37. Immunisation Against Infectious Disease

Question 1

What are some challenges with developing vaccines?

Answer 1

• Vaccines are administered to healthy people -> Risk of causing disease
• Expensive to develop
• Difficult pathogens
• Difficult hosts -> Some vaccines must be given to the old and frail

Question 2

Who created the first vaccine? [EXTRA]

Answer 2

• Edward Jenner
• He created the first vaccine for smallpox, after he realised that people who had previously exposed to cowpox were now immune to smallpox

Question 3

Give two examples of diseases that can be treated using passive immunisation.

Answer 3

• Ebola
• Diphtheria
• Tetanus

Question 4

What is immunisation?

Answer 4

Using vaccines or antibody‐containing preparations to provide immune protection vs. specific diseases.

Question 5

What are the two main types of immunisation?

Answer 5

• Active (vaccination)
• Passive (e.g. provision of antibodies)

Question 6

What are the advantages and disadvantages of active immunisation?

Answer 6

Advantages:

• Long duration

Disadvantages:

• Lag before it is active
• May require multiple vaccinations

Question 7

What are the advantages and disadvantages of passive immunisation?

Answer 7

Advantages:

• Immediately active
• Effective for post‐exposure prophylaxis
• No need for fully functional immune system (e.g. use in immunocompromised hosts, young, elderley)

Disadvantages:

• No memory
• Short-lasting

Question 8

Describe passive immunisation and what it involves.

Answer 8

Passive immunisation involves intravenous immunoglobulins (IVIg), which is a mixture of antibodies that is administered intravenously. These can be in different forms:

• Mix of standard immunoglobulins from animal/human donors
  
  • Contains multiple different antibodies
  • Non-specific -> Effective against many vaccines
• Human hyperimmune serum (high titre)
  
  • Similar to the normal mix, but it is produced from plasma from donors with a high titre of antibodies to a specific pathogen
  • Specific -> Effective against a single pathogen

Question 9

Give two examples of diseases treated using passive immunisation. [IMPORTANT]

Answer 9

• Rabies
• Hepatitis B

These are conditions where rapid response is required, so the IV antibodies are useful.

Question 10

What are some good qualities for a vaccine to have?

Answer 10

• Safe/no adverse reactions
• Stimulates an effective and appropriate immune response
• Inexpensive
• Stable
• Easy to administer Salk vs. Sabin polio vaccines
• Manufacturing is simple and quality can be monitored
• Cost effective

Question 11

Draw a graph to show how the number of antibodies changes after first and second contact with the pathogen. Include both IgG and IgM immunoglobulins.

Answer 11

Question 12

What are the 4 main types of vaccine?

Answer 12

• Live attenuated vaccines
• Killed vaccines
• Subunit vaccines -> Toxoids, Other purified microbial targets, Polysaccharide-based
• Vectored vaccines (i.e. nucleic acids)

Question 13

Compare living and non-living vaccinations in terms of:

• Preparation
• Administration
• Adjuvant
• Safety
• Heat susceptibility
• Cost
• Duration of immunity
• Immune response

Answer 13

• Preparation
  
  • Living vaccine -> Attenuation
  • Non-living vaccine -> Inactivation
• Administration
  
  • Living -> May be natural route (e.g. oral) and single dose
  • Non-living -> Injection with multiple doses
• Adjuvant
  
  • Living -> Not required
  • Non-living -> Usually required
• Safety
  
  • Living -> May return to virulence
  • Non-living -> Less risk, just pain from injection
• Heat susceptibility (in tropical climate)
  
  • Living -> Requires cold chain
  • Non-living -> Satisfactory
• Cost
  
  • Living -> Low
  • Non-living -> High
• Duration of immunity
  
  • Living -> Years
  • Non-living -> May be long or short
• Immune response
  
  • Living -> IgG and IgA, with cell-mediated activation
  • Non-living -> IgG, with no cell-mediated activation

Question 14

What is a live attentuated vaccine and how does it work?

