Vaccines Flashcards
This lecture
What is a vaccine – and is it a drug?
The (very) basics of human immune
response
The known historical origins of inoculation
against smallpox
Cowpox as the first successful ‘vaccine’
The microbiology era – Pasteur and rabies
The polio vaccine
The measles vaccine
The toxoid vaccines – diphtheria and
tetanus
Australia’s current
childhood immunisation profile
What is a
vaccine – and is
it a drug?
Vaccines are biological preparations designed to
stimulate or ‘train’ the body’s immune response.
The idea is to get your body to fight and resist a
disease if you’re exposed to it.
The body is trained by the vaccine to recognise
particular pathogens (not normally found in the
body).
Vaccines are designed to prevent disease, rather
than treat it.
They can be considered drugs:
they are biological preparations (like hormone-based
drugs, eg. insulin)
they are prophylactic (like malaria medication)
BUT: they are not chemical-based (like
aspirin, nitroglycerin, chloroform).
By the end of this lecture, you will
be able to …
Describe the basic
processes of human
immune response
Identify key processes
and individuals involved
in the development of
inoculation and
vaccination.
Explain the difference
between vaccines and
antitoxins.
Describe variations in
Australia’s current
childhood immunisation
profile
What’s going
on inside you –
non-specific
immunity
The human immune system has two levels of
immunity:
non-specific immunity
specific immunity
Non-specific immunity is also called innate
immunity.
It’s how the human body protects itself against
foreign material perceived to be harmful (eg. viruses,
bacteria, parasites, splinters).
The skin and mucuous membranes are the first line
of defence.
Pathogens that breach these barriers will be
attacked by phagocytes.
These surround a pathogen, take it in, and neutralise
it.
What’s going
on inside you –
specific
immunity
Specific immunity works alongside non-specific
immunity.
It provides a targeted response against a specific
pathogen.
This kind of immunity only exists in vertebrates!
The specific immune response relies on white blood
cells (lymphocytes).
These are produced in bone marrow and become
different types of cells, including:
B cells
T cells
For example -
influenza
You get the flu from someone = the virus enters your body and
starts to replicate.
The flu virus produces an antigen which your body recognises
from an earlier bout of flu.
Specific “flu trained” T helper cells respond to this antigen by
stimulating B cells to produce lots of plasma cells.
These produce flu antibodies to combat the virus.
Helper T cells also switch on some killer T cells to surround and
destroy virus-infected cells in the body.
Once the flu is on the run, regulatory T cells calm everything
down again and switch off the immune response.
What’s going
on inside you –
B cells
B cells can mature and differentiate into plasma
cells that produce antibodies.
B cells alone are not good at making antibodies –
they rely on T cells to signal to them when it’s time
to produce them.
An antigen is a foreign material that triggers a
response from T and B cells.
When a B cell gets the message and recognises
the antigen it is coded to respond to, it produces lots
of plasma cells.
The plasma cells then secrete large numbers of
antibodies, which fight specific antigens circulating
in the blood.
The human body has B and T cells specific to
millions of different antigens.
Early 1700s – from
Turkey to the UK
Lady Mary Wortley Montagu, wife of a British
Ambassador, travelled in the Ottoman Empire in the early 1700s
In 1715, Lady Mary contracted smallpox and survived with
scarring (she lost her eyelashes).
She noticed that few people in the Turkish region had
smallpox scars and asked why – learned about inoculation.
Lady Mary had her son inoculated against smallpox in
Constantinople by Embassy surgeon Charles Maitland in 1718.
Later in England in 1721-22 she had her daughter inoculated as
well.
Inoculation
Pus was harvested from the lesions of a person
with active smallpox.
It was transferred to a cut on the back of the hand
or arm and bound up.
The inoculated person would develop a milder case
of smallpox, and thereafter be immune to it.
The origins of
inoculation
Smallpox (variola virus) – at least 10,000 years
old.
3 out of 10 infected people died, and survivors
were often facially scarred for life.
