general classes of vaccines an induced mobilization of the immune response for the purpose of...

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 responseCD4+ T cells, B cellsMHC class II-dependent

Cellular responsecytotoxic CD8+ T cells,

NK cellsMHC class I-dependent

Classical success: polio virus

• vaccine: killed/attenuated virus• injected (Salk)• oral (Sabin)

• oral route of infection• initial replication in GI tract

Paroxysmal success: influenza

• killed/attenuated virus, protein• antibody to viral spike glycoprotein (hemagglutinin, HA) confers protection

• infects via airway• epithelial/systemic replication

HA genetic drift subverts antibody

Unmitigated failure: HIV

• killed/attenuated virus• recombinant envelope glycoprotein• poor protection, cumbersome trials

• infects via anal/vaginal epithelia• replication/residence in immune cells

>80 million infected individuals/victims

3.1 million new cases/year in Africa alone

Why have HIV vaccines failed?

• 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 antigen-specific 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:antigencapture

Mature:antigen

presentation

immature DC mature DC

Multiple inducers of DC maturation

various T cell responses

Microbial products / TLR ligandsViral productsInflammatory cytokinesSignaling receptors

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