Vaccine and adjuvants

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Vaccine and adjuvants

  1. 1. TOPIC ADJUVANTS PRESENTER/STUDENT:JONES OPOKU-MENSAHSUPERVISOR/LECTURER DANIEL DODOO (PhD) 1
  2. 2. Current state and future trends• the state of the adjuvant field and The future directions to adjuvant development.• Impediments and barriers to development and registration of new human adjuvants 2
  3. 3. NEW GENERATION VACCINE ADJUVANTS• INTRO• Vaccines are considered to be the most safe and effective medical intervention available• Vaccines have contributed to the steady decline in mortality and morbidity caused by infectious disease.• The currently available vaccines prevent up to 3 million deaths and 750 000 children are protected from serious disabilities every year.• Vaccine improvement include the addition of new adjuvants which are able to induce a higher immune response that covers a broad antigenic diversity 3
  4. 4. THE NEED FOR NEW AND IMPROVED VACCINES• Despite the success of current vaccines, there is the clear need for the development of vaccines against a number of infectious disease for which vaccines are not yet available, or inadequate. Eg HIV, HEP C, TB, Malaria, Neisseria meningitides etc• There is also the need for vaccines against emerging and re-emerging infectious disease like SARS, Hanta, Ebola etc 4
  5. 5. What are adjuvants• Adjuvants are compounds that enhance the specific immune response against co-inoculated antigens. 5
  6. 6. The role of Adjuvantimprove the immunogenicity of antigens/vaccines. Esprecombinant Proteins/peptides which lack most of thefeatures of the original pathogen and often weakimmunogens.Reduce the dose of antigen or the number of immunizationsneeded for protective immunity.Improve the efficacy of vaccines in newborns, the elderly orimmuno-compromised persons.As Antigen delivery systems for the uptake of antigens by themucosa. 6
  7. 7. The challenge of adjuvants• Adjuvant industry= To improve the safety and less reactogenic subunit vaccine.• Lower reactogenicity adjuvants came with reduced vaccine efficacy.• Safety and tolerability are critical regulatory issues facing the adjuvants.• In most cases increased adjuvant potency is associated with increased reactogenicity and toxicity. Eg CFA 7
  8. 8. Non-adverse reactions Factors1 should be cheap to produce2 not induce immune responses against themselvesBut promote an appropriate immune response i.e.cellular or antibody immunity depending onrequirements for protection.3 Adjuvants affordability4 be stable with long shelf life5 biodegradable (advax) 8
  9. 9. Adjuvant-caused adverse effects• classified into 1) local and 2)systemic.1) Local Reactions:local injection site Pain, inflammation, swelling, and necrosis, lymphadenopathy, granulomas, Ulcers and the generation of sterile abscesses etc2) Systemic reactions:• induction of Acquired immunodeficiency, immunosuppression, eosinop hilia, allergy, anaphylaxis, Nausea, fever, adjuvant arthritis, organ specific toxicity and immunotoxicity etc 9
  10. 10. The main problem with adjuvant production• Unsolved problem is how to achieve potency whiles avoiding reactogenicity or toxicity• This make their acceptance into community prophylactic vaccination particularly in paedics difficult.• Even alum which is FDA-approve still has significant adverse effect like local injection site Pain, inflammation, lymphadenopathy• Alum limitation: inability to induce CTL (CMI) response hence ineffective for some Ags. 10
  11. 11. Factors affecting Adjuvant selection1) the antigen e.g. alum not good for CTLresponse2) species to be vaccinated- some adjuvants maybe safe in one species but not another species3) route of administration e.g.intramuscular, mucosa4) side effects- weigh the risk and benefits atthat time 11
  12. 12. Classification of Adjuvantclassified according to their source, mechanism ofaction or physicochemical properties andadministration route, namely mucosal or parenteral. a) three groups:1) active immunostimulants, being substances thatincrease the immune response to the antigen;2) carriers, being immunogenic proteins that provideT-cell help3) vehicle adjuvants; being oil emulsions orliposomes that serve as a matrix for antigens as wellas stimulating the immune response. 12
  13. 13. Classification of Adjuvant 2• Classified based on route of administration- mucosal or parenteral• Classified based physicochemical properties Groups of gel- based, tensoactive agents, oil emulsions, particulate, fusion protein, Alum salts and other mineral adjuvants 13
