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Immunology Week 9 (Vaccines (Types (Inactivated / Killed (Safer than…

- - - - Whooping cough outbreaks in the US
      - Measles outbreaks in the US and Canada
      - Diptheria reemergence in the former Soviet Union
  - - - Broad HIV neutralizing Igs (trials) - targets multiple common epitopes, multiple Ags and stable Ags (those that don't change)
      - Antitoxins: black widow spider bite, snake bite, botulism, tetanus
      - Monoclonal Igs: Hep A and B, measles, rabies
  - - - Safer than recombinant attenuated - no reversion
      - More stable, easier to store and transport
      - Heat-killed or chemically killed
      - Require boosters or adjuvants (don't last as long)
    - - Inactivated exotoxins/toxoids
      - Pros/Cons similar to inactivated/killed vaccines #
      - Subunit: Purified macromolecules (inactivated capsular polysaccharides, surface glycoproteins) ((bulk of pathogen is removed so that we mainly have epitopes))
      - Conjugate: improve immunogenicity and outcome; couples weak immunogens with strong immunogens
    - - Attenuated (abnormal growth conditions ((slower than normal)), genetic engineering)
      - Not pathogenic but can grow in host - limited (promotes humoral and cell-mediated responses, often do not need boosters b/c of slow growth)
      - MMR, Hep A, Cholera
      - Recombinant: attenuated pathogen that is genetically engineered to carry and express another pathogen's genes
        
        Pros: same benefits as attenuated vaccines but with fewer risks
        
        Cons: similar to those seen with attenuated vaccines (especially stability issues)
    - - Plasmids carrying pathogen genes injected into muscle tissue, taken up by host cells and expressed internally
      - Pros: Induces humoral and cell-mediated immunity (gives us more control), prolongs expression which enhances memory, VERY stable and customizable, lets us target very specific Ags
      - Cons: Expensive and labor intensive, but largely unknown
  - - - Gelatin: temperature stabilizer, risk: allergy/anaphylaxis
      - Antibiotics: prevent contamination, risk: contact dermititis at injection site
      - MSG: stabilizer, risk of MSG symptom complex
      - Egg Protein: remnant from manufacturing, risk: allergy/anaphylaxis
    - - Systemic Immunity: Intramuscular or subcutaneous administration, create an insoluble Ag depot for slow release
      - Mucosal Immunity: adjuvant forms complex w/ Ag, aids in transport across epithelial barrier
      - Examples
        
        Squalene: natural oil emulsion that slows Ag deliver, found in influenza vaccines
        
        Lipsomes: fuse with membranes, used in various vaccines
        
        Aluminum salts: form insoluble depot, good at stimulations T helper2 cells, AS04 stimulated T helper1 cells, used in Hep A, rabies vaccines
        
        Modified endotoxins and Enterotoxins: mechanism of action possible due to increased Ag presentation, upregulation of B7 co-stimulatory molecules, and/or increased secretion of IgA
- - - - Epithelial Surfaces
      - Secretion of Chemicals & Microenvironment Set Up
    - - Complement system
      - Phagocytic Cells
      - Cytokines
  - - - e.g. Blocking TAP transporters in HIV
    - - e.g. in Influenza
  - - - Infection efficiency (how easily something is spread)
      - Use of non-host species vector (using a species to transmit virus from one host to another) - e.g. Mosquito for West Nile Virus
      - Long latency (dormant) period - e.g. AIDS virus
  - - - Complement Activity
      - Agglutination
      - Opsonization
      - Block Virus
    - - CTLs
      - ADCC
      - Antiviral cytokines
- - - - HSV inhibits TAP activity which effectively shuts down MHC Class l presentation to CD8+ T cells, also inhibits complement
      - Influenza constantly changes its surface antigens through antigenic drift.
        
