vaccinology (bio-301) credit hrs 3(2-1) dr. aneela javed
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VACCINOLOGY (BIO-301) Credit Hrs 3(2-1)
Dr. Aneela javed
Part 2: Principles of Vaccine Design
Immunologic Memory: T and B Cells memory
• Antigen Processing and Presentation by MHC Class I, II, and Nonclassical Molecules
• Understanding the Mucosal Immune System for Better Mucosal Vaccine Design
PART 1 : INTRODUCTION• Definition• History • Types• Combination vs single vaccine
Course Contents
Part 3: ANIMAL MODELS FOR VACCNE TESTING
• Utility of Mouse Models in Vaccine Design and Development,
• Utility of Nonhuman Primate Models for Vaccines,
VACCINE PRODUCTION
most of the highly successful vaccines have been made empirically, with little or no immunological insight
Recent advances in innate immunity have offered new insights about the mechanisms of vaccine-induced immunity and have facilitated a more rational approach to vaccine design.
the failure to develop vaccines against global pandemics such as infection with human immunodeficiency virus (HIV) despite decades of effort has underscored the need to understand the immunological mechanisms by which vaccines confer protective immunity
Part 2: Principles of Vaccine Design
Immunologic Memory: T and B Cells memory
• Antigen Processing and Presentation by MHC Class I, II, and Nonclassical Molecules
• Understanding the Mucosal Immune System for Better Mucosal Vaccine Design
1. distinct subsets of helper T cells, such as TH1, TH2 and TH17, are effective at protecting against different pathogens
2. Follicular helper T cells (TFH cells) produce interleukin 21 (IL-21) and help with the differentiation of B cells and generation of memory B cells.
3. In addition, differentiating memory CD4+ and CD8+ T cells can be subcategorized into central memory and effector memory cell subsets, each with a distinct functionality.
Pattern recognition receptors (PRRs) : proteins expressed by cells of the innate
immune system to identify pathogen-associated molecular patterns (PAMPs), which
are associated with microbial pathogens or cellular stress, as well as damage-associated
molecular patterns (DAMPs), which are associated with cell components released
during cell damage.
1. (PAMPs) and include bacterial carbohydrates (such as lipopolysaccharide or
LPS, mannose),
2. nucleic acids (such as bacterial or viral DNA or RNA), bacterial peptides
(flagellin, Xa21),
3. peptidoglycans and lipoteichoic acids (from Gram positive bacteria),
4. N-formylmethionine, lipoproteins and fungal glucans.
5. Endogenous stress signals are called danger-associated molecular
patterns (DAMPs) and include uric acid.
The innate immune system can sense microbes through pattern-recognition receptors (PRRs), such as
1. the Toll-like receptors (TLRs), which are expressed by various cells, including dendritic cells (DCs)
2. the C-type lectin-like receptors
3. the cytosolic Nod-like receptors
4. Cytosolic RIG-I-like receptors sense viral nucleic acids
There are many subsets of functionally distinct DCs, and it is now clear that the DC subset, as well as the nature of the PRR, have a key role in determining the magnitude and quality of adaptive immune responses.
1. dimers, homodimers, TLR2 forms heterodimers
2. endosomal TLRs comprising TLR3, TLR7, TLR8 and TLR9 recognize nucleic
acid derived from viruses as well as endogenous nucleic acids in context of
pathogenic events.
3. Activation of these receptor leads to production of inflammatory cytokines as
well as type I interferons (interferon type I) to help fighting viral infection.
TLRs may also depend on other co-receptors for full ligand
sensitivity, such as in the case of TLR4's recognition of LPS, which
requires MD-2. CD14 and LPS-Binding Protein (LBP) are known to
facilitate the presentation of LPS to MD-2.
When activated, TLRs recruit adapter molecules within the
cytoplasm of cells in order to propagate a signal. Four adapter
molecules are known to be involved in signaling. These proteins
are known as
1. MyD88,
2. Tirap (also called Mal),
3. Trif, and
4. Tram (toll-like receptor 4 adaptor protein).
TLR SIGNALING
MyD88-dependent pathway
utilized by every TLR except TLR3.
Its primary effect is activation of NFκB and Mitogen-activated protein kinase
MyD88 then recruits IRAK 4, IRAK1 and IRAK2. IRAK kinases then
phosphorylate and activate the protein TRAF6, which in turn polyubiquinates
the protein TAK1, as well as itself in order to facilitate binding to IKK-β. On
binding, TAK1 phosphorylates IKK-β, which then phosphorylates IκB causing
its degradation and allowing NFκB to diffuse into the cell nucleus and activate
transcription and consequent induction of inflammatory cytokines.[23]
TRIF-dependent pathway[edit]
Both TLR3 and TLR4 utilize the TRIF-dependent pathway,
which is triggered by dsRNA and LPS, respectively. For
TLR3, dsRNA leads to activation of the receptor, recruiting
the adaptor TRIF. TRIF activates the kinases TBK1 and
RIPK1, which creates a branch in the signaling pathway. The
TRIF/TBK1 signaling complex phosphorylates IRF3 allowing
its translocation into the nucleus and production of
Interferon type I. Meanwhile, activation of RIPK1 causes the
polyubiquitination and activation of TAK1 and NFκB
transcription in the same manner as the MyD88-dependent
pathway.[23]
.