Survivors, however, became immune.
Early descriptions involve the use of live
smallpox to deliberately infect children
and adults.
Practice was called ‘inoculation’ and later
‘variolation’ (after the variola virus).
We don’t know the origins of this practice –
anecdotal evidence for northern Africa? The
area around Turkey? China?
Most written accounts of inoculation date reliably
from the very early 1700s and describe
practices from the 1600s.
Expansion of
inoculation in the UK
Lady Mary championed inoculation with the Royal Family.
Charles Maitland was granted permission to perform a
trial on six prisoners in London on 9 August 1721.
Several court physicians, members of the Royal Society, and
members of the College of Physicians observed the trial.
All prisoners survived and later proved to be immune.
Maitland successfully repeated the experiment on
orphaned children.
17 April 1722: Maitland successfully inoculated the two
daughters of the Princess of Wales.
Cowpox and smallpox
Trainee doctor Edward Jenner observed and was told that dairymaids
who had cowpox were immune from smallpox.
Jenner hypothesised that cowpox was protective but could also
be transmitted from one person to another, like variolation.
May 1796: Edward Jenner took pus from a cowpox lesion on Sarah
Nelms (dairymaid) and inoculated an 8-year-old boy, James Phipps.
Phipps developed mild fever, discomfort in the armpits, loss of appetite,
but on day 10 felt much better.
July 1796: Jenner inoculated Phipps again with fresh pus from a smallpox
lesion.
No disease developed, and Jenner concluded that the cowpox
inoculation had worked.
Instead of ‘variolation’, Jenner called this ‘vaccination’ (vacca = cow;
vaccinia = cowpox)
Spread of vaccination –
and opposition
1853; Smallpox vaccination becomes compulsory for babies
in the UK.
Some claimed vaccination were unsafe, or unnecessary.
Others argued that compulsory vaccination was
government interference in people’s lives.
1879:Anti Vaccination Society of America founded.
1890s: National Anti-Vaccination League (UK).
In the UK it became possible to opt out of vaccination
(Vaccination Act 1898).
Dame Mary
Gilmore (1865-
1962) - childhood
vaccination
experience in 1870s
Australia
All our … neighbours inoculated their children with
lymph from a calf, the family instrument being an
ordinary darning-needle. But I had to be ‘properly’
vaccinated. So I was taken to town to be done.
When my arm was bared, whichever of the medical
men it was crossed to the mantlepiece, on which
was a slide of glass covered with flies. The flies
rose in a cloud as he lifted it, and the horrible
surface, lymph and all, was spotted with
flyspecks.Though only a child, with horror I
thought, ‘Am I to be done with that?’ …
I remember days or weeks later on, opening my
eyes out of a stupor as I lay in bed, and seeing my
father and an old white ‘nurse’ standing beside me.
‘If she lives, she will lose her arm; it is black to the
shoulder now,’ the woman was saying. ‘But she
can’t live, she is too far gone.’
After the delirium passed I did live, but I lost all my
fingernails and toenails, and my hair fell out like
a long-dead person’s.About seven years old, I was
left absolutely bald, and for a year I had to wear a
cap or a hood to hide my bare skull.
Pasteur and
rabies
1879: Pasteur discovered by accident that
some bacterial cultures lost virulence
over time if they were left exposed to air
(attenuation).
First experiments used attenuated
anthrax (bacteria) on animals – successful
immunisation.
Pasteur experimented with rabies (virus)
which he attenuated by passing it through
a series of animals – successful
immunisation in dogs.
6 July 1885: Pasteur ‘vaccinated’ 9-yearold Joseph Meister, bitten by a rabid dog.
Meister received a total of 13 treatments
over 11 days and survived.
1886: Pasteur treated 350 people with
rabies vaccine with almost 100% success
rate.
Poliomyelitis
Humans are the only known species to carry this disease.
o Attacks motor neurons in the CNS.
o Highly infectious viral disease – children under 5 most at
risk.
o Paralysed US President Franklin Delano Roosevelt.
