Modular Nanodevices for Creation of Smart Adaptable Vaccine

Modular Nanodevices for Creation of Smart Adaptable Vaccine

Modular Nanodevices for Creation of Smart Adaptable Vaccine
Delivery Vehicles
Tarek M. Fahmy
Dept. of Biomedical Engineering, Yale University
SUMMARY

In Vivo Vaccination

We describe a generalizable smart nanoparticle vaccine delivery
system using a simple, modular approach that can be easily adapted
to the requirements of a particular vaccine. Our approach tethers
individual DC recognition, Transepithelial and protective elements into
the surface of the nanodevice constructed from biocompatible
polyester poly (lactic-co-glycolic acid) (PLGA). The core of the device
is loaded with antigen or elements facilitating targeted release of
antigen into the correct intracellular compartments. In this work the
use of biodegradable polymer nanoparticles as a platform for designing
vaccines is being systematically and quantitatively explored.

Enhanced Antigen-Specific Cellular Proliferation with
DC targeted nanoparticle vaccines

OVA Release

% Total OVA Released

0.25
0.2
0.15

SUBCUTANEOUS
VACCINATION

LPS/OVA
MINUS/OVA

0.1

5.0

0.05
0
0

50

100

150

200

250

300

350

4.5
Proliferation x105

Time, hr

Particle size was analyzed using SEM images and were found to be
an average of 100-200 nm. Ovalbumin (OVA) was encapsulated as
the model antigen and a release profile (insert) was deduced using a
protein assay.

LPS-OVA

4.0
3.5
Untargeted
3.0

No OVA

2.5
0.2

Targeting Dendritic Cells
LPS/Particles

0

Blank Particles

150

0.8
Proliferation x105

0.7
0.6
LPS-OVA

0.5

Untargeted

0.4
0.3

Effective Antigen-Specific T cell Proliferation in
vitro with DC targeted nanoparticles

Untargeted

250

30

60

90

120

Vaccination against the West Nile Virus E-Protein

P < 0.0035 200 SubQ 150 100 50 Soluble OVA+Soluble LPS No OVA 0 -50 0 0.01 0.02 0.03 0.04 0.05 0.06 OVA Concentration (mg/ml) Dendritic cells were isolated and primed with blank nanospheres (No OVA ), unmodified OVA particles (Untargeted), LPS-modified OVA nanospheres (LPSOVA), blank nanospheres with soluble OVA (Soluble OVA), or blank nanospheres with soluble OVA and soluble LPS (Soluble OVA +Soluble LPS) and co-cultured with splenocytes from an OT-1 transgenic mouse. IL-2 release was measured by ELISA. % Surviving Animals IL-2 Release (pg/ml) LPS-OVA 300 0 Proliferation of spleen cells from mice subcutaneously or orally vaccinated with ovalbumin-encapsulating nanospheres.. Isolated spleen cells were challenged with different doses of ovalbumin antigen in a plate. Nanospheres modified with LPS encapsulating OVA , nanospheres encapsulating OVA with no external modification (Untargeted ), blank particles with no OVA and no surface modification (No OVA). Mice (N=3) In Vitro Vaccination 350 No OVA OVA (ug/ml) Lipopolysaccharide modified nanoarpticles encapsulating a dye are preferentially internalized by dendritic cells 1) Engineering individual nanoparticulate recognition units that effectively target DCs. 2) Examination of the uptake of the nanodevice by cultured dendritic cells and determining the efficacy of antigen presentation. 3) Engineering nanoparticulates to transit through epithelial cell layers. 4) Engineeringsmart protective coatings facilitating transport through low pH and corrosive environments. 100 ORAL VACCINATION 0.9 Several key variables are needed in the design of effective vaccines (Figure 1). The first variable is the form of the antigen itself. A second necessary component of a vaccine involves potentiating or stimulating the innate and adaptive arms of the immune system to the antigen subunit. Finally, to affect optimal stimulation to a given antigen a formulation is needed that delivers the correct amount of antigen in a repetitive or sustained fashion, to the appropriate immune cells and to the appropriate compartments within those cells. OBJECTIVES 50 100 90 Oral 80 70 60 No Vaccine 50 40 N=10 per group Animals injected with live virulent virus on day 0. 30 20 10 Days Post Challenge 0 0 5 10 15 20 Work supported by NSF-NIRT Award: 0609326

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