Vaccine induced immunity

1. Vaccine induced immunity

2. E. Jenner Origins of vaccination Edward Jenner - milk maids did not develop smallpox 1790s - vaccinated 8yr old boy with cowpox - protected from smallpox challenge E. Jenner vaccination - vaccinus (Latin) - relating to cows

3. How do vaccines work? • Vaccination works by mimicking natural infection • Use of NON PATHOGENIC (usually) components which present virus antigen(s) to host immune system • To produce a rapid (anamnestic) protective immune response if the pathogenic organism is later encountered

4. Immune-protection occurs in nature • Mother – maternally derived antibody (MDA) to young • Exposure to apathogenic strains protecting against clinical disease on exposure to pathogenic strains

5. natural infection Inoculation or application to mucosal surface RESISTANCE TO INFECTION AND/OR CLINICAL DISEASE * Successful vaccination Primes host immune system so that on exposure to field strain of virus, virus-specific immune response occurs Vaccine Ag(s) Induction of sterilising immunity Induction of other immune responses which clear pathogen * many viral vaccines reduce but do not prevent virus shedding NO CLINICAL DISEASE

6. Vaccine requirements: the “ideal” vaccine Aim : To generate an immune response that protects all vaccinated animals against challenge by the infectious agent under natural conditions of exposure • safe • induces protective immunity in [all] vaccinated animals • evokes long lasting immunity • commercial considerations - cost, cold chain requirement, compatibility with other vaccine components, marker vaccine?, updates required?

7. Types of vaccine • A. Traditional • Inactivated (killed) • Subunit • Live (attenuated/modified live) • B. New generation • ISCOMS (subunit) • Recombinant (live) vaccines • Recombinant vector vaccines • DNA vaccines

8. Non-living vaccines:subunit/killed/inactivated viral components administered in non-replicating form - chemically inactivated virus or viral subunits Whole inactivated virions feline leukaemia virus - Fevaxyn Newcastle disease virus - Nobilis Newcavac inactivation e.g. formalin Infectious virus Non-infectious virus Virion subunits feline herpesvirus :feliniffa RC

9. gene encoding antigen cloned into expression vector (e.g bacterial plasmid) antigen expressed in bacterial or eukaryotic cells promoter protein purified viral protein preparation antigen adjuvant Example : FeLV vaccine ‘Leucogen’ - purified FeLV envelope antigen p45 produced in E.coli subunit vaccine Genetically engineered subunit vaccines

10. Inactivated virus or DNA vaccines Subunit vaccines Envelope glycoprotein gp120 gp41 Matrix Capsid Monomeric envelope glycoprotein Epitopes non-conformational/linear All viral structural proteins Multimeric Env Epitopes in native conformation

11. Non-attenuated virus Live, virulent (timing/route) Orf – Scabivax Forte Natural avirulent Herpes virus of turkeys for MDV - Poulvac MD Traditional: Live viral vaccines • vaccine virus replicates within vaccinated animal • antibody and cell-mediated immune response

12. serial passage cell culture/eggs/different host (10s-100s times) selection of virus mutants adapted to growth in culture - reduced virulence in natural host Traditional: Live viral vaccines Modified live (attenuated) Modified live feline calicivirus, FHV, FPV Katavac Temperature sensitive BHV-1 Tracherine How are they attenuated? Problem!? genetic changes not characterised

13. Traditional viral vaccinesTypes of antigen + delivery system virion surface antigens (Ag) internal Ag Ag produced during infection Inactivated/killed vaccines - do not replicate in host live vaccines - replicate in host 1. Difference : which antigens presented to host immune system

14. replication endosome proteasome ER Antigen presentationGeneration of cell mediated immunity Live vaccine Subunit/killed vaccine APC: Macrophage/DC APC Th (CD4+) MHC class II exogenous pathway infected cells  Tc (CD8+) MHC class I endogenous pathway 2. Difference: how antigens presented to host immune system

