Vaccination

Question 1

Define immunisation

Answer 1

Immunisation is the process of initiating an adaptive immune response ^[B and T cells respond] through the introduction of an antigen into the body.

Question 2

Describe active immunisation

Answer 2

Active immunisation is the administration of a vaccine that elicits a protective immune response.
- killed or inactivated preparation of a pathogen
- live-attenuated pathogen
- conjugate vaccine
- subunit vaccine
- DNA vaccines
- peptide vaccines
- often requires use of an appropriate adjuvant

Question 3

Describe passive immunisation

Answer 3

Passive immunisation is the administration of antibodies that provide protection in the recipient

Question 4

Define vaccination

Answer 4

is the induction of an adaptive immune response to a pathogen via injection of a vaccine.

Question 5

Define herd immunity

Answer 5

Herd immunity is protection provided to non-vaccinated individuals in a population, due to majority being successfully vaccinated.

Question 6

Describe the principle of vaccination

Answer 6

Vaccination involves the introduction or exposure of a toxoid/primary antigen challenge to the body. This results in a small primary antibody response (IgM>IgG). Thus on secondary infection or natural infection with the actual toxin/a secondary antigen challenge, a secondary antibody response is generated. This secondary response constitutes acquired immunity (IgG predominant response).

The primary response following acute infection is mainly carried out by naive CD8+ T cells. Once pathogen is cleared a pool of memory T cells remains with rapid response of CTLs following re-exposure to the pathogen.

Question 7

Discuss the benefits and disadvantages and some examples of passive immunisation

Answer 7

Passive immunisation is the administration of products containing antibody or immune serum.
Previously horse-derived antibodies were used.

Treatments that persist include:
- anti-venom post snake and spider envenomation
- pooled human plasma (Abs directed against multiple pathogens) ^[e.g. for primary immunodeficiency]
- hyperimmune globulin (directed against specific pathogens including varicella zoster virus, RSV, HepB, CMV)
- antitoxins (equine/human origin)

Advantages
- immediate acquisition of antibodies
- in case of anti-venoms or antitoxins: neutralise circulating toxins

Disadvantages
- no immunological memory invoked
- risk of transmission of blood-borne pathogens
- risk of serum sickness or anaphylaxis if repeated administration (equine derived anti-sera)

Question 8

Describe, provide advantages and disadvantages and some examples of live attentuated vaccines

Answer 8

Active immunisation is the administration of a vaccine that elicits a protective immune response.
- killed or inactivated preparation of a pathogen
- live-attenuated pathogen
- conjugate vaccine
- subunit vaccine
- DNA vaccines
- peptide vaccines
- often requires use of an appropriate adjuvant

Live attenuated vaccines are the most effective of all vaccines.
These contains organisms cultured to reduced pathogenicity.
They retain some of the antigens of the virulent form. Examples include:
- Bacille Calmette-Guerin (BCG) ^[TB], Salmonella typhi
- Measles, mumps, rubella vaccines
- Varicella zoster
- Yellow fever

Advantages
Live, attenuated vaccines confer long lasting immunity: cell mediated, humoral and memory.

Disadvantages
However, there is a risk of restoration of virulence, or reversion, particularly in immunosuppressed or immunodeficient individuals ^[also consideration in vaccinating immunodeficient communities with BCG - IL-12 issue].
Unclear if there is an optimal number of vaccinations as eradication of natural disease occurs.

Question 9

Discuss inactivated vaccines, some examples, benefits and disadvantages

Answer 9

Killed or inactivated vaccines contain an inactive preparation of a pathogen.
It is less effective than live vaccines i.e. less immunogenic. However, it is more effective if antigen is a protein, and if adjuvant used.

Inactivated vaccines require booster doses to maintain efficacy.
It predominantly generates humoral immunity based on production of neutralising antibodies, with rapid production on re-exposure.

There is a limited cellular immune response due to absence of replicating organisms, and reduced production of secretory IgA.

