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Milestones

Milestones in
in
immunization
immunization
3000BC

1500BC

munculnya sniffing

Turki mulai terjangkit

powdered small pox crust


di Mesir

2000BC
Sniffing of small pox
crust di Cina

variolation

1700AD
Mulai

terjadi serangan
cacar (variolation) di
Inggris lalu di US.

Variolation:
Variolation: the
the start
start
British
British Ambassador
Ambassador Wife
Wife in
in Turky
Turky (March
(March 1717)
1717)
Write
Write about
about the
the smallpox,
smallpox, which
which attacked
attacked her
her son,
son,
to
to aa friend
friend in
in England:
England:
The
The small
small pox,
pox, so
so fatal,
fatal, so
so general
general amongst
amongst us,
us,
is
is entirely
entirely harmless
harmless here
here by
by the
the invention
invention of
of
ingrafting.
ingrafting. II am
am patriot
patriot enough
enough
to
to bring
bring this
this invention
invention into
into fashion
fashion in
in England.
England.

Milestones
Milestones in
in
immunization
immunization

1780AD

Edward Jenner
menemukan vaksin small
pox (cacar)

Edward Jenner

Discovery of small pox vaccine


5

Edward Jenner
Among patients awaiting small pox vaccination

Modern
Modern era
era of
of the
the
vaccine
vaccine
1885
Vaksin Rabies
(Pasteur)

1920s
Diphtheria and
Tetanus

1934
Pertussis

1955
Salk polio

Modern
Modern era
era of
of the
the
vaccine
vaccine
1960s
Mumps measles and
rubella virus (MMR)
Sabin polio

1990s
Hepatitis and
varicella

1985
Haemophilus

2000
Human Papillomavirus
(HPV)

Vaksin
Senyawa biologi yang meningkatkan

imunitas terhadap penyakit tertentu.


Istilah vaksin diambil dari Edward Jenner's
(1796) menggunakan cow pox (Latin:
variol vaccin, vaccn-us, dari vacca
sapi- cow), lalu diberikan kepada manusia,
sehingga dapat membantu mereka
bertahan terhadap serangan smallpox.

Karakteristik
Prophylactic (mencegah - mengurangi efek dari infeksi

pada masa mendatang oleh berbagai antigen alami atau


yang masih wild)
Therapeutic (penyembuhan)
Mengandung senyawa yang menyerupai mikroorganisme

penyebab penyakit.

Dapat dibuat dari mikroba yang dilemahkan, telah

dinon-aktifkan, atau dari toksin mikroba.

GOAL menstimulasi imun sistem tubuh dan

mengenalinya sebagai senyawa asing, lalu


menghancurkannya jika ada serangan kembali,
mempermudah proses eliminasi.

Prinsip Vaksinasi
Aturan Umum
Semakin mirip vaksin dengan
mikroorganisme penyebab
penyakit maka akan
semakin baik respon imun
terhadap vaksin tersebut,

Vaccines
Live attenuated
- viruses
- bacteria

Inactivated
seluruh bagian virus
- viruses
- bacteria

sebagian dari mikroba


- protein-based
- toxoid
- subunit

- polysaccharide-based
- pure
- conjugate

Live Attenuated Vaccines


Virus atau bakteri yang wild dilemahkan

(Attenuated)
Harus direplikasi agar efektif
Memiliki respon imun yang mirip dengan
infeksi natural
Umumnya efektif hanya dengan satu dosis
(*)
Reaksi severe mungkin terjadi
Bekerja bersama dengan antibodi yang
bersirkulasi
Fragile harus disimpan dan ditangani
dengan hati-hati.

(*) kecuali vaksin yang diberikan secara peroral

Live Attenuated Vaccines in


use

Viral

measles, mumps, rubella, varicella/zoster,


yellow fever, rotavirus, intranasal influenza,
vaccinia
Bacterial

BCG, oral typhoid

Inactivated Vaccines
Tidak dapat bereplikasi
Umumnya tidak seefektif vaksin yang berasal

dari mikroba hidup

Kurang interference dari antibodi yang

bersirkulasi dibanding live vaccines

Umumnya dibutuhkan 3-5 kali pemberian


Respon immune yang muncul umumnya

humoral

Titer antibodi dapat menurun seiring

berjalannya waktu

Inactivated Vaccines in
use
Viral
polio, hepatitis A, rabies, influenza
Bacterial

pertussi, typhoid, cholera


Subunit

Hepatitis B, influenza, acellular pertussis,


humanpapillomavirus, anthrax

Toxoid
Diphtheria, tetanus

Pure Polysaccharide
Vaccines
Tidak menimbulkan respon imunologi yang

konsisten pada anak usia di bawah 2 tahun.


