vaccine tech

• Vaccine


  A preparation of antigenic components consisting of, derived from or related to a pathogen, which exploits the natural defense mechanisms conferred upon us by our immune system
• Vaccination


  1. Administration of vaccine

  2. Activation of humoral and cell-mediated immune system

  3. Induction of long-term immunological protection
• Traditional vaccine preparations


  • Live, attenuated bacteria (e.g. BCG)
  • Dead or inactivated bacteria (e.g. cholera, pertussis)
  • Live attenuated viruses (e.g. measles, mumps, yellow fever)
  • Inactivated viruses (e.g. hepatitis A, polio (Salk))
  • Toxoids (e.g. diphtheria, tetanus)
  • Pathogen-derived antigens (e.g. hepatitis B, meningococcal, pneumococcal, Haemophilus influenzae)
• Attenuation


  The process of elimination or greatly reducing the virulence of a pathogen, traditionally achieved by chemical treatment, heat, adverse conditions, or propagation in an unnatural host
• Attenuated pathogens should still immunologically cross-react with the wild-type pathogen
• There is a theoretical danger that attenuated pathogens might revert to their pathogenic state, although this rarely occurs in practice
• Attenuated bacterial vaccine


  • BCG (a strain of tuberculosis bacillus that fails to cause tuberculosis but retains much of the antigenicity)
• Inactivation of pathogenic bacteria

  1. Heat treatment

  2. Treatment with formaldehyde or acetone

  3. Treatment with phenol or phenol and heat

  4. Treatment with propiolactone
• Attenuated viral vaccines


  Viral particles propagated in animal cell culture systems, often fertilized eggs or chick embryo tissue
• Attenuated viral vaccines


  • Mumps vaccine (live attenuated strains of Paramyxovirus parotitidis)
• Toxoid vaccines


  Toxins produced by pathogens (e.g. diphtheria, tetanus) that are inactivated by formaldehyde treatment
• Antigen-based vaccines


  Contain appropriate antigenic portions of the pathogen, usually surface polysaccharides
• Carbohydrate-based antigens are inherently less immunogenic than protein-based antigens, particularly in infants
• Conjugated vaccines


  Carbohydrate antigens chemically coupled to protein-based antigens to improve immunogenicity
• Conjugated vaccines


  • Haemophilus capsular polysaccharide conjugated to diphtheria toxoid, tetanus toxoid, or Neisseria meningitidis outer membrane protein
• Subunit vaccines


  Polypeptides normally present on the surface of pathogens, produced using recombinant DNA technology in non-pathogenic hosts
• Advantages of subunit vaccines

  • Clinically safe product
  • Unlimited supply
  • Consistent, defined product less likely to cause side effects
• First subunit vaccine


  • Hepatitis B surface antigen (rHBsAg)
• Peptide vaccines


  Synthetic peptides identical in sequence to short stretches of pathogen-derived polypeptide antigens
• Peptide vaccines generally require coupling to a carrier to elicit an immune response
• Peptide vaccine carriers


  • Tetanus toxoid, bovine serum albumin
• HIV


  Lentivirus subfamily of retroviruses, spherical enveloped particle containing RNA, binds to CD4 receptor on susceptible cells
• HIV infection


  1. Initial viral replication and high-level viraemia

  2. Decline in viral load and latent phase

  3. Depletion of CD4+ T-cells and development of AIDS
• Challenges for HIV vaccine development

  • Extensive genetic variation of HIV, particularly in env gene
  • HIV directly attacks the immune system by infecting and destroying T-helper cells
  • Immune responses ultimately fail to destroy the virus
  • Latent proviral DNA in cells is undetectable by the immune system
• S phase


  Continuous synthesis and destruction of viral particles, accompanied by high turnover rate of (CD4_) T-helper lymphocytes
• Levels of T-lymphocytes decline with time


  Antibody levels specific for viral proteins decline
• Circulating viral load increases

  Depletion of T-helper cells compromises general immune function
• Immune system fails


  Classical symptoms of AIDS-related complex (ARC) and full-blown AIDS begin to develop
• Difficulties in HIV vaccine development

  • HIV displays extensive genetic variation even within a single individual
  • HIV infects and destroys T-helper lymphocytes, an essential component of the immune system
  • Infected individuals display a wide range of antiviral immunological responses that ultimately fail to destroy the virus
  • After initial virulence subsides, large numbers of cells harbour unexpressed proviral DNA which the immune system cannot identify
  • Infection may be spread via direct transmission of infected cells harboring the proviral DNA, not just free viral particles
• Approaches being assessed for developing an effective AIDS vaccine


  • No safe attenuated form of the virus has been recognized
  • Inactivated viral particles as effective vaccines, but fears of accidental transmission of disease
  • Live vectors to stimulate T-cell and B-cell immune response, including envelope and core antigens expressed in recombinant viral systems
  • Modified vaccinia Ankara, canarypox and fowlpox viruses as vectors
  • Vaccination schedule variation of vector-based primary dose followed by subunit-based booster
• Induction of effective (broadly neutralizing) antibodies remains a challenge as the regions of HIV envelope proteins that are most highly conserved seem to be shielded from antibody access
• Large-scale clinical trials are likely to be the only way by which any HIV vaccine may be properly assessed
• A greater understanding of the immunological or other factors that delay onset of ARC/full-blown AIDS in some infected individuals may aid in the design of more effective vaccines
• Factors that cause development of an HIV vaccine to differ from other classic vaccines

  • Classic vaccines mimic natural immunity against reinfection generally seen in individuals recovered from infection, but there are almost no recovered AIDS patients
  • Most vaccines protect against disease, not against infection, while HIV infection may remain latent for long periods before causing AIDS
  • Most effective vaccines are whole-killed or live-attenuated organisms, but killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues
  • Most vaccines protect against infections that are infrequently encountered, while HIV may be encountered daily by individuals at high risk
  • Most vaccines protect against infections through mucosal surfaces of the respiratory or gastrointestinal tract, while the great majority of HIV infection is through the genital tract
• Animal model for HIV vaccine research

  • Monkeys can be infected with SIV or the chimeric SHIV, but the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled due to the great difficulty in stimulating antibodies that neutralize heterologous primary HIV isolates
  • Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge, but in clinical trials, individuals became infected after later exposure to HIV-1
  • There are some differences between SIV and HIV that may introduce challenges in the use of an animal model
• Cancer vaccines


  Designed to boost the body's natural ability to protect itself, through the immune system, from dangers posed by damaged or abnormal cells such as cancer cells
• Types of cancer vaccines approved by the FDA

  • Vaccines against the hepatitis B virus, which can cause liver cancer
  • Vaccines against human papillomavirus types 16 and 18, which are responsible for about 70 percent of cervical cancer cases
  • One cancer treatment vaccine for certain men with metastatic prostate cancer
• How vaccines stimulate the immune system

  1. White blood cells, or leukocytes, play the main role

  2. B cells make antibodies that bind to and help destroy foreign invaders or abnormal cells

  3. Cytotoxic T cells, or killer T cells, kill infected or abnormal cells

  4. Helper T cells and dendritic cells help activate killer T cells and enable them to recognize specific threats
• Antigen


  A substance that stimulates a specific immune response, can be a protein or other molecule found on the surface of or inside a cell
• Self antigens


  Identify normal cells as "self" and tell the immune system not to attack them