* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download study material-2012
Survey
Document related concepts
Duffy antigen system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immune system wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Herd immunity wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Whooping cough wikipedia , lookup
Adaptive immune system wikipedia , lookup
Innate immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Hepatitis B wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Childhood immunizations in the United States wikipedia , lookup
HIV vaccine wikipedia , lookup
DNA vaccination wikipedia , lookup
Transcript
1 VACCINES A vaccine can be defined as a preparation of bacterial, viral or other pathogenic agents or of their isolated antigens which is administered with the objective of stimulating a recipients protective immunity. After primary exposure of antigen to immunocompetent lymphocytes, there occurs an immune response called primary immune response. Primary immune response peaks on approximately the 14th day of antigen exposure. There are two main outcomes of primary response: first, specific immunocompetent cells (B and T cells) are activated; and second memory cells are formed. Subsequent exposure to the same antigen stimulates these memory cells which results in a rapid and more heightened immune response Thus, a vaccine is basically an antigen or its component that can induce secondary or adaptive immunity in the host. It aims to prevent severe complications of infections by reinforcing or broadening the defenses by introducing immunological memory. There are several types of vaccines that are currently and conventionally used. These include natural live ,live attenuated vaccine, inactivated vaccine, toxoid vaccine, polysaccharide vaccine, recombinant antigen vaccine live vector vaccine and DNA vaccine. 1. NATURAL LIVE VACCINE: These preparations include natural non-pathogenic organisms, but which still induce specific immunity. Currently, live natural vaccines are rarely used. Apart from the cowpox virus vaccine, no other natural organism is usually used, though live simian and bovine rotaviruses have been used in vaccination against infant diarrhoea with moderate success. The problems of these vaccines reside in their ability (albeit hidden) to mutate and convert into forms that could be pathogenic to human hosts. 2. LIVE ATTENUATED VACCINE: Attenuation (Latin: attenuare—to weaken) refers to the weakening of the pathogenic bacteria or virus by making it less virulent without altering its immunogenicity. Microorganisms are attenuated or weakened so that they do not cause any disease. Attenuation can be achieved by growing pathogenic microorganisms (bacteria or virus) for a long period of time in a foreign host such as embryonated eggs or tissue culture cells. The process of attenuation involves growing microbes (bacteria or viruses) under abnormal in vitro conditions, be it high bile concentration or passage through foreign cell/tissue such as embryonated eggs. These abnormal environmental conditions select those mutant cells that are able to survive and multiply under these conditions. These microbes are then harvested and used as vaccine. In a normal host, these "pathogenic" microorganisms either fail to multiply or multiply very slowly because these microbes are now "used to be grown" under abnormal conditions. ADVANTAGES OF ATTENUATED VACCINES Because of the slow growth of attenuated viruses under normal body conditions, attenuated vaccines provide for prolonged exposure of viral antigen to the immune system resulting in the production of a large number of B and T cells and, more importantly, memory cells. As a consequence, most of these vaccines are administered once in a lifetime and do not require repeated boosters. The attenuated vaccines that are given orally to children (e.g. Sabin polio vaccine type I) is given orally on sugar cubes or drops. The attenuated virus enters the gastrointestinal tract and induces the production of secretory IgA as well as humoral IgG. These antibodies serve as an important defense against naturally occurring poliovirus. DISADVANTAGES OF ATTENUATED VACCINES A major disadvantage of using live attenuated vaccine is the possibility of their reversion to the virulent form. Type 2 and type 3 Sabin polio vaccine have been shown to revert frequently to their wild type form. 2 Another disadvantage of live attenuated vaccines is that they cannot be given to persons having immunodeficiency diseases as the immune system of these patients is severely compromised and these pathogens, even though attenuated or weakened, can induce some damage. Sometimes attenuated viruses shed from a recently vaccinated individual via faeces revert to virulence and cause disease in other individuals. 