Vaksin dan Sera DEWI indonesian2014.ppt

Milestones in immunizationMilestones in immunization

2

1500BC Turki mulai terjangkit variolation

3000BC munculnya “sniffing powdered small pox crust” di Mesir

2000BC Sniffing of small pox crust di Cina

1700AD Mulai terjadi serangan

cacar (variolation) di Inggris lalu di US.

Variolation: the startVariolation: the start

British Ambassador Wife in Turky (March 1717)Write about the smallpox, which attacked her son, to a friend in England:

“The small pox, so fatal, so general amongst us, is entirely harmless here by the invention of ingrafting…. I am patriot enough to bring this invention into fashion in England.

British Ambassador Wife in Turky (March 1717)Write about the smallpox, which attacked her son, to a friend in England:

“The small pox, so fatal, so general amongst us, is entirely harmless here by the invention of ingrafting…. I am patriot enough to bring this invention into fashion in England.

3

Milestones in immunizationMilestones in immunization

4

1780AD Edward Jenner

menemukan vaksin small pox (cacar)

Edward Jenner

5

Discovery of small pox vaccine

Edward JennerAmong patients awaiting small pox vaccination

6

Modern era of the vaccine

Modern era of the vaccine

7

1920sDiphtheria and Tetanus

1934Pertussis

1955Salk polio

1885Vaksin Rabies (Pasteur)

Modern era of the vaccineModern era of the vaccine

8

1960sMumps measles and rubella virus (MMR)

Sabin polio

1990sHepatitis and varicella

1985Haemophilus

2000Human Papillomavirus(HPV)

Vaksin

Senyawa biologi yang meningkatkan imunitas terhadap penyakit tertentu.

Istilah vaksin diambil dari Edward Jenner's (1796) menggunakan cow pox (Latin: variolæ vaccinæ, vaccīn-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 efektifMemiliki respon imun yang mirip

dengan infeksi naturalUmumnya efektif hanya dengan satu

dosis (*)Reaksi “severe” mungkin terjadiBekerja 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

BacterialBCG, oral typhoid

Inactivated VaccinesTidak 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

Bacterialpertussi, typhoid, cholera

SubunitHepatitis B, influenza, acellular pertussis, humanpapillomavirus, anthrax

ToxoidDiphtheria, 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 in use pneumococcal

meningococcal Salmonella Typhi

Haemophilus influenzae type b pneumococcal meningococcal

Conjugate polysaccharide

Different types of vaccine at a glance1. Live attenuated – BCG, oral Polio2. Killed – Injectable polio, HAV3. Toxoid – TT, DPT, 4. Sub unit vaccine- HBsAg, Hib5. Conjugate vaccine – hexavalent,

Pentavalent, trivalent6. Recombinant vector – (vaccinia or Canary pox

virus-influenza, HIV-1 GP1207. Synthetic Peptides – Influenza, Picorna8. Anti-idiotype antibodies -HBV, rabies,

Newcastle disease virus and FeLV, reoviruses and polioviruses.

9. DNA vaccines – Influenza A10. Edible vaccine – HBV, Norwalk, ETEC (ST)11. Immunological contraceptive – Anti HCG12. Vaccine against cancer –HPV,EBV (BL,

NPC),HBV (HCC)

Different modes of acquiring immunity

Different modes of acquiring immunity

20

Natural resistance

ArtificialNatural

Passive

ArtificialNatural

Active

Immunity

Acquired

Passive ImmunityPassive Immunity

21

Natural Artificial

Colostral transfer of IgA

Placental transfer of IgG

Antibodies or immunoglobulins

Immune cells

Passive ImmunizationPassive Immunization

22

 disease  indicationantibody source

human, horsediphtheria, tetanus prophylaxis, therapy

vericella zoster humanimmunodeficiencies

gas gangrene, botulism, snake bite, scorpion sting

horse post-exposure

rabies, human post-exposure

hypogamma-globulinemia

human prophylaxis

Advantages and Disadvantages of Passive

Immunization

Advantages and Disadvantages of Passive

Immunization

23

Advantages Disadvantages

serum sicknessproteksi segera

Tidak ada proteksi jangka panjang

graft vs. host disease (cell graft only)

risk of hepatitis and Aids

Active ImmunizationActive Immunization

24

Natural Artificial

exposure to sub-clinical infections

Attenuated organisms

killed organisms

sub-cellular fragments

toxins

others

Live Attenuated VaccinesLive Attenuated Vaccines

25

tuberculosis

polio*not used in std. schedule

measles, mumps & rubella

yellow feverMilitary and travelers

Varicella zosterchildren with no history of chicken pox

hepatitis Astandard 2006

Influenza selected age group (5-49)