Around 19 out of every 20 people with poliovirus have no
symptoms = high risk of spreading.
Less than 1 in every 100 people will develop severe muscle
weakness.
In a small percentage of infections, can cause lifelong
paralysis or death.
1955 – Salk injectable polio vaccine approved for use in
the US.
1960 – Sabin oral polio vaccine approved for use in the
US.
Poliomyelitis
Australian 20th century epidemics: 1937-38, 1949 (Victoria), 1953
(NSW), 1961-62.
About four million Australians were infected in these epidemics (likely
under-reporting).
About 20,000 to 40,000 developed paralytic polio between 1930 and
1988.
Vaccination program began in Australia in 1956 (Salk vaccine).
Australia was declared officially polio-free in 2000 – but it is still a
notifiable disease.
Since 2014, poliovirus has only been found in Afghanistan and Pakistan.
Unvaccinated people may become infected if they travel to areas with
polio => may bring back polio to countries like Australia, where it could
affect unvaccinated people.
Diphtheria
antitoxin
Known in Europe since the 1600s; bacterium first identified in
1883.
Corynebacterium diphtheria releases a toxin that infects the
upper airways –> a membrane forms across the windpipe.
Can lead to suffocation and death; also CNS damage.
Children especially vulnerable.
Did not appear to attenuate – so how can we make
a vaccine?
Kitasato (1852-1931) and von Behring (1854-1917) successfully
produced a heat-treated toxin and treated guinea pigs with it.
Blood products from the guinea pigs contained an antitoxin
that worked to immunise against diphtheria.
Serum therapy or antitoxin therapy.
borrows antibodies made by another immune system that
will remain in the patient’s blood long enough to battle the
infection.
Measles
Highly contagious and dangerous virus (especially for
young children and pregnancy).
Ear infections occur in about 1 out of every 10 children
with measles.
Hospitalisation may be necessary.
Pneumonia. As many as 1 out of every 20 children with
measles gets pneumonia = common cause of death.
Blindness: corneal ulceration, keratitis.
Encephalitis. About 1 child out of every 1,000 who get
measles will develop encephalitis (swelling of the brain)
=> convulsions, deafness, cognitive impairments.
Death. Nearly 1 to 3 of every 1,000 children with
measles will die from respiratory and neurologic
complications.
Measles
vaccination
1954: measles outbreak at Boston
school = swabs and blood samples
taken.
Thomas Peebles MD successfully
cultured measles from samples
obtained from 11-year-old schoolboy
David Edmonston.
First vaccine developed by John
Enders from ‘Edmonston-B strain’ =
basis for US measles vaccines today.
Tested in the US 1958-1960
1961 = 100% effective and licensed
for public use in 1963.
Vaccine rolled out in Australia in
1969.
2014: Australia was declared
measles-free.
How is
diphtheria
antitoxin prod
uced now?
Toxin-producing C. diphtheriae is grown in liquid media.
The toxin produced is then converted to an inactive toxoid by treatment
with formalin (it ‘disinfects’ it).
This toxoid is adsorbed to aluminium salt as an adjuvant (this enhances
the immune response).
Thiomersal (ethylmercury derivative) is added as a preservative for multidose vials.
o Adsorption: when we apply atoms, ions or molecules from a gas, liquid or
dissolved solid to a surface, creating a film on that surface.
o Not to be confused with absorption, when a fluid is either dissolved by or
soaks into something else.
Diphtheria in Australia today
Diphtheria is rare in Australia.
School-based vaccination program from 1932.
National Immunisation Program vaccination from 1975.
Diphtheria-tetanus-acellular pertussis (DTPa and
dTpa vaccines) given routinely in childhood.
However, it remains endemic in many developing countries.
Most Australian cases of diphtheria are imported from overseas.
2018: An unimmunised person who had never been overseas
died from diphtheria myocarditis in Queensland.