3.INACTIVATED VACCINES Another commonly used method for vaccine production is to inactivate the whole pathogen and then use it for vaccination. The inactivation could be achieved by modifying the antigen (pathogen) chemically by formaldehyde treatment or physically by heat treatment. The killed bacteria or viruses are then used in vaccines. Heat inactivation of microbes has one potential problem. Heat inactivation of microbes causes the denaturation of surface proteins, that is, its antigenic determinants, and so their antigenic structure is altered. The antibody/immune response induced by vaccinating these altered antigens may not be effective against natural pathogen. Chemical inactivation gives better results. The bacteria or viruses are treated with formaldehyde, phenol or propionolactone or other amino acid modifying agents for a suitable period of time. This treatment usually results in the killing of the bacteria or virus with almost no change in the antigenic structure. However, chemically inactivated pathogens in vaccines are associated with some risks. The chemical agent sometimes does not kill all the pathogens present and, as a result, if these preparations (that contain chemically inactivated pathogen plus some live pathogen that has somehow escaped inactivation) are administered, it might result in the disease in the vaccinee (person receiving vaccination). One of the greatest advantages of using inactivated/killed pathogen in a vaccine is that there is no danger of mutation or reversion to the pathogenic form. Killed/inactivated vaccines induce sufficient humoral immunity (if boosters are given). However, they are less effective in inducing cell-mediated immunity or eliciting mucosal immunity. Since, these are killed pathogen inactivated vaccine can safely be used in immunodeficient patients. The disadvantages include the need for repeated boosters, higher cost, and sometimes, as mentioned previously, a failure in inactivation of virus or bacteria resulting in immunization with virulent virus. Advantages 1.No mutation or reversion to wild type forms since pathogenic organism is dead. Disadvantages Weak cell-mediated responses. 2.Provides sufficient humoral immunity. Requires booster stimulation since organism cannot replicate inside host. 3. Heat-stable. Higher cost. 4. Can be used in immunodeficient patients Inadequate killing of virulent organism can result in occurrence of the disease. 3 Theoretically, live vaccines (natural or attenuated), are generally more effective than killed ones. Live vaccines provide a large and continual antigenic challenge (slow-growing pathogen) that replicates to give a large antigenic dose which lasts for days or weeks. Hence there is no need for giving repeated booster doses. Moreover, antigens of live vaccine are presented by both class I and class IIMHC molecules inducing balanced response that includes Tcyt cell as well as TH cell and antibody responses. Killed whole organism vaccine microbes are presented mainly by the class 11 pathway and hence establish good humoral immunity. Dead microbe vaccines do not induce good Tcyt-cell responses; the immunity is short lasting (requires booster) and often not detectable against all of the viral antigens. 4. TOXOID VACCINES: The virulence of some pathogenic bacteria depends primarily on the production of exotoxin. If exotoxins can be neutralized by the body the disease will not occur. These exotoxins are isolated and chemically modified (usually with formaldehyde) so that their toxicity (but not immunogenicity) is lost. These non-toxic yet immunogenic derivatives of exotoxin, or toxoids, are commonly used in vaccines. Vaccination with a toxoid induces antitoxoid antibodies which are capable of binding the toxin and neutralizing it. Diphtheria and tetanus vaccines are among the most successful of all bacterial vaccines produced from toxoids. The toxoids are generally mixed with aluminum hydroxide which acts as an adjuvant resulting in an increased production of specific antibodies, encouraging its removal by phagocytic cells and hence stimulating T-cell response. There are two major drawbacks. a. Not all pathogenic organisms produce exotoxin. b. Those who do produce them secrete them in minuscule quantities so it is difficult to purify them. 5.POLYSACCHARIDE VACCINES: The surface of bacteria is the first thing that is exposed to the immune system. Therefore, the surface antigens can serve as an excellent vaccine. Moreover, some bacteria have resistance to phagocytic invasion because these cells have capsular polysaccharides that resist phagocytosis (for example, the polysaccharide capsules of S. pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae). The coating of these capsular polysaccharides with antibodies and/or complement components marks them for destruction by phagocytosis. These observations have paved the way for synthesizing vaccines against bacterial-purified polysaccharides. The current vaccine against the bacteria Neisseria meningitidis which causes meningococcal meningitis, contains purified capsular polysaccharide from types A and C. Another vaccine against Haemophilus meningitis which is caused by bacteria Haemophilus influenzae type b consists of purified capsular polysaccharide from H. influenzae type b (Hib). The vaccine for pneumococcal pneumonia, (which is caused by about 80 different types of strains of Streptococcus pneumoniae) consists of 23 antigenic ally different types of capsular polysaccharides. One major drawbacks of polysaccharide vaccines is their inability to TH cells or induce adequate memory response. Polysaccharide antigens can be made to stimulate TH cells by conjugating them to some sort of a protein carrier. The polysaccharide-protein conjugate activates TH cells which in turn enables the formation of memory B cells. Even though memory T cells are not formed for some unknown reasons and very few memory B cells are formed, these polysaccharide vaccines can often provide long-lasting immunity. 