Carbohydrate and Peptide †Based Vaccines: The Way Forward

AbstractExisting treatments and therapies pack supported a huge soma of diseases and infections, a significant example being antibiotics. However the increasing presence of multi-resistant bacteria, as well as emergenced changes observed in the mechanisms responsible for variability in vir exercises, involving accumulation of mutations within the genes that code for antibody- retaining sites (known as antigenic drift), has firmnessed in these new strains not being inhibited as in effect(p)ly by those treatments that in the beginning targeted them (Reche, Fernandez-Caldas, Flower, Fridkis-H atomic number 18li and Hoshino, 2014). The knock-on effect has been that the bacteria or virus is able to spread to a greater extent easily, and therapeutic treatments ( apply after a person contracts a disease), become less effective, uneffective to work by boosting the innkeepers own resistant system. As a result, it has been managed that the vaccinum offers the advantage of preventing the anticipation of disease occurrence, using happen action to playeract infection and chronic illness. Prophylactic, and to a lesser extent therapeutic, vaccinums are the most cost-effective and efficient alternative to separate treatments and prevention of infected and chronic diseases. They work by causing changes to the T- and B-cells of the adaptive tolerant system to eliminate or prevent pathogen growth (Plotkin, Orenstein, and Offit, 2013). Going back to the introduction of vaccinums more than 200 years ago, these were initially composed of killed pathogens, which although successful, in like manner ca determinationd unacceptably high levels of adverse reactions. During the years of interrogation that make believe since followed, as with the changes observed with antibiotics and other treatments worthy less effective, the necessitate for safer and more effective vaccines has also been acknowledged. In rundown, an ameliorated understanding of antigen presentatio n and subsequent recognition has supported the discipline of newer vaccine suits (Flower, 2013). Equally, whilst numerous a(prenominal) diseases and infections are controlled by vaccines, for any(prenominal), no vaccines grow been developed, including streptococcus pyogenes, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) (Wang and Walfield, 2005 Barrett and Stanberry, 2009). Efforts to develop new vaccines are discussed in more details, with a focus on peptide-based and carbohydrate-based vaccines. Challenges are also discussed, prima(p) to a summary of the potential direction of vaccination and look for, which describes a vivid future.Peptide-based vaccinesAn example of a newer family line of vaccine is peptide-based vaccines. Peptides are short sequences of proteins, and diseases/infections use these proteins as part of their attack on the resistive system. In many cases, the immune system has the ability to recognise the proteins associated with an att ack by disease or infectious causing pathogens and can respond effectively. However as observed with many cancers, HIV, HCV and other conditions, an effective immune response is not triggered, hence the privation for newer vaccine developments including those based on peptides, which encompass single proteins or synthetic peptides encompassing many antigenic determinants (B- and T-cell epitopes) (Flower, 2013). Peptide vaccines are a type of subunit vaccine, which presents an antigen to the immune system, using the peptide of the original pathogen, supporting immunity. Such peptide-based vaccines avoid the adverse effects described with traditional whole-organism vaccines (Moisa and Kolesanova, 2012) with additional benefits also noted (Ben-Yedidia and Arnon, 1997), including The absence of infectious material An immune response that is peculiar(prenominal), focusing nevertheless on the targeted epitope, with the induction of site-specific antibodies No risk of an immune attack o r cross-reactivity with the swarm tissues Flexibility, with an ability to modify products accordingly Improved effectiveness in relation to manufacturing on a large scale, and long-term storage where necessary e.g. a pandemic. However, a number of difficulties have been encountered during the development of such vaccines (Simerska, Moyle and Toth, 2011 Dudek, Perlmutter, Aguilar, Croft and Purcell, 2010) including A short biological activity of peptides due to degradation by enzymes The trigger of a powerless immune response when used alone i.e. single peptidesFinding optimal delivery systems.As a result, and to overcome the difficulties mentioned above, synthetic peptide vaccines have been developed, on the stand that a greater more accurately targeted immune response will be achieved. 