2022: An unimmunised toddler required ICU admission for
respiratory diphtheria.
Tetanus antitoxin and
toxoid
Clostridium tetani found in soil – can
enter wounds.
Produces neurotoxin that acts on CNS
and causes muscle rigidity and spasms
(‘lockjaw’).
As with diphtheria, horses were
infected and then bled to harvest
antitoxin serum for human
administration.
1924: Tetanus toxoid (immunisation).
Inactivated form of the toxin – body will
produce antibodies against it.
The vaccine was not frequently used
until World War II
How do we
produce
tetanus
antitoxin now?
Horse-based antitoxin was effective - but some people developed
serum sickness.
Immune reaction to the non-human proteins in the antitoxin serum.
o It can also be triggered by bee stings and snake anti-venom!
o Could take up to 14 days to appear.
o Joint pains, swollen glands, fever, rash, feeling sick.
Modern tetanus anti-toxin is by growing toxigenic strains of C.
tetani in liquid media.
The toxin is purified and inactivated using formalin to produce the
toxoid antigen.
Tetanus toxoid is adsorbed with aluminum or calcium salts.
Administered by intramuscular injection in cases of exposure to
tetanus in unvaccinated humans.
Regional
variations -
post-COVID19
May 2024 data
WA’s lowest rates of childhood immunisations:
WA Pilbara: two-year-old vaccinations at 82.15%.
WA Augusta – Margaret River – Busselton: two-year-old vaccinations
at 82.53%.
WA Augusta – Margaret River – Busselton: one-year-old vaccinations
at 83.95%.
Other national low-rate areas include NSW North Coast, Qld Sunshine
Coast, Gold Coast, western Queensland.
The ACT has among the highest rates for all age groups:
96.47% for 1-year olds.
94.54 % for 2-year-olds.
95.45% for 5-year-olds.
Learning outcomes
In this lecture we will discuss (i) controversies around vaccines, including
By the end of this lecture, you should be able to:
▪ list the COVID-19 vaccines used in Australia and controversies surrounding them
▪ define and describe vaccine hesitancy, including the main contributors to
hesitancy
▪ cite examples of vaccine disasters in history and lessons learnt
▪ list factors contributing to vaccine advancement, including examples
vaccines against COVID-19, (ii) factors influencing vaccination uptake,
including the impact on vaccine uptake after the false claimed link between
vaccines and autism (MMR case); and (iii) vaccine disasters and failures. In
addition, new vaccine approaches and future directions will be discussed.
Recommended readings:
Cited literature
Australian Immunisation Handbook
How vaccines
have changed
the world
Vaccines are drugs that have changed the world.
Eradication of smallpox in 1980 (still lives in lab
samples!)
According to WHO, immunisation is second only to
clean water in its reduction of the burden of
infectious disease globally.
Immunisation for common fatal and disabling
diseases is mostly administered to y0ung children.
Yet: Western online culture of vigorous opposition
to immunisation for a range of reasons:
Sometimes uses ‘science’ to argue.
Sometimes uses ‘anti-science’.
Vaccination: a cornerstone
of public health
▪ Stimulating immune responses against microbes
through vaccination is the most effective method for
protecting individuals against infections.
▪ Vaccination has led to the worldwide eradication of
smallpox, the only human disease that has been
eliminated from civilization by human intervention.
Since the first smallpox
vaccine was developed by
Edward Jenner in 1796,
skepticism and suspicions
about vaccines and the
motivations behind their use
have existed.
By 1977, coverage against pertussis had declined
from 77 to 33% in the UK, falling as low as 9% in
some districts. The first of what would become
three major epidemics of whooping cough
followed soon thereafter.
In 1974, a
retrospective study
was published
which described 36
children who
suffered severe
neurological
complications with
DTP.
In Australia, the whole
-cell DTP vaccine was
replaced with acellular DTP vaccine in 1996.
DTPa is safer than DTPw
.
