Immuno Week 11

Who pioneered the use of the first vaccine, and approximately when

Edward Jenner, approximately 200 years ago

After what was vaccination named, and what is it

Named after Vaccinia, the cowpox virus

What was the first deliberate scientific attempt to prevent an infectious disease

Vaccination (Jenner's smallpox vaccine)

What was the principle behind Jenner's vaccine

Infection with a mild disease (cowpox) might protect against infection with a similar but much more serious one (smallpox)

What did Pasteur use to generate enhanced immunity against the fully virulent organism

Altered preparations of microbes

What did Pasteur investigate in 1879, and how did he attenuate the pathogen

He investigated anthrax in 1879; he heated anthrax bacilli to attenuate them

What was the first vaccine against rabies, and how was it made

First vaccine against rabies – made from dried rabies-infected rabbit spinal cords

What type of vaccine was Pasteur's rabies vaccine

First inactivated vaccine

what did Frank Burnet do

propose Clonal selection theory (1957)

what did Nossal and Miller do

Discovery of T & B cells (1965)

What does antigen induce in specific T/B cells

Clonal expansion, creating memory cells

What happens upon secondary exposure to the same antigen compared to primary response

More rapid and effective response than primary response (class switching)

What happens upon tertiary exposure to the same antigen

Response would be faster, with higher serum antibodies

what has been the result of vaccinations in Aus

very limited number of deaths from diseases which previously had high death rates

What are the two ways protective immunity can be achieved

Active or passive immunisation

How does passive immunisation work

By delivery of preformed antibody

For which conditions is passive immunisation still warranted

• For use in patients with immune deficiency

• Toxin or venom exposure with immediate threat to life

• Useful if pathogens would cause death faster than effective immune response can develop (e.g., rabies)

• Pregnant women exposed to viral infection

What hypersensitivity types can passive immunisation lead to

Type I or Type III hypersensitivities

Why can passive immunisation lead to hypersensitivity reactions

Non-specific binding to tissues

What does sufficient immune individuals in a population do

Reduce transmission of infection (herd immunity)

How can a population be immune

Either through vaccination or immunity developed through previous infection

What does the proportion of the population that needs immunity to prevent epidemics depend on

The nature of the infection

What happens if the organism is highly infectious (e.g., measles)

One person can infect several non-immune individuals

What proportion of the population must be immune to maintain herd immunity for a highly infectious organism

high proportion

If the infection is less readily transmitted, what proportion of immunity may be sufficient

Immunity in a lower proportion

what are the 3 principles of effective vaccines

1. Must be safe to administer (minimal/no side effects)

2. Induce the correct type of immunity (neutralising antibodies)

3. Be affordable by the population (E.g., developing countries)

what are some reccomended childhood vaccines

hepatitis B

tetanus

measles

What kind of antigens are better to retain in a vaccine

A diverse range of microbial antigens (usually more are better)

Which tend to be more effective: living or killed organisms, and why

Living organisms tend to be more effective; they also trigger PAMPs expressed on pathogen infected cells

What are 2 exceptions to the "living organisms are more effective" rule

Diseases where a toxin is responsible for the pathology – vaccine can be based on toxin alone

A vaccine in which microbial antigens are inserted into a vector and expressed in a host cell

What is the strategy of attenuation in vaccine development

To attenuate a human pathogen, aiming to diminish virulence while retaining desired antigens

What is an example of an attenuated bacterium, and how was it developed

Mycobacterium bovis (BCG vaccine) – during 13 years (1908–1921) of in vitro culture developed much less virulent forms

What is an example of an attenuated virus, and how was it obtained

The 17D strain of yellow fever virus obtained by passage in mice and chicken embryos (1937)

For which other diseases have similar attenuation approaches been used

Polio, measles, mumps, and rubella

What is the difference between natural and attenuated pathogens

Natural strains have potential to cause disease; attenuated strains are usually less virulent

What is a risk associated with attenuated vaccines

Potential to revert to virulent form

What successful vaccines led to a decline in four diseases between 1950 and 1980

Vaccines for polio, measles, mumps, and rubella

What does passaging lead to in microorganisms

Attenuation – changes microorganisms to make them less able to grow and cause disease in their natural host

What is attenuation usually due to

A natural loss of specific virulence genes

What are live, attenuated vaccines made from

Weakened pathogens

What ability do live, attenuated vaccines retain, and what responses do they promote

Retain their ability to replicate, promoting both humoral and cell-mediated responses

Do live, attenuated vaccines often need boosters

Often do NOT need boosters (life-long immunity)

What is a risk of live, attenuated vaccines regarding mutation

May mutate back (revert) to pathogenic form

What is a disadvantage of live, attenuated vaccines

May have more side-effect complications

What storage requirement may live, attenuated vaccines need

May require a "cold chain" for stability during transport

what is an example of a Live, attenuated vaccine

Rotavirus vaccine

What are rotaviruses the most common cause of

Diarrheal disease among infants

What happened to the first live attenuated rotavirus vaccine developed in 1998

It had serious outcomes (fatal bowel disease) in some children, leading to its removal from human use

What enabled the development of safer rotavirus vaccines after the first failure

Greater understanding and manipulating the virus in vitro

How is Rotarix produced

Live attenuated virus produced by repeated passage in animal cell lines in the laboratory

What is RotaTeq

A complex of 5 different hybrid viruses providing immunity to the 5 most prevalent viral strains

