Download Vaccination

Examination dates
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- 25 gennaio 12.00-14.00 aula da definire
- 08 febbraio 12.00-14.00 aula da definire
- 22 febbraio 12.00-14.00 aula da definire
- 15 giugno 12.00-14.00 aula da definire
- 28 giugno 12.00-14.00 aula da definire
- 12 luglio 12.00-14.00 aula da definire
- 30 settembre 12.00-14.00 aula da definire
Immunity
• Active
•
Preferred, it induces immunological
memory
• Passive
Immunological memory
• At the cellular level, immunological memory
depends on epigenetic changes in T
lymphocytes and B lymphocytes that allow a
faster effector response to pathogens.
Immunological memory in B cells may also
reflect genetic alterations as immunoglobulin
M (IgM) antibodies switch to IgA or IgG and
somatic mutations enhance antibody affinity.
There are two main kinetic patterns of expression for genes that are expressed at higher levels
in memory T cells than in naive T cells. First, there are genes that are highly expressed in
resting memory T cells compared with resting naive T cells. These highly expressed genes in
resting memory T cells include genes involved in migration, homeostasis and readiness for
activation. Second, there are genes that are highly expressed only after the activation of
memory T cells; these genes are termed poised genes. Such poised genes are tightly regulated
when the T cell is in the resting state but are rapidly induced after T cell activation. It is
apparent that the function of these poised genes is not desired in the resting state, and
therefore they are minimally expressed. These two patterns of expression for genes that are
highly expressed in memory T cells show that the expression of such genes is precisely
controlled in a time- and space-dependent manner to fulfil the function of memory T cells.
An example from macrophages
Vaccination
The World Health Organization (WHO)
estimate that vaccination averts 2-3 million
deaths per year (in all age groups), and up to
1.5 million children die each year due to
diseases which could have been prevented by
vaccination. They estimate that 29% of
deaths of children under five years old in
2013 were vaccine preventable.
Vaccines: a success story in modern medicine
“with the exception of safe
water, no modality, not even
antibiotics, has had a major
effect on mortality reduction
and population growth”
Plotkin ‘A Short History of Vaccination’ in Vaccines
Vaccines are one of the most
important successes in modern
medicine and immunology
The greatest triumph in vaccination has
been the global eradication of smallpox,
announced by the World Health
Organization in 1979.
What vaccines do
• Most vaccines generate antibodies that neutralize the
pathogen and its associated toxins, and stop infection
• In many cases, pre-existing antibodies must already be
present at the time of infection (so vaccination must be
performed before the subject is exposed to the pathogen)
– Example: tetanus, for which you need antibodies to neutralize
the fast damage caused by the powerful toxin
• Indeed the toxin is so powerful that disease inducing doses may not
be sufficient to induce an immune response, and survivors of tetanus
need to be immunized anyway…
• Immune responses to infectious agents generate several
different antibodies, but only some of them are protective
– Vaccination strategy should optimize the selection of protective
antibodies
Features of effective vaccines
• Close to 100% safe (even a low level of toxicity is not
acceptable)
• Very effective: most if not all of the immunized
people must be protected
• Long-lasting: it is not practical to immunize entire
populations repeatedly, the vaccine must generate
memory
• Cheap
• Concept of “herd immunity”: as long as most of the
individuals are immunized and therefore protected,
not necessarily all of the individuals must be
immunized (even unvaccinated members of the
community are well protected, because the chance
to encounter the pathogen is decreased)
• Anyway, 80% or >80% levels of immunized
population are required, so that when levels fall
below sporadic epidemics can occur
Vaccination in history
• 2000 bC: Athenians who survived the 1st outbreak
of plague were resistant to the disease when a
2nd outbreak occurred
• E. Jenner (1749-1823)
– Optimized “variolation” using cowpox
• Smallpox from sick people was originally used, with several
people dying from the disease (3-4%)
• Jenner introduced cowpox and demonstrated its efficacy by
intentionally infecting vaccinated people with smallpox
(small amounts)
– None of these approaches could have been considered acceptable
by current ethical standards
Limitations in vaccination strategies
• Vaccination works extremely well for diseases
that can be efficiently tackled by a strong Abmediated response
• Many diseases (AIDS, malaria, tubercolosis)
need both Ab- and cell-mediated immunity
• Current vaccination approaches are relatively
weak in eliciting a strong cell response
Evolution in the development of
vaccines
• Initial approaches
– Use of organisms with reduced pathogenicity started as a purely
empirical approach, and evolved to the generation of genetically
attenuated pathogens
• Functional genomics studies of the pathogens
• Identify genes important for disease
• Generate strain with mutated genes: unable or with dramatically reduced
ability to induce disease
• Use these strains to vaccinate
– Alternative approach: use killed organisms, or purified components of
organisms
• Example of “inactivated” purified component: use of inactivated toxins for
tetanus
– Modern vaccinology: based on better understanding of
pathogenicity/immunogenicity, response to pathogenes, regulation of
the immune system
Public Health
Clinical Medicine
Public Health
Individual Health
Etica Medica
Pub.Health Ethics
Needs of the society vs individuals
Autonomy
Vaccination and public health
Prospettiva individuale:
Cosa dobbiamo agli altri?