        Slower and a minor change compared to antigenic shift
      - Hep C overcomes INF antiviral effects by blocking/inhibiting PKR
      - Antigenic Shift
        
        Faster than Ag drift because it has a recombination event (RNA genome segments can be swapped in new virus, new HA/NA combinations can be formed)
        
        Responsible for variation in epidemic influenza strains
        
        Occurs when different virus types infect a single cell
        
        Responsible for pandemics (population may have little to no resistance against a new combination)
        
        Allows wild aquatic birds to carry all known strains of influenza
    - - Cell-mediated immunity is important for viral control and clearance once infected
      - Replication occurs inside cell (error-prone through mutations, triggers humoral and cell-mediated adaptive mechanisms)
      - Typically enter host cells through a cell-surface receptor (Igs prevent binding to a target cell receptor )
      - Review Innate response, viral evasion strategies (mediating adaptive immunity),
      - Responsive cell types: CD8+, CD4+, NK cells
  - - - Bacterial Proliferation
        
        Host uses phagocytosis & Ig- + C3b- mediated opsonization
        
        Host uses complement-mediated lysis and localized inflammatory response
      - Bacterial invasion of host tissues
        
        Host uses Ig-mediated agglutination
      - Bacterial attachment to cells
        
        Host blocks attachment by secretory IgA
      - Bacterial Toxin-induced damage to host cells
        
        Host neutralizes toxins though Igs, e.g. diptheria vaccine
      - Bacteria adapt to evade and a bacterial infection similar to first bacterial infection occurs #
      - Host cellular response: CD4+ and T cells coordinate macrophage response, e.g. TB infection
    - - Gonorrhea Neisseria gonorrhoeae
        
        highest in 20-24, lowest in 40-44
        
        Immune Response
        
        Intense Inflammation
        
        Infected epithelial cells release cytokines and chemokines
        
        Neutrophils influx the genital tract (puss forms in inflammatory response) #
        
        Natural gonococcal infections don't always induce a state of protective immunity as circulating and vaginal anti-gonococcal Igs are kept low
        
        Evasion Strategies
        
        Host cell attachment w/ Ag variation in attachment structures
        
        Resistant to complement mediated lysis #
        
        Releases proteases that cleave IgA (which is created in response) #
        
        Releases factors that suppress adaptive response (ie against T helper cells)
      - Chlamydia is the most common STD
  - - - Often have both blood-born stages and infection of host cells
      - Possess several ways of escaping immune response
        
        Immune response is IgE mediated - humoral response
        
        Igs trigger release of Basic (pH) Protein by Eosinophils that raise pH and are cytotoxic
      - Malaria,
        
        Complicated life cycle: Blood --> liver cells --> RBCs
        
        Evasion
        
        Intracellular proliferation --> makes it difficult for humoral response
        
        Maturation --> Antigenic shift #
        
        Sporozoite is only in the blood for 30 minutes and can slough off it's Ag coat.
        
        No. 1 cause of parasite-induced death worldwide
        
        Drug resistance is becoming an issue
      - African sleeping sickness (Trypanosoma)
    - - Blood-flukes (Schistosoma), roundworms, tapeworm
      - Guinea work: Enter the body as a small parasite and go through lifecycle in the whole body and grow. Gross AF.
      - Immune system has limited to exposure to Helminth because..
        
        Can last in the body for 20 years or more (many, not all)
        
        Their mobility and size make clearance difficult
        
        One individual will only carry a few, and they do not multiply in the host
      - Evasion Strategies of Helminths
        
        Decrease external Ag expression
        
        Wrap themselves in host proteins (hide). We. hate. them.
        
        Secrete various factors
        
        Ig-splitting proteases
        
        Immunosuppressive components
        
        Protease inhibitors
        
        Prostaglandins
        
        Antioxidants
  - - - Host defences against mycosis
        
        PRRs on innate cells
        
        Competition with normal flora
        
        Controlled by innate barriers
        
        Infection triggers inflammation # (similar to Gonorroheae response)
        
        Phagocytosis by neutrophils
        
        Activation of complement
    - - Capsules prevent PRR binding
      - Fungi-induced expulsion from macrophages
      - Usually not severe in healthy individuals but pose a problem if immuno-compromised (ie thrush becomes prevalent when someone is immunocompromised)
- - - - 2 day incubation
      - Fever, cough, headache, muscle and joint pain, malaise, sore throat, runny nose
    - - C detected less frequently
      - A and B circulate, cause outbreaks
  - - - HSV-1: spread through oral-oral contact, causes oral herpes (coldsores) and potentially genital herpes. More common; 3.17 billion people have HSV-1
      - HSV-2: sexually transmitted causing genital herpes. Less common; 417 million people have HSV-2
    - - TAP evasion
      - A glycoprotein binds C3b which prevents the formation of the C5 convertase, blocking action of the complement pathway