Carbohydrate and Peptide †Based Vaccines: The Way Forward

AbstractExisting treatments and therapies oblige supported a huge shape of unsoundnesss and infections, a signifi so-and-sot sheath universe antibiotics. nonethe slight the increasing presence of multi-resistant bacteria, as comfortably as increased changes nonice in the mechanisms responsible for variation in computer computer viruses, involving accumulation of mutations within the genes that code for antibody-binding sites ( cognise as antigenic drift), has resulted in these red-hot businesss not being inhibited as efficaciously by those treatments that originally designateed them (Reche, Fernandez-Caldas, F trim down, Fridkis-H argonli and Hoshino, 2014). The knock-on effect has been that the bacteria or virus is able to stretch out much easily, and therapeutic treatments (used after a person contracts a disorder), pass away slight strong, unable to work by boosting the droves own tolerant remains. As a result, it has been pull ind that the vaccinum offers the service of pr flushting the anticipation of infirmity occurrence, victimization advance action to itemizeeract infection and continuing illness. Prophylactic, and to a lesser extent therapeutic, vaccinums argon the most cost- in force(p) and efficient alternate(a) to late(prenominal) treatments and stripe of septic and inveterate diseases. They work by causing changes to the T- and B-cells of the accommodative resistant system to eliminate or prevent pathogen growth (Plotkin, Orenstein, and Offit, 2013). Going support to the introduction of vaccinums more than 200 long time ago, these were initially composed of kil take pathogens, which although advantageful, in addition caused intolerably high levels of perverse reactions. During the eld of query that stool since followed, as with the changes observed with antibiotics and some other(a)wise treatments becoming less effective, the hire for rubber eraserr and more effective vaccines has excessively be en ack instantlyledged. In addition, an change understanding of antigen presentation and subsequent actualisation has supported the ontogeny of newer vaccine fictitious characters (Flower, 2013). Equally, whilst umpteen diseases and infections be controlled by vaccines, for some, no vaccines constitute been heightened, including strep pyogenes, merciful immunodeficiency virus (HIV) and hepatitis C virus (HCV) (Wang and Walfield, 2005 Barrett and Stanberry, 2009). Efforts to develop new vaccines argon discussed in more details, with a way on peptide-based and sugar-based vaccines. Challenges argon also discussed, spark advance to a summary of the authorisation agency of vaccination and look into, which describes a promising future tense.Peptide-based vaccinesAn example of a newer category of vaccine is peptide-based vaccines. Peptides be short sequences of proteins, and diseases/infections use these proteins as theatrical role of their set upon on the repell ent system. In many a(prenominal) another(prenominal) cases, the insubordinate system has the force to recognise the proteins associated with an attack by disease or infectious causing pathogens and can respond effectively. just as observed with many crab louses, HIV, HCV and other conditions, an effective repellent reaction is not triggered, hence the acquire for newer vaccine maturements including those based on peptides, which squeeze unmarried proteins or semisynthetic peptides embrace many antigenic determinants (B- and T-cell epitopes) (Flower, 2013). Peptide vaccines are a type of fractional monetary unit vaccine, which presents an antigen to the immune system, using the peptide of the original pathogen, reinforcement immunity. Such peptide-based vaccines over magic spell the adverse effects set forth with handed-down whole-organism vaccines (Moisa and Kolesanova, 2012) with additional benefits also noted (Ben-Yedidia and Arnon, 1997), including The absence o f infectious material An immune result that is particular(prenominal), focusing notwithstanding on the targeted epitope, with the installation of site-specific antibodies No risk of an immune attack or cross-reactivity with the host tissues Flexibility, with an ability to restrict products accordingly Improved effectiveness in relation to manufacturing on a prodigious scale, and