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-i nduced responses to corresponding antigens. Appropriate delivery systems and oft virulent adjuvants have demonstrated effective immunity, however, although many adjuvants are described in the literature, only a a couple of(prenominal) have been approved for use with vaccines for delivery in humans due to their toxicity and admit 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) have been used in clinical trials. Focusing on liposomes as another example, researchers have demonstrated that use of lipid core peptide (LCP) technology (lipidation of peptides) improves the effectiveness of a self-adjuvanting vaccine delivery system, targeting a specific disease and triggering an effective immune response. This system provides a promising platform for human vaccine development (Zhong, Skwarczynski and Toth, 2009 Moyle and Toth, 2008). In fleshly model s, peptide vaccines have been effective in generating the required immune response, and during recent years, peptide-based vaccines have advanced from living organism models and pre-clinical studies, to human clinical trials (Yang et al., 2001). Although currently, all known peptide vaccines under development for humans remain at the stage of clinical trials, these trials should build on the promising indorse resulting from research to date of the potential coat of vaccine candidates based on a LCP system, as well as other strategies. Prevention of not only many infectious diseases including hepatitis C virus, malaria, human immunodeficiency virus and conference A streptococci), but also for cancer immunotherapy and improved allergen specific tolerance, remains an exciting, and very literal possibility.Carbohydrate-based vaccinesThe development of vaccines based on carbohydrates not only has quite a history, but is also an area that is fast moving in the current research world. The literature provides evidence as far back as the early 1900s where researchers discovered a connection between type-specific polysaccharides and the induction of antibodies being developed against received types of pneumococci (Francis and Tillett, 1930). This was confirmed by evidence of pneumococcal capsular polysaccharides being used as vaccines, providing effective and long lasting 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 put on hold. As mentioned earlier however, due to change magnitude resistance to existing treatments such as antibiotics, coupled with the recognition for a need of newer treatments including improved vaccines, renewed interest into preventive vaccines has resulted in novel approaches, which include carbohydrate vaccines. Vaccines are commonly made from weakened pathogens, or, a s we now know, other approaches also use immunogenic proteins or polysaccharides. Carbohydrates have been the centre of attention in the research field of vaccination because not only do they exhibit more stability than proteins, but they have roles in both physiology and pathophysiology, including cell interaction and signalling, inflammation, pathogen host adhesion/recognition, to name a few examples (Doshi, Shanbhag, Aggarwal, Shahare and Martis, 2011). During the last ten years or so, they have been used as adjuvants, as carriers for protein antigens to aid immunotherapy, and as targets for vaccines against bacteria. Additionally, as observed with DNA and proteins, carbohydrates are now recognised 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 carbohydrate twists, led to the development of glyco mergeds, which in turn led to carbohydrate vaccine development (Holemann and Seeberger, 2004). Glycoconjugates are present in the surfaces of cells, as well as in the surrounding extracellular matrices and connective tissue. Therefore both the identified structure and presence of glyconjugates, plus the role they play, means they are a suitable basis for the development of new vaccines. Induction of protecting(prenominal) antibodies is key to an effective immune response as a result of a vaccine, and as with peptide vaccines, challenges have been evident in the research to develop effective carbohydrate vaccines, including the following Glycans attempt to effectively induce protective antibodies Carbohydrates have a low immunogenic impact by themselves (as observed with peptides). There are two main carbohydrate vaccine types 1. Natural carbohydrate vaccines these include small amounts of impurities 2. Synthetic carbohydrate vaccines these are produced with no contaminants, and ar e cost-effective due large-scale production. Synthetic 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 crucial aspects need to be considered for the design of carbohydrate-based vaccines (Astronomo and Burton, 2010) The antigen source glycan antigens are diverse, ranging from large polysaccharide capsules, to small monosaccharides, to oligosaccharides, all of which have been shown to be adequate for preparation of vaccines. The carrier this is most often proteins, although other materials have been investigated, with the aim of ensuring that the link between the antigen and the carrier is specific. The method of conjugation (or ligation) protein conjugates, lipid conjugates and polyvalent scaffold conjugates have been developed. The success of a conjugate vaccine depends partly on the method of conjugation employed. This should be simple and efficient, as well as causing minimal distortion to the individual components involved, with many differing techniques used (Zou & Jennings, 2009 Ada and Isaacs, 2003). The choice of adjuvant required to improve immunogenicity of the carbohydrate antigens being targeted, with a limited 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 Streptococcus (GAS), HIV/AIDS and Haemophilus flu type b. GAS 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 global burden on health that this disease causes in particular in less developed countries. More than 500,000 deaths result from the GAS each year, with the bacteria causing a range of both less complicated and life-threatening 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 divers(prenominal) strains identified, of which the genetic sequence for several different 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 constant arrangement of these chains suggests conjugate