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BIOTECH 7001 Drug Discovery And Development

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BIOTECH 7001 Drug Discovery And Development Question: You are required write a report on one of the following topics: The production and use of Vaccines Answer: Introduction The concept of vaccination was first introduced by Edward Jenner. Its contribution is well known for the treatment of smallpox (Kupper 2012). Vaccine is capable of generating both active and passive immunity. However, it is regarded as a potent medium to generate active immunity. However, there still remains a crying need to the production of vaccines against several deadly diseases, especially to those for AIDS (Picker, Hansen and Lifson 2012). Moreover, increase in the incidence of multi drug resistant bacteria has further up regulated the need for vaccine to combat infectious diseases caused by micro-organisms (Reardon 2014). Recently trials have also been made for the generation of vaccine against cancer. The report here sheds lights on different types of vaccines that are produced so far along with its advantages and disadvantages. Discussion Vaccines confer immunity to the infectious micro-organisms and this is achieved via active and passive immunization (Owen, Punt and Stranford 2013). Types of immunization Active immunization Passive Immunization Agents used for Immunization Immunization with microbial pathogen or antigenic determinant of microbes that elicit immune response but do not cause infection Antibodies derived from human or animals or performed antibodies. Naturally passive immunization occurs via transmission of maternal antibodies through placenta and milk Common agent used Vaccines Agents Diseases Attenuated organisms Horse antivenin Botulism Inactivated organisms Horse antivenin Bite of black widow spider Cloned micro-organisms Hepatitis Pooled human gamma globulin Purified micro-organisms Measles Pooled human gamma globulin Recombinant proteins Rabies Pooled human gamma globulin Multivalent proteins Snake bite Horse antivenin DNA and toxoid Tetanus Pooled human gamma globulin and horse antitoxin Advantages and Disadvantages Active immunization is acquired artificially via administration of vaccines. Vaccines promotes the proliferation of T-cells and B-cells and subsequent formation of memory cells Performed antibodies produced from another species generate strong iso-typic response. This response may generate IgE mediated mast cell degranulation and systemic anaphylaxis. Diseases which are cured Hepatitis B vaccines, Diphtheria-pertussis, tetanus, inactivated salk vaccines, sabin vaccines, measles-mumps-rubella, influenza, varicella zoster, pneumococcal conjugate vaccine Diphtheria, Rabies, Hepatitis B Table: Comparison between active and passive immunity (Source: Owen, Punt and Stranford 2013) Whole-Organism Vaccines The whole organisms which are used as vaccines are bacteria or virus which are either inactivated or live but in an attenuated stated (avirulent). Attenuated means, the virus or the bacteria have already lost their ability to generate significant pathogenic response. However, they have retained their capacity of transient growth within the body of the inoculated host (Todd et al. 2013). Figure: Classification of Whole Organism Vaccines (Source: Owen, Punt and Stranford 2013)  Attenuation is achieved by growing the pathogenic microorganisms under abnormal condition for a prolong time. For example Bacillus Calmatte-Guerin (BCG), was developed via growing Mycobacterium bovis in medium containing bile. 13 years later strain adapted its growth under the adverse condition leading to the generation of attenuated strain of M. bovis (Kawai et al. 2013). Another example of attenuated vaccine is Sabin and Measles vaccines (attenuated strains of virus) (Owen, Punt and Stranford 2013). Attenuated Vaccines Advantages Disadvantages Latest Advancement Prolong immune response causing increased immunity and generation of immune response. Possibility of reverting back to the virulent form. This has led to the generation of inactivated polio vaccines, Salk vaccine.   Heat inactivation causes the degeneration of the antigenic epitopes that is responsible to the generation of immuno-genecity   Attenuation is done irreversibly via the application of genetic engineering technique. This is done via gene silencing. Removal or silencing of the virulence causing genes.   