13 Vaccines

VACUNAS Una aproximación teórico-práctica

Persio D. López Saturday, November 7, 2009

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¿CÓMO ABORDAREMOS? Lo que nunca se queda: historia El ABC: lo básico Los ujieres: adjuvantes ¿Qué tenemos y qué esperamos? Pinticas negras en el vestido blanco: efectos adversos Recomendaciones finales: el esquema dominicano Saturday, November 7, 2009

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HISTORIA 1796 Jenner vs. viruela

1896 Koch (MOs enteros, muertos) vs. cólera, tifoidea, plaga y otras

1880 Pasteur vs. cólera (fallida), antrax y rabia

1924 BCG (viva atenuada) vs. tuberculosis

1920s-1930s Progresivas (de toxoides y toxinas) vs. difteria y tétanos

1955 Salk (IV) vs. polio

1945 Vs. influenza, en fluido alantoico de embrión de pollo

1961 Sabin (oral) vs. polio

1960-1969 Progresivas vs. sarampión, paperas y rubéola

1974-1984 Progresivas vs. gram(+) encapsuladas – meningococo, pneumococo y Haemofilus

1981 Vs. HBV con Ag de superficie

1986 Recombinante de levadura vs. HBV

1983 Vs. Haemofilus influenzae con conjugados CH2Oproteína

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Table 40.1, Chief Landmarks in the History of Vaccinology; p. 1234. Saturday, November 7, 2009

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PRINCIPIOS BÁSICOS

1. Inmunogenicidad 2. El rol de los TLRs y otros PRRs 3. Inmunización pasiva vs. inmunización activa 4. Reactogenicidad y algunas consideraciones al respecto

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PRINCIPIOS BÁSICOS Inmunogenicidad

Es la capacidad de una molécula de inducir una respuesta inmunitaria, humoral o mediada por células, o ambas.

Goldsby RA. Immunology. 5th ed. New York: W.H. Freeman; 2002.

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phoma, as well as in lymph nodes draining the tumor site.43,44 All these studies led to the conclusion that an evaluation of the immune response in and around the tumor should be included in the prognostic evaluation and in treatment decisions.

MHC I or II

PRINCIPIOS BÁSICOS Inmunogenicidad

igins of cancer

Im munosuppr e s sion a nd T umor Pro gr e s sion

CD4 T cells

CD8 T cells Tumors can suppress immunity both systemically and in the microenvironment of the tumor A Tumor B (Fig. 3).45 In addition to producing immunosuppressive molecules such as transforming growth factor β (TGF-β)46 and soluble Fas ligand,47 many human tumors produce the immunosuppressive enzymeDendritic indolamine-2,3-dioxygenase (IDO).48,49 This enzyme cell was previously known for its role in maternal tolerance to antigens from the fetus50 and, more recently, as a regulator of autoimmunity that mediates inhibition of T-cell activation.51 MHC I or II Stereoisomers of 1-methyl-tryptophan inhibit IDO,52 and when administered to tumor-bearing mice, they restore immunity and thereby allow immune rejection of the tumor.53 Such stereoisomers might have a role in the treatment of patients with cancer. CD4 T cells The tumor microenvironment can be dominated by regulatory T cells that suppress antitumor CD8 T cells effector T cells by producing the immunosuppressive cytokines TGF-β and interleukin-10.54 High B Figure 2. Tumor Antigens Eliciting T-Cell Immunity When Presented numbers of these cells can be detected in non– to Naive T Cells by Antigen-Presenting Dendritic Cells. 55 small-cell lungNcancer and2008 ovarian cancer. Mu- Figure Dendritic cells in the tumor or theT-Cell tumor-draining lymph Presented node take up Finn OJ. Cancer immunology. Engl J Med. Jun 19;358(25):2704-15. 2, Tumor Antigens Eliciting Immunity When to tumors that produce TGF-β convert andying tumor cells, tumor proteins, and tumor peptides and process and Naive T Cells rine by Antigen-Presenting Dendritic Cells; can p. 2707 display them in their major-histocompatibility-complex (MHC) class I titumor effector T cells into regulatory T cells, and class II molecules, as shown in Panel A. If properly activated by thereby escaping their own destruction by immune

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immunostimulatory tumor products or other factors in the tumor micro- 4

PRINCIPIOS BÁSICOS Inmunogenicidad

Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002 Jun;1(6): 457-62. Figure 1, Some of the many factors that influence the immunogenicity of biopharmaceuticals; p. 458. Saturday, November 7, 2009

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PRINCIPIOS BÁSICOS Los TLRs otros PRRs) P E R S P(yE C TIVES Peptidoglycan (Gram-positive) Lipoteichoic acids (Gram-negative) Lipoproteins Lipoarabinomannan (Mycobacteria) Zymosan (yeast)

LPS (Gram-negative) Endogenous ligands Flagellin CD14

CD36

TLR6

TLR4

TLR5

MD2

Profilin-like (Toxoplasma gondii) Uropathogen?