A poisonous tree as
metaphor for the
effects of smallpox
vaccination as seen by
anti-vaccinationists in
the early 1900s.
French caricature from around 1800 shows
that fear of vaccination quickly produced
reactions among artists.
COVID-19 vaccine
controversies
▪ Novel vaccine
technologies
▪ Accelerated vaccine
development and clinical
trials
▪ Vaccine efficacy and
effectiveness studies
▪ Vaccine safety and
adverse events
▪ Vaccine acceptance and
vaccine mandates
▪ Vaccination of children
▪ Politicization of a public
health issue
COVID-19 vaccine strategies
▪ mRNA vaccines - fully synthetic vaccines
encoding the spike protein
▪ Synthetic gene expressed by a viral
vector, such as a non-replicating
adenovirus
▪ Purified spike protein after synthetic
gene expression (subunit/VPL)
▪ Inactivated vaccines
Australia vaccine rollout:
▪ Comirnaty (Pfizer) and Spikevax (Moderna)
– recommended
▪ Nuvaxovid (Novavax) – ancestral vaccine no
longer available/ updated vaccine under
development
▪ Vaxzevria (AstraZeneca) and Janssen
(Johnson & Johnson) – no longer available
h
How were mRNA COVID-19
vaccines developed so quickly?
(i) Seminal research in mRNA technology, (ii) priority and collaboration, (iii)
funding, (iv) large-scale manufacturing (fully synthetic vaccine), (v) volunteers
for clinical trials
mRNA vaccines
Lipid nanoparticle-formulated, 5
nucleoside-modified RNA
(modRNA) that encodes for the
SARS-CoV-2 full-length spike,
modified by two proline
mutations to lock it in the
prefusion conformation
Bivalent vaccines are formulated to
protect against both the original strain
and Omicron subvariants BA.4 and
BA.5. The most updated vaccine
encodes the viral spike protein of
SARS-CoV-2 Omicron XBB.1.5.
How were mRNA COVID-19
vaccines developed so quickly?
▪ Lessons learnt from other human coronaviruses, e.g., SARS-CoV and
MERS-CoV were important to understand the biology of SARS-CoV-2
and COVID-19
▪ Rapid SARS-CoV-2 genome sequencing allowed the identification of
potential vaccine targets (reverse vaccinology)
▪ Previous understanding of how to engineer proteins in the “correct”
conformation so the immune system can recognise it (structural
vaccinology)
Variety of vaccine
platforms,
administration routes,
polyvalent vaccines
and improvements in
adjuvants and delivery
systems
How were mRNA COVID-19
vaccines developed so quickly?
▪ Cells of the immune system recognise in vitro transcribed mRNA as a
foreign substance, which leads to their activation and the release of
inflammatory signaling molecules.
▪ In 2005, Karikó and Weissman produced different variants of mRNA,
each with unique chemical alterations in their bases.
▪ The inflammatory response was almost abolished when base
modifications were included in the mRNA.
Katalin Karikó and Drew Weissman, winners of the
2023 Nobel Prize in Physiology or Medicine
How were mRNA COVID-19
vaccines developed so quickly?
▪ in 2010, several companies were working on developing mRNA
vaccines, including vaccines against Zika virus and MERS-CoV.
▪ LNP surface modifications by poly-ethylene glycol (PEG)
enabled lipid nanoparticles to survive for longer; the use of
cationic lipids enabled efficient self-assembly and
encapsulation of the mRNA.
Myocarditis and pericarditis
after COVID-19 vaccination
▪ A small increased risk of myocarditis and/or pericarditis has
been observed in people following vaccination with an mRNA
vaccine compared with unvaccinated people - mostly reported in
males under 40 years of age, and mostly after the second dose.
▪ Most vaccine-associated myocarditis events have been
mild and responded to treatment. The mechanism for
the pathogenesis of post-vaccine myopericarditis has
not been established.