What is the hybrid virus in RotaTeq based on, and why is this useful

Based on bovine rotavirus, which is naturally attenuated in human hosts

What human rotavirus proteins are incorporated into the hybrid virus, and what are they targets of

VP4 or VP7; targets of natural immunity in human rotavirus infection

What are inactivated vaccines also called, and how are they made

Inactivated or "killed" vaccines; heated or chemically treated to inactivate

What are examples of inactivated vaccines

Cholera

Influenza

HepA

Plague

Polio (Salk vaccine)

Rabies

what are pros of inactivated vaccines

No reversion to pathogenic form

Often more stable/easy to store and transport

what are cons of inactivated vaccines

Often require booster shots

Don’t replicate in host, so often don’t induce cell-mediated immunity (humoral only)

Possible chemical exposures/adjuvants often required

Potentially dangerous if not all pathogen is killed/inactivated

What can formalin do to toxins

Formalin can inactivate toxins into toxoids

What are the most successful of all bacterial vaccines, and what are they based on

Tetanus and diphtheria vaccines; based on inactivated exotoxins

What is CRM197, and what is it used for

An inactive, mutant form of diphtheria toxin; used as the basis for several newly generated conjugate vaccines

what are subunit vaccines

vaccines that use only specific purified macromolecules from a pathogen, not the whole organism

Do subunit vaccines use entire proteins or organisms

no

what are the three specific target antigens of subunit vaccines

inactivated exotoxins/toxoids

inactivated capsular polysaccharides

inactivated surface glycoproteins (or recombinant protein Ag)

How do the pros/cons of subunit vaccines compare to inactivated/killed vaccines

Similar to those of inactivated/killed vaccines

How can subunit vaccines be produced

Can be produced through recombinant DNA technology

What is an example of a subunit vaccine, and what does it consist of

Acellular pertussis vaccine, consisting of a small number of proteins purified from the bacterium

As part of which combination vaccine is the acellular pertussis vaccine usually administered, and to whom

As part of DTaP (Diphtheria, Tetanus, Pertussis) combination vaccine routinely given to infants

What is a conjugate vaccine

Purified polysaccharides linked to carrier proteins (e.g., tetanus or diphtheria toxoid) to induce a stronger immune response

Why do purified polysaccharides (e.g., from bacterial capsules) need to be conjugated

They are usually poorly immunogenic

How can protein carriers be produced

Can be produced in highly purified form by recombinant DNA techniques

What do protein carriers recruit, and what is the result

Recruit Th cells; conjugates induce IgG antibody responses and more effective long-lasting protection

Name three examples of conjugate vaccines

• Haemophilus influenzae B (Hib)

• Neisseria meningitidis (strains A, C, Y, W-135)

• Streptococcus pneumoniae (pneumonia) — 7-valent conjugate vaccine

Why are conjugate vaccines needed for some molecules

Some molecules aren't strong enough antigens on their own to stimulate a strong immune response.

What can conjugate/multivalent vaccines improve

Immunogenicity

What does conjugation involve

Coupling antigen with an immunogenic substance (e.g., toxoid)

What is a limitation of simply linking a weak antigen with a stronger one

It may still not give the desired outcome. Need to consider what type of immune response is needed

what are 2 considerations for conjugate vaccines

Is the conjugate good at antibody induction?

What if you want to induce CTL responses?

How must antigen be delivered to induce CTL responses

Antigen must be delivered into cells for presentation in MHC class I molecules (endogenous antigen pathway)

How can antigen be delivered into the MHC class I pathway

Through creation of lipid carriers known as immuno-stimulating complexes (ISCOMs) for antigen delivery

How are recombinant vector vaccines produced

Produced through recombinant DNA technology

What do recombinant vector vaccines use as a delivery vehicle

Use an attenuated pathogen (e.g., adenovirus, vaccinia virus)

What are recombinant vector vaccines genetically engineered to do

Genetically engineered to carry and express pathogen's genes

Which company is using a type of vaccinia virus viral vector

AstraZeneca

What are the two pros of recombinant vector vaccines

• All the benefits of attenuated vaccines

• Fewer risks – not using the actual pathogen, but something else entirely

What is a con of recombinant vector vaccines

some of the attenuated vaccine problems are still present (especially stability issues)

what are adjuvants

substances added to vaccines to boost immune responses

Why might purified or recombinant antigens need adjuvants

Purified or recombinant antigens can be weakly immunogenic on their own

What do adjuvants do

Adjuvants boost immune responses

What discovery was made in the 1920s regarding adjuvants

Aluminium salts (alum), added to or emulsified with an antigen, greatly enhanced antibody production – they act as adjuvants

What adjuvant is still widely used with diphtheria and tetanus toxoids

Aluminium hydroxide

what are advantages of adjuvants

Promoting inflammation → recruit more immune cells to the area → enhance effectiveness

Slowing down antigen release → promote longer interactions → enhance effectiveness

Depending on the vaccine, adverse/side effects can include what

Minor local pain or swelling at the injection site

Mild fever and muscle aches, fatigue, headaches, joint pain

Pathogen reversion to wild type – more virulent infection

Insufficient deactivation of pathogen (presence of live pathogen)

What do epithelial body surfaces contain

Non-specific physical and chemical defence mechanisms preventing entry of pathogens

what are secretions of epithelial barriers

mucus, saliva, tears, urine, milk, sweat