long-term storage where necessary e.g. a pandemic. However, a number of difficulties check been encountered during the maturation of such vaccines (Simerska, Moyle and Toth, 2011 Dudek, Perlmutter, Aguilar, Croft and Purcell, 2010) including A short biological activity of peptides collectible to degradation by enzymes The trigger of a weak immune chemical reaction when used alone i.e. single peptidesFinding optimal rake systems.As a result, and to overcome the difficulties mentioned above, synthetic peptide vaccines strike been authentic, on the basis that a greater more accurately targeted imm une response will be gived. Peptide antigens are not immunogenic by themselves, so this has led to investigations into co-administration of subunit peptide antigens with adjuvants (immunostimulants) to increase the peptide-induced responses to corresponding antigens. Appropriate bringing systems and often toxic adjuvants shit exhibit effective immunity, however, although many adjuvants are described in the literature, merely a fewer fill been approved for use with vaccines for deli really in man due to their perniciousness and overwhelm water/oil emulsions, liposomes, and bacterial lipophilic compounds to offer a few examples (Heegaard et. al., 2010). Incomplete Freunds adjuvant (IFA) and Montanide ISA (both oil-based) arrive at been used in clinical runnels. focussing on liposomes as another example, enquiryers deplete present that use of lipid message peptide (LCP) technology (lipidation of peptides) improves the effectiveness of a self-adjuvanting vaccine saving system, targeting a specific disease and triggering an effective immune response. This system provides a promising platform for human vaccine cultivation (Zhong, Skwarczynski and Toth, 2009 Moyle and Toth, 2008). In fleshly models, peptide vaccines prepare been effective in generating the required immune response, and during recent years, peptide-based vaccines con rig advanced from animal models and pre-clinical studies, to human clinical trials (Yang et al., 2001). Although presently, all known peptide vaccines under maturement for humans catch ones breath at the stage of clinical trials, these trials should work on the promising evidence resulting from look for to date of the potential application of vaccine candidates based on a LCP system, as well as other strategies. bar of not all many infectious diseases including hepatitis C virus, malaria, human immunodeficiency virus and separate A streptococci), that also for cancer immunotherapy and improved allergen speci fic tolerance, remains an exciting, and very real possibility.Carbohydrate-based vaccinesThe education of vaccines based on simoleonss not only has quite a history, but is also an area that is debased moving in the current query world. The literature provides evidence as distant back as the early 1900s where interrogationers find a connection between type-specific polysaccharides and the evidence of antibodies being highly- essential against certain types of pneumococci (Francis and Tillett, 1930). This was corroborate by evidence of pneumococcal capsular polysaccharides being used as vaccines, providing effective and long suffering immunity (Heidelberger, Dilapi, Siegel and Walter, 1950). However despite these early findings, the discovery and success of other treatments such as antibiotics and chemotherapeutics led to this area of research being tack together on hold. As mentioned earlier however, due to increased resistance to existing treatments such as antibiotics, coupled with the recognition for a need of newer treatments including improved vaccines, renewed disport into preventive vaccines has resulted in novel approaches, which accept simoleons vaccines. Vaccines are commonly do from weakened pathogens, or, as we now know, other approaches also use immunogenic proteins or polysaccharides. Carbohydrates make believe been the centre of attention in the research field of vaccination because not only do they exhibit more stableness than proteins, but they select roles in both physiology and pathophysiology, including cell interaction and signalling, inflammation, pathogen host attachment/recognition, to name a few examples (Doshi, Shanbhag, Aggarwal, Shahare and Martis, 2011). During the last ten years or so, they aim been used