TLR2 TLR1

TLR11

MYD88

TIRAP TRAM

TRIF TLR7

ssRNA NF-
B, IRF and MAPK signaling

Unmethylated CpG DNA

TLR3

dsRNA

Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009 Jan;9(1):57-63.

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TLR9

Figure 1 | Physiological functions of Toll-like receptors (TLRs). TLRs are involved in recognition of microbial and endogenously derived molecular patterns. This occurs both at the plasma membrane

prote sis 1 mem intra indu TICA kina of ty natu infec TLR such

TLRs In ad defen are i hom regen resto arch tion, thou ing p apop of in exten signa TLR 4

PBS

0

86

Los TLRs (y otros PRRs)

(Fig. 3a and Supplementary Table 2). The D2–C interface, in contrast, is entirely mediated by van der Waals interactions (Fig. 3b and Supplementary Table 2). Residues at the D1–A interface are more a

b

B

D2 A

C

FcR D1

D1

A

C D2

FcR

D

E

D

SAP

c D2

d

G A′

FcR

COOH

SAP

E

BC-loop D11 MBL-mediated complement attack. Figure Mannose-binding lectin (MBL) complexed with the MASPs binds NH3 B FcR A′ G microorganism and mediates a complement attack through MASP2. MASPs denote MBL-associated serine protease 28 F A Lu J, Marnell LL, Marjon KD, Mold C, Du Clos TW, Sun PD. Structural recognition and functional activation of FcgammaR by innate pentraxins. COOH O C′ A B C NH3 A Figure 2, Crystal structure of 35 Nature. SAP-FcgRIIIa complex; p. 990. C 2008 Dec 18;456(7224):989-92. D2 A E E C′ F C

Figure 2 | Crystal structure of SAP–FccRIIa complex. a–c, The view is from

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NLRB

N active complexes with Ficolin-1 (M-ficolin), not translated into protein; thus, th M BFicolin-2 L Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO. Mannose-binding and its genetic variants. Genes Immun. 2006 Mar;7(2):85-94. Figure 1, ident (L-ficolin) and Ficolin-3 (H-ficolin lectin or Hakata script encodes a polypeptide Kantigen), C D1 18–20 MBL-mediated complement 86. defence collagens. D H whichattack; are p.also predominant transcript. The vast I E produced by the liver originates F Geddes K, Magalhaes JG, Girardin SE. Unleashing the therapeutic potential of NOD-like receptors. Nat Rev Drug Discov. 2009 Jun;8(6):465-79. G initiated at exon 1, but roughly 10– J SAP Figure 1, The NOD-like receptor (NLR) family; p. 466. from exon 0 initiated transcripts.29 The organization of the humanSAP-A MBL2 gene

b

ble AP, to jor .6) ,19 . to

PRINCIPIOS BÁSICOS

PBS

NLRA subfamily CIITA

ule nd n2). sa ed on. of or d). he on ed he m.s. ng in nal of

PBS

a

PBS

Mannose-binding lectin and its genetic variants P Garred et al

which suggests the existence of a common stimulus, triggered downstream of all these PAMPs and/or DAMPs (see REFS 13,14 for recent reviews on this topic). It has been proposed that this common trigger could be stimulated by reactive oxygen species or lysosomal damage15–17. The other recently identified molecular patterns that trigger NLRs include flagellin (sensed by NLR family, CARD domain-containing 4 (NLRC4; also known as IPAF) and NLR family, apoptosis inhibitory protein (NAIP))18,19 and the lethal toxin of Bacillus anthracis

1

SAP

10 8 6 4 2 0

(sensed by NLRP their specific PA of signalling pat host response to review articles hav function5,13,21. Ind is emerging as a responses to bac adaptive immunit In this Review, are discussed; ho ciated with disea (the mutation of (the mutation of syndromes)23, is sti NOD2 have been malignant diseases

2

TNF-α (n

3

4

PRINCIPIOS BÁSICOS Inmunidad pasiva vs. inmunidad activa

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PRINCIPIOS BÁSICOS Inmunidad pasiva vs. inmunidad activa

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Figure 9.3, Initial helper T cell regulated checkpoints in memory B cell evolution; p. 294. Saturday, November 7, 2009

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PRINCIPIOS BÁSICOS Reactogenicidad y relacionados

Derivada de vacunas de microorganismos atenuados

Derivada de vacunas de microorganismos muertos o sus derivados

Replicación del microbio

Inflamación local

Versión miniatura de la enfermedad

Rxs sistémicas (fiebre, anorexia, cefalea, etc.)

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Chapter 40,Vaccines; p. 1234-90. Saturday, November 7, 2009

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PRINCIPIOS BÁSICOS Reactogenicidad y relacionados

¿Qué debemos considerar?