Killed Whole-Organism VaccinesKilled Whole-Organism Vaccines

26

polio

influenzaelderly and at risk

typhoid, choleraepidemics and travelers

rabiespost exposure

pertussis replaced by the acellular vaccine

Q feverpopulation at risk

Microbial Fragment VaccinesMicrobial Fragment Vaccines

27

Bordetella. Pertussis

virulence factor proteinHaemophilus

influenzae Bprotein conjugated polysaccharide

Streptococcus pneumoniae

Polysaccharide mixtureNeisseria

meningitidispolysaccharide

Microbial Fragment VaccinesMicrobial Fragment Vaccines

28

Clostridium tetani (tetanus)

inactivated toxin (toxoid)

Corynebacterium diphtheriae

inactivated toxin (toxoid)

Vibrio cholerae

toxin subunits

Hepatitis B virus

cloned in yeast

Modification of Toxin to ToxoidModification of Toxin to Toxoid

29

toxin moiety antigenic determinants

chemical

modification

Toxin Toxoid

Future VaccinesFuture Vaccines

anti-Idiotype Vaccine

30

Immuno-dominant peptide

DNA

Anti-idiotype antibodies as vaccine

antibodyantigen

Antigen may be protein,carbohydrate,etc.

Antigenicdeterminant

Miceimmunized idiotype1

First antibody selectedfor high affinity forimmunizing antigen,made monoclonal

Anti-idiotype antibodiesRaised against idiotype 1

Second antibodiesscreened for similarityto original antigen

Anti-idiotype 1

Anti-idiotype 1

like antigen unlike antigen

vaccine

32

anti-Idiotype Vaccine

33

Antiidiotype antibody in toleranceAntiidiotype

antibody productionAntiidiotype

mediated tolerance

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.

AdjuvantsAdjuvants

35

• Salts:• Al(OH)3; AlPO4;

CaPO4• Be(OH)2

YesYesNo

Human use Mode of action

Slow release of antigen; TLR interaction and cytokine induction

Adjuvant type

Slow release of antigenNo• Mineral oils without

bacteria

Yes• Bacteria in Mineral oils

(Mycobacteria, Nocardia)

No

Slow release of antigen TLR interaction and cytokine induction

AdjuvantsAdjuvants

36

Human use Mode of actionAdjuvant type

• Synthetic polymers:• Liposomes• ISCOM• Poly-lactate

Slow release of antigenNo

Yes• Bacteria:

• Bordetella pertussis• Mycobacterium bovis

(BCG and others)No

TLR interaction and cytokine induction

• Bacterial products:• Myramyl peptides No

TLR interaction and cytokine induction

AdjuvantsAdjuvants

37

• Poly-nucleotides:• CpG No*

Human use Mode of action

TLR interaction and cytokine induction

Adjuvant type

• Cytokines:• IL-1, IL-2, IL-12,

IFN-γ, etc. No*Activation of T and B cells and APC

*Used in experimental immunotherapy of human malignancies

Recommended Childhood Immunization Schedule

38MMWR, 55: Jan 5, 2007

Recommended age range Catch-up immunization Certain high risk groups

Recommended Immunization Schedule for Ages 7-18

39

MMWR, 55: Jan 5, 2007

Recommended age range Catch-up immunization Certainigh risk groups

Adverse Events OccurringWithin 48 Hours DTP of Vaccination

Adverse Events OccurringWithin 48 Hours DTP of Vaccination

41

 Event  Frequencylocalredness, swelling, pain

1 in 2-3 doses

systemic: Mild/moderatefever, drowsiness, fretfulness vomiting anorexia

1 in 2-3 doses1 in 5-15 doses

systemic: more serious persistent crying, fevercollapse, convulsionsacute encephalopathypermanent neurological deficit

1 in 100-300 doses1 in 1750 doses1 in 100,000 doses1 in 300,000 doses

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, Hepatitis B, 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 (Freund’s 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 NF-κB (nuclear factor κB) 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-β (interferon β)] (TLR3 and 4) and TRAM (TRIF related adaptor molecule) (TLR4).

Another signalling molecule suggested to be involved in PRR signalling is NIK (NF-κB-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-κB. PRR signalling has been recently reviewed by O’Neill 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-κB receptor most significantly, whereas TRIF was able to activate the IFN-β promoter. By utilizing a dual promoter system, MyD88 was shown to induce a significant IgG antibody response with a significant IFN-γ and CTL (cytotoxic T-lymphocyte) 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 anti-influenza responses in a challenge model.

Another signalling molecule, NIK, was shown to be an effective vaccine adjuvant.

NIK overexpression can induce an NF-κB 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-α, 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-γ 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-γ - 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-γ 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