4.11 - Vaccination

Question 1

What is a vaccine?

Answer 1

• something that stimulates the immune system without causing serious harm or side effects
• the aim of the immunisation is to provoke immunological memory to protect individuals against a particular pathogen if they later encounter it

Question 2

What are the features of the ideal vaccine?

Answer 2

• completely safe
• easy to administer
• single dose, needle-free (higher chance people take)
• cheap
• stable (so can move between site of manufacture and site of administration properly)
• active against all variants
• lifelong protection

Question 3

How do vaccines stop infection?

Answer 3

• vaccination is the generation of immune memory in the absence of harmful infection

1. prevention of entry of pathogen into cells through antibodies
   - bind to virus and neutralise it to stop it from ever infecting cells in the first place
   - opsonisation of the virus that leads to macrophages engulfing it - driven by Fc on AB
2. boosting immune response - antigens in vaccine will be recognised by CD4 T cells in context of MHC II –> these cells boost immune response e.g. train CD8 T cells to kill infected cells, working with B cells to make antibodies
3. enables killing of infected cells

Question 4

What kind of intervention are vaccines?

Answer 4

Population, not individual

Question 5

What is R0?

Answer 5

• basic reproduction number
• the number of cases one case generates on average over the course of their infectious period
• if R0 < 1 the infection will die out in the long run
• if R0 > 1 the infection will be able to spread in a population
• R0 can change - depends on population behaviour

Question 6

How do vaccines reduce R0?

Answer 6

• more vaccinated people in the population
• less chance of an infected person meeting a susceptible unvaccinated individual to pass on the virus –> decreases R0
• herd immunity - when a large percentage of the population is vaccinated, it makes it harder for the virus to spread to susceptible individuals as they are protected indirectly by vaccinated individuals

Question 7

What is in a vaccine?

Answer 7

• antigen - in one of these forms:
  1. inactivated protein e.g. tetanus toxoid
  2. recombinant protein e.g. hep B
  3. live attenuated pathogen e.g. polio / BCG
  4. dead pathogen e.g. split flu vaccine
  5. carbohydrate e.g. S. pneumoniae
• adjuvant - normally alum, sometimes something proprietary
• stabilising stuff (buffers - PBS)
• water

Question 8

What are the five classes of vaccine used in the UK?

Answer 8

• inactivated toxoid vaccine
• recombinant protein vaccine
• conjugate vaccine
• dead pathogen vaccine
• live attenuated vaccine

Question 9

What is an inactivated toxoid vaccine?

Answer 9

• e.g. tetanus toxoid
• vaccine has a chemically inactivated form of toxin - no longer toxic
• vaccine induces antibody which blocks the toxin from binding to cells (nerves in tetanus case)
• advantages: cheap, well characterised, safe, in use for many decades
• disadvantages: requires good understanding of biology of infection, not all organisms encode toxins

Question 10

What is a recombinant protein vaccine?

Answer 10

• e.g. hep B surface antigen
• recombinant protein from pathogen
• the gene from one organism is isolated and moved into a different organism –> protein is mass produced
• induces classic neutralising antibodies that combine the protein and stop the virus getting into cells
• advantages: pure, safe
• disadvantages: relatively expensive, not very immunogenic, has not proved to be the answer to all pathogens (protein structure affects this)

Question 11

How does protein structure affect recombinant protein vaccine?

Answer 11

• e.g. RSV has a spike protein on its surface with two different forms - prefusion and postfusion (after it has bound to cell - this is how the virus injects its contents into cell)
• vaccines are made for the prefusion structure but the proteins in the vaccine lapse into the second structure, which if injected, will make the wrong-shaped antibodies so the body won’t be able to see the virus properly so you don’t get immunised against the virus
• this issue happens with many viruses and can be solved but you need to be aware of it

Question 12

What is the issue when it comes to bacteria with inactivated toxoid vaccines and recombinant protein vaccines?

Answer 12

• work well for protein antigens but bacteria often have a polysaccharide capsule surrounding them, not protein
• this is not good at inducing a B cell response (it is a T independent antigen)
• alternative approaches needed

Question 13

What is a conjugate vaccine?