Prospettiva sociale:
Quando l’intervento dello stato è giustificato?
Giustizia sociale:
Costi e benefici sono distribuiti equamente?
Il dilemma centrale delle
politiche vaccinali
• LIBERTÀ DI SCELTA INDIVIDUALE?
È un diritto dell’individuo l’astenersi dalla partecipazione alle
campagne vaccinali? Queste scelte vanno rispettate come
libera espressione dell’autonomia individuale? Sono da
biasimare in quanto scelti miopi/egoistiche?
• VACCINAZIONI OBBLIGATORIE?
Lo stato ha il diritto di imporre campagne vaccinali
obbligatorie? In quali casi (epidemie? pandemie?) Su quali basi
giuridiche e morali? L’imposizione dell’obbligo vaccinale è un
caso di paternalismo statale ingiustificato?
Vaccino Salk(1952): virus
inattivato, somministrato
per via intramuscolare
Vaccino Sabin(195): virus
attenuato, somministrato
per via orale
I casi di polio negli USA
diminuiscono drasticamente:
1952  58.000 casi
1955  inizio campagne
vaccinali
1957  5.600 casi
1961  161 casi
…la luna di miele con i vaccini
Europa polio-free
(OMS)
Epidemia in Olanda
Ultimo caso
polio in Italia
Vaccinazione
obbligatoria in
Italia
Introduzione vaccino
virus attenuato -Sabin
8300 casi di polio
in Italia
Introduzione
vaccino virus
ucisso - Salk
1957 1958 1964
1966
1983 1992
2002
 Le campagne vaccinali di massa (obbligatorie) hanno permesso
di eliminare malattie pericolose e invalidanti come il vaiolo e la
poliomielite.
 Queste campagne hanno permesso, inoltre, di raggiungere
l’immunità di gruppo: una certa percentuale di individui vaccinati
protegge dall’infezione anche gli individui non vaccinati
 L’immunità di gruppo è un bene pubblico da mantenere
•Vaccines must also be perceived to be safe. Bordetella pertussis causes
whooping cough, which in small infants results in significant
hospitalization (32% of cases), pneumonia (10% of cases)and death
(0.2% of cases)
•The whole cell vaccine against Bordetella pertussis was developed in
the 1930's and childhood vaccination in the US reduced the annual rate
of infection from 200/100,000 in the 1940's to less than 2/100,000.
•Whole cell vaccine, given with tetanus and diphtheria toxoids, was
associated with inflammation at the injection site. In a few children,
high temperature and persistent crying occurred; very rarely, seizures
or a transient unresponsive state were seen.
•Anecdotal reports that irreversible brain damage might be a rare
consequence of pertussis vaccination, coupled with two deaths in
Japan, lead to a decline in vaccination rates in the late 1970's and a rise
in whopping cough and death due to pertussis infection, especially in
Japan and in Great Britain.
•As a result of those 2 deaths in Japan that were feared to have been
due to the vaccine, the vaccine was temporarily suspended, the given
only to older children
•A few years later there was a big outbreak (13000 cases) and 41 kids
died.
•Careful studies did not confirm that pertussis vaccination was a
primary cause of brain injury, but in response to public concerns an
acellular vaccine was developed containing purified antigens that
induce protective immunity
•This vaccine is as effective as the whole cell vaccine and does not
induce the common side-effects of the original vaccine.
