Download Immunostimulation with Vaccines

Immunostimulation with
Vaccines
이승주
UTIs
• >70-80% caused by uropathogenic E. coli (UPEC)
• affect 8 million women annually in the US
• high recurrence rate: >25% of all UTIs recur
within 6 months
• Antibiotics: primary means of prophylaxis
– Emergence of increasing numbers of drugresistant bacteria
• Alternative prevention strategies
– Vaccines
Contents
1. Pathophysiology of UTIs
2. Immunology of UTIs
3. Vaccines for UTIs
UTI etiology
• Uropathogens from
intestinal flora
sequentially colonize
mucosal surfaces of
the vagina and
urethra prior to
establishing an
infection on the
bladder mucosa
Pathogenesis of cystitis
COLONIZATION
Establishment of bacteria
on host cell surfaces
Commensal State
Opportunists
Infection
Pathogens
(Extreme range of
virulence and infectivity)
The first step to
colonization is
adherence to a
host cell surface.
Adherence Mechanisms
• Adherence is required for extracellular colonization as
well as internalization of bacteria.
• Adhesins - General term for bacterial structures
involved in adhesion.
– Pili or fimbriae – Gram-negative bacteria
– Non-pilus adhesins – Gram-positive and
negative bacteria
• Bacteria often have a variety of both types of adhesins.
Afimbrial adhesin
Type I fimbriae
Type IV fimbriae (= bundle forming pilus)
Curli
Fimbriae or Pili
• Filamentous organelles
expressed on the surface of
gram-negative bacteria and
mediate attachment to host
tissues.
• First described by Duguid et al.
in 1955
– Duguid JP, Smith IW, Dempster G,
Edmunds PN. Non-flagellar
filamentous appendages
(“fimbriae”) and haemagglutinating
activity in Bacterium coli, Journal
of Pathol Bacteriol, 70, 335, 1955.
• Found on a variety of gramnegative bacteria including
saprophytes, commensals and
pathogens.
P or Pap pili:
Uropathogenic strains
of E. coli associated
with pyelonephritis
Genes (11) in pap
gene cluster (PapAPapK)
Thick, rigid filaments;
Rod is composed of
several thousand pilin
units tightly wound in a
right-hand helix to form
a hollow cylinder with
an outer diameter of
~7 nm and an inner
diameter of 1.5 – 3 nm.
Flexible, more narrow tip
(fibrillum) with adhesin
on distal end.
~ 1000-2000 nm long
Adhesin binds
to Gal(1,4)Gal moieties
of glycolipids on uroepithelial cells
Type 1 pili – similar to P pili
Found in E. coli and most
Enterobacteriaceae.
Important virulence factor
In cystitis-associated E. coli.
Genes in Fim gene cluster
(FimA-FimH)
Fibrillum is shorter and stubbier.
FimH also intercalates with
rod at buried sites that may
Adhesin (FimH) binds to mannose
be exposed when breakage
oligosacchaarides attached to
occurs at these sites.
uroplakin on surface
of urinary bladder epithelium
Adhesins recognize and bind to specific
receptors on host cells. This may
activate complex signal transduction
cascades resulting in:
• Activation of innate defenses
• Subversion of cellular processes
facilitating bacterial invasion
• May activate expression of new
genes in bacterial cell that are
important in pathogenic process
• Important UTI vaccine candidate
Contents
1. Pathophysiology of UTIs
2. Immunology of UTIs
3. Vaccines for UTIs
Mucosal
peripheral
central
NALT
BALT
***
#
GALT
***
#
RALT
***
The secondary lymphoid organs can be subdivided into the Systemic (***) and Mucosal
immune systems
MALT
(Mucosal Associated Lymphoid System)
• Differs fundamentally from systemic immune
responses in that:
– major isotype in mucosal secretions is
secretory IgA
– most of the antibody-producing cells and
effector T occur in the MALT
– separate inductive and effector lymphoid sites
Mucosal immune response
Mucosal Inductive Sites
Effector Sites
MALT
Integrated
system
Contents
1. Pathophysiology of UTIs
2. Immunology of UTIs
3. Vaccines for UTIs
UTI vaccine
• efficacy & safety
• Ideally, the vaccine will increase patient
resistance to the most common
uropathogens without causing significant
adverse effects.