Example: Herpes simplex virus vaccines for pigs:  virulent gene, thymidine kinase (tk) is removed   Recently attenuated vaccines for rotavirus (which causes diarrhoea) is prepared via genetic engineering They require only single dose of immunization (Exception is Sabin vaccine used for polio virus which requires three doses of immunization) in comparison to the killed vaccines which require multiple booster doses They generate cell-mediated immune response in comparison to killed vaccines that is only capable of generating humoral immune response. Table: Advantages and Disadvantages of Attenuated Vaccines (Source: Owen, Punt and Stranford 2013) Purified Macromolecule Vaccines The risk of the killed whole organism vaccines and the attenuated vaccines lead to the discovery of purified macromolecule vaccines (Nascimento and Leite 2012). Figure: Classification of Purified Macromolecule Vaccines (Source: Owen, Punt and Stranford 2013) Bacterial Polysaccharide Capsules Polysaccharide capsules for bacteria are selected as a target for vaccine production because virulence of several bacteria depends on the antiphagocytic properties of these polysaccharide capsules which are hydrophilic in nature. The logic is, coating of these capsular polysaccharide with antibody uplift the ability of neutrophils and macrophages to phagocyte the pathogens. However, polysaccharide vaccines only activate TH cells. It also activates B-cell in an thymus independent type 2 manner (TI-2). TI-2 causes only IgM maturation but no affinity maturation and class switching and thus little or no development of memory cells (Lockyer et al. 2015; Vinuesa and Chang 2013). Advanced are being made via conjugation of polysaccharide capsules with a protein in order to generated memory response. Bacterial Exotoxin Vaccines Diphtheria and tetanus vaccines are produced via purifying bacterial exotoxin and then the inactivation is done via formaldehyde and then the compound is known as toxoid. These toxoid produced anti-toxin antibodies are thus capable of neutralizing the harmful bacterial toxins. Genetic engineering techniques are used to clone genes of these toxins in order to produce toxoid in substantial amount (Tanom et al. 2013). Synthetic Peptide Vaccines Synthetic peptides are used also used as vaccines. However, peptides due to their small structure are not as immunogenic as proteins and hence lag behind in generating humoral and cell mediated immunity. Synthetic peptides are now administered with adjuvants and conjugates in order to generate protective immunity. At present peptide vaccines are in a trial for the generation effective vaccination remedy against cancer (Vacchelli et al. 2012).  Recombinant Vector Vaccines Vaccina is large complex virus with 200 genes (Smith et al. 2013). It is used as an attenuated vaccine to treat smallpox. At present it is genetically engineered to propagate dozen of foreign genes without tampering its ability to infect host cells and simultaneous replication. This genetically engineered vaccina virus is infected in the host body via scratching of skin that causes localised infection (Wyatt, Earl and Moss 2015). Figure: Production of Vaccina vector vaccine (Source: Owen, Punt and Stranford 2013) Other virus which are used as vectors for the recombinant vaccine production include canarypox virus. It is usually engineered to carry bacteria that cause cholera and typhoid (Teigler et al., 2014). DNA Vaccine DNA vaccine is the most recent advancement in the field of vaccine. It is generally produced via plasmid DNA that is being genetically engineered containing antigenic proteins. Plasmid DNA is directly injected into the muscle cells. The cells take up the DNA leading to the generation of both humoral and cell-mediated immune response. Muscle is used as the target of injection because muscle cells have greater power to express the injected DNA. DNA injected either gets integrated into the chromosome (passed on to generation) or remains within the cell as an episomal form (Williams 2013). The main advantage of DNA vaccine is gets expressed into the host in its natural from with no denaturation. Thus the immune response generated is exactly like that of the antigen that injects the cell. DNA vaccine generates both cell mediated and humoral immunity. Moreover, the DNA vaccine does not require refrigeration and thus do not require storage, reducing the cost of maintenance (Tretyakova et al. 2013). Moreover, gene gun method promotes rapid administration of the DNA vaccine (Xu et al. 2012; Shah et al. 2014). Figure: DNA vaccine generating both humoral and cell mediated immune response (Source: Owen, Punt and Stranford 2013) Multivalent Subunit Vaccine Multivalent subunit vaccine is an advanced mode of the synthetic peptide vaccine that contains multiple copies of the given peptide. It is generally injected intra-cellularly in order to generate cytotoxic T-cells (Azmi et al. 2014). Protein micelles, liposomes and immunostimulating complexes (ISCOMs) are used to deliver multivalent subunit vaccine (Cruz-Bustos et al. 2012). Figure: Delivery of Multivalent subunit vaccine via ISCOMS (Source: Owen, Punt and Stranford 2013) Figure: Comparative study between different vaccines (Source: Owen, Punt and Stranford 2013) Conclusion