VaccinesPassive vs Active ImmunityPassive ImmunizationHow do vaccines work?Preventive vs Therapeutic vaccinesSmallpox---Vaccine SuccessIssues for Vaccine Design Establishing Protective ImmunityIssues for Vaccine Design How to establish protective immunity?Issues for Vaccine Design Prevent potential pathogenesisIssues for Vaccine Design Route of immunizationIssues for Vaccine Design Routes of immunizationIssues for Vaccine Design AdjuvantsOther ways to enhance immunogenicityIssues for Vaccine Design Antigenic VariationTypes of Vaccines Attenuated vaccines aka "Live Vaccines"Types of Vaccines Attenuated vaccinesSlide 17Types of Vaccines Inactivated VaccinesSlide 19Types of Vaccines Inactivated Flu VaccineFlu Vaccine Issues in USWhy have attenuated vaccines been so successful?Attenuated (self-replicating/ live) vs Inactivated (non-replicating/ killed)Success of Polio Vaccination Attenuated Oral Polio Vaccine (OPV) Sabin 1954 Inactivated Polio Vaccine (IPV) Salk 1957Types of Vaccines Recombinant proteins/ synthetic peptidesTypes of Vaccines Recombinant proteins/ synthetic peptidesHuman Papilloma virus (HPV) vaccine (causes warts and cervical cancer)Subunits in live vectorsTypes of Vaccines Subunits in live vectorsTypes of Vaccines HIV Canarypox vaccinePowerPoint PresentationTypes of Vaccines DNA vaccinesVaccines currently in useGeneral Issues to Consider in Vaccine DevelopmentSlide 35Slide 36VaccinesRobert BeattyMCB150Passive vs Active Immunity Passive immunization transfer of antibodiesVaccines are active immunizations(mimic natural infections)Passive ImmunizationLasts as long as antibodies are present. Does not establish memory. e.g. gammaglobulin shots (pooled human IgG).How do vaccines work?Vaccines are active immunization to provide protection from disease by establishing memory T and B cells. Some vaccines prevent disease but not infection.Preventive vs Therapeutic vaccinesPreventive Most vaccines in use now provide protection from primary infection or prevent disease. Therapeutic vaccinesGiven to infected people to prevent disease, reduce effects of chronic infection, or stimulate anti-tumor response.Smallpox---Vaccine SuccessReasons for the smallpox success storyNo animal reservoir. Lifelong immunity. One serotype (no antigenic variation). Effective attenuated vaccine. Successful eradication of smallpox last known case in world in 1977. Smallpox vaccine is Vaccinia virus.Issues for Vaccine Design Establishing Protective ImmunityWhich antigens are immunodominant? What type of immune response provides protection from disease? How to elicit long-term immune protection?Issues for Vaccine DesignHow to establish protective immunity? Which antigens at what stage in life cycle do you vaccinate with?What type of immune response protects? MalariaRbc stagePre-liver stageIssues for Vaccine Design Prevent potential pathogenesisDisease often a result of a immune response.Some vaccine trials actually resulted in worse disease. Vaccines must avoid immune pathology.Issues for Vaccine Design Route of immunizationImmunization site will influence where immune responses are elicited. Important to know route of infection in order to elicit protective immunity. Primary vaccine routes –Intramuscular (IM) –Intravenous (IV)–OralIssues for Vaccine Design Routes of immunizationIntranasal live vaccine for influenza was designed so that it will replicate only in nasalpassagesRoutes for vaccination may include skin, subcutaneous, or intranasal."Flu-mist"Issues for Vaccine DesignAdjuvantsAdded to non-replicating vaccines in order to enhance immunogenicity. (Bind TLRS, provide inflammatory response, and activate APCs) Inorganic salts are routinely used in humans. •Aluminum hydroxide•Aluminum phosphate•Calcium phosphateNew lipid adjuvants •Liposomes •Immune stimulating complexes (ISCOMs)Other ways to enhance immunogenicityInject vaccine with other pathogen to provide adjuvant-like effectE.g. Bordetella pertussis (whooping cough) is given with tetanus toxoid and diptheria toxoid.Inject cytokines with vaccine E.g. GM-CSF injected with vaccine or inserted in plasmid.Issues for Vaccine DesignAntigenic VariationViruses have different antigenic subtypes and high mutation rates. –Example: Antigenic drift of influenza usually means a new vaccine formulation each year. NOTE**any potential HIV vaccine will have to deal with different serotypes and high mutation rate.Types of Vaccines Attenuated vaccinesaka "Live Vaccines"Attenuated vaccines are made by growing pathogen in non-human cell culture. Less virulent in humans. –Examples Sabin Oral polio vaccine (OPV). Measles. Mumps. Rubella. Varicella zoster virus (VZV).Types of Vaccines Attenuated vaccinesPathogen is passaged in non-human cell culture until it has low replication in human cells.Types of Vaccines Attenuated vaccinesAdvantages: –Self-replicating–Authentic antigen presentation–More effective at eliciting CTLsDisadvantages: –Reversal of virulence–One lab-adapted strain does not deal with strain variabilityTypes of Vaccines Inactivated VaccinesWhole, killed, non-replicating organismInactivated by heat, chemicals, or irradiation –Examples Influenza. Hepatitis A virus, Pertussis, Salk inactivated polio vaccine (IPV)Types of Vaccines Inactivated VaccinesAdvantages: –No virulence–All antigens presentDisadvantages: –No replication of pathogen–Poor antigen presentation for CMITypes of Vaccines Inactivated Flu VaccineTraditional approach: Cell culture– Identify target "new virulent" strains–Grow in eggs with "harmless" flu strain–Genetic reassortment--expand and inactivateNew approaches: Reverse genetics = clone in virulent H or NRecombinant H grown in insect cellsFlu Vaccine Issues in USStandard Inactivated vaccine. –Usually 100 million doses available each year.  Flu-mist –Live vaccine and only 1-2 million doses. Recombinant vaccine still in clinical trials.Many H5N1 vaccines in the works.Why have attenuated vaccines been so successful? Advantages of replicating live vaccines: – low cost, single dose, no adjuvant, generates IgG, IgA, and cell mediated immunity. Big disadvantage is potential for revirulence.Attenuated (self-replicating/ live) vs Inactivated (non-replicating/ killed)Success of Polio VaccinationAttenuated