VACUNAS

Una aproximación teórico-práctica

Persio D. López

Saturday, November 7, 2009 1

 ¿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 2

 HISTORIA
1896
1796 1924 1974-1984
Koch
Jenner 1961 Progresivas vs.
(MOs BCG (viva
vs. Sabin gram(+)
enteros, atenuada)
viruela (oral) encapsuladas – 1986
muertos) vs.
vs. polio meningococo, Recombinante
vs. cólera, tuberculosis 1955
pneumococo y de levadura
tifoidea, Salk (IV)
Haemofilus vs. HBV
plaga y vs. polio
otras

1945 1981
1920s-1930s Vs. HBV
Vs.
Progresivas (de con Ag de 1983
influenza, 1960-1969
1880 toxoides y superficie Vs.
en fluido Progresivas
Pasteur toxinas) vs. Haemofilus
alantoico vs.
vs. cólera difteria y tétanos influenzae con
de sarampión,
(fallida), conjugados
embrión paperas y
antrax y CH2O-
de pollo rubéola
rabia proteína
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 3
 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

Saturday, November 7, 2009 4

 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.

Saturday, November 7, 2009 4

 phoma, as well as in lymph nodes draining the
tumor site.43,44 All these studies led to the con- MHC I or II
clusion that an evaluation of the immune response

PRINCIPIOS BÁSICOS
in and around the tumor should be included in the
prognostic evaluation and in treatment decisions.

Im munosuppr e s sion a nd T umor Inmunogenicidad CD4 T cells

igins of cancer Pro gr e s sion
CD8 T cells
Tumors can suppress immunity both systemi-
cally and in the microenvironment of the tumor
A Tumor
(Fig. 3).45 In addition to producing immunosup- B
pressive molecules such as transforming growth
factor β (TGF-β)46 and soluble Fas ligand,47 many
human tumors produce the immunosuppressive
indolamine-2,3-dioxygenase (IDO).48,49
enzymeDendritic
This enzyme cell was previously known for its role in
maternal tolerance to antigens from the fetus50
and, more recently, as a regulator of autoimmu-
nity 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 stereoiso-
mers might have a role in the treatment of patients
CD4 T cells with cancer.
The tumor microenvironment can be dominat-
ed by regulatory T cells that suppress antitumor
CD8 T cells
effector T cells by producing the immunosuppres-
B sive cytokines TGF-β and interleukin-10.54 High 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.
small-cell lungNcancer and2008
ovarian 55
cancer. Mu- Figure
Finn OJ. Cancer immunology. Engl J Med. Jun 19;358(25):2704-15. Dendritic cells in
2, Tumor the tumor
Antigens or theT-Cell
Eliciting tumor-draining lymph Presented
Immunity When node take up
to
Naive T Cells rine tumors that produce
by Antigen-Presenting TGF-β
Dendritic Cells; can convert an-
p. 2707 dying tumor cells, tumor proteins, and tumor peptides and process and
titumor effector T cells into regulatory T cells, display them in their major-histocompatibility-complex (MHC) class I
thereby escaping their own destruction by immune and class II molecules, as shown in Panel A. If properly activated by
Saturday, November 7, 2009 56,57 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 4

 PRINCIPIOS BÁSICOS
Los TLRs
P E R S P(yE C
otros PRRs)
TIVES

Peptidoglycan (Gram-positive) prote

Lipoteichoic acids (Gram-negative) sis 1
Lipoproteins LPS (Gram-negative) mem
Lipoarabinomannan Endogenous ligands
(Mycobacteria) intra
Zymosan (yeast) Flagellin indu
CD14 TLR4 TICA
TLR5
TLR6 MD2 Profilin-like kina
CD36 (Toxoplasma gondii)
Uropathogen? of ty
TLR2 natu
TLR1 infec
TLR11
TLR
such
TIRAP TRIF
MYD88 TRAM
TLRs
TLR7 In ad
defen
are i
ssRNA hom
regen
NF-
B, IRF and resto
MAPK signaling Unmethylated TLR3 arch
CpG DNA
tion,
dsRNA
thou
Rakoff-Nahoum S, Medzhitov R. Toll-like ing p
receptors and cancer. Nat Rev Cancer. apop
2009 Jan;9(1):57-63. TLR9 of in
exten
signa
Figure 1 | Physiological functions of Toll-like receptors (TLRs). TLRs are involved in recognition TLR
Saturday, November 7, 2009 of microbial and endogenously derived molecular patterns. This occurs both at the plasma membrane 4
 3 10

adaptive immunit
review articles hav
(sensed by NLRP

syndromes)23, is sti

malignant diseases
are discussed; ho
responses to bac
8

function5,13,21. Ind
TNF-α (n

NOD2 have been

ciated with disea
In this Review,
of signalling pat

(the mutation of
their specific PA

is emerging as a
2

(the mutation of
host response to
SAP 6
4
Mannose-binding lectin and its genetic variants
1

