Vaccines and Vaccination

Vaccines and Vaccination • • • • • • • Successful Human Vaccines • Must choose protective antigen and appropriate delivery Chapter 21 Components of a vaccine Selection of antigens to be used in a vaccine Immune effector mechanisms activated by vaccines Practical consideration for vaccine development and use Examples of successful vaccines Factors that prevent development of vaccines against certain microorganisms • Current vaccines in human use: – Purified and protein-conjugated capsular polysaccharides of bacteria – Inactivated toxins (toxoids) – Recombinant protein antigens (hep B) – Inactivated bacterial cells and viral particles (Killed) – Attenuated bacterial cells and viral particles (Live) – Immune serum (rabies) 1 Successful Human Vaccines 2 Inactivated Vaccines • Patron Saint of Killed Vaccines: • Jonas Salk • Licensed and Routine – Salk Polio vaccine – Influenza vaccine • Made killed flu vaccine with Thomas Francis Jr. • Special Risk Groups • Proved polio vaccine worked in massive 1954 field trial – Hepatitis A vaccine – Rabies – Japanese Encephalitis 3 4 1 Inactivated Vaccines Inactivated Vaccines Pros and Cons • • • • • • • Sufficient humoral immunity if boosters given No mutation or reversion Can be used with immunodeficient persons Can induce CD4 responses Poor at inducing CD8 responses Need to be given multiple times Safety concerns 5 Attenuated Vaccines 6 Attenuated Vaccines • Licensed and Routine – – – – – MMR Varicella Rotavirus (Sabin Polio vaccine) (Smallpox) • Special Risk Groups Only – Adenovirus – Yellow Fever 7 8 2 Genetic Attenuation Process Classic Attenuation Process from, Principles of Virology, 2nd edition 9 10 from, Principles of Virology, 2nd edition Attenuated Vaccine Pros and Cons Successful Human Vaccines? • Must choose protective antigen and appropriate delivery • • • • Local immunity is possible No boosters are necessary Immunity is rapid May lead to elimination of wild type virus in the field • Can induce T and B cell responses • Safety concerns • Experimental vaccines: • Tried only in animals or in early studies in humans – – – – – – – – – Shedding – Reversion – Induction of atypical infections 11 Anti-idiotype (Figure 8.7) Peptide-based DNA-based Antigen presentation from infected or transfected APCs Live recombinant attenuated viruses Recombinant bacterial cells expressing vaccine antigens for other organisms Inclusion of adjuvants Inclusion of purified cytokines or cytokine genes 12 3 Anti-idiotype Vaccines Anti-idiotype Vaccines • Idiotypic network theory • The variable region of an antibody molecule represents a completely novel molecular epitope • Host animal cannot have encountered previously • Cannot be tolerant or immune • The antibody will elicit an anti-idiotype antibody • Specific for the first antibody’s antigen binding site • It should mimic the three dimensional shape of the original antigen • Antibody 2 can be used in place of antigen as a vaccine • Use one or more antibodies in the vaccine • Mouse monoclonal Abs may induce anti-mouse response • Human monoclonal Abs may induce autoimmune reactions 13 Peptide-based Vaccines 14 Peptide-based Vaccines • Synthetic or recombinant peptides mimicking known protective B or T cell epitopes on pathogens could be delivered safely • Poor immunogenicity without adjuvants • Can couple peptide to immunogenic support, to immunostimulating complexes (ISCOMS), or to a carrier • Must first identify the peptide epitopes • Universally immunogenic peptides to T cells • Usually not good for B cell epitopes and Ab production is low 15 16 4 Peptide-based Vaccines Peptide-based Vaccines Pros and Cons • Can induce antibody responses • Can be taken up, degraded, and presented by MHC Class II if coupled to a carrier • Overloading with peptide can force presentation by MHC class I (cross priming) • Expensive to make • Escape is common • Responses often weak and short lived from, Principles of Virology, 2nd edition 17 DNA-based Vaccines 18 DNA-based Vaccines • The DNA is a recombinant bacterial plasmid with the gene for the microbial antigen is expressed by a strong promoter • DNA is injected and taken up into cells • Transcription and translation occurs • Cells present these intracellular recombinant microbial antigens on MHC class 1 19 from, Principles of Virology, 2nd edition 20 5 DNA-based Vaccines DNA-based Vaccines 21 DNA-based Vaccines Pros and Cons • • • • • • from, Principles of Virology, 2nd edition 22 Adjuvants • substances that when co-introduced with antigen enhance the immunogenicity of that antigen Inexpensive and do not need refrigeration Can incorporate multiple genes in one plasmid Made de novo in cell Have been successful in animal models for HIV, Ebola, CMV Low dose seems to induce long lived immunity Do not necessarily need adjuvants • Antigen has to be protein in nature • Insertional mutagenesis a possible concern - recombination into genome • Anti-DNA antibodies • Immune tolerance from, Principles of Virology, 2nd edition 23 24 6 Adjuvant Mechanisms of Action Pathways of Adjuvant Activation 25 26 Antigen Production in Infected or Transfected Mammalian Cells Adjuvants • Expression of protective antigen in mammalian APCs • APCs will present protective antigen • Donor collected APCs can be transfected and then reintroduced into original donor • Or expose APCs to microbial antigens, ingest, process, and present on MHC, then reintroduce into original donor • Also testing for use with tumor antigen presentation 27 28 7 Antigen Production in Infected or Transfected Mammalian Cells Live Recombinant Attenuated Viruses • Creation of attenuated strains of bacteria or virus that can be used to deliver antigens from another pathogen • Pathogenic antigen expression from recombinant DNA inserted into attenuated bacterial or viral genome • Attenuated strains are usually genetically modified so that the virulence genes are removed while the genes necessary for replication and packaging are intact 29 • Therefore, it can infect, replicate, package and reinfect new cells, but not cause disease. 30 Live Recombinant Attenuated Viruses Live Recombinant Attenuated Viruses X 31 X from, Principles of Virology, 2nd edition 32 8 Live Recombinant Attenuated Viruses Pros and Cons Reverse Vaccinology • Can be made from viral vectors that can infect but cannot replicate in human cells • Can achieve high titers • Can deliver via mucosal routes • Host usually immunized against viral vector along with antigen • Cannot be used in immunocompromised hosts • Immunity often weak • Computer prediction of surface antigens capable of eliciting an immune response by using the genome sequence of the pathogen • Use recombinant DNA of these identified genes to make a vaccine through DNA vaccines, transfected cells, or live, recomb vaccine • Large number of recombinant proteins can be made quickly and easily • Expressed and evaluated as vaccine candidate by using in vitro serology or CMI experiments as for live, recomb Vaccines 33 34 Reverse Vaccinology Candidate Testing Reverse Vaccinology X 35 X from, Principles of Virology, 2nd edition 36 9 Routes of Vaccination • Must be introduced to a site where vaccine antigens will encounter immune effector cells • Usually intramuscular • Can form precipitates that persist and are very slowly dissolved and reabsorbed • Increases the time of immune effector cell encounter • Muscle tissue is filled with DCs - great APCs • Routinely survey muscle tissue for antigens and transport those to the lymph nodes to activate T cells • Readily accessible -large muscles like deltoid, quadracept, and gluteous maximus 37 10