4 6. RECOMBINANT ANTIGEN VACCINES With the advent of recombinant DNA technology, virtually any gene-encoding immunogenic protein can be introduced and expressed in yeast, bacterial or even mammalian cells, using recombinant DNA technology. These cells are then cultured in the laboratory and the protein produced endogenously is harvested. The genes that are selected for making recombinant antigen vaccine are usually surface antigens (mostly glycoproteins). A number of genes coding for various surface antigens have been successfully cloned in bacterial, yeast and mammalian cells cultures. Yeasts have emerged as a better choice for making these surface antigens as they add and process carbohydrate molecules on the protein in their. One such vaccine approved for human use is hepatitis B vaccine. A single gene for the major surface antigen of hepatitis B virus (HbsAg) is cloned in yeast cells. Recombinant antigen vaccines have both advantages and disadvantages. The advantages include i)the inexpensive production of a large amount of antigens ; ii) genetic manipulation of antigens. As a foreign gene is introduced from outside into the yeast cell, and usually the gene sequence of this gene is known, genetic manipulation of the gene is possible. iii) Exotoxins of tetanus and diphtheria, can be genetically inactivated. Similarly, antigens can be made more immunogenic. The main limitation of this technique is the same as of inactivated vaccine. i) The recombinant antigens evoke humoral response, stimulating B cells and TH cells (since antigen is processed by class II MHC pathway) but do not generate potent Tcyt-cell response. ii) Another limitation which is inherent to the technique itself is that recombinant DNA technology cannot be used to synthesize carbohydrate antigen. Therefore, this technique is ineffective in producing antigen if it is a carbohydrate. 7. L I V E V E C T O R V A C C I N E S In live vector vaccines, the desired gene coding for target antigens of the virulent pathogen is put into a vector (attenuated bacteria or virus) and then this vector is infected (or administered orally) to the vaccinee. This vector slowly replicates inside the inoculated individual and it serves as a source of the antigen, delivering a large amount of antigen into the system and provoking a strong immune response. A number of organisms have been used as vectors. The most commonly used viral vectors are the vaccinia virus (the smallpox vaccine virus), adenovirus and canary pox virus (that infects cells but does not replicate in humans). The bacterial vectors include attenuated Salmonella typhi (Ty2la), BCG strain o f Mycobacterium bovis.. In fact, all of the attenuated viral/bacterial vaccines have been suggested as possible vectors for their use in live vector vaccines. The greatest advantage of using live vector vaccine is that there is complete immune response, that is, both humoral and cell-mediated protection systems are activated. a)VIRAL VECTOR VACCINE The most commonly used viral vector is the vaccine virus, though genetically engineered recombinant viral vectors such as pox viruses or adenovirus are also deliberated upon. Genes that have the potential to induce protective immunity (such as coat antigens) are inserted into attenuated live virus. Vaccinia, a commonly used virus has a large, doublestranded genome (about 187,000 kb and approximately 200 genes). The advantages of viral vector vaccine include induction of both cell-mediated and hum. r immunity against the foreign antigen expressed by the vaccinia virus. 5 Advantages Disadvantages Strong humoral and cell-mediated immune responses. Several segments of DNA encoding antigens from different pathogens can be inserted in a single virus vector. Can be targeted to specific tissues due to viral tropism. Danger of reversion to virulence is always there. No interference in protection produced Immune response to virus infected cells may cause damage to vaccine by other types of vaccine. Some viruses have transforming capabilities making infected cells cancerous. Inexpensive and easy to transport. b) Bacterial Vector Vaccine: Like the live viral vectors, some attenuated bacterial strains have been engineered to carry genes of virulent pathogens. The DNA encoding the antigenic determinants is inserted into the attenuated bacterial genome. The bacteria then express the antigen along with its own protein .The production and expression of antigen by the bacterial vector inside