HISTORICAL PERSPECTIVES2Jenner 1796 : Cowpox• 1800’s Compulsorychildhood vaccination• 1930’s Last natural UKcase• 1940’s last natural US case• 1958 WHO program• October 1977: Last case(Somalia)
ImmunizationImmunisation is the process of conferringincreased resistance (or decreasedsusceptibility) to infection
Active Vs Passive Immunization Active immunization Can be achieved through natural infection by amicroorganism or it can be acquired artificiallythrough the administration of vaccines Antibodies produced in response to aninfection e.g. natural measles virus Antibodies produced in response to a vaccine(live, inactivated or toxoid) Individuals make their own antibodies
Active Vs Passive ImmunizationPassive Immunity Individual gains antibodies from another who has produced them Transfer of maternal antibodies through theplacenta or in breast milk Administration of antibodies collected fromactively immune humans or animals e.g.varicella zoster immunoglobulin VZIG
What is a Vaccine? A preparation of the causative agent of adisease, specially treated for use in vaccination,in order to induce or increase immunity Typically contains an agent that resembles adisease-causing microorganism, and is oftenmade from Weakened or killed microorganismsor subunits (purified protein subunits,polysaccharides).
What is a Vaccine? Based on 2 key elements of adaptiveimmunity:Specificity and Memory Stimulation of an individual’s ownimmune system to produce antibodies byadministration of a vaccine
Active Immunization throughdesigning Vaccines9Before designing any vaccine, two thingsshould be considered: Activation of humoral and cell mediatedimmune response shown by a particularantigen Development of immunologic memoryby the particular antigen
The Mechanism of a Vaccine In an ideal scenario,whenever a vaccine is firstadministered, it isphagocytized by an antigenpresenting cell. Recent research suggestthat it is particularlyimportant that the vaccinebe taken up by a dendriticcell. This is because dendriticcells play a key role inactivating T cells, whichbecome helper T cells
From there, theactivated Th cells goeson to activate matureB-cells. These activated B-cellsdivides into two celltypes, antibody-producing plasma cellsand, most importantly,memory B cells.The Mechanism of aVaccine
Importance of Secondary ImmuneResponse During the secondary immune response, the bodymounts a quicker, more robust attack on thepathogen. Thus, the pathogen is cleared from the bodybefore it has the chance to cause an infection.
Adjuvants An adjuvant is achemical substance thatcan be added to avaccine in order toenhance the immuneresponse to the vaccine. There are three types ofadjuvants.
AdjuantsAluminum Hydroxide and Aluminum Phosphate (Alum) Alum is an inorganic salt thatbinds to proteins and causesthem to precipitate. Whenever the alum/vaccinecomplex is injected into thebody, it slowly dissolves,releasing the vaccine. Bacterial extracts can be added,which enhances the immuneresponse. Alum is the only adjuvantapproved for use in humans.
AdjuantsFreund’s Adjuvant In Freund’s adjuvant, thevaccine is suspended in oildroplets. When injected into the body,the vaccine slowly diffuses outof the oil drop. Bacterial antigens can be addedin order to enhance the immuneresponse. Not used in humans because ofrisk of severe inflammation.
Routes of Administration There are three different routesof administration: Intradermal administration. Three types are intravenous,intramuscular, andsubcutaneous. Oral administration. Vaccine is usually given inliquid form. Foods, such as tomatoes, havebeen engineered to produce avaccine. Intranasal administration.
Boosters For most vaccines, theimmunity against a particularpathogen has a tendencyto wear off over time. In this case, a periodic“booster” administration mustbe given in order tostrengthen and lengthenthe duration of immunity.
Active immunization byartificial means can be achievedby:18Attenuated organisms (avirulent)Inactivated organisms (killed)Purified microbial macromoleculesCloned microbial antigensSynthetic peptidesAnti-idiotype antibodiesMultivalent complexes
Live-attenuated Vaccine21Oral Polio Vaccine (Sabin)MMR (measles, mumps and rubella)VaricellaBCGRotavirusOral typhoid etc.
