BPHA3151 Lecture 7 Vaccines - Idea to Production PDF

Vaccine development: from idea to product  Review Infectious diseases are still a serious global health problem – Example of bacterial pathogen of public health relevance - Example of viral pathogen of public health relevance  Review There are 3 levels of immunity – Which...

Vaccine development: from idea to product  Review Infectious diseases are still a serious global health problem – Example of bacterial pathogen of public health relevance - Example of viral pathogen of public health relevance  Review There are 3 levels of immunity – Which are they? - Which cells in the blood mediate innate immune response?  Review The adaptive immune response offers great advantage to vertebrates - Name the 2 components of adaptive immunity - What is immunologic memory? Immunologic Memory  Review Pathogens: Bacteria and Virus Levels of Immunity: – Barriers  First line of defense – Innate  Inflammation Phagocytes Complement – Adaptive  Immunologic memory Antibody mediated immunity  Extracellular pathogens Cell mediated immunity  Pathogens within cells Diversity to recognize 100 million antigens  How can technology help? Science 1. Understanding biology: pathogens & disease immune system Engineering 2. Developing vaccines: from idea to product - vaccine design - production - testing safety & effectiveness 3. Addressing challenges for vaccine development: - Developed vs. developing countries - The AIDS vaccine challenge  How can technology help? Science 1. Understanding biology: pathogens & disease immune system Engineering 2. Developing vaccines: from idea to product - vaccine design - production - testing safety & effectiveness 3. Addressing challenges for vaccine development: - Developed vs. developing countries - The AIDS vaccine challenge Lecture map Viral Life cycle The case of the Flu Antigenic drift Antigenic shift & pandemics Vaccines Types of vaccines Are they effective? History of Vaccines Childhood Immunizations in US and the World The HERD effect Are they safe? FDA approval process The thimerosal debate Vaccine manufacture How are vaccines made? Challenges for vaccine development Lecture map Viral Life cycle The case of the Flu Antigenic drift Antigenic shift & pandemics Vaccines Types of vaccines Are they effective? History of Vaccines Childhood Immunizations in US and the World The HERD effect Are they safe? FDA approval process The thimerosal debate Vaccine manufacture How are vaccines made? Challenges for vaccine development  The case of the flu Influenza virus A (B, C) Infects respiratory tract -Cells killed by virus or immune response Immune mediators: Interferon -fever -muscle aches -headaches -fatigue Adaptive immunity: Humoral & cell-mediated responses clear infection & create immune memory, but: - Yearly outbreaks, in spite of previous infections - Yearly vaccination needed  Influenza 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: reassortment  Influenza A virus -RNA core: 8 segments -Protein capsid: w/RNA polymerases -Envelope -2 major glycoproteins: -Hemagglutinin (HA) subtypes :1,2,3…16 -Neuraminidase (NA) subtypes: 1, 2…9 Size = 80-120nm  The influenza virus life cycle: HA- mediates entry, -main target of humoral immunity NA- mediates release The Adaptive Immune response to influenza  The influenza virus life cycle: Antigenic drift: HA- mediates entry, -Viral RNA polymerases don’t -main target of humoral immunity proofread reproduction NA- mediates release -point mutation changes in HA/NA change antigenicity  The 1918 Spanish Influenza Flu Pandemic -Population lacked immunity to new H1N1 strain: 40 million deaths in 80% of the world’s children receive basic vaccines – Each year: 3 million lives saved  Are vaccines effective? 1977: Goal to immunize at least 80% of world’s children against six antigens by 1990  Effectiveness through THE HERD effect 1-2 out of every 20 immunized people will not develop and adequate immune response Still, -Vaccinated people are much less likely to transmit a pathogen to others -So even people that are not vaccinated are protected 85-95% of the community must be vaccinated to achieve herd immunity http://www.npr.org/templates/story/story.php?storyId=11226682 Effectiveness through THE HERD effect The case of diphteria in the Soviet Union Lecture map Viral Life cycle The case of the Flu Antigenic drift Antigenic shift & pandemics Vaccines Types of vaccines Are they effective? History of Vaccines Childhood Immunizations in US The HERD effect Are they safe? FDA