Vaccines Flashcards

(64 cards)

1
Q

This lecture

A

 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

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2
Q

What is a
vaccine – and is
it a drug?

A

 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).

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2
Q

By the end of this lecture, you will
be able to …

A

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

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2
Q
A
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3
Q

What’s going
on inside you –
non-specific
immunity

A

 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.

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3
Q
A
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3
Q

What’s going
on inside you –
specific
immunity

A

 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

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4
Q
A
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4
Q

For example -
influenza

A

 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.

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5
Q

What’s going
on inside you –
B cells

A

 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.

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6
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7
Q

Early 1700s – from
Turkey to the UK

A

 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.

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7
Q

Inoculation

A

 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.

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7
Q
A
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8
Q

The origins of
inoculation

A

 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.

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9
Q

Expansion of
inoculation in the UK

A

 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.

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10
Q

Cowpox and smallpox

A

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)

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11
Q

Spread of vaccination –
and opposition

A

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).

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12
Q

Dame Mary
Gilmore (1865-
1962) - childhood
vaccination
experience in 1870s
Australia

A

 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.

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13
Q

Pasteur and
rabies

A

 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.

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14
Q

Poliomyelitis

A

 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.

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14
Q

Poliomyelitis

A

 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.

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14
Q

Diphtheria
antitoxin

A

 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.

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15
Q

Measles

A

 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.

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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.
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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.
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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.
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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
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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.
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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.
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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
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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’.
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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.
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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.
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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 .
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A poisonous tree as metaphor for the effects of smallpox vaccination as seen by anti-vaccinationists in the early 1900s.
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French caricature from around 1800 shows that fear of vaccination quickly produced reactions among artists.
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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
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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
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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
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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.
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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)
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Variety of vaccine platforms, administration routes, polyvalent vaccines and improvements in adjuvants and delivery systems
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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.
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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.
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Risks of myocarditis from COVID vaccines
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MMR vaccine and autism
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Global measles resurgence of 2018–2019
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Lessons learnt
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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
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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.
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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
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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
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Factors influencing vaccination uptake
▪ Complex and multidimensional reasons ▪ Low perceived risk of disease ▪ Fear and misinformation ▪ Vaccine failures
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Future directions in vaccines
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Future directions in vaccines
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Future directions in vaccines
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Future directions in vaccines
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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
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