vaccines to be an attractive and achievable option, with animal models supporting this theory (Cunningham, 2000). Synthetic carbohydrate vaccines, although only studied in a limited set of GAS infections, have demonstrated a protective immune response (Robbins et al., 2009). In addition, some areas of research have center on the molecular analysis 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 caus e 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 goal of researchers for many years. A number of vaccines have been in research development to offer protection against GAS, with the research vaccine strategies focusing on either M protein, or non-M protein antigens (Smeesters, 2014). However only those vaccines that use the M protein as the antigen have progressed to clinical trials (McNeil et. al., 2005), and have included conserved antigens coverage across the many strains of GAS, a type-specific vaccine based on the N-terminal fortune of the M protein, and a recombinant vaccine that reached stagecoach II clinical trials (Pandey, Wykes, Hartas, Good and Batzloff , 2013 Bauer, 2012). However no vaccine has currently reached licensing and so the diseases caused remain uncontrolled in many areas, with reviews 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 positive impact of the vaccines would be much lower due to a greater strain diversity (Smeesters, McMillan, Sriprakash, and Georgousakis, 2009 Steer, Law, Matatolu, Beall and Carapetis, 2009 McMillan and Sanderson, 2013). Equally, antibiotic treatment is either impractical with regards to implementation (specifically in less developed countries) or ineffectual. One research group targeted the bacteria by synthesising a new self-adjuvanting vaccine candidate, incorporating a carbohydrate carrier and an amino acid-based adjuvant, resulting in successful synthesis and ch aracterisation of the vaccine candidate. This whitethorn 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/AIDS One of the main challenges researchers have faced within the field of vaccine development against HIV/AIDS, is that the virus surface is covered with layers of glycans, which conceal underlying viral antigens that are potential frank targets in the production of vaccines (Scanlan, Offer, Zitzmann, and Dwek, 2007). They are produced by the host cell, which makes the virus appear 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 tie in mannose residues. Such lectins are being investigated as possible therapeutic tools (Tsai et al., 2004) although the fact that lecti ns 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 activity. Another strategy based on the same principle of developing 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 manner (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 altered glycan structure constructs that support immune recognition in the develop ment 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 approximately differently on cancer cells and HIV-infected cells, in comparison to healthy cells. (Galonic and Gin, 2007). These approaches have not as yet led to clinically effective vaccines, but it is lapse 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 highly promising approach. Further exploration is required based on the carbohydrate coat of the virus, which may lead to improved prevention treatment of HIV. Haemophilus influenza type bThe first synthetic vaccine for human application was developed in 2003 for protection against Haemophilus influenza type b vaccine, not only providing protection against this bacterium, but also against all the associated diseases it causes r anging 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 opposed to the GAS bacteria and HIV virus described earlier. This structural information armed researchers with the knowledge that carbohydrate polysaccharide conjugate vaccines would be required to ensure the development of an effective vaccine (Verez-Bencomo et. al., 2004). As a result, carbohydrate-based vaccines have been licensed for protection in humans against haemophilus influenza type b, using oligomerization and a carrier protein (Doshi et. al., 2011).Evidence of progressTo end this section 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 pharmaceutical 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 pneumonia variants 2 carbohydrate-based vaccines are licensed via 2 different pharmaceutical companies Prevnar and Pneumovax 23.Examples of carbohydrate-based vaccines in development include the following, where the disease is described in addition to the conformation of development (Astronomo and Burton, 2010) Breast cancer with 1 vaccine at the preclinical phase and a second at phase I prostatic 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 streptococcus 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 parts of the world continue to affect the lives of people 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 co nvenient 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 advent 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 disease, with the potential for further vaccines to follow. Finally, and perhaps most importantly, it should be remembered that unlike drug-based medicines, vaccines primarily 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 developi ng sweet solutions to sticky situationsNature Reviews Drug Discovery. 9 p. 30-324.Barrett, A.D.T. & Stanberry, L.R. (Eds.). (2009). Vaccines for Biodefense and Emerging and Neglected Diseases. 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