Introduction to vaccines

Define adjuvants.

Adjuvants are substances that enhance, prolong and accelerate induction of the immune response to a vaccine antigen. They reduce the amount of antigen required in the vaccine and provide a general stimulus to the immune system.

How do adjuvants work?

retain and concentrate antigens in location of lympocytes (‘Depot effect’) or deliver antigens to APCs. Induce cytokine production and regulate lymphocyte activity.

How can adjuvants direct the immune response?

Adjuvants can direct the immune response by binding to a pattern recognition receptor (PRR). Different cytokines are produced depending on which receptor is ligated. Depending on which adjuvant used, you can lean the response to a bias to a Th1 or Th2 direction.

What adjuvants are used for vaccines?

natural, synthetic or endogenous. Main used are aluminium gels.

Give an example of adjuvants in use for vaccines.

monophosphoryl lipid A (MPL), combined with aluminium in the HPV vaccine. An experimental kind is beryllium hydroxide

How do vaccines work?

elicit a high affinity, long-lasting, specific immune response

What is the active component in different vaccines?

can include toxoid (inactivated toxin), toxin sub-unit, polysaccharide (based on a capsule and must be linked to carrier protein), live bacteria, killed bacteria

What does the current UK infant vaccine schedule contain?

The current UK infant vaccine schedule contains immunizations against diseases such as DTaP/IPV/Hib, pneumococcal disease and meningitis B, along with MMR.

How do vaccines work?

induced immunity, immune memory, location of immunity, adjuvants

Describe the immunology of vaccinology.

immature B-cells bind to and recognise antigen and produce IgM. They then produce a germinal centre and start to proliferate and secrete antibodies from the lymph nodes. Follicular dendritic cells then present the antigen to B-cells and select for high affinity. This then leads to differentiation and affinity maturation due to somatic hypermutation and VDJ recombination, resulting in memory B-cells and long-lasting immunity.

What do naive B cells produce when bound to an antigen that triggers proliferation of antigen-specific cells due to support of CD4+ T cells?

primarily long-lived plasma B cells but also memory B cells

What do naive T cells produce when bound to an antigen that triggers proliferation of antigen-specific cells?

Central memory T cells (Tcm) and primarily effector memory T cells (Tem) which circulate in the blood or remain in the tissue

Define opsonisation.

The process by which pathogens are marked for destruction by immune cells through the binding of antibodies or complement proteins, enhancing their recognition and uptake.

What type of response do mature plasma B-cells produce?

immediate antibody response to pathogens.

What type of response do memory B-cells produce?

delayed antibody response upon re-exposure to the same antigen.

What kind of antibodies can be generated from mature plasma B cells?

neutralising, opsonising, and activating complement antibodies.

How do neutralising antibodies work?

Neutralising antibodies bind to specific antigens on pathogens, blocking their ability to infect cells and preventing disease progression.

How fast is the naive cell (initial) response?

5-10 days

How fast is the memory B cell (vaccine) response?

2-5 days

What is the difference in the antibody type affinity between the primary and secondary response?

The primary response produces low affinity IgM antibodies, while the secondary response generates high IgG and IgA affinity antibodies due to affinity maturation.

How many subclasses does IgG have?

IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4.

What are the targets of IgG1 and IgG3?

target proteins

What does IgG2 target?

targets polysaccharides

What type of mechanism does IgA have?

blocking mechanism (so not killing or opsonic like IgG)

Immunoglobulins are produced by?

the spleen, regional lymph nodes, submucosal lymphoid tissue such as the MALT, NALT and Peyer's patches.

How many types of IgA are there?

monomeric found in the blood or serum (IgA1) and dimeric/polymeric found in secretions (IgA2 in lower GI tract)

Why is IgG known as the functional antibody?

Because it can opsonize pathogens, activate complement, and mediate antibody-dependent cellular cytotoxicity (ADCC), providing strong immune defense.