approval process The thimerosal debate Vaccine manufacture How are vaccines made? Challenges for vaccine development  Are vaccines safe? Testing safety and effectiveness: The case of Thimerosal (mercury preservative) in vaccines and autism - Andrew Wakefield Lancet’s paper (1998): Temporal relation between chronic gastro-intestinal disease and autism, and MMR vaccination. - Advocates single vaccination over combined shot. - MMR vaccination rates in UK drop from 80% to 62% - Study tainted by conflict of interest! Autism in the news: http://youtube.com/watch?v=u1TZUoG6mPk http://www.cbsnews.com/stories/2007/06/11/health/main2911164.shtml Are vaccines safe? Testing safety and effectiveness - Laboratory testing : Cell models Animal models - Human trials: Phase I Phase II Phase III Post-licensure surveillance  Are vaccines safe? Human trials: - Phase I 20-100 healthy volunteers Determine vaccine dosages & Last few months side effects - Phase II Several hundred volunteers Last few months to years Effectiveness & safety Controlled study: vaccine vs. placebo (or existing vaccine) - Phase III Several hundred to several thousand volunteers Last Years Controlled double blind study: vaccines vs. placebo (Neither patient nor physicians know which) - Post-licensure surveillance : Vaccine Adverse Effect Reporting System VAER S: 12,000/yr, only ~2000 serious  Are vaccines safe? National Institutes of Medicine: Immunization Safety Review Committee 1999: Evidence inadequate to accept or reject a causal relation. -Relation biologically plausible -Recommends “Full consideration be given to removing thimerosal from any biological product to which infants, children and pregnant women are exposed”. 2004: More evidence from Denmark , Sweden, UK and more biological studies: reject causal relation. FDA recommendations: http://www.fda.gov/Cber/vaccine/thimerosal.htm#thi Lecture map Viral Life cycle The case of the Flu Antigenic drift Antigenic shift & pandemics Vaccines Types of vaccines Are they effective? History of Vaccines Childhood Immunizations in US The HERD effect Are they safe? FDA approval process The thrimersoal debate Vaccine manufacture How are vaccines made? Challenges for vaccine development  How are vaccines made? The trivalent influenza vaccine 1. CDC/WHO experts gather to decide which strains to target. 2. Virus reassortment in cell culture 3. 300 million fertilized eggs are cleaned and inoculated with reassorted virus 4. Viral fluid from eggs is harvested, centrifuged and filtered. Virus is inactivated with formalin 5. Purified inactivated virus from each strain is combined and packaged into doses  How are vaccines made? The influenza vaccine An alternative production approach: 1. Genetic engineering of virus 2. Growth in tissue culture cells  How are vaccines made? The influenza vaccine  Challenges for vaccine development - In the developed world - Cost of development: facilities, regulations, litigation - Market size : only given once, 57% bought by public sector - Litigation costs: National Vaccine Injury Compensation Program - In the developing world - Storage and transportation conditions - UV protection - The ‘cold chain’ / Freeze watch label - Syringe use - Auto-disposable syringes eg. Solo-shot syringe - Needle free methods - Cost - GAVI: Unicef, WHO, Gates, NGOs  How can technology help? The case of Smallpox One of world’s deadliest diseases – Vaccine available in early 1800s – Difficult to keep vaccine viable enough to deliver in developing world Elimination of smallpox – 1950: stable, freeze dried vaccine – 1950: Goal  Eradicate smallpox from western hemisphere – 1967: Goal achieved except for Brazil – 1959: Goal  Eradicate smallpox from globe Little progress made until 1967 when resources dedicated, 10-15 million cases per year at this time – Strategies: » Vaccinate 80% of population » Surveillance and containment of outbreaks – May 8, 1980: world certified as smallpox free!  Vaccines: what is still needed? - The big three: - HIV - Malaria - Tuberculosis  Summary of lecture 9 How do vaccines work? – Stimulate immunity without causing disease Different types of vaccines – Non-infectious vaccines – Live, attenuated bacterial or viral vaccines – Carrier Vaccines – DNA Vaccines Are vaccines effective? How are vaccines tested? – Lab/Animal testing – Phase I-III human testing – Post-licensure surveillance Reading -Read: The Covid-19 vaccines There will be a “pop quiz” on this reading during class. If you read the article you will do well on the quiz. The end