15. Adjuvants • potentiate the immune response to killed vaccines • vitamins, aluminium salts, bacterial products • prolonged antigen release • stimulation of immune cells (T, B lymphocytes) • increased surface area for antigen presentation • recruitment of antigen presenting cells integral component of inactivated/subunit vaccines - not generally required in live vaccines

16. Inactivated vs Live Vaccines • Live vaccines may produce good cell mediated and humoral (antibody) responses • Killed vaccines typically produce poor cellular responses but good humoral immunity • Mucosal responses require mucosal delivery of (live) vaccine

17. 2. Types of viral vaccine • A. Traditional • Inactivated (killed) • Subunit • Live (attenuated/modified live) • B. New generation • ISCOMS (subunit) • Recombinant (live) vaccines • Recombinant vector vaccines • DNA vaccines

18. equine influenza vaccine Equip F [Schering-Plough] 3 equine influenza strains : antigens encapsulated in ISCOMs Non-living vaccines : new generation ISCOM vaccines = immunostimulating complex Can generate CMI cage-like structure : Quillaja saponins, cholesterol, phospholipids, antigen

19. Recombinant (live) vaccines Identify genes associated with pathogenicity and immunogenicity Using recombinant technology delete pathogenicity gene(s) to attenuate virus Assess 1) safety and 2) efficacy in target host Almost complete antigenic repertoire, known genetic mutation, reversion less likely

20. vaccination challenge attenuated :safe + protective vaccination challenge under-attenuated unsafe over-attenuated safe/ineffective • Getting the balance right!

21. Recombinant vector vaccines Gene(s) encoding antigen(s) of another pathogen(s) inserted into viral genome (vector) rabies G glycoprotein gene vaccinia vector genome (genetically attenuated) • rabies vaccine VRG - rabies G glycoprotein expressed in attenuated vaccinia (pox) virus • FeLV vaccine Eurifel - FeLV env/gag in canarypox vector • ProTeq Flu – Equine influenza HA gene in canarypox

22. Canarypox as vaccine vector Vector derived from pox lesion on canary Attenuated by 200x serial passage in chick embryo fibroblast “Kanapox” = licensed for vaccination of canaries in France Further purified = “ALVAC” Licensed: Equine influenza FeLV West Nile Virus (for use in horses) Rabies (for use in cats) Canine distemper (for use in dogs and ferrets) ALVAC does not replicate in mammalian cells. No requirement for adjuvant

23. Muscle Other cells Viral Proteins DNA vaccines promoter ori gene encoding vaccine immunogen pVACCINE Antibiotic Resistance? polyA signal Viral antigen made inside cells  MHC I/II

24. Non-living Vaccines: summary antigenicity may be altered by chemical inactivation or through production in non-host expression system • subunit vaccines - limited antigenic repertoire • presented mainly through exogenous route (MHCII) so poor stimulation of CMI • not amplified in host so dependent on administration of large vaccine dose (increased cost) • must be applied with adjuvants • >1 administration usually required • concerns : reaction to adjuvant

25. Live Vaccines: summary • antigenic repertoire : few key Ag (vector vaccines) – most • Ag (minus Ag encoded by deleted genes) • viral antigens synthesised in infected cells of host • presented through MHCI and MHCII • good CMI and antibody responses • amplified in host so low dose of antigen (virus) is sufficient • no adjuvant required • cheaper to produce large quantities • concerns : reversion to virulence, contamination, use in pregnancy/is animals, susceptibility to inactivation by MDA

26. DNA Vaccines: antigens • - limited antigenic repertoire (unless whole virus genome used) • - viral antigens synthesised in infected cells of host • - presented through exogenous (MHCII) and • endogenous routes (MHCI) • – stimulates humoral and cell-mediated immunity • - dose affected by method (efficacy) of administration • no adjuvant required?? (immunostimulatory sequences in plasmid) • relatively poor efficacy in large animals (great in mice!)