1Vaccine development: from idea to productVeronica Leautaud, Ph.D.vl2@ rice.eduKeck Hall 224 / 232-labLecture 9BIOE 301-Bioengineering and World HealthReview of lecture 8• Pathogens: Bacteria and Virus• Levels of Immunity:– Barriers Æ First line of defense–InnateÆ Inflammation•Phagocytes•Complement–AdaptiveÆ Immunologic memory• Antibody mediated immunity ÆExtracellular pathogens• Cell mediated immunity Æ Pathogens within cells• Diversity to recognize 100 million antigensReview of lecture 8• Infectious diseases are still a serious global health problem– Example of bacterial pathogen of public health relevance- Example of viral pathogen of public health relevanceReview of lecture 8• There are 3 levels of immunity– Which are they?- Which cells in the blood mediate innateimmune response?Review of lecture 8• The adaptive immune response offers great advantage to vertebrates- What is adaptive immunity? - What is immunologic memory?How can technology help?1. Understanding biology: pathogens & diseaseimmune system2. Developing vaccines: from idea to product- vaccine design-production- testing safety & effectiveness3. Addressing challenges for vaccine development:- Developed vs. developing countries- The AIDS vaccine challenge ScienceEngineering2How can technology help?1. Understanding biology: pathogens & diseaseimmune system2. Developing vaccines: from idea to product- vaccine design-production- testing safety & effectiveness3. Addressing challenges for vaccine development:- Developed vs. developing countries- The AIDS vaccine challenge ScienceEngineeringLecture mapThe case of the FluVaccinesTypes of vaccinesAre they effective?Are they safe?FDA approval processThe thimerosal debateHistory of VaccinesChildhood Immunizations in US and the WorldThe HERD effectVaccine manufactureHow are vaccines made?Challenges for vaccine developmentViral Life cycleAntigenic driftAntigenic shift & pandemicsLecture mapThe case of the FluVaccinesTypes of vaccinesAre they effective?Are they safe?FDA approval processThe thimerosal debateHistory of VaccinesChildhood Immunizations in US and the WorldThe HERD effectVaccine manufactureHow are vaccines made?Challenges for vaccine developmentViral Life cycleAntigenic driftAntigenic shift & pandemicsThe case of the fluInfluenza virus A (B, C)Infects respiratory tract-Cells killed by virus or immune responseImmune mediators: Interferon-fever-muscle aches-headaches-fatigueAdaptive immunity: Humoral & cell-mediated responses clear infection, but:- Yearly outbreaks, in spite of previous infections- Yearly vaccination neededInfluenza A• Viral Spread– Infected person sneezes or coughs– Micro-droplets containing viral particles inhaled by another person– Penetrates epithelial cells lining respiratory tract• Influenza kills cells that it infects• Can only cause acute infections• Cannot establish latent or chronic infections• How does it evade immune extintion?• Antigenic drift• Antigenic shift: reassortmentInfluenza A virus -RNA core: 8 segments-Protein capsid: w/RNA polymerases-Envelope-2 major glycoproteins:-Hemagglutinin (HA)-Neuraminidase (NA)Size = 80-120nm3The influenza virus life cycle:HA- mediates entry, -main target of humoral immunityNA- mediates releaseThe Adaptive Immune response to influenzaThe influenza virus life cycle:HA- mediates entry, -main target of humoral immunityNA- mediates releaseAntigenic drift:-Viral RNA polymerases don’t proofread reproduction-point mutation changes in HA/NA change antigenicityThe 1918 Spanish Influenza Flu Pandemic -Population lacked immunity to new H1N1 strain: 40 million deaths in <1 yr!-Today widely circulating human viruses: H1, H2, H3-Birds are predominant host for all H1-H16/ N1-N9 strainsAntigenic shift and flu pandemicsShift (Reassortment): viral gene segments randomly reassociate-Achieved by co-infection of a single cell with these viruses How does this happen?1. Virus shed in bird feces gets into pigs drinking water2. Humans handle and/or cough on the pig= New virus: segments from human birds & pigs virusChina: Guangdong Province-breeding ground: proximity of humans, pigs, birds:- H5N1: 50% lethal, no human-human transmission yetAntigenic shift and flu pandemicsShift - Reassortment: viral gene segments randomly reassociate-Achieved by co-infection of a single cell with these viruses How does this happen?1. Virus shed in bird feces gets into pigs drinking water2. Humans handle and/or cough on the pig= New virus: segments from human birds & pigs virusChina: Guangdong Province-breeding ground: proximity of humans, pigs, birds:- H5N1: 50% lethal, no human-human transmission yet4Lecture mapThe case of the FluVaccinesTypes of vaccinesAre they effective?Are they safe?FDA approval processThe thrimersoal debateHistory of VaccinesChildhood Immunizations in US and the WorldThe HERD effectVaccine manufactureHow are vaccines made?Challenges for vaccine developmentViral Life cycleAntigenic driftAntigenic shift & pandemics2. Humoral Immunity:B and T cell receptors must see virus or viral debrisAdaptive immunity and vaccinesWhat do we need to achieve MEMORY?B cell: antibodies(neutralize & bridge)T-helper cellKiller T cellAntigen presentationAntigen presentationmacrophagemacrophageinfected cell1. Cellular Immunity:Antigen presentation by APCs or infected cellsTypes of vaccines• Non-infectious vaccines• Live attenuated vaccines• Carrier vaccines• DNA vaccinesNon-infectious vaccines• Inactivated or killed pathogen: Salk Polio Vaccine, rabies vaccine• Subunit vaccines: Hepatitis A & B, Haemophilus Influenza type B • Toxoid vaccines: diphteria, tetanus and pertussis-Will not make memory killer T cells-Booster vaccines usually needed-Will make B-memory cells and T-helper memory cells = good antibody responseLive attenuated vaccines• Grow pathogen in host cells • Produces mutations which:-weaken pathogen so it cannot produce disease in healthy people - yet still elicits strong immune reaction: and protection• Sabin Polio Vaccine, Measles, Mumps Rubella, VaricellaSome viral shedding: can produce disease in immunocompromisedhost-Makes memory cells: B-cells, T helper and Killer T cells- Usually life-long immunity5Carrier vaccines• Use virus or bacterium that does not cause disease to carry viral genes to APCs– e.g. vaccinia for Smallpox vaccine–
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