TLR signaling ultimately leads to the induction of thousands of genes. TLRs
constitute one of the most pleiotropic yet tightly regulated gateways for gene
modulation
Receptor Ligand(s)[27]Ligand
location[27]Cell types[27]
TLR 1 multiple triacyl lipopeptidesBacteria
monocytes/macrophages a subset of dendritic cells B lymphocytes
TLR 2
multiple glycolipids Bacteria
monocytes/macrophages neutrophils [28]
Myeloid dendritic cells[29]
Mast cells
multiple lipopeptides Bacteria
multiple lipoproteins Bacteria
lipoteichoic acid Gram-positive bacteria
HSP70 Host cells
zymosan (Beta-glucan) Fungi
Numerous others
TLR 3double-stranded RNA, poly I:C
viruses Dendritic cells B lymphocytes
TLR 4
lipopolysaccharide Gram-negative bacteria
monocytes/macrophages neutrophils [28]
Myeloid dendritic cells[29]
Mast cells B lymphocytes [30]
Intestinal epithelium
several heat shock proteinsBacteria and host cells
fibrinogen host cells
heparan sulfate fragments host cells
hyaluronic acid fragments host cells
nickel
Various opioid drugs
TLR 5
flagellin Bacteria
monocyte/macrophages a subset of dendritic cells Intestinal epithelium
[[profilin[31]]]Toxoplasma gondii
TLR 6 multiple diacyl lipopeptides Mycoplasma
monocytes/macrophages Mast cells B lymphocytes
TLR 7
imidazoquinolinesmall synthetic compounds
monocytes/macrophagesPlasmacytoid dendritic cells[29]
B lymphocytes
loxoribine (a guanosine analogue)
bropirimine
single-stranded RNA RNA viruses
TLR 8small synthetic compounds; single-stranded RNA
monocytes/macrophages a subset of dendritic cells Mast cells
TLR 9unmethylated CpG Oligodeoxynucleotide DNA
Bacteria, DNA viruses
monocytes/macrophagesPlasmacytoid dendritic cells[29]
B lymphocytes
TLR 10 unknown
TLR 11 ProfilinToxoplasma gondii[32]
monocytes/macrophages liver cells kidney urinary bladder epithelium
TLR 12 ProfilinToxoplasma gondii[34]
Neurons[35]
plasmacytoid dendritic cells conventional dendritic cells macrophages
TLR 13 [36][37]
bacterial ribosomal RNA sequence “CGGAAAGACC”
Virus, bacteria monocytes/macrophages conventional dendritic cells
Cell type TLR
Monocyte 1,2,4,5,6,7,8,9
Macrophages
Dendritic cells
Conventional DC
Plasmacytoid DC
B cells
Neutrophils
Mast cells
Intestinal epithelium
•Cellular immunity• Maximizes the killing efficacy of the macrophages •proliferation of cytotoxic CD8+ T cells.•promotes the production of opsonizing antibodies. (IgG, IgM and IgA but not IgE antibodies)
•Humoral immune system.
•Stimulates B-cells into proliferation,
•induce B-cell antibody class switching,
•Increasesneutralizing antibody production
(IgG, IgM and IgA as well as IgE antibodies)
Th17 helper cells mediate host immunity
against extracellular bacteria and fungi.
The regulatory T cells (Tregs), formerly known as suppressor T cells, maintain tolerance to self-antigens, and abrogate autoimmune disease.
IMMUNE MEMORY
T cell-dependent activation
1. The T cell is stimulated to produce autocrines, resulting in the proliferation or
differentiation to effector or memory T cells.
2. A certain portion of the resulting effector T cells then activate specific B cells through
a phenomenon known as an Immunological synapse.
3. Activated B cells subsequently produce antibodies that assist in inhibiting pathogens
until
T cell-independent activation
1. An advantage of forgoing T cell involvement is that an expedited immune response can be mobilized,
2. germinal center formation, isotype switching and affinity maturation do not occur during this form of activation.
3. Also, because almost all memory B cells are derived from germinal centers, effective antibody-mediated memory is
4. against polysaccharide capsules of encapsulated bacteria
Live attenuated vaccines such as those against smallpox or yellow fever are the
most successful vaccines ever made and can confer lifelong memory, whereas
nonliving vaccines induce protection of much shorter duration and require
booster vaccination to maintain protective immunity. Thus, a single dose of the
smallpox vaccine maintains serum antibody titers for more than 50 years and
cellular immunity is also maintained for decades.
engagement of multiple innate pathogen recognition receptors is key to
generating T-cell responses of different magnitudes and functional profiles
[6, 12–14], suggesting that, the overall breath, functionality and
duration of acquired immune responses are dictated by early
innate signals triggered by live attenuated vaccines [6, 12–14].
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