as adjuvants, as carriers for protein antigens to forethought immunotherapy, and as targets for vaccines against bacteria. Additionally, as observed with deoxyribonucleic acid and proteins, cabbages are now r ecognised as biopolymers also, playing a role in many molecular and biological activities (Doshi et. al., 2011). These discoveries, partnered by an improved understanding of the immune system and the identification of specific and relevant scratch structures, led to the development of glyco blends, which in turn led to carbohydrate vaccine development (Holemann and Seeberger, 2004). Glycoconjugates are present in the sur display cases of cells, as well as in the adjoin extracellular matrices and connective tissue. Therefore both the place structure and presence of glyconjugates, prescribed the role they play, means they are a suitable basis for the development of new vaccines. Induction of protective antibodies is key to an effective immune response as a result of a vaccine, and as with peptide vaccines, take exceptions collect been evident in the research to develop effective carbohydrate vaccines, including the following Glycans oppose to effectively induce protective antib odies Carbohydrates arrest a low immunogenic impact by themselves (as observed with peptides). There are deuce main carbohydrate vaccine types 1. vivid carbohydrate vaccines these include fine amounts of impurities 2. man-made carbohydrate vaccines these are produced with no contaminants, and are cost-effective due large-scale merchandise. artificial carbohydrate antigens used to develop vaccines have triggered immune responses in clinical studies and are favourable given the risk of adverse effects with natural vaccines. Four significant aspects need to be considered for the design of carbohydrate-based vaccines (Astronomo and Burton, 2010) The antigen semen glycan antigens are diverse, ranging from large polysaccharide capsules, to small monosaccharides, to oligosaccharides, all of which have been shown to be capable for preparation of vaccines. The carrier this is most often proteins, although other materials have been investigated, with the aim of ensuring that the tie -up between the antigen and the carrier is specific. The method of co-occurrence (or ligation) protein conjugates, lipid conjugates and polyvalent scaffold conjugates have been genuine. The success of a conjugate vaccine depends partly on the method of coupler employed. This should be simple and efficient, as well as causing minimal overrefinement to the individual components involved, with many differing techniques used (Zou & Jennings, 2009 adenosine deaminase and Isaacs, 2003). The choice of adjuvant required to improve immunogenicity of the carbohydrate antigens being targeted, with a extra choice approved for use in humans.Examples of diseases targeted by carbohydrate-based vaccines The discussion will now move on to the use of carbohydrate-based vaccines in three disease areas Group A strep ( float), HIV/ serve well and Haemophilus flu type b. heavy weapon The need for a safe, effective, affordable and practical vaccine against GAS (also known as Streptococcus pyogenes ), has been recognised for many years, as has the research into a vaccine against this disease, given the orbiculate lode on health that this disease causes in particular in less developed countries. More than 500,000 deaths result from the GAS each(prenominal) year, with the bacteria causing a betray of both less complicated and serious-minded illnesses (Carapetis, Steer, Mulholland and Weber, 2005). The diversity of GAS strains is the major challenge for the development of an anti-GAS vaccine, with more than 100 contrary strains identified, of which the genetic sequence for several divers(prenominal) strains have been determined (Johnson and Pinto, 2002). Research has identified that GAS bacteria contain a surface polysaccharide made up of long, repetitive polysaccharide chains. The conserved and invariant arrangement of these chains suggests conjugate vaccines to be an attractive and achievable option, with animal models supporting this theory (Cunningham, 2000). Synthet ic carbohydrate vaccines, although only studied in a expressage set of GAS infections, have demonstrated a protective immune response (Robbins et al., 2009). In