Tidak ada respon penguat (booster response)
Antibodi yang dihasilkan kurang fungsional
Imunogenisitasnya meningkat dengan

konjugasi

Polysaccharide Vaccines
use
in
pneumococcal
meningococcal
Salmonella Typhi

Conjugate
polysaccharide
Haemophilus influenzae type b
pneumococcal
meningococcal

Different types of vaccine at


1.
Live attenuated BCG, oral Polio
a glance
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.

Killed Injectable polio, HAV


Toxoid TT, DPT,
Sub unit vaccine- HBsAg, Hib
Conjugate vaccine hexavalent,
Pentavalent, trivalent
Recombinant vector (vaccinia or Canary pox
virus-influenza, HIV-1 GP120
Synthetic Peptides Influenza, Picorna
Anti-idiotype antibodies -HBV, rabies,
Newcastle disease virus and FeLV, reoviruses and
polioviruses.
DNA vaccines Influenza A
Edible vaccine HBV, Norwalk, ETEC (ST)
Immunological contraceptive Anti HCG
Vaccine against cancer HPV,EBV (BL,
NPC),HBV (HCC)

Different
Different modes
modes of
of acquiring
acquiring
immunity
immunity

Immunity
Natural Acquired
resistance
Passive

Active

ArtificialNatural Artificial Natural


20

Passive
Passive Immunity
Immunity

Natural
Placental transfer
of IgG

Colostral transfer
of IgA

Artificial
Antibodies or
immunoglobulins
Immune cells

21

Passive
Passive Immunization
Immunization
disease
diphtheria, tetanus

antibody source
human, horse

indication
prophylaxis, therapy
immunodeficiencies

vericella zoster

human

gas gangrene,
botulism, snake
bite, scorpion sting

horse

post-exposure

human

post-exposure

human

prophylaxis

rabies,

hypogammaglobulinemia

22

Advantages
Advantages and
and
Disadvantages
Disadvantages of
of Passive
Passive
Immunization
Immunization

Advantages

Disadvantages
Tidak ada proteksi
jangka panjang

proteksi segera

serum sickness
risk of hepatitis and
Aids
graft vs. host disease
(cell graft only)

23

Active
Active Immunization
Immunization
Natural

Artificial
Attenuated
organisms
killed organisms

exposure to subclinical infections

sub-cellular
fragments
toxins
others

24

Live
Live Attenuated
Attenuated Vaccines
Vaccines
polio*
not used in std. schedule

measles,
mumps &
rubella
Varicella zoster
children with no history
of chicken pox

hepatitis A
standard 2006

yellow fever
Military and travelers

Influenza
selected age group (549)

tuberculosis

25

Killed
Killed Whole-Organism
Whole-Organism
Vaccines
Vaccines
polio

Q fever
population at risk

influenza
elderly and at risk

rabies
post exposure

typhoid, cholera
epidemics and travelers

pertussis
replaced by the
acellular vaccine

26

Microbial
Microbial Fragment
Fragment
Vaccines
Vaccines
Bordetella.
Pertussis
virulence factor protein

Haemophilus
influenzae B

protein conjugated polysaccharide

Streptococcus
pneumoniae

Polysaccharide mixture

Neisseria
meningitidis

polysaccharide
27

Microbial
Microbial Fragment
Fragment
Vaccines
Vaccines
Clostridium tetani
(tetanus)
inactivated toxin (toxoid)

Corynebacterium
diphtheriae
inactivated toxin (toxoid)

Vibrio
cholerae

toxin subunits

Hepatitis B
virus
cloned in yeast
28

Modification
Modification of
of Toxin
Toxin to
to
Toxoid
Toxoid
Toxin

Toxoid
chemical
modification

toxin moiety

antigenic determinants

29

Future
Future Vaccines
Vaccines

anti-Idiotype Vaccine
DNA
Immuno-dominant peptide

30

Anti-idiotype antibodies as
vaccine
antigen

antibody

Antigen may
First antibody selecte
Antigenic
be protein,
Mice
determinant immunized idiotype1 for high affinity for
carbohydrate,
immunizing antigen,
etc.
made monoclonal
Anti-idiotype antibodies
Raised against idiotype 1

vaccine

Antiidiotype 1
like antigen

Antiidiotype 1
unlike antigen

Second antibodies
screened for similarity
to original antigen

anti-Idiotype Vaccine

32

Antiidiotype antibody in
tolerance
Antiidiotype
antibody production

Antiidiotype
mediated tolerance

33

Adjuvant
Adjuvant = Antibody enhancing agents Chemical

substances which are supposed to enhance the


immune response to the vaccine.
Induce local inflammation stimulate influx of APCs
to sites of antigen exposure.
Adjuvants activate APCs expression of
costimulators and to produce soluble proteins
(cytokines), that stimulate T cell responses.
Adjuvants act on APCs to prolong the persistence of
peptide-MHC complexes on the cell surface.
Terbuat dari: microbes produce substances, such as
killed mycobacteria.
It is not possible to use most of these microbial
adjuvants in humans because of the pathologic
inflammation that microbial products elicit.