•Recent anecdotal reports of association between childhood
vaccination (particularly with MMR) and autism have raised concerns in
parents; worldwide studies have found no association between the
incidence of vaccination and autism.
Il vaccino MMR è un vaccino
trivalente contro morbillo, parotite e
pertosse. Nel 1998 un medico
inglese
Andrew
Wakefield
pubblica uno studio su Lancet,
proponendo
una
possibile
associazione
tra
campagne
vaccinali e casi di autismo.
Propone che i tre vaccini vengano
somministrati separatamente
Nel Febbraio 2010, Lancet ritira la
pubblicazione. Wakefield colpevole di
frode scientifica
Si possono giustificare campagne
obbligatorie?
Se sì, con quali argomenti?
L’argomento del danno agli altri
“the only purpose for which power can be
rightfully exercised over any member
of a civilized community, against his
will, is to prevent harm to others. His
own good, either physical or moral, is
not a sufficient warrant”
John Stuart Mill, On Liberty, 1859
La ratio legale per l’obbligatorietà
• 1905: la Corte Suprema decide il caso
Jacobson vs. Massachusetts:
“There are manifold restraints to
which every person is necessarily
subject for the common good.
[…] a community has the right to
protect itself against an epidemic
of disease which threatens the
safety of its members”
Il problema dei free-rider
Sono definiti free-rider coloro che
godono dei benefici di un bene
pubblico (nel nostro caso immunità di
gruppo) senza partecipare alla sua
creazione
Il caso dei free-rider pone particolari
problemi morali?
Alcuni sostengono che, se l’immunità
di gruppo non è minacciata, il
comportamento dei free-rider non è
moralmente reprensibile. Sarebbe
sbagliato vaccinare oltre la soglia di
immunità di gruppo
Il valore morale dell’astensione non
dipende dall’azione in sé ma dalle
conseguenze.
Figure 14-21
Live-attenuated viral vaccines
• Many currently used antiviral vaccines
(developed decades ago) consists of attenuated
or inactivated viruses
– Inactivated: treated to make them unable to replicate
– Attenuated: grown by culturing the virus in vitro using
nonhuman cells, they become less able to grow in
human cells
• They induce immunity but not disease
• Compared to inactivated vaccines, they are >>>potent
because they elicit efficient CD4 and CD8 T cell responses
Figure 14-24 part 1 of 2
Figure 14-24 part 2 of 2
Caveats of attenuated vaccines
• virus reactivation and induction of the disease
– extremely rare, especially with new approaches to
attenuation
• In immuno-compromised individuals,
attenuated viruses can be virulent and cause
disease
New approaches to development of
attenuated vaccines
• Identification of virulence genes
– Introduce several mutations/delete the gene
• Extremely rare the reactivation
• Generation of an avirulent (nonpathogenic)
virus that can be used to vaccinate
Figure 14-25 part 1 of 2
Figure 14-25 part 2 of 2
Attenuated vaccines against bacteria
and parasites
• BCG: protects children against disseminated
tubercolosis, but not effective against the
adult pulmonary disease
• Originally obtained from a pathogenic isolate
of Mycobacterium bovis
– More recent derivatives exploit recombinant DNA
technologies ( example: BCG overexpressing a
M.tubercolosis-antigen)
Genetically attenuated parasites
• Sporozoites with key mutated genes cannot infect productively liver cells, but can
circulate in the bloodstream and elicit an immune response that (preclinical
studies) is protective against infection by WT sporozoites
Route of vaccination
• It is important to consider the point of entry of the infectious agent
– Even if immunity is systemic, it is possible to have differences in the
efficacy of the immune response in different organs, and therefore
one goals it to achieve maximum efficacy at the usual point of entry
for the pathogen (i.e. lungs for influenza virus, etc…)
• Usually vaccination occurs by injection
– Intranasal vaccines are more effective to protect from upper
respiratory tract infections by influenza viruses
– Injected vaccines are more effective to protect from lower respiratory
tract complications of the disease
– Injection is expensive, requires trained people, etc….