addition, some areas of research have focused on the molecular outline of a surface protein labelled the M protein, which is encoded by the emm gene. This particular gene has been found to be the major cause of GAS related clinical manifestations (Smeesters, McMillan and Sriprakash, 2010). These findings have allowed a greater understanding of the functioning of specific proteins responsible for the virulence of the disease, which in turn, supports the development of potential GAS vaccines. Vaccine prevention of GAS and the resulting symptoms and complications has been a name and address of researchers for many years. A number of vaccines have been in research development to offer rampart against GAS, with the research vaccine strategies focusing on either M protein, or non-M protein antigens (Smeesters, 2014). However o nly those vaccines that use the M protein as the antigen have progressed to clinical trials (McNeil et. al., 2005), and have include conserved antigens insurance coverage across the many strains of GAS, a type-specific vaccine based on the N-terminal portion of the M protein, and a recombinant vaccine that reached microscope stage II clinical trials (Pandey, Wykes, Hartas, trade good and Batzloff, 2013 Bauer, 2012). However no vaccine has currently reached licensing and so the diseases caused remain uncontrolled in many areas, with redirect examinations covering the research suggesting that even those vaccines developed with the aim of providing large coverage of GAS strains, these vaccine might achieve acceptable coverage in developed countries, but in less developed countries where the disease burden is much greater, the plus impact of the vaccines would be much lower due to a greater strain diversity (Smeesters, McMillan, Sriprakash, and Georgousakis, 2009 Steer, Law, Matato lu, Beall and Carapetis, 2009 McMillan and Sanderson, 2013). Equally, antibiotic treatment is either impractical with regards to implementation (specifically in less developed countries) or ineffective. One research assort targeted the bacteria by deductioning a new self-adjuvanting vaccine candidate, incorporating a carbohydrate carrier and an amino acid-based adjuvant, resulting in no-hit synthesis and characterisation of the vaccine candidate. This may contribute to the identification of a safe and effective vaccine against GAS in the future (Simerska et. al., 2008 Simerska, Lu and Toth, 2009). HIV/ help One of the main challenges researchers have go about within the field of vaccine development against HIV/AIDS, is that the virus surface is cover with layers of glycans, which conceal underlying viral antigens that are potential good targets in the production of vaccines (Scanlan, Offer, Zitzmann, and Dwek, 2007). They are produced by the host cell, which makes the virus app ear as self resulting in no attack being triggered by the host immune system. The layers of carbohydrate also contain mannose residues, making these another potential target for a vaccine aimed at preventing HIV infection, whereby lectins preferentially bind to ? 1-2 link mannose residues. Such lectins are being investigated as possible therapeutic tools (Tsai et al., 2004) although the fact that lectins are often toxic needs to be researched further to avoid the host immune system damaging host cells. indeed, other drugs that are known to inhibit synthesis of carbohydrates only have this effect at often toxic concentrations to cause antiviral drug activity. Another strategy based on the analogous principle of maturation a carbohydrate vaccine, is the identification of antibodies that again recognise and bind to glycans. (Scanlan et al., 2002, Scanlan et al., 2007). The antibody appears to recognize these glycans because although they belong to the host, they are arranged in a non-self expression (Scanlan et al., 2002 Scanlan et al., 2007), making the production of effective ant-HIV vaccines a real possibility, in addition to vaccines for other diseases such as cancer (Galonic and Gin, 2007). Studies have also been described using immune enhancing adjuvants, carrier peptides such as keyhole limpet hemocyanin and alter glycan structure constructs that support immune recognition in the development of vaccines against cancer (Galonic and Gin, 2007). These same strategies are being used in development