Effective Vaccine Mechanisms and Requirements

Effective Vaccine Mechanisms

• An effective vaccine requires the presence of pre-existing antibodies upon exposure for protective immunity against microbes. For example, pre-existing antibodies against bacterial exotoxins are necessary for protection against the disease.
• Immune responses produce antibodies targeting multiple pathogen epitopes, but only a subset provides protection.
• Early vaccination against respiratory syncytial virus (RSV) elicited T-cell responses, leading to inflammation but no neutralizing antibodies and pathologic effects without protection.

Vaccine Requirements

• Effective vaccines induce:
  • Antibody generation
  • T-cell targeting of correct pathogen epitopes
• Vaccine constraints:
  • Safety: Must be safe for large-scale administration with minimal infections.
  • Protection: Must provide protective immunity to the majority.
  • Long-term effects: Protection should last years.
  • Affordability: The vaccine should be cost-effective for broad population use.

Conjugate Vaccines

• Conjugate vaccines are effective against bacteria with polysaccharide antigens (e.g., Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae).
• The polysaccharide coating on these antigens hinders recognition and immune response in children.
• Effective defense: Antibody opsonization of the polysaccharide coat.
• Vaccination aims to produce antibodies against the bacterial capsule polysaccharide.
• Polysaccharide harvesting from bacterial growth mediums.
• T-cell-independent antigens are used for vaccines.
• Problem: Children under 2 cannot effectively produce T-cell-independent antibody responses and therefore cannot be effectively vaccinated with polysaccharide vaccines.
• Solution: Chemically conjugating bacterial polysaccharides to protein vaccines.
• Peptides can recognize specific T cells, converting T-cell-independent responses into T-cell-dependent anti-polysaccharide antibody responses.

Adjuvants

• Adjuvants enhance antigen immunogenicity.
• Example: Tetanus toxoid is not immunogenic, but tetanus vaccines include aluminum salts to bind and stimulate antibody responses selectively.
• Other examples include cells and parts of bacteria.
• Freund's complete adjuvant: In vivo use to modify antibody responses. Contains water-oil emulsion and killed mycobacteria.
• Muramyl dipeptide (a complex glycolipid): From mycobacterial cell walls, contains adjuvant activity similar to whole killed mycobacteria.
• Mechanism of action: Adjuvants act on antigen-presenting cells (APCs), primarily dendritic cells (DCs).
• DCs, detecting pathogens, take up antigens via phagocytosis, migrate to lymphoid tissue, and present antigens to lymphocytes.

DC Activation

• DCs detect pathogens in two ways:
  • Direct: Activation by pathogen receptors (e.g., complement, Toll-like receptors).
  • Indirect: Activation by inflammatory cytokines (e.g., GM-CSF) triggered by infection.
• Activated DCs secrete cytokines and express co-stimulatory molecules, activating and differentiating antigen-specific T cells.
• This mimics an active infection, stimulating an immune response.

Synthetic Peptides for Vaccines

• Synthetic peptides of protective antigens can elicit protective immunity.
• T-cell epitopes: Peptides from antigens, recognized by T-cell receptors (TCRs) bound to MHC molecules on APCs.
• Immunogenicity depends on the associated MHC molecules' polymorphic variants.
• Vaccine development techniques:
  • Systemic synthesis of overlapping peptides from immunogenic proteins, testing each for protective immunity.
  • Reverse immunogenetics: Examining populations for MHC molecule variants associated with resistance to a disease (e.g., HLA-B53 variant resistant to cerebral malaria).

Synthetic Peptide Limitations & Solutions

• Limitations:
  • Synthetic malaria peptides may not be immunogenic in individuals lacking HLA-B53.
  • MHC high polymorphism necessitates identifying proactive T-cell epitope panels for vaccine construction.
  • Peptides are not strongly immunogenic.
  • Difficult to generate MHC class I-specific responses by in vivo immunization with peptides.
• Solutions:
  • Genetically engineering peptide integration into a carrier protein (e.g., viral factor) for better processing.
  • Using ISCOMs (immune stimulatory complexes): Lipid carriers as adjuvants with minimal toxicity. Deliver peptides to cell cytoplasm, activating MHC I-restricted T-cell responses.
  • Lipid micelles fuse with cell membranes, delivering peptides to the APC cytosol and binding to MHC I molecules.

Live-Attenuated Viral Vaccines

• Basic information: Use inactivated or live-attenuated viruses, with treated viruses unable to replicate.
• Live-attenuated viral vaccines are more potent, eliciting more effector CD8 T cells.
• Inactivated vaccines cannot produce proteins in the cytosol. Peptides from viral antigens cannot be presented by MHC class I, hindering CD8 T-cell production.
• Examples: Polio, measles, mumps, rubella, and COVID-19.
• Risks: Risk of immune-deficient recipients treating vaccine as virulent. Opportunistic and virulent behaviors in compromised hosts.
• Risks of live-attenuated virus use in immunodeficient infants: Increased disease possibility due to uncontrolled virus replication and chance of mutation.

Recombinant DNA Technology and Bacterial Vaccines

• Isolating and in vitro mutating specific viral genes, replacing wild-type genes in the virus. Generates reconstituted virus genomes.
• Live-attenuated bacterial vaccines (e.g., Salmonella typhi):
  • Mutation of wild-type bacteria (e.g., using nitrosoguanidine) generates new strains.
  • Defective enzyme: Blocks lipopolysaccharide synthesis.
  • Recent approach: Targets genes coding for enzymes responsible for pathogenicity.
  • Creating auxotrophic organisms: Mutated bacteria grow poorly in the gut without external nutrient supply, but still function as vaccines to induce effective immune response.

Route of Vaccination

• Injection (common) is often less effective and less popular.
• Development of mucosal vaccine delivery (oral, nasal inhalation) to better mimic natural pathogen entry.

DNA Vaccinations

• Injecting DNA encoding microbial antigens and human cytokines into muscles.
• Use nonreplicating bacterial plasmids encoding proteins for gene therapy.

This quiz explores the essential mechanisms and requirements for effective vaccines. It covers topics such as the importance of pre-existing antibodies, T-cell responses, and the constraints of safety, protection, long-term effects, and affordability in vaccine development. Test your understanding of how vaccines achieve protective immunity against various pathogens.