Examples of inactivated vaccines include polio (Salk), influenza, HepA, rabies, pertussis, cholera.

Advantages
- safety
- easy to produce and store
- less affected by pre-existing antibody (maternal antibody can interfere with the response to immunisation)
#### Disadvantages
- requires boosters
- may not preserve the immunoprotective antigen
- poor induction of T cell immunity (CD8+)
- poor inducers of mucosal immunity
- potential for immune response to tissue antigens derived *from cells to which vaccine is produced (allergy)**

Question 10

Describe toxoid vaccines

Answer 10

Some bacterial pathogens such as diphtheria and tetanus produce exotoxins.
Toxoid production involves the purification of the exotoxin, followed by inactivation with formaldehyde.

Vaccination with toxoid induces anti-toxoid antibodies capable of binding to, and neutralising the effects of, the exotoxin.
Therefore, the epitope structure of the toxoid must be maintained in order to ensure efficacy.

Question 11

Describe conjugate vaccines

Answer 11

Encapsulated organisms are an important cause of morbidity and mortality in those under 2 years of age.
This is due to impaired response to polysaccharide antigens in this group.
A solution to this is conjugate vaccines.
These contain polysaccharide antigens conjugated to a carrier protein to which the immune system has already been exposed such as diphtheria, tetanus toxoids or OMPC.

The resultant immune response is T cell dependent and rapid antibody production.
It also significantly reduces morbidity associated with Hib and S. pneumoniae.

• T independent antigen
• cross linking with B cell receptors
• leads to differentiation into plasma cells
• no affinity maturation or memory B cells i.e. can’t mount effective response on re-exposure
• Conjugate vaccine = processing of carrier peptide specific T cells along with polysaccharide specific B cells
• delayed but specific
• class switching, memory, and production of high affinity antibody
• faster and better response on re-exposure

Question 12

Describe subunit vaccines

Answer 12

Subunit vaccines rely on recombinant DNA technology.
Examples include HepBsAg.
The immunogenicity is compounded due to spontaneous aggregation into virus like particles.

However, failure has been demonstrated in a small group (MHC linked - HLA A1, B8, DR3) ^[receive immunoglobulin therapy].

Another example is the acellular pertussis vaccine, which is a purified subunit vaccine containing defined protein constituents prepared from B. pertussis.

Question 13

Describe another example of a subunit vaccine

Answer 13

An example is the HPV vaccine.
Virus-like particles or VLPs self-assemble when L1 protein of HPV is produced in isolation.
Vaccines comprise a mixture of types 16, 18, 6, 11; or types 16 and 18 alone.

This vaccine is highly immunogenic, and contain an aluminium salt adjuvant that precipitates VLPs, resulting in a slow release of antigen and monocyte activation ^[macrophages to site of infection that process antigen].

The second HPV vaccine contains monophosphoryl lipid A, which activates the innate immune response via TLR-4.

Both vaccines result in the production of virus-neutralising antibodies.

Question 14

What are some considerations in designing an effective vaccine?

Answer 14

• should not cause infection in the recipient
• should protect against disease resulting from exposure to the pathogen
• generation of neutralising antibody
• production of an appropriate cell mediated immune response
• acceptable side effect profile
• easy to store and administer
• able to be produced in large quantities and at low cost

Question 15

Describe the role of adjuvants in vaccination

Answer 15

There is variability in the immunogenicity of proteins or polysaccharides
Adjuvants are substances that have the ability to increase the immune response to an antigen:
- aluminium precipitation with the use of aluminium hydroxide or phosphate
- act as a depot for slow release of the antigen
- recruitment of antigen presenting cells
- signal induction, enhancement of production of stimulatory molecules
Note: RISK of side effects e.g. red and swollen limbs

Examples of adjuvants include:
- aluminium salts most common
- inactivated toxins: cholera and pertussis
- (outdated) cell wall extracts: Complete Freund’s extract: oil and water emulsion containing killed mycobacteria
- bacterial polysaccharides
- bacterial HSPs

Note many adjuvant substances are toxic and are unable to be used in humans.