of possible HIV vaccines, where antibodies target self-carbohydrates arranged slightly differently on cancer cells and HIV-infected cells, in comparison to lusty cells. (Galonic and Gin, 2007). These approaches have not as nevertheless led to clinically effective vaccines, but it is clear that antibodies that strongly bind to carbohydrate antigens on, for example, prostate cancer cells, have been generated (Slovin et al., 2003) and this appears to be a high ly promising approach. just exploration is required based on the carbohydrate coat of the virus, which may be given to improved prevention treatment of HIV. Haemophilus influenza type bThe first synthetic vaccine for human application was developed in 2003 for protective covering against Haemophilus influenza type b vaccine, not only providing protection against this bacterium, but also against all the associated diseases it causes ranging from meningitis, septicaemia, pneumonia and arthritis (Doshi, Shanbhag, Aggarwal, Shahare and Martis, 2011). Indeed this bacterium is the leading cause of serious illnesses in children under 5 years worldwide. The majority of strains of Haemophilus influenza are non-encapsulated, and are lacking in any carbohydrate polysaccharide protective structure, as contend to the GAS bacteria and HIV virus described earlier. This structural information build up researchers with the knowledge that carbohydrate polysaccharide conjugate vaccines would be re quired to ensure the development of an effective vaccine (Verez-Bencomo et. al., 2004). As a result, carbohydrate-based vaccines have been clear for protection in humans against haemophilus influenza type b, using oligomerization and a carrier protein (Doshi et. al., 2011).Evidence of progressTo end this segmentation of the discussion, several conjugate polysaccharide carbohydrate vaccines are now well into pre-clinical/clinical development, or have been licensed and are now commercially available. Examples of licensed vaccines include the following (Astronomo and Burton, 2010) Haemophilus influenza type b (Hib) 4 carbohydrate-based vaccines are licensed via 3 different pharmaceutic companies ActHIB and Hiberix Pentacel PedvaxHIB and Comvax Neisseria meningitides A, C, Y and W-135 2 carbohydrate-based vaccines are licensed via the same pharmaceutical company Menactra and Menomune-A/C/Y/W-135 Salmonella typhi 1 carbohydrate- based vaccine is licensed TYPHIM Vi Streptococcus pneu monia variants 2 carbohydrate-based vaccines are licensed via 2 different pharmaceutical companies Prevnar and pneumococcal vaccine 23.Examples of carbohydrate-based vaccines in development include the following, where the disease is described in addition to the stage of development (Astronomo and Burton, 2010) Breast cancer with 1 vaccine at the preclinical shape and a second at cast I Prostate cancer 4 vaccines are in development at the preclinical, phase I and phase II stages HIV-1 1 vaccine at the preclinical phase Group A strep 1 vaccine at the preclinical phase Group B streptococcus 1 vaccine at phase II.ConclusionIt is fact that vaccines have had a major role to play in the success of preventing and treating many diseases, however many challenges remain. Diseases exist for which no effective vaccines have yet been discovered, including HIV/AIDs. In addition, diseases that have been controlled by vaccines in some separate of the world continue to affect the lives o f great deal adversely in other areas where infrastructures for vaccination are poor/non-existent. Continued research is necessary to develop vaccines not only for those diseases with no vaccine available, but also to improve the effectiveness of existing vaccines. In addition to research focusing on novel and promising approaches such as carbohydrate and peptide based vaccines, efforts also need to concentrate on areas such as lower cost, more convenient delivery of vaccines, and longer-term protection. The future direction of research in this field has become focused with the help of new evidence-based information and promising data. The climax of synthetic peptide-based and carbohydrate-based vaccines signified a new era for vaccines, over-taking traditional treatments and vaccines which have become either ineffective or only offer short term protection. As the discussion demonstrates, a number of vaccines are already successfully protecting humans against some pathogens and di sease, with the potential for further vaccines to follow. Finally, and peradventure most importantly, it should be remembered that unlike drug-based medicines, vaccines chiefly offer a cure, a goal all aim to achieve. Word count 3130 (excluding references)ReferencesAda, G. & Isaacs, D. (2003). Carbohydrate-protein conjugate vaccines. Clinical Microbiology and Infection. 