Transcript Mucosal Vaccines

VACCINOLOGY
MUCOSAL VACCINES:
THE PROMISE
AND THE CHALLENGE
Pamela A. Kozlowski1
Marian R. Neutra 2
1Children’s Hospital and Department of Pediatrics, Harvard
Medical School, Boston, Massachusetts, USA.
2 Children’s Hospital, Enders Boston, Massachusetts, USA.
Published in: Nature Immunology, February 2006
ABSTRACT
Most infectious agents enter the body at mucosal
surfaces and therefore mucosal immune responses
function as a first line of defence. Protective mucosal
immune responses are most effectively induced by
mucosal immunization through oral, nasal, rectal or
vaginal routes, but the vast majority of vaccines in use
today are administered by injection. As discussed in
this review, current research is providing new insights
into the function of mucosal tissues and the interplay of
innate and adaptive immune responses that results in
immune protection at mucosal surfaces. These
advances promise to accelerate the development and
testing of new mucosal vaccines against many human
diseases including HIV/AIDS.
CONTENTS
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Mucosal Surface
Epithelial cells
Immune Effector Mechanism
Adaptive Immune protection at mucosal
Surface
Induction of Mucosal Immune System
Mucosal Immunization
Challenges in vaccine design
Conclusion
COMPARISON BETWEEN
PARENTERAL VACCINES
MUCOSAL VACCINES
 Poor inducers of mucosal
 Efficiently induce it
immunity
 Rapid generation of Abs
etc
 Measurable immune
response
 So, high approval ratio
from FDA
 Slightly delayed
 Indeterminate
 Only a few have been
approved including
rotavirus, typhoid and
cholera
MUCOSAL SURFACES
 ENORMOUS SURFACE AREA:
 INNATE DEFENCES AT MUCOSAL SURFACES:
 delicate epithelial membrane
 associated glands produce enzymes like proteases
 lymphoid and Antigen Presenting Cells are also present in the
mucosal surface
FUNCTIONS OF EPITHELIAL CELLS
 So, epithelial cells of the intestine function
as;
 Sensors that detect antigens microbial
components through PRRs (like TLRs).
 Send cytokine and chemokine signals to
underlying mucosal cells, such as dendritic cells
(DCs) and macrophages, to trigger innate,
nonspecific defences and promote adaptive
immune responses
 Induce tolerance against nonthreatening nutrients
and the normal intestinal flora that could lead to
mucosal inflammation
MULTIPLE IMMUNE EFFECTOR
STRATEGIES
Pathogen infection of
Mucosal Membrane
Mucosal
Immunity
Block adherence &Invasion
Ag capture by DCs
Opsonization
Cell Mediated Killing
ADCC
Neutralization
Entrapment &Clearance
ADAPTIVE IMMUNE PROTECTION
 Four principal players in adaptive immune
mechanism at the mucosal membrane;
 IgA
 IgG
 Modification in Antigen uptake mechanism
 Cyotoxic T lymphocytes
•Immune exclusion
•Clearance of
infection
CTLs
•M-cells
•Presentation
sIgA
Adaptive
Immune
Protection
Uptake
Mech.
•Hindrance
•ADCC
IgG
•Neutralize the
pathogen
•prevent systemic
infection
Block adherence &Invasion
Ag capture by DCs
Opsonization
Cell Mediated Killing
ADCC
Neutralization
Entrapment &Clearance
INDUCTION OF MUCOSAL IMMUNE
RESPONSES
Steps included in the induction/ initiation of
mucosal immune response are;
i.
ii.
Antigen Sampling
Focusing the Immune response
1. ANTIGEN SAMPLING
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The first step is the antigen sampling at mucosal surfaces.
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The pathogens are identifies and exposed to the regional lymh nodes, causing
the activation of the immune system.
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The diagram represents the sampling of the antigen by the immune tissue at
various locations.
MUCOSAL Ag SAMPLING IN GUT
 There are organized mucosal inductive sites at
various locations within the mucosal tissue like in
the gastrointestinal tract;
 There are aggregates of mucosal lymphoid follicles
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which form the Peyer’s patches in the ileum,
These mucosal lymphoid follicles causes the
differentiation to a specialized form of epithelium called
follicle-associated epithelium (FAE)
These FAE contain Microfold cells (M cells)
The M cells form pockets into which lymphocytes
migrate
These lymphocytes deliver samples of foreign material
directly into the pocket and to underlying DCs.