What are some key characteristics of vaccines?

must be efficacious, produce long-lasting protection, must be broad-spectrum, must be safe, must be stable and easily administered, must be easy to deliver, and must induce a strong immune response that could aid in herd immunity.

What are some key characteristics when thinking of developing a vaccine program? 5!

age or target group, cost-benefit ratio (number of cases, hospitalisation costs, unit cost of vaccine, generates herd immunity), effect on commensals (does it serve a risk to natural immunity), potential for bacteria to escape vaccine, impact on other vaccines

What are the stages in vaccine development?

target validation (identifying conserved surface antigen), testing for immunogenicity and generation of a protective immune response that produces antibodies, testing for coverage of all pathogenic strain of that organism, safety testing to understand function, thinking on how you’ll present the antigen, preparation of vaccine batch

What causes whooping cough?

Bordetella pertussis

What are some of the characteristics of Bordetella pertussis?

small, gram negative, aerobic coccobacillus, fermentative, thrives in blood-rich areas

What are some of the characteristics of whooping cough?

highly infectious, colonises upper respiratory and can cause pneumonia if it enters lower respiratory tract, complications can lead to seizures and pneumonia

What are some of the symptoms of whooping cough?

cold-like symptoms, dry cough which can worsen to prolonged coughing bouts

Describe the background of the Pertussis Field Trial.

Trialed vaccine over three years in 5,815 children, control group was of a similar size, age and districts as immunised group, vaccinated group was “all children of an acceptable age and history who presented themselves for vaccination”.

What was a necessary step that Kendrick and Eldering needed to do prior the the trial starting?

Assess the levels of disease in the population to determine baseline incidence rate (how long the disease lasted, when the infected individuals were producing infectious organisms)

Define epidemiology.

The study of how diseases affect the health and illness of populations, focusing on patterns, causes, and effects of health and disease conditions.

How did Eldering and Kendrick assess the baseline incidence rate for B. pertussis?

developed a new growth media which allowed for faster and more abundant growth of b. pertussis colonies which improved diagnostics. This media was then offered as a cough plate to doctors.

What were the findings from the epidemiological studies for the whooping cough vaccine trial?

determine that an infected child was most infectious during the first 3 weeks and posed no risk after 5 weeks so were able to determine a quarantine period.

What occurred during Phase I of the Whooping cough vaccine trial?

inactivated the bacilli with thimersol at cold room temperature for about 1 week, sterility and safety testing in animals and human subjects showed that vaccine was safe, small-scale trials in children showed 4 doses were tolerated well.

What occurred during Phase II/III of the Whooping cough vaccine trial?

trial in children who were the main demographic where disease was observed, vaccine doses were given at weekly intervals, needed to recruit a test and control population of similar size

What was the age group of the children involved in the Whooping cough vaccine trial?

8 months to 4 years old

How many doses weekly for the Whooping cough vaccine trial?

4 doses at weekly intervals but later studies showed 3 doses were sufficient

What occurred during Phase IV of the Whooping cough vaccine trial?

vaccine trial was a success and indicated that a whooping cough vaccine should be rolled out countrywide (USA) which required production of consistent batches of vaccine

Explain the phases of modern day clinical trials.

phase I trial (safety and reactogenicity), phase II trial (efficacy test), phase III trial (large-scale efficacy test), phase IV trial (post approval trials to test a range of factors).

Explain phase I of modern day clinical trials.

safety and reactogenicity, 20-80 subjects to assess safety of the vaccine in a small group, may be open label where everyone knows what they are getting (in comparison to double-blind)

Explain phase II of modern day clinical trials.

efficacy test, 100+ subjects, usually randomised and may be double-blind with a placebo.

Explain phase III of modern day clinical trials.

large-scale efficacy test, over 1,000 subjects, comparison to other therapies

Explain phase IV of modern day clinical trials.

post approval trials to test a range of factors. looks at age group, number of doses, adjuvant type, etc.