Answer 14

• Administration of either an attenuated form of the pathogen or an immunologically related organism
• The organism multiplies inside the human host and provides strong antigenic stimulation
• It provides prolonged immunity (years to life), often with single dose
• Vaccine often provides cell‐meditated immunity

Question 15

What are the advantages and disadvantages of live attenuated vaccines? [EXTRA]

Answer 15

Advantages:

• Lost-lasting immunity
• Easy to administer
• Inexpensive production
• Induces the cell-mediated response (as well as the humoral response)

Disadvantages:

• Can revert to virulent form
• More severe reactions than killed vaccines
• Cannot be given to immunocompromised patients
• Difficult to store due to heat lability

Question 16

Give three examples of diseases that can be vaccinated against using a live attenuated vaccine. [IMPORTANT]

Answer 16

• Using an attenuated virulent organism
  
  • Measles
  • Sabin polio vaccine
  • Rubella [EXTRA]
  • Yellow fever 17D vaccine [EXTRA]
• Using an immunologically related organism
  
  • Vaccinia (basically cowpox) used as a vaccine for smallpox

Question 17

How does a vaccine containing killed whole micro-organisms work?

Answer 17

• Does not multiply in human host
• Immune response depends on antigenic content of vaccine
• Induced reaction due to MAMPs/PAMPs
• Multiple doses of vaccine required with subsequent booster doses

Question 18

What are the advantages and disadvantages of killed whole-organism and subunit vaccines? [EXTRA]

Answer 18

Advantages:

• Safer (no possibility of vaccine-associated infection)

Disadvantages:

• Multiple doses of vaccine required with subsequent booster doses + Shorter lasting immunity
• Provides little cell‐mediated immunity
• Expensive

Question 19

Give examples of diseases that can be vaccinated against using a killed whole organism. [IMPORTANT]

Answer 19

• Cholera
• Pertussis
• Typhoid fever [EXTRA]

Question 20

What are subunit vaccines and how do they work?

Answer 20

• Vaccines that contain a fragment of the pathogen and elicits an appropriate immune response
• These fragments can be genetically engineered if required
• The fragment may be:
  
  • Protein -> Toxoid (inactivated toxin) or cell-surface antigen
  • Polysaccharide -> Found in capsule of some bacteria
  • Conjugate (of two antigens)

Question 21

Give an example of a pathogen, name its virulent components and how these can be used to create a subunit vaccine against it. [EXTRA?]

Answer 21

Bordella pertussis:

• Attachment
  
  • Fimbriae
  • Filamentous haemagglutinin (FHA)
  • Pertactin
• Toxins
  
  • Pertussis toxin
  • Tracheal cytotoxins

The vaccine is created using pertussis toxoid, FHA, pertactin and fimbrial antigens.

Question 22

Give some examples of diseases that can be vaccinated against using subunit vaccines. [IMPORTANT]

Answer 22

• Toxoid
  
  • Tetanus toxoid
  • Diphtheria toxoid
• Genetically engineered subunit
  
  • Influenza

Question 23

What are toxoids?

Answer 23

• Derivatives of bacterial exotoxins
• Rendered non‐toxic by treatment with chemicals or by genetic engineering but remain immunogenic
• They are used in subunit vaccines

Question 24

How often must tetanus boosters be given?

Answer 24

Every 10 years

Question 25

Describe the subunit in the influenza subunit vaccine.

Answer 25

It is a genetically engineered subunit from HBV and HPV.

Question 26

What are conjugate vaccines and how do they work?

Answer 26

• They are a type of subunit vaccine
• A weak antigen (polysaccharide) is combined with a stronger antigen (usually a protein), which acts as a carrier to increase the immunogenicity of the weak antigen
• The protein carrier provides peptides for MHC presentation, thus providing T cell help for polysaccharide-specific B cells to make antibodies
• It is often used to increase the response to polysaccharides in the bacterial cell wall

Question 27

What is vaccine escape and how can it be overcome?