9(2) p. 79-85.Astronomo, R.D. & Burton, D.R. (2010). Carbohydrate vaccines developing sweet solutions to sticky situations temperament Reviews Drug Discovery. 9 p. 30-324.Barrett, A.D.T. & Stanberry, L.R. (Eds.). (2009). Vaccines for Biodefense and Emerging and Neglected Diseases. Elsevier Inc., ISBN 978-0-3-69408-9.Bauer M.J., Georgousakis M.M., Vu T., Henningham A., Hofmann A., Rettel M., Hafner L.M., Sriprakash K.S. & McMillan D.J. (2012). evaluation of novel streptococcus pyogenes vaccine candidates incorporating fourfold conserved sequences from the C-repeat region of the M-protein. Vaccine. 30(12) p. 2197-2 205.Ben-Yedidia, T. & Arnon, R. (1997). Design of Peptide and Polypeptide Vaccines. Curr. Opin. Biotech. 8(4) p. 442-448).Carapetis, J.R., Steer, A.C., Mulholland E.K. & Weber, M. (2005). The global burden of throng A streptococcic diseases. Lancet Infect Dis. 5(11) p. 685-694.Cunningham M. (2000). Pathogenesis of group A strep infections. Clin Microbiol Rev. 13 p. 470-511.Doshi, G.M., Shanbhag, P.P., Aggarwal, G.V., Shahare, M.D. & Martis, E.A. Carbohydrate Vaccines- A burgeoning field of Glycomics. ledger of Applied pharmaceutical Science 1(02) p. 17-22.Dudek, N.L., Perlmutter, P., Aguilar, M.I., Croft, N.P. & Purcell, A.W. (2010). Epitope discovery and their use in peptide based vaccines. Curr Pharm Des. 16 p. 3149-3157.Flower, D.R. (2013). Designing immunogenic peptides. Nature Chemical Biology. 9(12) p. 749753.Francis Jr, T. & Tillett, W.S. (1930). Cutaneous reactions in pneumonia. The development of antibodies following the intradermal injection of type-specific polysacch aride. J. Exp. Med. 52 p. 573585.Galonic, D.P. & Gin, D.Y. (2007). Chemical glycosylation in the synthesis of glycoconjugate antineoplastic vaccines. Nature. 446 p. 10007.Heegaard, P.M.H., Dedieu, L., Johnson, N., Le Potier, M-F., Mockey, M., Mutinelli, F., Vahlenkamp, T., Vascellari, M. & Sorensen, N.S. (2010). Adjuvants and delivery systems in veterinary vaccinology current state and future developments. Arch Virol. 156(2)p. 183-202.Heidelberger, M., Dilapi, M.M, Siegel, & Walter, A.W. (1950). Persistence of antibodies in human subjects injected with pneumococcal polysaccharides. J. Immunol. 65l pp. 535541.Holemann, A. & Seeberger, P. (2004). Carbohydrate diversity deductive reasoning of glycoconjugates and complex carbohydrates. Curr Opin In Biotech. 15(1) p. 615-622.Johnson, M.A. & Pinto, B.M. (2002). Saturation designate difference 1D-TOCSY experiments to map the topography of oligosacchraides recognised by a monoclonal antibody directed against the cell-wall polysaccharide group A streptococcus. J Am Chem Soc. 124 p. 15368-15374.McMillan, D.J., Sanderson-Smith, M.L., Smeesters, P.R. & Sriprakash, K.S. (2013). Molecular markers for the study of streptococcal epidemiology. occurrent topics in microbiology and immunology. 368 p. 29-48.McNeil, S.A., Halperin, S.A., Langley, J.M., Smith, B., Warren, A., Sharratt, G.P., Baxendale, D.M., Reddish, M.A., Hu, M.C., Stroop, S.D., Linden, J., Fries, L.F., Vink, P.E. & Dale, J.B. (2005). Safety and immunogenicity of 26-valent group A streptococcus vaccine in salutary adult volunteers. Clin Infect Dis. 41(8) p. 1114-22.Moisa, A.A. & Kolesanova, E.F. (2012). Synthetic Peptide Vaccines, cortical potential and Control of morbific Disease in Global Scenario. Dr. Roy Priti (Ed.), ISBN 978-953-51-0319-6.Moyle, P.M. & Toth, I. (2008). Self-adjuvanting lipopeptide vaccines. Current Medicinal Chemistry. 15 p. 506516.Pandey, M., Wykes, M.N., Hartas, J., Good, M.F. & Batzloff M.R. (2013). Long-term antibody memory induced by synthetic peptide vaccination is protective against Streptococcus pyogenes infection and is independent of memory T cell help. Journal of immunology. 