Vaccine development: from idea to product Example of bacterial - PDF document

Review of lecture 8 • Infectious diseases are still a serious global health problem Vaccine development: from idea to product – Example of bacterial pathogen of public health relevance - Example of viral pathogen of public health relevance Veronica Leautaud, Ph.D. vl2@ rice.edu Keck Hall 224 / 232-lab Lecture 9 BIOE 301-Bioengineering and World Health Review of lecture 8 Review of lecture 8 • There are 3 levels of immunity • The adaptive immune response offers great advantage to vertebrates – Which are they? - Name the 2 components of adaptive immunity - Which cells in the blood mediate innate immune response? - What is immunologic memory? Immunologic Memory Review of lecture 8 • 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? How can technology help? Science Science 1. Understanding biology: pathogens & disease 1. Understanding biology: pathogens & disease immune system immune system Engineering Engineering 2. Developing vaccines: from idea to product 2. Developing vaccines: from idea to product - vaccine design - vaccine design - production - production - testing safety & effectiveness - testing safety & effectiveness 3. Addressing challenges for vaccine development: 3. Addressing challenges for vaccine development: - Developed vs. developing countries - Developed vs. developing countries - The AIDS vaccine challenge - The AIDS vaccine challenge Lecture map Lecture map Viral Life cycle Viral Life cycle The case of the Flu The case of the Flu Antigenic drift Antigenic drift Antigenic shift & pandemics Antigenic shift & pandemics Vaccines Vaccines Types of vaccines Types of vaccines Are they effective? Are they effective? History of Vaccines History of Vaccines Childhood Immunizations in US and the World Childhood Immunizations in US and the World The HERD effect The HERD effect Are they safe? Are they safe? FDA approval process FDA approval process The thimerosal debate The thimerosal debate Vaccine manufacture Vaccine manufacture How are vaccines made? How are vaccines made? Challenges for vaccine development Challenges for vaccine development The case of the flu Influenza A Influenza virus A (B, C) • Viral Spread – Infected person sneezes or coughs Infects respiratory tract – Micro-droplets containing viral particles inhaled by another -Cells killed by virus or immune response person – Penetrates epithelial cells lining respiratory tract Immune mediators: Interferon -fever • Influenza kills cells that it infects -muscle aches • Can only cause acute infections -headaches -fatigue • Cannot establish latent or chronic infections Adaptive immunity: Humoral & cell-mediated responses • How does it evade immune extintion? clear infection & create immune memory, but: • Antigenic drift • Antigenic shift: reassortment - Yearly outbreaks, in spite of previous infections - Yearly vaccination needed

Influenza A virus The influenza virus life cycle: -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 HA- mediates entry, -main target of humoral immunity NA- mediates release Size = 80-120nm The Adaptive Immune response to influenza The influenza virus life cycle: Antigenic drift: - Viral RNA polymerases HA- mediates entry, -main target of humoral immunity don’t proofread reproduction NA- mediates release -point mutation changes in HA/NA change antigenicity The 1918 Spanish Influenza Flu Pandemic Antigenic shift and flu pandemics Shift (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 water 2. Humans handle and/or cough on the pig = New virus: segments from human birds & pigs virus -Population lacked immunity to new H1N1 strain: 40 million deaths in <1 yr! China: Guangdong Province - breeding ground: proximity of -Today widely circulating human viruses: H1, H2, H3 humans, pigs, birds: -Birds are predominant host for all H1-H16/ N1-N9 strains - H5N1: 50% lethal, no human-human transmission yet http://www.nytimes.com/2006/03/28/science/28flu.html

Antigenic shift and flu pandemics Shift - 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 water 2. Humans handle and/or cough on the pig = New virus: segments from human birds & pigs virus China: Guangdong Province - breeding ground: proximity of humans, pigs, birds: ? - H5N1: 50% lethal, no human-human transmission yet Immunologic Memory 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 thrimersoal debate Vaccine manufacture How are vaccines made? Challenges for vaccine development What do we need to achieve MEMORY? Types of vaccines An effective 1 st adaptive response! macrophage • Non-infectious vaccines macrophage 1. Cellular Immunity: Antigen presentation by • Live attenuated vaccines APCs or infected cells Antigen presentation T-helper cell • Carrier vaccines Antigen presentation • DNA vaccines 2. Humoral Immunity: Killer T cell infected cell B and T cell receptors must see virus or viral debris B cell: antibodies (neutralize & bridge)

Live attenuated vaccines Non-infectious vaccines • Grow pathogen in host cells • Inactivated or killed pathogen: Salk Polio Vaccine, • Produces mutations which: rabies vaccine - weaken pathogen so it cannot produce disease in healthy • Subunit vaccines: Hepatitis A & B, Haemophilus Influenza people type B - yet still elicits strong immune reaction: and protection • Toxoid vaccines: diphteria, tetanus and pertussis • Sabin Polio Vaccine, Measles, Mumps Rubella, Varicella -Will make B-memory cells and -Makes memory cells: B-cells, T T-helper memory cells -Will not make memory helper and Killer T cells = good antibody response killer T cells - Usually life-long immunity Some viral shedding: can produce disease in -Booster vaccines usually immunocompromised needed host Carrier vaccines DNA vaccines • Use virus or bacterium that does not cause disease to carry viral genes to APCs • DNA injections can transduce cells so antigens are expressed and presented. – e.g. vaccinia for Smallpox vaccine – http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp • Reasons are not fully understood, but it can make memory B cells and memory T killer cells! -Makes memory B cells, memory helper T cells, AND • Make a DNA vaccine from a few viral genes -Immuno-compromised individuals memory killer T cells can get infection from carrier - Does not pose danger of real -Pre-existing immunity to carrier • No danger that it would cause infection infection might block effect (must use different carrier for booster) How do vaccines work? Types of vaccines • Non-infectious vaccines – No danger of infection – Does not stimulate cell mediated immunity Antigen •Live attenuated virus – Usually need booster vaccines presentation T-helper cell •Carrier vaccines • Live, attenuated bacterial or viral vaccines •DNA vaccines Antigen – Makes memory B cells, memory helper T cells, AND memory presentation killer T cells – Usually provides life-long immunity – Can produce disease in immuno-compromised host Killer T cell •Non-infectious • Carrier Vaccines vaccines – Makes memory B cells, memory helper T cells, AND memory killer T cells B cell: antibodies – Does not pose danger of real infection (neutralize & bridge) – Immuno-compromised individuals can get infection from carrier …By inducing adaptive immunity & memory! • DNA Vaccines