  14. 14. adjuvant challenges• Toxicity• Stability• Bioavailability• Cost• Production difficulty• Epitope modification potential during formulation.• Pre-existing immunity to carrier protein 14
  15. 15. Adjuvant regulatory reguirement• Need for pre-clinical studies (toxicology) prior to phase 1 trail• Dose and frequency of adjuvants to be increased during pre-clinical studies to identify any potentials safety problens 15
  16. 16. Few adjuvants types• Oil-in-Water emulsion- eg montanide, adjuvant 65, lipovant etc. they are irritants, local inlfammation common, induces chemotactic signal => macropahge invasion=> rapid ingestion. Used in cancer and HIV• formation of a depot at the injection site,• enabling the slow release of antigen• stimulation of antibody producing plasma cells.• Limitations: Excessive reactogenicity, Frequent side- effects of emulsions include inflammatory reactions, granulomas and ulcers at the injection site. 16
  17. 17. Saponins are tensoactive glycosides. Eg Bark of tree,QS21(Saponin)they integrate into cell through interaction withcholesterol/ membrane of macrophages, resulting inpores through which antigens enter macrophages.Subsequently, peptides from these antigens may beprocessed and presented via MHC class I, stimulating aCD8 CTL response.Limitations: Severe injection site pain is a major limitingfactor in QS21 use. 17
  18. 18. Bacteria-derived adjuvantsEg LPS and TDM(trehalose dimycolate).MPL is a chemically detoxified derivative of native Lipid Afrom Salmonella minnesota R595, which is used incomplex adjuvant formulations withalum, QS21, liposomes, and emulsions.Mechanism: interacts with TLR4 onmacrophages, resulting in the release of proinflammatorycytokines including TNF, IL-2 and IFN-gamma, whichpromote the generation of Th1 responses.Limitations: consistency of preparation, formulation, and cost. 18
  19. 19. MF 59a replacement for CFA. Too toxic for human.Current version now used in inflenza. Superiorto alum in inducing Ab response to hep B inhumans and baboons.ISCOMsimmunostimulating complexes containingsaponin, a sterol and opatioally a phospholipid.Generate CTL response to Ags like HIVenveloped in GP. == cost, manufacturingdifficulty, malaise, reactogenic and safety issues 19
  20. 20. Liposomessynthetic phospholid spheres encapsulating Ag.Act as Ag delivery vehicle and adjuvant.Mech= fuses with macrophage and delivers Agto the cytoplasm.Limit= cost, manufacturing difficulty, stability. 20
  21. 21. carbohydrate adjuvant - Advax• Nanocrystal of inulin (plant derived polysac, linear chain of fructose capped with glucose)• Enhances both CMI and HI responses without reactogenic effects. Long shelf life, no safety issues, not metabolized in man but secreted unchanged in urine as fructose and small qntt os glucose.• 21
  22. 22. Aluminium Salts (Alum)inorganic salt that binds to proteins and causesthem to precipitate. The trapping of soluble antigenin the alum gel may also increase the duration ofantigen interaction with the immune system. Alum is the only adjuvant approved for use inhumans. induce antibody (th2) response cellular(th1) responseLIMITATIONS: potential to cause severe local andsystemic side-effects including sterileabscesses, eosinophilia and myofascitis. 22
  23. 23. Polymeric microspherical adjuvants• These are compactible and biodegradable microspheres of lipids able to incorporate different Ags.• Controlles time of Ag release.• Cytokines adjuvants• IFN-y enhances CMI through a variety of mechanism• Others are GM-CSF 23
  24. 24. Adjuvant formulations• New adjuvant formulations have resulted from the mixture of different adjuvants in the same formulation.• As a general rule, two or more adjuvants with different mechanisms of action are combined to enhance the potency and type of the immune response to the vaccine antigen. For example, alum salts can be formulated in combination with other adjuvants such as Lipid A to increase immunogenicity. 24
  25. 25. Conclusions• There are major barriers rather than scientific knowledge about adjuvants standing in the way of new adjuvants availability1) Unacceptable side-effects and toxicitypreclude the use of many candidate adjuvants2) Since the invention of alum as the firstadjuvant, there has been significantly raisedstandards by regulatory bodies 25
  26. 26. Conclusions 23) Some adjuvants have not been approved as aresult of their conjunction with a vaccine. It ispossible that good adjuvants have failed due tothe vaccine adjuvant combinations. So they arerejected whiles the fault may be from thevaccine not the adjuvant. Thus throwing out thebaby with the bath water .4) Funding/cost of development Etc etc etc 26

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