• Edad de inmunización: hay edades más vulnerables e • •

influyen factores como Ac maternos. Relación costo-beneficio: ¿cuántas veces inyectaremos un bebé? ¿realmente vale la pena una vacuna contra X enfermedad? Consideraciones culturales: ¡rumores anti-vacuna! (p.e. Nigeria; U.K.) Paul WE. Fundamental immunology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2003. Chapter 40,Vaccines; p. 1234-90.

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ADJUVANTES

Es una sustancia (o una estrategia) capaz de aumentar la inmunogenicidad de los antígenos incorporados en o coadministrados con ella.

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Chapter 40,Vaccines; p. 1235-90.

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ADJUVANTES Adjuvantes

Potenciadores inmunes

Sistemas de entrega de antígenos

Adjuvantes integrados

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Chapter 40,Vaccines; p. 1235-90.

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ADJUVANTES Alum: sales de aluminio Estimula Ac

Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 2009 Apr;9(4):287-93. Figure 2, Stimulation of adaptive immune responses by aluminium salts; p. 292. Saturday, November 7, 2009

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ADJUVANTES

MF59: aceite en agua Estimula Ac + + CD4 (Th2)

O'Hagan DT, Wack A, Podda A. MF59 is a safe and potent vaccine adjuvant for flu vaccines in humans: what did we learn during its development? Clin Pharmacol Ther. 2007 Dec;82(6):740-4. Figure 1, Enhanced protection against lethal influenza virus challenge in mice achieved by the inclusion of MF59 in the vaccine; p. 741. Saturday, November 7, 2009

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VACUNAS YA PRESENTES Virus vivos atenuados

Polio, paperas, rubéola, rabia…

Bacterias vivas atenuadas

BCG, Ty21a (fiebre tifoidea)

Virus muertos completos

Polio (IV-Salk), influenza, HVA, rabia

Bacterias muertas completas

Tosferina, cólera, ántrax…

Toxoides

Difteria, tétano

Vacunas moleculares: proteínas

Tosferina acelular, subunidades influenza…

Vacunas moleculares: CH2O

Hib, meningocócica, neumocócica…

Vacunas moleculares: conjugados proteína-CH2O

Hib, meningocócica, neumocócica…

Vacunas combinadas

DPT, DPT-Hib, pentavalente

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Table 40.4, Classification of Licensed Vaccines; p. 1253. Saturday, November 7, 2009

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LO QUE SE ESPERA Vacunas en vectores

Virus/bacteria atenuada con capacidad de infección limitada lleva gen/genes para antígenos de un patógeno X

Vacunas de ácidos nucleicos

Plásmidos con genes para antígenos de un patógeno X: el mismo cuerpo produce el antígeno

Vacunas peptídicas

Construcción de un polímero de péptidos (con frecuencia epítopes de céls. T), creando un inmunógeno

Vacunas de mucosas

Administrar el antígeno vía una superficie mucosa

Vacunas transdérmicas

Administrar el antígeno vía la piel

Vacunas comestibles

Ingeniería genética sobre una planta, de modo que presente los antígenos de modo inmunogénico

Vacunas cebadoras

Administrar 2 versiones de la misma vacuna: vacuna ADN seguida por vacuna en vector, o cualquiera de éstas seguida por una vacuna proteica

Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Table 40.5, Newer Approaches to Vaccine Design; p. 1255. Saturday, November 7, 2009

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EL “PERO” 3 consideraciones sobre la seriedad del asunto:

las vacunas son dadas a individuos sanos la mayoría de las vacunas son dadas a niños las epidemias (en países industrializados) parecen cosa del pasado

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EL “PERO” 1 de cada 100,000 desde inflamación hasta abcesos anafilaxis trombocitopenia artritis aguda

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DPT–convulsiones febriles (1/2,000) polio–reversión a polio (1/2.7 millones) sarampión–encefalitis (sin confirmar)

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VACUNA

EDAD

# DOSIS

REFUERZOS

BCG

Recién nacido

1

-

DPT

2,4,6 meses

3

18 meses / 4 años

HB

RN; 2,4,6 meses

3

-

HiB

2,4,6 meses

3

18 meses

PENTAVALENTE

2,4,6 meses

3

18 meses / 4 años

ANTI-POLIO

2,4,6 meses

3

18 meses / 4 años

SARAMPIÓN

9 meses

1

(SRP)

SRP

12 meses

1

-

UNICEF Dominican Republic. Supervivencia y desarrollo infantil: inmunización y la pentavalente [Internet]. Santo Domingo: UNICEF; c1946. [Tabla] Esquema de inmunización – PAI; [citado 2009 Oct 29]; [aprox. 2 pantallas]. Disponible en: http://www.unicef.org/republicadominicana/health_childhood_4411.htm.

CÓMO LO HACEMOS EN DOMINICANA PROGRAMA AMPLIADO DE INMUNIZACIÓN Saturday, November 7, 2009

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GRACIAS POR SU ATENCIÓN (En serio.)

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