Adjuvants
Adjuvants
Adjuvant type

Human use

Mode of action

Salts:
Al(OH)3; AlPO4;
CaPO4
Be(OH)2

Yes
Yes
No

Slow release of antigen; TLR


interaction and cytokine
induction

Mineral oils without


bacteria

No

Slow release of antigen

Bacteria in Mineral oils


(Mycobacteria, Nocardia)

Yes

Slow release of antigen TLR


interaction and cytokine
induction

No

35

Adjuvants
Adjuvants
Adjuvant type
Bacteria:

Human use

Bordetella pertussis
Mycobacterium bovis
(BCG and others)

Yes
No

Bacterial products:

Myramyl peptides

Synthetic polymers:
Liposomes
ISCOM
Poly-lactate

No

No

Mode of action

TLR interaction and


cytokine induction

TLR interaction and


cytokine induction

Slow release of antigen

36

Adjuvants
Adjuvants
Adjuvant type
Poly-nucleotides:
CpG
Cytokines:
IL-1, IL-2, IL-12,
IFN-, etc.

Human use

Mode of action

No*

TLR interaction and


cytokine induction

No*

Activation of T and B cells


and APC

*Used in experimental immunotherapy of human


malignancies

37

Recommended Childhood
Immunization Schedule

Recommended age range Catch-up immunization Certain high risk groups


MMWR, 55: Jan 5, 2007
38

Recommended Immunization
Schedule for Ages 7-18

Recommended age range Catch-up immunization Certainigh risk groups


MMWR, 55: Jan 5, 2007
39

Adverse
Adverse Events
Events Occurring
Occurring
Within
Within 48
48 Hours
Hours DTP
DTP of
of Vaccination
Vaccination

Event

Frequency

local

redness, swelling,
pain

1 in 2-3 doses

systemic: Mild/moderate

fever, drowsiness,
fretfulness vomiting
anorexia
systemic: more serious

persistent crying, fever


collapse, convulsions
acute encephalopathy
permanent neurological
deficit

1 in 2-3
doses
1 in 5-15
doses
1
1
1
1

in
in
in
in

100-300 doses
1750 doses
100,000 doses
300,000 doses
41

Vaccine and Sera Products


By type:

Adenovirus, AIDS/HIV, Animal, Anthrax,


BCG (TB), Bird flu vaccine, Bubonic
Plague, Chicken Pox, Cholera, Diptheria,
DPT/DT/DTPH/aP, Encephalitis
(Japanese), Flu, FSME, HepatitisB,
Hepatitis A, Hib/Hemophilus, HPV
Lyme disease, "Lymph" (smallpox),
Measles, Meningitis, MMR/MR, Military,
Polio, Rabies, Pneumococcal, Rubella,
Rotavirus, Swine flu vaccine 1976

By brand name/type:
Agrippal (Flu), Cervarix, Daptacel, Flumist (flu), Gardasil, Infanrix,

Immravax (MMR)-1992, Lymerix (lyme disease)-2002, Menactra,


Meningitec, (meningitis C), MeNZB vaccine (meningococcal),
Menjugate meningitis C (Chiron)
Orimune (OPV), Pandemrix, 5 in 1Pentacel (DPT, Polio, Hib),

Quadracel (DPT, Polio)


Pavivac (mumps), Pediarix, Pediacel, Pluserix (MMR)-1992,

Pneumovax (pneumococcal), Prevnar (pneumococcal), Priorix,


ProQuad

Combination Vaccines
DTaP/Hib (TriHIBit)
DTaP-IPV-HepB (Pediarix)
HepA-HepB (Twinrix)
DTaP-IPV/Hib (Pentacel)
Hib-HepB (Comvax)
DTaP-IPV (Kinrix)
MMR-Var (ProQuad)

PRRs
(pattern recognition receptors)

crucial in innate immunity


consist of extracellular TLRs (Toll Like

Receptors), as well as intracellular


receptors [some TLRs, Nod (Nuclear
Oligomerization Domain) etc.].
PRRs are able to recognize microbial
components, known as PAMPs
(pathogen-associated molecular
patterns).

TLR pathways a good target during

vaccination
- comes from the use of FCA (Freunds
complete adjuvant).
FCA is made from an oil emulsion
contains homogenized mycobacteria. - This
adjuvant induce strong immune
responses (likely due to the PAMPs of the
mycobacteria)
BUT, no definite prove as FCA is not
licensed for use in humans.
so, the use of individual PRR ligands must
be examined.