▪ COVID-19 is estimated to cause myocarditis at a rate of
approximately 30-32 excess cases per million. Post COVID-19
condition (“long COVID”) is also associated with several
cardiovascular complications
▪ In males aged 16-40 years, it is uncertain whether the risk following
COVID-19 remains higher than the risk following vaccination.
Risks of myocarditis from COVID vaccines
MMR vaccine and autism
Global measles resurgence of 2018–2019
Lessons learnt
Vaccine failures and disasters
The Bundaberg Tragedy1
– Australia - 1928
▪ Diphtheria vaccine was contaminated with Staphylococcus aureus
▪ 21 children were injected, 12 died between 15 and 34 hours after
inoculation
The Lübeck Disaster2
– Germany - 1929–1933
▪ 251 neonates were orally given three doses of the new Bacille
Calmette–Guérin (BCG) antituberculosis (TB) vaccine
▪ Vaccines were contaminated with fully virulent Mycobacterium
tuberculosis
▪ 173 infants developed clinical or radiological signs of TB but
survived, 72 died from tuberculosis
Global measles resurgence after COVID-19
▪ In 2022, there were an estimated 136 000 measles deaths globally,
mostly among unvaccinated or under vaccinated children under the age
of 5 years
▪ In 2023, WHO reported 79% increase in global measles cases compared
to the previous year.
▪ The WHO European Region is experiencing an alarming rise in measles
cases. Over 30 000 measles cases were reported by 40 of the Region’s 53
Member States between January and October 2023. Compared to 941
cases reported in all of 2022, this represents a more than 30-fold rise.
▪ The COVID-19 pandemic significantly impacted immunization system
performance in this period, resulting in an accumulation of un- and
under-vaccinated children.
Vaccine failures and disasters
The Cutter incident1
– United States - 1955
▪ Inactivated polio vaccines (IPV) (Salk) were not properly inactivated with
formalin
▪ 120,000 children were vaccinated, 40 000 developed abortive polio, 51
were permanently paralysed and 5 children died
▪ Cutter’s vaccine also started a polio epidemic: 113 people in the children’s
families or communities were paralysed, and 5 died
Dengvaxia controversy2
– Phillipines – 2016-2017
▪ Dengvaxia was found to pose a significantly higher risk of a more severe form of
dengue in individuals who have never had a dengue infection before
▪ Over 800,000 Filipino schoolchildren had been inoculated prior this knowledge, 3
children died of dengue after vaccination
▪ Dengvaxia reduces the overall risk of severe dengue and hospitalisations due to
dengue in individuals who had a prior history of dengue infection
▪ Licenced in 20 countries, but never indicated for primary prevention of initial
dengue infection
Vaccination hesitancy
▪ Delay in acceptance or refusal of vaccines despite availability of
vaccine services
Vaccine hesitancy model (Butler, WHO)
▪ Complex and context
specific varying across
time, place and vaccines
▪ Vaccine hesitancy
model: confidence,
complacency,
convenience (or
constraints), risk
calculation, and
collective responsibility
Factors influencing
vaccination uptake
▪ Complex and
multidimensional
reasons
▪ Low perceived risk of
disease
▪ Fear and
misinformation
▪ Vaccine failures
Future
directions in
vaccines
Future directions in vaccines
Future directions in vaccines
Future directions in vaccines
Summary
▪ Vaccines prevent 3.5-5 million deaths every year from more than 20 lifethreatening diseases
▪ Misinterpreted scientific observations have contributed to the creation of myths
and controversies surrounding vaccines
▪ Disasters in vaccination history have had serious individual and societal
consequences, including increase of vaccination hesitancy
▪ Human beliefs and behaviors have defined, and always will define, views about
the cause-effect relationship of diseases; and vaccination programs must
consider many factors influencing vaccination uptake to be successful
▪ Vaccine and vaccine platforms are continually evolving – improved targets,
adjuvants, delivery routes, etc.
▪ Therapeutic vaccines, including cancer vaccines, have progressed tremendously
in the last decade, and hundreds of novel vaccines are currently on trial