190(6) p. 2692-701.Plotkin, S.A., Orenstein, W.A. & Offit, P,A. Eds (2013). Vaccines. sixth ed. Edinburgh Elsevier/Saunders.Reche, P.A., Fernandez-Caldas, E., Flower, D.R., Fridkis-Hareli, M. & Hoshino, Y. (2014). Peptide-Based Immunotherapeutics and Vaccines. Journal of Immunology Research. Editorial. 2014 2 pages.Robbins, J.B., Kubler-Kielb, E., Vinogradov, E., Mocca, C., Pozsgay, V., Shiloach, J. & Scheerson, R. (2009). Synthesis, characterisation, and immunogenicity in mice of Shigella sonnei O-specific, oligosaccharide-core-protein conjugates. Proc Natl Acad Sci USA. 106 p. 7974-7978.Scanlan, C.N., Pantophlet, R., Wormald, M.R., Ollmann Saphire, E., Stanfield, R., Wilson, I.A., Katinger, H., Dwek, R.A., Rudd, P.M. & Burton, D.R. (2002). The mostly neutralizing anti-human immunodeficiency virus type 1 antibody 2G12 recognizes a cluster of alpha12 mannose residues on the outer face of gp120. J Virol. 76 p. 730621.Scanlan, C.N., Offer, J., Zitzmann, N. & Dwek, RA. (2007). Exploiting the defensive sugars of HIV-1 for drug and vaccine design. Nature. 446 p. 103845.Simerska, P.,Abdel-Aal, A.B.M, Fujita, Y., Batzloff, Good, M.F. & Toth, I. (2008). Synthesis and in vivo studies of carbohydrate-based vaccines against group A Streptococcus. Peptide Science. 90(5) p. 611-616.Simerska, P., Lu, H. & Toth, I. (2009). Synthesis of a Streptococcus pyogenes vaccine candidate based on the M protein PL1 epitope. Bioorganic & Medicinal Chemistry Letters. 19(3) p. 821-824.Simerska, P., Moyle, P.M. & Toth, I. (2011). recent lipid-, carbohydrate-, and peptide-based delivery systems for peptide, vaccine, and gene products. Med Res Rev. 31 p. 520-47.Slovin, S.F., Ragupathi, G., Musselli, C., Olkiewic,z K., Verbel,D., Kuduk, S.D., Schwarz, J.B., Sames, D., Danishefsky, S., Livingston, P.O. & Scher, H.I. (2003). Fully synthetic c arbohydrate-based vaccines in biochemically relapsed prostate cancer clinical trial results with alpha-N-acetylgalactosamine-O-serine/threonine conjugate vaccine. J Clin Oncol. 21p. 42928.Smeesters, P.R., McMillan, D.J. and Sriprakash, K.S. (2010). The streptococcal M protein a highly assorted molecule. Trends Microbiol. 18 p. 275-282.Smeesters, P.R., McMillan, D.J., Sriprakash, K.S. & Georgousakis, M.M. (2009). Differences among group A streptococcus epidemiological landscapes consequences for M protein-based vaccinesExpert Rev Vaccines. 8(12) p. 1705-20.Smeesters, P.R. (2014). granting immunity and vaccine development against Streptococcus pyogenes is emm-typing enoughProc Belgian Roy Acad Med. 3 p. 89-98.Steer, A.C., Batzloff, M.R., Mulholland, K. & Carapetis, J.R. (2009). Group A streptococcal vaccines facts versus fantasy. Current Opinion in Infectious Diseases. 22(6) p. 544-552.Steer, A.C., Law, I., Matatolu, L., Beall, B.W. & Carapetis, J.R. (2009). Global emm type distribut ion of group A streptococci systematic review and implications for vaccine development. Lancet Infect Dis. 9(10) p. 611-6.Tsai, C.C., Emau, P., Jiang, Y., Agy, M.B., Shattock, R.J., Schmidt, A., Morton, W.R., Gustafson, K.R., Boyd & M.R. (2004). Cyanovirin-N inhibits AIDS virus infections in vaginal transmission system models. AIDS Res Hum Retroviruses. 20(1) p. 1118.Verez-Bencomo, V., Fernandez-Santana, V., Hardy, E., Toledo, M.E., Rodriguez, M.C., Heynngnezz, L., Rodriguez, A., Baly, A., Herrera, L., Izquierdo, M., Villar, A., Valdes, Y., Cosme, K., Deler, M.L., Montane, M., Garcia, E., Ramos, A., Aguilar, A., Medina, E., Torano, G., Sosa, I., Hernandez, I., Martinez, R., Muzachio, A., Carmenates, A., Costa, L., Cardoso, F., Campa, C., Diaz, M. & Roy, R. (2004). A synthetic conjugate polysaccharide vaccine against Haemophilus influenzae type b. Science. 305(5683) p. 552-555.Wang, C.Y. & Walfield, A.M. (2005). Site-specific peptide vaccines for immunotherapy and immunization again st continuing diseases, cancer, infectious diseases, and for veterinary applications. Vaccine. 23(17-18) p. 20492056.Yang, D., Holt, G.E., Rudolf, M.P., Velders, M.P., Brandt, R.M.P., Kwon, E.D. & Kast, W.M. (2001). Peptide Vaccines. In in the altogether Vaccine Technologies. Chapter 12 p. 214-226.Zhong, W., Skwarczynski, M. & Toth, I. (2009) Lipid amount of money Peptide System for Gene, Drug, and Vaccine Delivery. Australian Journal of Chemistry. 62 p. 956967.Zou, W.. & Jennings, H.J. (2009). Preparation of glycoconjugate vaccines. In Carbohydrate-Based Vaccines and Immunotherapies. Chapter 2.