the host body stimulates the immune system. The advantage of this type of vaccine includes the fact that attenuated strains of S. typhimurium, V. cholera and BCG are easily available and their genomes can easily be manipulated. The use of such bacterial vaccine will produce immune response both against the vector as well as the inserted antigen (an inserted gene product). The use of some bacteria such as Salmonella has an additional advantage: the bacteria not only induces cell-mediated and humoral immunity but also mucosal immunity (IgA production) since these bacteria survive in the GI tract. Immunity against the pathogens of gonorrhoea and cholera are best provided by mucosal IgA. The disadvantages of bacterial vector vaccine include reversion and emergence of the pathogenic form of bacteria, rejection and elimination of bacterial vector before it can express the recombinant protein (as most of the population is already vaccinated against the bacteria being used as vector). Moreover, antigens formed inside the bacteria may be proteolysed by endogenous bacterial enzymes. 6 Advantages Strong humoral and cell-mediated immune responses. Several segments of DNA encoding antigens from different pathogens can be inserted in a single virus vector. Can be targeted to specific tissues due to viral tropism. No interference in protection produced Disadvantages Danger of reversion to virulence is always there. Some viruses have transforming capabilities making infected cells cancerous. Immune response to virus infected cells may cause damage to vaccine. by other types of vaccine. I n expensive and easy to transport. 8. DNA VACCINE: The term “DNA vaccine” is misnomer. It wrongly implies that the DNA is used as an antigen and antibodies are formed against DNA. This is not the case. The DNA vaccine (or more properly DNA-based vaccine) represents a new class of vaccines in which there is a deliberate introduction of a DNA plasmid usually into the muscle cell of the recipient. The plasmid contains a protein-coding gene (of antigen) that gets expressed in the cell leading to both humoral and cell-mediated immune responses. The plasmid DNA can be introduced into the muscle cell either by infection or by bombarding the skin with DNA-coated gold particles with a fine air gun (gene- gun) Currently, attempts are also underway to introduce DNA into nasal tissue via nasal drops. Once inside the cells of the recipient, the plasmid does not replicate, but only expresses itself, that is, protein is produced. Usually bacterial plasmid is used. The DNA vaccines have several advantages. i) They are heat-stable as the DNA is a stable molecule-and so the storage and transport of these vaccine are easy. ii) The chimeric plasmids can be easily made in a laboratory in large amounts and, if the need slight modifications in the DNA sequence (and hence the antigens' amino acid sequence) can b e introduced. iii) The DNA vaccines stimulate both cell-mediated and humoral responses. The major drawbacks of the DNA vaccine is : i) The concern over potential integration plasmids into the DNA of cells. Such an integration could lead to insertional mutagenesis and cause the cell to become cancerous. ii) Danger of induction of anti-DNA antibodies causing pathological autoimmune reactions. iii) DNA vaccine can only be formed against protein antigens. 7 Advantages Disadvantages Insertion of foreign DNA into host genome may cause cell to become cancerous. Danger of autoimmune response due to formation anti DNA antibodies. Easy to manufacture in large amounts. Stable and easy to transport DNA sequence and hence antigen can easily be changed. Mixture of plasmids could be used to form broad-spectrum vaccine. May induce immunologic tolerance by antigen(s) expressed inside host body. Cannot be formed against polysaccharide antigens. Absence of protein components ensures there is no strong immune response against vaccine NEW VACCINE STRATEGIES Vaccine Strategy Synthetic Vaccine Micro encapsulation delivery system SMAA Liposomes and Micelles ISCOMS Anti-idiotype Vaccine Antigen Cochelate Disease(s) against which it is currently directed or explored Currently been experimented against diseases such as AIDS, malaria, schistosomiasis, hepatitis(B). Use of multiple antigenic peptides increases immune response Influenza (inactivated virus), tetanus (toxoid) Clinical trials ongoing for several infectious diseases Hepatitis A Measles Hepatitis B Currently been explored for number of infectious diseases AN IDEAL VACCINE i) Vaccine should be able to generate immunological memory. Both memory B cells and T cells should be formed. ii) A vaccine should provide lifelong immunity with a single dose. iii) It should be preferably introduced into the recipient by non-invasive methods such as oral administration or nasal spray. iv) It should not e any side effects. v) Vaccines should stimulate both arms of the immune system—humoral and -mediated immunity. vi) Vaccines should be inexpensive, easily manufactured and stable in extremes of temperature or humidity Ref: The Elements of Immunology by Fahim Halim Khan 8