Vaccine Immunology

Question 1

Where did the first vaccine come from?

Answer 1

-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

Question 2

How is global eradication of viruses ( smallpox) possible?

Answer 2

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)

Question 3

What are the goals of vaccination against viruses?

Answer 3

-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

Question 4

Current human viral vaccines

Answer 4

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

Question 5

What is virus attenuation? What are the benefits/ risks?

Answer 5

-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

Question 6

What are split inactivated vaccines?

Answer 6

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

Question 7

What are subunit vaccines?

Answer 7

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

-Vaccine formulation
●Adjuvants?

Question 8

What are adjuvants?

Answer 8

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

Question 9

How do vaccines work?

Answer 9

-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

Question 10

How do vaccines work?

Answer 10

-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

Question 11

What are B-Epitopes?

Answer 11

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

Question 12

What are the T cell epitopes?

Answer 12

-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+)

Question 13

What is the difference between viral vaccines and therapeutics?

Answer 13

Vaccines

• Healthy individualss
• Mass administration
• Disease prevention
• Low risk tolerance
• Low cost

Therapeutics-

• Sick individuals
• Targeted administration
• Disease treatment
• High risk tolerance
• High cost

Question 14

What are the most common vaccine adverse effects?

Answer 14

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

Question 15

What are the most common/ serious vaccine adverse effects?

Answer 15

• 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

Question 16

Vaccine research and development

Answer 16

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