Thus from the above discussion it can be concluded that vaccines are an effective agent for controlling infectious disease. Vaccine help in the generation of both humoral and cell mediated immune response that helps to combat recurrent infection via generating memory cells. However, there lies certain disadvantage of using vaccine like the live attenuated vaccines can reverse back to its virulent form, resulting in an epidemic. Recent researchers are most concentrated in the development of DNA vaccines, synthetic peptide vaccines and multivalent subunit vaccines via the application of genetic engineering techniques. Though DNA vaccines are cost-effective in terms of storage, there lies huge expenditure of cost in generation of these. Moreover, further research are required in this field in order to generate vaccines against the most fatal disease that are prevalent in mankind like cancer and HIV AIDS (Human Immunodeficiency Virus-Acquired Immuno Deficiency Syndrome). References Azmi, F., Ahmad Fuaad, A.A.H., Skwarczynski, M. and Toth, I., 2014. Recent progress in adjuvant discovery for peptide-based subunit vaccines. Human vaccines & immunotherapeutics, 10(3), pp.778-796. Cruz-Bustos, T., González-González, G., Morales-Sanfrutos, J., Megía-Fernández, A., Santoyo-González, F. and Osuna, A., 2012. Functionalization of immunostimulating complexes (ISCOMs) with lipid vinyl sulfones and their application in immunological techniques and therapy. International journal of nanomedicine, 7, p.5941. Kawai, K., Miyazaki, J., Joraku, A., Nishiyama, H. and Akaza, H., 2013. Bacillus Calmette–Guerin (BCG) immunotherapy for bladder cancer: current understanding and perspectives on engineered BCG vaccine. Cancer science, 104(1), pp.22-27. Kupper, T.S., 2012. Old and new: recent innovations in vaccine biology and skin T cells. Journal of Investigative Dermatology, 132(3), pp.829-834. Lockyer, K., Gao, F., Derrick, J.P. and Bolgiano, B., 2015. Structural correlates of carrier protein recognition in tetanus toxoid-conjugated bacterial polysaccharide vaccines. Vaccine, 33(11), pp.1345-1352. Nascimento, I.P. and Leite, L.C.C., 2012. Recombinant vaccines and the development of new vaccine strategies. Brazilian Journal of Medical and Biological Research, 45(12), pp.1102-1111. Owen, J.A., Punt, J. and Stranford, S.A., 2013. Kuby immunology (pp. 427-444). New York: WH Freeman. Picker, L.J., Hansen, S.G. and Lifson, J.D., 2012. New paradigms for HIV/AIDS vaccine development. Annual review of medicine, 63, pp.95-111. Reardon, S., 2014. Antibiotic resistance sweeping developing world: bacteria are increasingly dodging extermination as drug availability outpaces regulation. Nature, 509(7499), pp.141-143. Shah, M.A.A., He, N., Li, Z., Ali, Z. and Zhang, L., 2014. Nanoparticles for DNA vaccine delivery. Journal of biomedical nanotechnology, 10(9), pp.2332-2349. Smith, G.L., Benfield, C.T., de Motes, C.M., Mazzon, M., Ember, S.W., Ferguson, B.J. and Sumner, R.P., 2013. Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. Journal of General Virology, 94(11), pp.2367-2392. Tanom, A., Farajnia, S., Peerayeh, S.N. and Majidi, J., 2013. Cloning, expression and characterization of recombinant exotoxin A-flagellin fusion protein as a new vaccine candidate against Pseudomonas aeruginosa infections. Iranian biomedical journal, 17(1), p.1. Teigler, J.E., Phogat, S., Franchini, G., Hirsch, V.M., Michael, N.L. and Barouch, D.H., 2014. The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys. Journal of virology, 88(3), pp.1809-1814. Todd, T.E., Tibi, O., Lin, Y., Sayers, S., Bronner, D.N., Xiang, Z. and He, Y., 2013. Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates. BMC bioinformatics, 14(6), p.S3. Tretyakova, I., Lukashevich, I.S., Glass, P., Wang, E., Weaver, S. and Pushko, P., 2013. Novel vaccine against Venezuelan equine encephalitis combines advantages of DNA immunization and a live attenuated vaccine. Vaccine, 31(7), pp.1019-1025. Vacchelli, E., Martins, I., Eggermont, A., Fridman, W.H., Galon, J., Sautès-Fridman, C., Tartour, E., Zitvogel, L., Kroemer, G. and Galluzzi, L., 2012. Trial watch: Peptide vaccines in cancer therapy. Oncoimmunology, 1(9), pp.1557-1576. Vinuesa, C.G. and Chang, P.P., 2013. Innate B cell helpers reveal novel types of antibody responses. Nature immunology, 14(2), pp.119-126. Williams, J.A., 2013. Vector design for improved DNA vaccine efficacy, safety and production. Vaccines, 1(3), pp.225-249. Wyatt, L.S., Earl, P.L. and Moss, B., 2015. Generation of recombinant vaccinia viruses. Current protocols in molecular biology, pp.16-17. Xu, L., Liu, Y., Chen, Z., Li, W., Liu, Y., Wang, L., Liu, Y., Wu, X., Ji, Y., Zhao, Y. and Ma, L., 2012. Surface-engineered gold nanorods: promising DNA vaccine adjuvant for HIV-1 treatment. Nano letters, 12(4), pp.2003-2012.

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