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