Answer 13

• e.g. S. pneumoniae
• vaccine is a polysaccharide coat component that is coupled to an immunogenic ‘carrier’ protein i.e. a sugar molecule stuck to a protein molecule, which B cell recognises
• protein enlists CD4 help to boost B cell response to the polysaccharide
• DC engulfs the whole antigen and presents the protein part onto MHC II - a B cell takes up the polysaccharide
• TfH primed by DC through interacting with the DC’s MHC II presented peptide and then goes to the matching B cell and boosts it
• B cells produce anti-sugar antibodies
• advantages: improves immunogenicity, highly effective at controlling bacterial infection
• disadvantages: cost, carrier protein interference, very strain specific, polysaccharide alone is poorly immunogenic

Question 14

What is a dead pathogen vaccine?

Answer 14

• e.g. influenza split vaccine
• rather than using a single antigen, it is a chemically killed pathogen
• this induces antibody and T cell responses
• advantages: leaves antigenic components intact and in context of other antigen, immunogenic because of the inclusion of other components, cheap, quick
• disadvantages: fixing/killing can alter chemical structure of antigen, quite ‘dirty’, requires the capacity to grow the pathogen, vaccine induced pathogenicity a risk, risk of contamination with live pathogen

Question 15

What is a live attenuated vaccine?

Answer 15

• e.g. BCG, live attenuated influenza vaccine, OPV
• pathogens are attenuated by serial passage - leads to a loss of virulence factors = virus looks the same but cannot cause damage
• because they replicate in situ, they trigger the innate response and boost the immune response
• advantages: induce a strong immune response, can induce a local immune response in the site where infection might occur
• disadvantages: can revert to virulence, can infect immunocompromised, attenuation may lose key antigens, can be competed out by other infections

Question 16

What is an adjuvant?

Answer 16

• they are substances used in combination with a specific antigen that produce a more robust immune response than the antigen alone
• induce ‘danger signals’ that activate dendritic cells to present antigen to T cells
• part of licensing the response
• alum stores the vaccine at site of injection which enables the DCs to see more of it = inflammation

Question 17

Why do we need new vaccines?

Answer 17

• changing (aging) demographics - some infections aren’t severe in young adults but are for elderly
• changing environment (dengue / other arboviruses)
• new diseases (COVID-19)
• old diseases we still can’t fix (HIV/TB/malaria)
• antibiotic resistance (MRSA, all bacteria)

Question 18

What are some barriers to future vaccine development?

Answer 18

• scientific challenges
• injection safety - don’t want to spread secondary infection by sharing needles
• logistics / cold chain - easy for high income countries to get vaccination but harder for LICs
• development issues - time (15 years), cost of vaccine development high, cost of the product
• public expectation of risk-free vaccines

Question 19

What kinds of pathogens make it harder for traditional vaccines to combat?

Answer 19

• traditional vaccines effecting at eliciting humoral responses and are protective against invariant pathogens
• however, the more diversity in the pathogen, the less protective - many circulating viruses and classic immune memory only recognises one of these strains and therefore vaccine antigens need to cover all the variety
• serotype - one viral strain recognised by one family of antibodies

Question 20

What are the phases of a clinical trial?

Answer 20

• preclinical - lab, hypothesis testing, vaccine developed
• drug approved for testing in humans
• phase 1 - 20-80
• phase 2 - 100-300
• phase 3 - 1000-3000
• drug submitted for FDA approval
• FDA review to confirm safety and effectiveness
• drug approved
• phase 4 - 1000+

Question 21

What are the steps and organisations involved in introducing new vaccines in the UK?

Answer 21

• recommendations for vaccine policy - Joint Committee on Vaccination and Immunisation (JCVI)
• vaccine policy decisions - department of health (DH)
• licensing of vaccine - Medicines and Healthcare products Regulatory Agency (MHRA)
• purchase of vaccine - DH from pharmaceutical companies
• control of vaccine (including batch release) - National Institute for Biological Standards and Control (NIBSC)
• post license assessment and changes - PHE/JCVI (epidemiology, assessment, trials)

Question 22

What are the considerations for scheduling vaccines?

Answer 22

• aim
• need
• scheduling with other vaccines
• availability
• cost
• population accessibility
• cultural attitudes and practices
• facilities available for delivery