• Orally administered antigens may induce tolerance rather than
protection
– it is important to understand the rules of mucosal immunity, a task
that is ongoing
Conjugate vaccines
• Effort to produce acellular vaccines using isolated constituents of a
pathogen
• A single constituent rarely if ever can be obtained from a single
antigen
– Need to activate different types of immune cells to initiate an effective
immune response
• Conjugate vaccines: example vaccines against H. influenzae type B,
responsible for meningitis
– Vaccines directed against capsular polysaccharides
• Children <2 yrs of age cannot develop good antibodies (because they need T
cells to develop protective antibodies, while in older children and adults
protective antibodies against capsule polysaccharides do not need T cells)
– Bacterial polysaccharides have been coupled to protein carriers, that
provide peptide antigens recognized by T cells
• Now there is an effective T cell response
Protective effect of vaccination against
group C N. meningitis using conjugate
vaccines
Peptide-based vaccines
• Approach to identify antigenic peptides:
– Empirical
– Reverse immunogenetics (see tomorrow for more details)
• Peptide-based vaccines have drawbacks:
– Difficult to identify antigens that are presented equally well by all MHC
molecules
– Tolerance my be induced
– MHC class I processing pathway is not involved, so activation of CD8 T
cells is restricted
– Are not sufficient to stimulate the immune system, requiring
adjuvants
• Development of new peptide vaccines (example new HPV vaccines)
– Use of very long peptides (100aa long), that can generate when
processed several peptide epitopes that can be presented by different
MHC molecules
Figure 14-26
Computer Aided Vaccine Design
• Problem of Pattern Recognition
– ATGGTRDAR
– LMRGTCAAY
– RTTGTRAWR
– EMGGTCAAY
– ATGGTRKAR
– GTCVGYATT
Epitope
Non-epitope
Epitope
Non-epitope
Epitope
Epitope
• Commonly used techniques
– Statistical (Motif and Matrix)
– AI Techniques
Adjuvants
• Peptide-based vaccines require adjuvants to
mimic how infection activates innate immunity,
that induces dendritic cells to become optimally
stimulatory for T cells
• Alum (inorganic aluminum salts) are approved in
US for use as adjuvants, In Europe also squalene
(an oil) is used
– Alum activates NLRP3 (innate immunity bacterial
sensor mechanisms), thus inducing the inflammatory
reactions that in the end lead to adaptive immune
response
DNA vaccination
• Intramuscular injection of DNA (plasmids)
encoding viral immunogens in mice->
– Umoral and cellular response that results in
immunization of the mouse
• In preclinical models, vaccination by DNA
induces weak protection in many cases
– Potentiation by plasmids expressing cytokines, or
co-stimulatory molecules
Figure 14-28 part 1 of 2
Figure 14-28 part 2 of 2
Could vaccines breed viciousness?
•
Gandon et al. used mathematical modeling to show that vaccines
designed to reduce pathogen growth rates, or neutralize toxins,
can diminish selection against virulent pathogens (host mortality)
•
The idea is that immunity (say to the toxin) reduces the risk of
host death and shifts the optimal virulence higher. If hosts don’t
suffer from the toxin, the pathogen can evolve to higher levels of
virulence if that helps transmission (increases R0)
•
Post-vaccination, pathogens evolve to higher levels of intrinsic
virulence in unvaccinated individuals
•
Can erode population-wide benefits and even increase overall
mortality rates
•
Infection-blocking vaccines don’t have this problem
Virulence-antigen vaccines
•
In principle, vaccines can also be used as evolutionary tools to
favor evolution towards benignness, and Gandon et al.’s results
do not apply generally.
•
Vaccines can exert selective forces: influenza, measles, hepatitis
B
•
The virulence-antigen strategy describes how to use evolution to
our advantage:
•
Target just the most virulent forms of a pathogen by making the
virulence gene the target
•
Such vaccines should disproportionately suppress severe forms,
but leave behind mild forms that can act as natural “vaccine”
Virulence-antigen vaccines
•
The diptheria vaccine works in just this way
•
Active component is derived from diptheria toxin
•
When iron levels are low, Corynebacterium diptheriae produces
the toxin, killing nearby cells and freeing up iron
•
Toxin is impotent in immunized person, just a waste of energy
(about 5% of the protein budget to make a product that doesn’t
work)
•
Toxigenic variants should be at a disadvantage
•
Accordingly, diptheria, but not C. diptheriae, has disappeared in
areas using the vaccine
•
Mild forms persist even after immunization stops