Answer 27

• Vaccine escape is the loss of effectiveness of a vaccine in combating a certain pathogen
• It is usually due to recombination of DNA encoding antigens, so that the antigens are no longer recognisable by the immunoglobulins that the body produces
• This could perhaps be overcome by combining multi-component polysaccharide conjugate vaccines [IMPORTANT]

Question 28

What are vectored vaccines and how do they work?

Answer 28

• Viral vector vaccines use live viruses to carry recombinant DNA into human cells.
• The DNA contained in the virus encodes antigens that, once expressed in the infected human cells, elicit an immune response.

Question 29

For a vectored vaccine, give an example of a vector and antigen that may be used.

Answer 29

• Vector -> Adenovirus, Pox virus
• Antigen -> HIV gag

Question 30

What sort of response do vectored vaccines aim to elicit? [IMPORTANT]

Answer 30

Designed to primarily elicit T cell responses.

Question 31

What are adjuvants?

Answer 31

• Agents that are added to a vaccine in order to improve the immune response to the vaccine.
• Examples include aluminium hyroxide and paraffin oil.

Question 32

How do adjuvants work? [IMPORTANT]

Answer 32

• Act as a depot for the antigen, presenting the antigen over a longer period of time, thus maximizing the immune response before the body clears the antigen.
• Can include PAMPs to stimulate innate immunity via PRRs.

Question 33

Describe the two types of vaccine against Streptococcus pneumoniae.

Answer 33

• Polysaccharide vaccine (against 23 different capsule types)
• Polysaccharide-protein conjugate

The conjugate gives longer-lasting immunity, especially in children.

Question 34

Why are conjugation vaccines especially good at eliciting T cell-dependent memory responses?

Answer 34

The stronger (protein) antigen is internalised by B cells, which recruits T cells. This then helps the maturation of B cells into plasma cells and the development of memory cells.

Question 35

Give an example of a clinical study about herd immunity. [EXTRA]

Answer 35

• (Whitney, 2003) - “Decline in invasive pneumococcal disease after introduction of protein-polysaccharide conjugate vaccine”
• Study looked at vaccination in children under 2
• Aside from the rates of pneumococcal disease falling within the <2 years group of the population, the rates in the >65 years group also fell, showing that the infant group acts as a reservoir for the pathogen

Question 36

Describe changes in serotypes of a pathogen following a vaccination program. [EXTRA?]

Answer 36

After a vaccine is roled out against only certain serotypes (variations with a species), the number of cases caused by these serotypes falls, BUT the number of cases caused by other serotypes increases. This prompts the production of vaccines for a wider range of serotypes.

Question 37

What types of vaccine mimick bacterial capsules?

Answer 37

Polysaccharide vaccines -> Stimulate a response against the polysaccharides in the bacterial capsule.

Question 38

Describe how genome sequencing can be used in vaccine development. [EXTRA?]

Answer 38

• The sequences coding for antigens can be found.
• These can then be tested by using large-scale expression, immunisation and looking for appropriate immune responess.
• Looking at the genome of many strains also tells us the degree of antigenic variation, so that the antigens can be targeted combinatorially.

Question 39

Do monoclonal antibodies have to be derived from mice?

Answer 39

No, recently there have been attempts to isolate B cells, screen them for functional antibodies, clone the sequences and transfect that into cells.

Question 40

What are the mian routes of administration of vaccines?

Answer 40

• Most vaccines are given by injection, due to poor absorption through the intestine.
• Some live vaccines can be given orally (polio, rotavirus).

Question 41

How does the creation of live attenuated vaccines work?

Answer 41

• A pathogenic virus is repeatedly grown in a different organism (e.g. monkeys)
• This allows selection of pathogens with mutations that allow them to survive and replicate in the other organism, but prevent them from extensively replicating in humans
• This means that they can replicate slightly and trigger an immune response, but they are not dangerous
• This does mean that there is a small risk of a return to virulence

Question 42

How are inactivated (dead) vaccines created?