• administered easily
• low cost
• broad patient acceptance
UTI Vaccines
currently in development
• Urovac® (SolcoBasel, Basel, Switzerland and
Protein Express, Cincinnati, OH)
• Uro-Vaxom® (OM Pharma, Myerin,
Switzerland)
• Urvakol (Institute of Microbiology; Olomouc,
Czech Republic)
• Urostim (Bulbio; National Center for Infectious
and Parasitic Diseases, Sofia, Bulgaria)
• FimCH (Medimmune, Gaithersburg, MD)
Components of vaccine
• Intact bacteria (whole cells) or crude lysates
– contain a large number of urovirulence factors
– potentially afford protection against many different
strains of uropathogens
– cause unacceptable adverse reactions by bacterial
components such as endotoxin
• Detoxified bacterial lysates or purified
virulence factor
– less toxic
– decrease ability to protect against a wide range of
pathogens
Route of administration
• Mucosal
– Immunogen onto the
mucosal surface that
may infected or onto a
distant mucosal site
because of the
integrated nature of the
mucosal immune
system
• Parenteral
– Induce lower amounts
of specific antibody in
mucosal secretions
Urovac®
• Inactivated whole-cell; 10 uropathogens
– six E. coli strains
– Proteus mirabilis, Proteus morganii,
Klebsiella pneumoniae, Enterococcus
faecalis
– Final concentration: 1 x 109
bacteria/dose
• Intramuscular injection (initially in 1987)
• Vaginal suppository; primary + monthly
booster (mucosal immunization)
J Urol 2007;177:1349-1353
75 paients, Urovac vaginal suppositories, 6 months
Percent infection-free
Any bacterial strain
E. coli
•No significant adverse events
Uro-Vaxom®
• Extract from 18 uropathogenic E. coli
strains
– Induction of antibody to Proteus,
Klebsiella, Enterococcus species
• Oral capsule; daily for 3 months + three
10-day boosters (mucosal immunization)
European Urology 2005;47:542-548
1 year
9 EU countries
52 centers
N=454
12 University hospitals, 50 female patients, 6 months
•No significant adverse events
Urvakol & Urostim
• Urvakol
– inactivated, whole E. coli, P. mirabilis,
Pseudomonas aeruginosa, E. faecalis
– Oral tablet; daily for 3 months (mucosal
immunization)
Bratisl lek Listy 1999;100:246-251
• Urostim
– freeze-dried excipient plus lysates of killed E.
coli, P. mirabilis, K. pneumoniae, and E. faecalis
– Oral tablet; daily for 6 months (mucosal
immunization)
Adv Exp Med Biol 2000;485:325-329
FimCH
• E. coli type 1 fimbrial adhesin (FimH) and its
caperone protein (FimC)
• Parenteral; intramuscular injection
• Animal (Cynomolgus monkey) study
J Infect Dis 2000;181:774-778
• Phase 1 trial, 48 adult women
– Intramuscular injection at 0, 1, and 4 months
– Increases in anti-FimH antibodies in serum,
urine, or vaginal secretions
Personal communication of Dr. Uehling
Summary
Mucosal immunogen
vaccine
•Urovac & Uro-Vaxom
Adhesin vaccine
•Vaginal or Oral route
•FimCH (type 1 fimbriae)
PapDG (P pili)
•Parenteral route
•induce protective
antibodies on the
mucosal surfaces of the
vagina and bladder
•interrupt a key initial
step of bacterial
adhesion to the
urogenital mucosa