PRINCIPIOS BÁSICOS
PBS PBS 2 PBS PBS P Garred et al
0 0
86

ule
nd
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
n- Supplementary Table 2). Residues at the D1–A interface are more
2).

triggered downstream of all these PAMPs and/or DAMPs

(NAIP))18,19 and the lethal toxin of Bacillus anthracis

been proposed that this common trigger could be stimu-
lated by reactive oxygen species or lysosomal damage15–17.
The other recently identified molecular patterns that

IPAF) and NLR family, apoptosis inhibitory protein

which suggests the existence of a common stimulus,

CARD domain-containing 4 (NLRC4; also known as

trigger NLRs include flagellin (sensed by NLR family,
(see REFS 13,14 for recent reviews on this topic). It has
sa a b
B
ed
D2 FcR
on.
A D1
of C
or D1
A
d). C
he
on D2 FcR
ed
D E
he D E SAP
m.s.
ng SAP
in c d
G
nal D2 FcR COOH
A′
E BC-loop
of C′ F
Figure D11 MBL-mediated complement attack. NH3 Mannose-binding lectin (MBL) complexed with the MASPs binds
B
A′ G
C FcR
microorganism
F
and mediates a complement 28 attack through MASP2. MASPs denote MBL-associated serine protease
Lu J, Marnell LL, Marjon
A KD, Mold
C′ C, Du Clos TW, Sun PD. Structural recognition
COOH O and functional activation of FcgammaR by innate pentraxins.

subfamily CIITA
A B C
ble C 2008 Dec 18;456(7224):989-92.
Nature. A Figure 2, Crystal structure of 35 NH3
SAP-FcgRIIIa complex; p. 990.
E D2 A
AP, active complexes with Ficolin-1 (M-ficolin), N
M BFicolin-2 not translated into protein; thus, th
Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO. Mannose-binding L
to (L-ficolin) and Ficolin-3 (H-ficolin lectin and its genetic
or Hakata
C
variants. Genes
Kantigen),
Immun.
script 2006 Mar;7(2):85-94.
encodes Figure 1, ident
a polypeptide
MBL-mediated complement D1 18–20
jor whichattack;
are p.also
86. defence collagens.
I
H
E
D predominant transcript. The vast

NLRA
produced by the liver originates

NLRB
.6) F
Geddes K, Magalhaes JG, Girardin SE. Unleashing the therapeutic potential of NOD-like
G receptors. Nat Rev Drug Discov. 2009 Jun;8(6):465-79.
,19
. SAP
Figure 1, The NOD-like receptor (NLR) family; p. 466. J initiated at exon 1, but roughly 10–

b
a
to The organization of the humanSAP-A MBL2 gene from exon 0 initiated transcripts.29
Saturday, November 7, 2009
Figure 2 | Crystal structure of SAP–FccRIIa complex. a–c, The view is from 4
 PRINCIPIOS BÁSICOS
Inmunidad pasiva vs. inmunidad activa

Saturday, November 7, 2009 4

 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 4
 PRINCIPIOS BÁSICOS
Reactogenicidad y relacionados

Derivada de vacunas de
Derivada de vacunas de
microorganismos muertos o sus
microorganismos atenuados
derivados

Replicación del microbio Inflamación local

Rxs sistémicas (fiebre, anorexia,

Versión miniatura de la enfermedad
cefalea, etc.)

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

Saturday, November 7, 2009 4

 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.

Saturday, November 7, 2009 4

 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.

Saturday, November 7, 2009 5

 ADJUVANTES
Adjuvantes

Potenciadores Adjuvantes
inmunes integrados
Sistemas de
entrega de
antígenos
Paul WE. Fundamental immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. Chapter 40,Vaccines; p. 1235-90.

Saturday, November 7, 2009 5

 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 5
 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 5

 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
Hib, meningocócica, neumocócica…
proteína-CH2O
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 6
 LO QUE SE ESPERA
Virus/bacteria atenuada con capacidad de infección limitada
Vacunas en vectores lleva gen/genes para antígenos de un patógeno X
Plásmidos con genes para antígenos de un patógeno X: el
Vacunas de ácidos nucleicos mismo cuerpo produce el antígeno
Construcción de un polímero de péptidos (con frecuencia
Vacunas peptídicas 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

Ingeniería genética sobre una planta, de modo que presente los

Vacunas comestibles antígenos de modo inmunogénico
Administrar 2 versiones de la misma vacuna: vacuna ADN
Vacunas cebadoras 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 7
 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

Saturday, November 7, 2009 8

 EL “PERO”

1 de cada 100,000
DPT–convulsiones
desde inflamación febriles (1/2,000)
hasta abcesos
polio–reversión a
anafilaxis polio (1/2.7 millones)

trombocitopenia sarampión–encefalitis
(sin confirmar)
artritis aguda

Saturday, November 7, 2009 8

 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 9
 GRACIAS POR SU ATENCIÓN
(En serio.)

Saturday, November 7, 2009 10