Transcript Presentation slides - Yale School of Medicine

General classes of vaccines
An induced mobilization of the immune response for
the purpose of therapeutic benefit.
Preventative: infectious agents
Therapeutic: cancer
General classes of vaccines
Antibody response
CD4+ T cells, B cells
MHC class II-dependent
Cellular response
cytotoxic CD8+ T cells, NK cells
MHC class I-dependent
Classical success: polio virus
• oral route of infection
• initial replication in GI tract
• vaccine: killed/attenuated virus
• injected (Salk)
• oral (Sabin)
Paroxysmal success: influenza
• infects via airway
• epithelial/systemic replication
• killed/attenuated virus, protein
• antibody to viral spike glycoprotein
(hemagglutinin, HA) confers protection
HA genetic drift subverts antibody
Unmitigated failure: HIV
• infects via anal/vaginal epithelia
• replication/residence in immune cells
• killed/attenuated virus
• recombinant envelope glycoprotein
• poor protection, cumbersome trials
>80 million infected individuals/victims
3.1 million new cases/year in Africa alone
Why have HIV vaccines failed?
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gp120 genetic drift subverts antibody
virus is rarely extracellular
wrong viral component, wrong delivery?
underdesigned?
or…overdesigned?
Typical antigen formulations
• peptides bound to carriers (adjuvants)
• recombinant proteins
• killed or attenuated virus/bacteria
• DNA or mRNA encoding protein antigen
Typical vaccine delivery vehicles
• injection in adjuvant (skin, muscle)
• oral, nasal
• recombinant or synthetic viral vector
• transformed microbial vector
Engineering rational vaccines
• understand biology of target
• understand biology of response
bioengineering
Production of MHC class I & II-peptide complexes
Virus-encoded
proteins
“Cross presentation” of exogenous antigens on MHC
class I: CD8 responses to extracellular agents
Dendritic cells initiate antigenspecific immune responses
• most efficient of all APCs
• high MHC class I, II & costimulators
• efficient cross presentation
• stimulate naïve T cells (CD4, CD8)
initiate Ag-specific immune responses
All immunization strategies must target DCs
Immature:
antigen
capture
Mature:
antigen
presentation
Multiple inducers of DC maturation
immature DC
Microbial products / TLR ligands
Viral products
Inflammatory cytokines
Signaling receptors
mature DC
various T cell
responses
Targeting DCs to elicit immunity:
engineering requirements
• The optimal delivery device…
• will be targetable to selected DC populations
• can be coupled to DC maturation agents
(microbial, inflammatory, other?)
• can accomodate any type of antigen
• permits intracellular targeting (cross-presentation
from cytosol favors cytotoxic T cell responses)
• traceable (does it reach DCs, nodes?)
• modular (permits efficient, small-scale trials)
• synthetic, stable, orally available for global use