Innate immunity plays an important role in the facilitation of B cell responses to both thymus dependent and independent antigens.
Many adjuvants provide PAMPs recognised by PRRs.

TLRs are the most important PRRs and recognise specific microbial ligands:
- upregulation of cytokine production
- promotion of DC maturation
- induction of antigen specific T cell responses

Note some TLRs located on cell surface. Some intracellular.

The same pathways that process antigens are utilised to mount an immune response post-immunisation

Question 16

Describe adverse events and reporting, and some examples

Answer 16

Mechanisms are in place to ensure and encourage reporting of adverse events.
- care needs to be taken when reporting
- links between MMR, Crohn’s and autism have been refuted but have potential to cause significant damage
- Each adverse reported is associated with a reduction in vaccination rates and a subsequent increase in reported morbidity and mortality e.g. MMR, covid-19 anxiety and hesitancy

Adverse effects are related to the properties of the vaccine.
For example, B. pertussis:
- whole cellular preparations can cause localised erythema, pain, swelling, fever and irritability
- a 1/2000-3000 risk of febrile convulsions, and rare neurological complications
- note that risk is probably lower with acellular preparations, has reduced drastically with subunit vaccines

Another example is live, attenuated vaccines, where there is an increased risk of disease in immunodeficient patients e.g. HIV.
However mild disease can occur even in normal populations e.g. mumps, measles, VZV.

Other examples of adverse effects include:
- reversion to virulence e.g. Sabin and polio - in the past
- unexplained and unexpected side effects: intussuception with administration of rotavirus vaccine ^[unclear why]
- disease enhancing e.g. for dengue and RSV
- deferring mild infections to a later age when more severe illness may occur (e.g. ?)
- use of live vaccines in large populations of immunocompromised e.g. HIV/AIDS
- reactions to excipients present in the vaccine e.g. thiomersal in the past
- allergy to growth media or antibiotics used in egg culture e.g. egg allergy/influenza, yellow fever vaccines
- rapid changes in the antigen of the target pathogen e.g. influenza and antigenic drift, malaria, HIV, leishmaniasis

Question 17

Provide examples of new approaches to vaccines

Answer 17

• vaccines that result in development of specific T cell responses (Th1 and Tc)
  
  • likely to be required for successful vaccines against HIV, malaria
• DNA vaccines: injection of naked DNA into host
  
  • insertion into bacterial plasmids
  • transdermal or intradermal delivery most promising
  • DNA coding HBsAg coated gold beads associated with antibody and CD8 T cell response
• use of bacterial vectors
• viral vectors
• transgenic edible plants containing human vaccine antigens
• alternative routes e.g. intranasal and influenza ^[not routinely available], sublingual, transcutaneous
• use of ISCOMS
  
  • immune stimulatory complexes: lipid carriers
  • loaded with peptide
  • facilitate entry of peptide into the cytoplasm where it can be taken up and processed by antigen presenting cells
  • this allows MHC Class I restricted T cell responses
• use of mannose to promote antigen uptake via mannose receptors on antigen presenting cells
• CpG containing oligonucleotides
• antigen polymerisation
• coadministration of cytokines
  
  • IL-1, IL-2, IFN-y, IL-12

Question 18

Describe the features of mRNA vaccines

Answer 18

mRNA encodes antigen of interest packaged in lipid or other nanoparticle
- this facilitates uptake into the cytoplasm
- utilises cell machinery to transcribe and express protein resulting in robust immune response
- easy and rapid to make
- highly immunogenic i.e. garners both antibodies and T cell response

Question 19

Describe viral vector vaccines

Answer 19

This utilises a replication-deficient viral vector to transport gene of interest into the cell, resulting in transcription.
It is highly immunogenic i.e. garners both antibodies and T cell response.