TLR ligands
shown to be effective vaccine adjuvants
Vaccines for HIV contained ligands for TLR4, TLR2 and 6,

TLR7 and 8, and TLR9 enhance specific antibody


responses.
BUT the drawbacks:

- if ligands are administered systemically inherent toxicity


cause aberrant responses and exacerbate disease states
in vaccines.
E.g: LPS is involved in neurodegenerative disorders.
- the TLR ligand must be present in the extracellular milieu
to act upon its cell-surface receptor.
Once there, the ligand will not necessarily act upon the
same cell as the antigen but on other cells in the vicinity
as well

The targeting of intracellular signalling networks, rather

than extracellular ones, would alleviate these problems. If


a DNA or viral-based expression system were used, the
molecular adjuvant would not have to be exported from
the vaccine-transfected cell. Therefore
(i) the adjuvant would target the same cell as the antigen,
allowing greater specificity.
(ii) As the adjuvant stays in the cell, if too much adjuvant
is produced, it would not cause a systemic but rather a
unicellular toxicity, which is arguably advantageous to the
immune response.
(iii) The adjuvant would reach threshold levels with faster
kinetics due to its confinement within the cell, rather than
being diluted in the extracellular milieu.
The targeting of intracellular PRR networks would allow a

more specific and less toxic response.

PPR signalling
The signalling networks induced by PRRs are complex

and some of the key adaptors are discussed below.


The principal adaptor for TLR signalling is MyD88
(myeloid differentiation factor 88) as it was shown to
be involved in all TLR signalling except for TLR3. The
TIR [Toll/IL (interleukin)-1 receptor] domain of TLRs
recruits the adaptor proteins to mediate the
activation of various transcription factors, such as NFB (nuclear factor B) and members of the IRF
(interferon regulatory factor) family. Other signalling
molecules include Mal (MyD88-adaptor-like) (TLR2
and 4), TRIF [TIR domain-containing adaptor protein
inducing IFN- (interferon )] (TLR3 and 4) and TRAM
(TRIF related adaptor molecule) (TLR4).

Another signalling molecule suggested to be involved


in PRR signalling is NIK (NF-B-inducing kinase). NIK is
most notably involved in signalling through TLR2 [4] as
well as Nods [5]. There are also several mechanisms to
suppress TLR signalling that include SOCS1 (suppressor
of cytokine signalling 1). This mediates the degradation
of phosphorylated Mal to suppress the signalling from
TLR4 toNF-B. PRR signalling has been recently
reviewed by ONeill and Bowie [6] and is detailed in
Figure 1. All of these targets are attractive as molecular
adjuvants and recent studies have addressed these
strategies

Targeting PRR signalling


MyD88 was able to activate the NF-B receptor

most significantly, whereas TRIF was able to


activate the IFN- promoter. By utilizing a dual
promoter system, MyD88 was shown to induce
a significant IgG antibody response with a
significant IFN- and CTL (cytotoxic Tlymphocyte) response upon re-stimulation. TRIF
was shown to induce a lesser antibody response
but greater cellular response than MyD88.
MyD88 mutants are able to further increase this
cellular response
TRIF was an effective adjuvant in inducing antiinfluenza responses in a challenge model.

Another signalling molecule, NIK, was shown to be an


effective vaccine adjuvant.

NIK overexpression can induce an NF-B reporter gene


without the presence of upstream stimuli . When
overexpressed in dendritic cells, NIK was able to induce a
mature phenotype with increased cytokine production (TNF-,
IL-12, IL-15 and IL-18) and the presence of cell-surface
markers (MHCI/II and co-stimulatory molecules)

Adenoviruses were used to express both a reporter antigen


and NIK.

NIK was able to increase the antibody response above that of


antigen alone and directed the antibody profile towards
IgG2a. NIK also induced a strong IFN- and CTL response
above that of antigen alone, indicating the efficient activation
of cell-mediated responses

Overexpression of transcription factors themselves has also been


examined.

overexpressed IRF-1, -3 and -7 in a DNA vaccine: IRF-1 induced


strong antibody immune responses, whereas IRF-3 and -7 induced
strong cellular immune responses. The cellular responses were
shown to be a mixture of IFN- - and IL-4-producing T-cells.

The down-regulation of intracellular signalling repressors has also


been examined

The presence of this siRNA caused dendritic cells to be more


responsive to cytokines and TLR ligands. Dendritic cells treated
with the siRNA and pulsed with antigen ex vivo were introduced
into the host as a vaccine. These treated cells were able to induce
strong IFN- and CTL responses, which were able to clear a
tumour challenge. When HIV antigens were used to pulse these
cells, a strong IgG2a antibody response was seen where the
immune response lasted greater than 6 months