te organism was used as a weapon or bioterrorism. So the development o a vaccine is an excellent approach or the prevention o spread o the disease. Until 20 th  century many people and animals had been killed by anthrax. First vaccine was prepared against anthrax by Pasteur [44-46]. Te reverse vaccinology approach was used or the ormulation o a candidate vaccine. Te antigenic determinants were ound out by using EMBOSS. Te antigenic determinant with greater LCV value was used or designing a molecule or vaccine candidate. Docking was also done with MHC I molecule showing stable interaction [47]. Conclusion Te conventional way o vaccine development includes culturing o pathogens in laboratory but this is not possible in case o highly inectious pathogens that are hazardous to culture in laboratory. Hence a new approach has been discovered to design an efficient vaccine i.e. reverse vaccinology. Te only requirement o the technique is the availability o whole genome sequence o the organism. With the advent o reverse vaccinology, the genome sequences o a large number o isolates can be screened or homology. Te whole genome sequence is required or the prediction o epitopes and other surace protein; which is the important part o reverse vaccinology or the designing o a successul candidate vaccine. Te examples given in this review article show that reverse vaccinology is useul or the preparation o epitope based vaccines against the most dangerous pathogens. References 1. Sanou MP, De Groot AS, Murphey-Corb M, Levy JA, Yamamoto JK (2012) HIV-1 Vaccine Trials: Evolving Concepts and Designs. Open AIDS J 6: 274-288.2. http://www.cdc.gov/ 3. Lara HH, Garza-Treviño EN, Ixtepan-Turrent L, Singh DK (2011) Silver  nanoparticles are broad-spectrum bactericidal and virucidal compounds. J Nanobiotechnology 9: 30.4. LM L: New strategies for vaccine development, SPCV 2010 2: e45.  Ananya Manda, Vaccines History. 6. Sollner J, Grohmann R, Rapberger R, Perco P, Lukas A, et al. (2008) Analysis and prediction of protective continuous B-cell epitopes on pathogen proteins. Immunome Res 4: 1.7.  A vaccine produced by genetic engineering? Why not!8. Buasri W, Impoolsup A, Boonchird C, Luengchaichawange A, Prompiboon P, et al. (2012) Construction of Bordetella pertussis strains with enhanced production of genetically-inactivated Pertussis Toxin and Pertactin by unmarked allelic exchange. BMC Microbiol 12: 61.9. Rinaudo CD, Telford JL, Rappuoli R, Seib KL (2009) Vaccinology in the genome era. J Clin Invest 119: 2515-2525.10. Rappuoli R (2000) Reverse vaccinology. Curr Opin Microbiol 3: 445-450.11. Flower DR, Macdonald IK, Ramakrishnan K, Davies MN, Doytchinova IA (2010) Computer aided selection of candidate vaccine antigens. Immunome Res 6 Suppl 2: S1.12. Lefébure T, Stanhope MJ (2007) Evolution of the core and pan-genome of  Streptococcus: positive selection, recombination, and genome composition. Genome Biol 8: R71.13. Zhao Y, Wu J, Yang J, Sun S, Xiao J, et al. (2012) PGAP: pan-genomes analysis pipeline. Bioinformatics 28: 416-418.
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