Advantages of Attenuated Vaccines22••Raises immune response to all protectiveantigens.• More durable immunity• Low cost• Quick immunity in majority of vaccinees• In case of polio and adeno vaccines, easyadministration• Easy transport in field•Disadvantages of Attenuated VaccinesMutation; reversion to virulence (often frequent)
26Advantages of inactivated vaccinesGives sufficient humoral immunity if boostersgiven• No mutation or reversioDisadvantages of inactivated vaccines• Many vaccinees do not raise immunity• Boosters needed• No local immunity (important)• Higher cost• Shortage of monkeys (polio)• Failure in inactivation and immunizationwith virulent virus
Vaccines from whole organismsMany of the currently used vaccines to dateconsist of inactivated or live but attenuatedbacterial cells or virus particlesBacterial cellsPlague , pertusis, choleraInactivatedTuberculosisAttenuated BCGViral particalsInfluenza , rubella virus InactivatedPolio (Salk) InactivatedPolio (Sabin) AttenuatedYellow fever Attenuated
Attenuated Vs Inactivated VaccinesAttenuated InactivatedMethod of production:Virulent strain grown under Virulence is inactivatedby adverse culture conditions chemical treatment orby prolonged growth inunnatural radiationhost or passage throughdifferent unnatural hostsRequirement of booster dose:Generally single booster dose Multiple booster dosesis required are requiredStability:Less stable More stable andresistantto natural temperature
Attenuated Vs Inactivated VaccinesType of host Immune responses:Produce both cell mediated Mainly producesand humoral immune response humoral responseTendency to revert:May revert to original virulent Does not revert tovirulent strain by recombination virulent formwith wild type strain or reversemutationAttenuated Inactivated
Subunit Vaccines• Risks associated with attenuated orkilled whole vaccines can be avoided bysubunit vaccines• Consist of specific, purifiedmacromolecules derived pathogens31
Subunit Vaccines32 Protein subunit (toxoid)- diphteria, tetanus Bacterial polysaccharide- S. pneumoniae, Nisseriameningitidis Viral glycoproteins- Herpes simplex virus glycoprotein D Synthetic peptides produced from active epitopes ofantigen are used as vaccines.Synthetic peptide vaccines for HIV, influenza, diphtheriatoxin, hepatitis B virus and malaria parasite are currentlybeing evaluated for their efficacyNot very successful as peptides are not as immunogenic asproteins
Subunit Vaccines Recombinant pathogen proteins-Gene coding any immunogenic protein cloned byrecombinant DNA technologyE.g. hepatitis Bs Ag gene cloned in yeast
Recombinant Vectors VaccinesAttenuated viruses and bacteria serve asvectorsGenes encoding major antigens of virulentpathogens can be introduced into theseWide range of organisms used as vectors:vaccinia virus,attenuated polio virus,canary pox virus, adenovirus,BCG strain of Mycobacterium bovis
The Hierarchy of VaccinesFirst generation vaccines are whole-organism vaccines– either live and weakened, or killed forms.The so-called second generation vaccines are subunitvaccines, consisting of defined protein antigens (suchas tetanus or diphtheria toxoid)or recombinant protein components (such as thehepatitis B surface antigen).DNA vaccines are third generation vaccines
DNA Vaccines - The Third GenerationVaccines37• 1796 Jenner: wild type animal-adapted virus• 1800’s Pasteur: Attenuated virus• 1996 DNA vaccines
DNA VaccinesMade up of plasmid that has been geneticallyengineered to produce one or two specific proteins(antigens) from a pathogen.The vaccine DNA is injected into the cells of thebody, where the "inner machinery" of the host cells"reads" the DNA and converts it into pathogenicproteins.Because these proteins are recognised as foreign,when they are processed by the host cells anddisplayed on their surface, the immune system isalerted, which then triggers a range of immune
Applications of DNAVaccinesDNA vaccines are in their early phaseof clinical trials.There are no DNA vaccines in marketat present.At present human trials are under wayfor malaria, influenza, AIDS, Ebola andHerpes.
Advantages of DNA Vaccines40Plasmids are easily manufactured in large amountsDNA is very stableDNA resists temperature extremes so storage andtransport are straight forward. Refrigeration isnot requiredStable for storageElicit both humoral & cell mediated immunityFocused on Antigen of interestLong term immunity
Disadvantages of DNA VaccinesLimited to protein immunogen onlyExtended immunostimulation leads tochronic inflammationPlasmid used is resistance to antibiotics forselection. Can raise the resistance to sameantibiotic in the host
Conjugate Vaccines Certain bacteria havepolysaccharide outercoats that are poorlyimmunogenic (Tindependent Ags) By linking these outercoats to proteins (e.g.toxiods), the immunesystem can be led torecognize thepolysaccharide as if itwere a protein antigen Haemophilus influenzaetype B vaccine42
Combination vaccines43 DTP - Combination vaccine prevents three diseasesin one shotDiphtheria, Tetanus (lockjaw), Pertussis (whoopingcough) MMRMeasles, Mumps, Rubella
Edible vaccines44 Antigens or antibodies expressed in plants Oral administration Cheaper Exhibit good genetic stability Do not require special storage conditions Since syringes and needles are not used,chances of infection are also less
Anti-idiotype vaccines Idiotype- unique amino acid sequence of Vdomain of a given Ab – Ag binding site as wellas antigenic determinantGeneration of an effective immuneresponse to a dangerous pathogenwithout exposing the individual to anyform of pathogen as vaccineIt is known as anti-idiotype antibodiesVaccines of this type have been developedagainst pathogens of viral, bacterial orparasitic type
Why arent vaccines available for alldiseases ?51 The procedure for developing a vaccine is time taking and veryexpensive Vaccines are prioritized in following order: Vaccines that fight diseases that cause the most deaths anddamage, like meningitis Vaccines that prevent severe diseases like measles and influenza Vaccines, like the one for rotavirus, that prevent significantsuffering Companies must get significant return on investment Some viruses mutate so quickly that traditional vaccines areineffective. A prime example is the HIV/AIDS virus