Vaccine Immunology

-Edward Jenner (18thcentury) -Dairy maids infected with cowpox (mild disease) – resistant to smallpox -1796 –inoculated 8 year old boy with fluid from dairy maid cowpox pustule -6 weeks later – exposed boy to smallpox- No symptoms developed Coined term “vaccine” –from “vaca” (Latin for cow) Initially criticised but subsequently vaccine widely adopted

Smallpox- Virus biology ●No animal reservoir ●Lifelong immunity ●Sub-clinical cases rare ●Infectivity does not precede overt symptoms ●One serotype ●Good vaccine (vaccinia virus) -Global commitment ●Governments ●WHO (1965) -Steps along the way ●Last case in UK (1930’s) ●Last case in US (1940’s) ●26 Oct. 1977 last case worldwide (Somalia)

-Induce immunity in individual hosts that… ●Prevents or eliminates viral disease ●Causes no or minimal associated morbidity or mortality. -Induce “herd” immunity that … ●Greatly restricts virus circulation in a given community ●Protects vulnerable members of the community for whom the vaccine is proscribed -Virus eradication

Live attenuated- MMR, polio, influenza, smallpox, rotavirus, yellow fever, varicella zoster, adenovirus- must be kept COLD (cold chain) Inactivated/ whole- polio, influenze, hep A, japanese encephalitis, rabies Inactivated/ split- influenza Subunit- Hep A/B, influenza, HPV, varicella zoster

-Cell culture adaptation ●Repeated passage in non-natural cells ●Reduced ability to replicate in natural host -Sub-clinical infection -Induction of protective immune responses ●Usually long lasting -Complicating risk ●Reconversion to wild-type ●Contaminating infectious agents in cell culture

Inactivated vaccines - split • Virus grown in cell culture or eggs • Lyse culture • Extract virus vaccine antigen • Purify vaccine antigen • No possibility of infection • Duration of immunity less than for live attenuated vaccines

-Recombinant subunit vaccines ●Antigen gene cloned into expression vector ●Antigen expression in suitable cells -Eukaryotic (diploid) -Bacteria -Yeast ●Antigen purification -Vaccine formulation ●Adjuvants?

Function ●Greatly enhances immune responses to antigens -Licensed adjuvants ●Aluminium hydroxide ●Aluminium phosphate ●MP-54 -Adjuvantsin research ●ISCOMs (immune stimulating complexes) ●Oil/water emulsions -Freund’s complete and incomplete -TiterMax -MontanideISA ●Toll-like receptor agonists

-Vaccine antigen introduced to body ●Mucosal ●Parenteral -Antigen taken up by antigen presenting cells (APCs) -APCs present antigen to B and T cells in correct conformation -Clonal expansion of epitope-specific memory B and T cells -Accelerated response to virus upon infection -Protection from disease ●Neutralising antibodies ●Cytotoxic T cells

-Vaccine antigen introduced to body ●Mucosal- nose, lungs, vagina etc ●Parenteral- injection -Antigen taken up by antigen presenting cells (APCs) -APCs present antigen to B and T cells in correct conformation -Clonal expansion of epitope-specific memory B and T cells -Accelerated response to virus upon infection -Protection from disease ●Neutralising antibodies ●Cytotoxic T cells

Linear peptides ●Contiguous chain of amino acids within a protein ●Antibodies can recognise primary structures -Conformational peptides ●Non-contiguous chains of amino acids within a protein ●Antibody recognition dependent of tertiary folding of protein

-T helper (Th1 and Th2) cells (CD4+) ●Linear peptides ●Presented by MHC class II -Cytotoxic T (Tc) cells (CD8+) ●Linear peptides ●Presented by MHC class I -T regulatory (Treg) cells (CD4+CD25+)

Vaccines • Healthy individualss • Mass administration • Disease prevention • Low risk tolerance • Low cost Therapeutics- • Sick individuals • Targeted administration • Disease treatment • High risk tolerance • High cost

• Injection site hypersensitivity • Injection site oedema • Rash • Myalgia • Fever • Headache • clinical example- primary vesticulopustular response is related to the vaccinia virus vaccination

• Injection site hypersensitivity • Injection site oedema • Rash • Myalgia • Fever • Headache Serious adverse events, albeit rare, include life threatening illness and death(temporal but not causal association in most cases) • clinical example- primary vesticulopustular response is related to the vaccinia virus vaccination ezcema vaccinatum can occur in smallpox to those suffering from eczema

Pre-clinical ●Vaccine construction and formulation ●Animal models (immunogenicity/protective efficacy) Phase I clinical ●1st in human ●small numbers of healthy volunteers, e.g., <100 ●Safety; safety; safety ●Immunogenicity (antibody and/or T cell responses) Phase II clinical ●Larger numbers of healthy volunteers (e.g., 100-1000) ●Safety, safety, safety ●Dose ranging -Immunogenicity (antibody and/or T cell responses) Phase III clinical ●Very large numbers (e.g., >10,000) in target populations ●Safety, safety, safety ●Efficacy ●Immunogenicity -Registration and deployment if phase III is successful. Phase IV ●Post-marketing monitoring of safety/adverse events and efficacy