FAE
DC
Peyer’s
• Deliver samples of foreign material to the pockets
• Attract the lymphocytes and DCs by chemokinesis
• High density of phagocytic cells at the site of entry
• ↑local Ag sampling &↓systemic infection
• Ag to draining lymph node
• Interface with systemic immune system
FUNCTIONS OF THE FOLLICLE
ASSOCIATED EPITHELIUM
1. Chemokine release
2. Cytokine release
3. DC activation
2. FOCUSING THE MUCOSAL
IMMUNE RESPONSE
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The activated B and T cells upregulate the expression of
tissue-specific adhesion molecules and chemokine
receptors that function as ‘homing receptors’ to guide the
lymphocytes back to the mucosa through recognition of
endothelial counter-receptors in the mucosal vasculature.
 This broad recognition system explains why mucosal
immunization at one site can result in the secretion of specific
IgA antibodies in other mucosal or glandular tissues; this is
referred to as the ‘common mucosal immune system’.
There Are Receptor-mediated Recognition Systems That
Serve To Focus The Immune Response At The Site Where
An Antigen Or Pathogen Was Initially Encountered
IgA+ B cells
(intestinal
inductive sites )
Bloodstream
Migrate back
due to homing
receptors
T Cell activation
Upregulation of
adressins
Signal
Generation
MUCOSAL IMMUNIZATION
 Mucosal immunization routes also can
induce
 the production of serum IgA and IgG
 Activation of mucosal DCs and migration
to spleen and lymh nodes
 Memory CD8+ T cells
WHAT IS THE BEST IMMUNIZATION
ROUTE?
 CHOICE OF MUCOSAL IMMUNIZATION
ROUTE DEPENDS UPON:
 consideration of the species- humans, non
humans etc
 the nature of the vaccine- peptide, VLPs,
conjugate etc
 the expected site of challenge- respiratory,
gut, rectal etc
VACCINATION STRATEGY
 Optimal protection is likely to require both
mucosal and systemic immune effectors,
and the most effective mucosal vaccine
strategies might be prime–boost
combinations that involve both mucosal
and systemic delivery.
 Experimentally, mucosal immunization
priming with systemic boosting has been
found to be quite effective.
CHALLENGES IN MUCOSAL VACCINE
DESIGN
PROBLEM
SOLUTION
HOST DEFENCES
• Diluted in the mucosal secretions
•Proteolytic degradation etc
Larger dose (but increasing the dose
can further complicate the situation)
So, particulate vaccines may be used
to overcome this as they have greater
adherence and lesser clearance
ALERTING THE IMMUNE SYSTEM
Use of adjuvants (list discussed
later)
BREACHING THE EPITHELIAL
BARRIERS
Various mucosal vaccines have
different mechanisms to overcome
this barrier (discussed in table
below)
BREACHING THE EPITHELIAL
BARRIER
AGENTS
MECHANISM
GOAL
Protein,Peptide,
DNA, live
↑ adherence, entry into
epithelial cells
↑Ag uptake,
↑Immune Response
Particulate
Ags with micro. can
pass through the M
cells
Easy transport, taken
up by mucosal DCs,
Provide Ag depot
VLPs,
Bacterial vesicles
Size provides an
advantage for crossing
the M cells
↑Innate activity,
↑Immune Response
ADJUVANTS EMPLOYED IN MUCOSAL
VACCINES
 The best-known mucosal adjuvants are
 the secreted enterotoxins of V. cholerae
and E. coli,
 Immunomodulatory cytokines-IL-12,
granulocyte/macrophage colony-stimulating
factor (GM-CSF) or a combination of both
 TLR Ligands- CpG-containing
oligonucleotides, flagellin and bacterial porins.
RISKS ASSOCIATED
 The
mucosal vaccines have some
safety and acceptability issues;
 Might reflect local inflammation, such as mild
enteritis-like symptoms
 Possibility of retrograde transport to the
brain through olfactory nerves (live attenuated
adenovirus).
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CONCLUDING REMARKS
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Much has been learned from animal studies about the attributes of
effective mucosal vaccines and the immune effectors that could
function together to prevent and control mucosal transmission of
HIV and other mucosally transmitted diseases.
 The current challenge is to apply this knowledge to vaccine design
and to carry out collaborative, comparative clinical trials that
systematically monitor all parameters of the immune response —
humoral and cellular, mucosal and systemic — in serum, local
secretions and mucosal tissues.
 Available data indicate that mucosal HIV vaccines should be
particulate or live vectored, include components that alert the
innate immune system, and include immunogenic, conserved
forms of the envelope protein gp41 as well as gp120.
 Mucosal HIV vaccines would ideally be administered as part of a
prime–boost strategy that induces both mucosal and systemic
immunity. Much work remains to be done, but current research
continues to clarify the concepts and provide the tools that are
needed to exploit the full potential of mucosal vaccines.
THANKYOU