Answer 42

Using heat or formaldehyde.

Question 43

What are recombinant vaccines?

Answer 43

The gene encoding a viral protein is inserted into yeast or bacteria to produce proteins of the pathogen of interest, which are then purified and used as the active ingredient in a vaccine.

Question 44

What were the two main vaccines for polio?

Answer 44

• Salk vaccine -> Inactivated (dead) vaccine
• Sabin vaccine -> Live attenuated vaccine

Question 45

Compare the outcomes and effectiveness of the Sabin and Salk vaccine for polio.

Answer 45

• Salk developed his dead polio vaccine first, which had strong immunogenicity.
• However, Sabin then developed his live attenuated vaccine, which had even higher effectiveness and was more easily administered (oral), but also produced a small number of cases of paralytic poliomyelitis.
• Ultimately, the Sabin vaccine was more widely used and helped to eradicate polio from many countries, which demonstrated a trade off between herd immunity and a small proportion of cases showing side effects.

Question 46

Give an example of mass vaccination going wrong.

[EXTRA]

Answer 46

Cutter incident:

• 1955: The Salk polio vaccine was licensed.
• Shortly afterwards, in April 1955, 200,000 children in the USA received a polio vaccine which had been incompletely inactivated (manufactured by Cutter Laboratories).
• This resulted in 40.000 cases of polio -> 200 children were paralyzed, 10 died.

Question 47

What are the main problems of vaccine development?

Answer 47

Most vaccines induce the induction of neutralising antibodies. This is very efficient for protection from toxins (tetanus, diphtheria), extracellular bacteria (pneumococci) and viruses that pass through the bloodstream (polio, rabies). But viruses are intracellular pathogens and cannot be reached by antibodies when they are inside the cell.

Question 48

Compare vaccine creation against influenza and polio.

Answer 48

Influenza:

• Vaccines for influenza include inactivated and live attenuated vaccines, but these need to be developed each year. This is because of antigenic drift, which involves small changes in the HA and NA structure due to random mutations.
• The reason this is so significant effect in influenza A is because the RNA polymerase is highly error-prone, without any proof-reading mechanism.
• Pandemics are larger scale outbreaks, which can occur due to antigenic shift. This involves more major changes in the antigens due to genetic reassortment of vRNP segments when two influenza viruses infect a host cell simultaneously. In these situations, there is no population immunity and the virus can spread easily.
• Pigs are considered to be mixing vessels for the virus because they present both α-2,3 and α-2,6 linked sialic acid on their cells, meaning that both avian and human influenza strains can infect them.
• There are efforts to create a universal pneumonia vaccine, by targeting highly conserved regions, such as the stalk of haemagglutinin, but these have had limited success.

Polio:

• We have a successful vaccine program for polio because it has much higher antigenic conservatism.
• There are only 3 main serotypes.
• Similar to influenza and other RNA viruses, poliovirus has a high mutation rate, so the conservatism has been explained by a low functional tolerance for mutations.
• In other words, most mutations change the function of the proteins they encode in such a manner that the fitness of the virus is greatly reduced.
• Similar to influenza, poliovirus vaccines include inactivated and live attenuated vaccines, but they have not required new vaccines in over 60 years.

Question 49

What vaccines are currently available against tuberculosis?

Answer 49

• Bacille Calmette-Guerin (BCG) -> Live attenuated bovine tuberculosis bacterium (Mycobacterium bovis)
• This bacterium lost its virulence towards human hosts by growth in special culture medium, Middlebrook 7H9
• Efficiency of vaccination is variable (0-80%).
• Very efficient against tuberculous meningitis in children, but not so efficient against pulmonary tuberculosis. Not effective in adults.
• There is increasing emergence of multidrug resistant forms of M. tuberculosis, which makes efficient vaccine a priority.