Lecture 33 - Vaccination BioMi2900 Fall 2024 PDF

Lecture 33 – Vaccination BioMi2900 Fall 2024  Cell Mediated Immunity In cell-mediated immunity, activated helper T Cells release cytokines to activate Cytotoxic T Cells Any cell can display an antigen on the MHCI receptor protein on the cel...

Lecture 33 – Vaccination BioMi2900 Fall 2024  Cell Mediated Immunity In cell-mediated immunity, activated helper T Cells release cytokines to activate Cytotoxic T Cells Any cell can display an antigen on the MHCI receptor protein on the cell surface. A cytotoxic T cell with a TCR receptor that CD8 recognizes the antigen (stabilized by CD8) is activated. (some become memory T cells). The cytotoxic T cell kills the infected cell.  But how does a T-cell receptor know its antigen? Self- reactive T cells are removed in the Thymus. Naïve T-cell Figure 27.2 Where do lymphocytes and APCs meet? Lymphoid Tissues and Lymphatic Circulation Lymphoid precursor cells differentiate into B or T cells in the Bone marrow or Thymus. These immature (naïve) lymphocytes are carried to peripheral lymphoid organs (in blue) These are locations where they can interact with specific antigens => maturation. Putting it all together… humoral response Pathogen (virus/bacterium) B- Phag cell o- s cyte s MHCII Th cell memor (CD4 yB-cell ONC: +) Opsonize Neutralize Complement  Putting it all together… cell-mediated response Pathogen (virus/bacterium) Any cell MHCI cT- cells (CD8 +) (left out for dramatic purposes: cytotoxic T-cell activation also requires T-helper cells!)  Summary The humoral response is mediated by B-cells and antibodies (antibodies neutralize toxins and pathogens) The cell-mediated response relies on T-cells. T-cells come in two varieties: Cytotoxic T-cells that kill infected cells, and helper T-cells that activate B-cells (among other things) The immune system generates pathogen-reactive B- and T-cells through a random change process The immune system exhibits memory function, but differentiating some B and T-cells into long-lived memory cells that can reactivate once they encounter the same pathogen again  Lecture 33 – Vaccination 1. Vaccines – introduction 2. Vaccines – general mechanism 3. Types of vaccines/case study 4. Vaccine Development stages 5. Herd immunity  1. Vaccination - A history of amazing successes… Smallpox (variola virus) was once one of the most feared diseases, Kills 1 in 3 infected people. Due to vaccination, limited host range for virus, and super-human efforts by public health officials of the WHO, smallpox has been eradicated! Last natural case reported in 1977. (also: First ”vaccine”!) Polio: last US case in 1986, nearly eradicated globally Measles, mumps, and rubella: CDC estimates that in the 10-yr interval of 1994- 2014 332 million cases prevented and 732,000 lives saved by vaccination In some rare cases, Polio virus attacks the nerves for e.g., muscles that help you breathe – some patients had to spend almost their entire live in the iron long (a pressure- based respiration system). No time for complacency: Vaccine efficacy is dwindling for some pathogens http://www.sciencema g.org/news/2017/04/h eres-visual-proof-why- vaccines-do-more-goo d-harm https://bits.blogs.nyti mes.com/2013/11/27/ the-vaccination-effect -100-million-cases-of- contagious-disease-pr evented/?emc=eta1& _r=0 “The range of 75 million to 106 million cases prevented by vaccines is probably  2. Vaccination – general mechanism Now that you know everything about adaptive immunity, it is probably obvious to you how vaccines work! Vaccines exploit the memory function of the adaptive Immune System Secondary Response Faster Stronger Protection lasts longer…  Antigen binding (often + helper cell) activates B-cells Antigen of new pathogen Clonal propagation + Refinement (somatic hypermutation) differentiation Memory B-cell  Memory B-cells rapidly react after second exposure to same antigen Memory B-cell  Vaccine design – a moving target onsiderations for vaccine design: - What is a good antigen? (How much do we know about pathogen biology? -> basic science!) - What is a safe antigen? - How do different immune systems react (remember: This is all random chance!) - How quickly does the pathogen evolve? - Do you need antibodies to stick around or are memory B-cells enough? How long-lived are either of them? From Melissa Moore’s (CFO of Moderna) talk, October 2022, 3. Types of vaccines Vaccines are nontoxic antigens that are injected, ingested or inhaled and used to elicit a specific immune response without having to endure an infection. Vaccines can be in one of several different forms: – “Whole-cell” or “whole-virus”: either the killed inactivated microbial disease agent (injected influenza vacc) or live attenuated strains (MMR - measles, mumps, rubella) – Acellular or subunit (split or subvirion): purified macromolecules or structurally destroyed virus (acellular pertussis) – Toxoid: treated, inactive “detoxified” toxin (tetanus, need regular booster) – Conjugated: increase immune response to poor antigen by binding it to a compound that elicits a strong immune response (Haemophilus influenzae, capsule polysaccharide linked to a carrier protein) – Recombinant vector: gene coding for a major antigen of a disease-causing microbe may be introduced into a benign microbe (the vector) by molecular cloning and the protein product used as the vaccine – RNA/DNA vaccines: code for pathogen protein, taken up and expressed by host Vaccine case study: Covid-19 e.g. lung cell SARS-CoV-2 infection cycle mRNA vaccines: First trial, first success! ??  Drs. Ugur Sahin and Özlem Türeci Dr. Katalin Karikó from Hungary, a vice from Germany, Founders of president of BioNTech, solved the RNA BioNTech, in collaboration with problem Pfizer, solved the delivery problem Nobel Prize 2023!Problem: mRNA by itself induces an immune response! (strong side effects)  Why could you still be infectious after you have become vaccinated/infected? Lung Cell ??? Complications: - Need strong antibody response (B cells) to prevent infection (antibodies have to accumulate in the lung fluid) - Main immunity T-cell mediated (i.e., cell death) - Spike protein may mutate Why do we need boosters? Is immunity after infection better than  4. Vaccine development stages – why does it take so long? 1. Research and Development e.g.: Immune response/safety in mice? 2. Phase I clinical trial small number of people (~