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Aerosols and Aerobiology
Chad J
...
D
...
communicable
(natural) infection
• disease (model) development
– microbial
susceptibility/infectivity
– ‘quantal’ biological
response
– comparative
pathogenesis/size modality
An exemplar of natural airborne infection:
communicable transmission of M
...
tb?
1e+6
sneeze
cough
8e+5
number of particles
• transmission of M
...
• host
– innate susceptibility
– the nature and number of
interactions with ‘producers’
– P is dynamic (too much so
to model)
• pathogen
– innate microbial fitness
– source (from host)
– particle aging/duration while
in transit
– dynamic size while in transit
M
...
0e+7
1
...
0e+5
-14d
1
...
0e+3
1
...
0e+1
+7d +14d +21d +28d +35d +42d +49d +56d +63d
postexposure
•
•
1
...
0e-1
1
...
3
0
...
0
5
...
immune evasion mechanisms employed by some
pathogens
• Modeling aerosol-acquired disease in appropriate animal species
• differential pathogenesis from exposure to distinct particle distributions
modeling airborne-acquired infection
source generation
airborne
droplet nuclei
pretreatment
generation
viability
delivery
Y
...
coli
Bacillus globigii, vegetative
Bacilus globigii, spore
Bacillus smegatis
Strepococcus hemolyticus
Strepococcus viridans
Staphylococcus aureus
Bacteriophage
Influenza virus
Mycobacterium tuberculosis
runs
relative
vunerability*
6
5
9
4
13
13
5
-
1
...
68
0
...
52
0
...
93
1
...
14
1
...
84
Sample Efficiencies of Biological Threat Agents in Aerosol
Impact of Viability upon Estimated Aerosol Concentration
1e-5
spray factor
1e-6
1e-7
1e-8
1e-9
Y
...
anthracis
B
...
mallei v
...
pseudomallei
1e-4
BP wild-type
(saprophyte)
1e-5
spray factor
1e-6
BM wild-type
(obligate)
1e-7
1e-8
1e-9
1e-10
1e-11
ATCC23344C
10266C
Aerosol biophysical characteristics
• Concentration
– a function of the number and size of particles
generated
• Particles characterized by:
– geometric and aerodynamic size
– shape, density and surface area
– electrical charge / conductance
– number and strength of interactions
– between other particles or cloud components
Biological Aerosol Size
•
Use equivalent diameter that derives from particle property relevant to
bioaerosol exposures
– Mechanism of deposition
– Particle size
•
Aerodynamic diameter: diameter of a unit-density sphere having the
same gravitational settling velocity as the particle being measured
Irregular Shape
Varying Densities
Equivalent Diameter
= 1 g/cm3
= 4 g/cm3
= 9 g/cm3
= 1 g/cm3
d=?
d = 3 m
d = 2 m
d = 6 m
particle generation methods for
infectious agents
• Standard generation
methods employed
for generating larger
particle pathogencontaining aerosols
that retain viability
– spinning top aerosol
generator
– compared to
standard industrial
nebulizer and
resulting distribution
1e+5
SPG - number
SPG - mass
LPG - number
LPG - mass
1e+4
1e+3
1e+2
1e+1
1e+0
1e-1
1e-2
1e-3
1e-4
1e-5
0
2
4
6
8
10
particle diameter (m)
12
14
Source-Based Particle Distribution
10
MMAD,1
...
4
10
8
6
2
1
10
particle size ()
>25
10
...
0
5
...
0-5
...
5-1
...
1
0
...
5
dM/dlogDp
1
Initial Deposition and Clearance
• Particle deposition defines the organs/tissues
with first contact
• Clearance defines the duration the body is in
contact with the agent
– bulk clearance
– mucociliary clearance
– alveolar clearance
• Ultimately both play major roles in the agents
pathology and pathogenesis
Human deposition patterns
From ARL, PSU, 2007
From Edwards et al
...
0
URT
TB
LRT
TOTAL
deposition fraction
0
...
6
0
...
2
0
...
01
0
...
g
...
g
...
Epifluorescent ricin
particles localized to the olfactory
epithelium in the turbinates (A; 40X)
whereas particles are localized to all
levels of the olfactory epithelium (B;
100X)
...
The lungs of the
mouse exposed to the nonrespirable
aerosol (A) shows no significant lesions
...
from Roy et al
...
, Experiment of mass aerogenic vaccination against anthrax (1959)
et al
...
, Simultaneous aerosol immunization of monkeys with live tularemia and live VEE vaccines (1964)
4 Muromstev et al
...
, Aerosol vaccination with tetanus toxoid (1966)
6 Cohn et al
...
, Humoral immunity to aerosolized SEB vaccinated with SEB toxoid-containing microspheres (1995)
8 Fernadez de Castro et al
...
, Rubella virus immunization in pre-school children via the respiratory tract (1974)
10Sepulveda-Amor, J
...
, A randomized trial demonstrating successful boosting reaponses following simultaneous
aerosols of measles and rubella (MR) vaccines in school age children (2002)
2 Eigelsbach
Early Abandonment of the Effort
lack of advanced technology paired with suboptimal reagents
• early crude vaccines were reactogenic
• mainly live attenuated or toxoids used
– adverse events over injection
– no identified mucosal adjuvants
• Individual inhalation devices largely
unavailable
• failure to identify ‘dual immunity’ concept
• troop compliance
– was ‘cold chain’ logistical support up to the task?
Alternative Delivery: Inhalation
recent trends in biopharmaceuticals
• Therapeutics1
–
–
–
–
–
–
–
–
calcitonin (osteoporosis)
teriparatide (osteoporosis)
rGH (GH disorder)
interferon (hepatitis C)
heparin (deep-vein thrombosis)
insulin (diabetes)
extendin-4 (diabetes)
1-antitrypsin (congenital emphysema)
• Vaccines
– (EZ) measles
– influenza
1Minter,
B
...
, Emerging Delivery Systems for Biopharmaceuticals, Decision Resources, 2001
Aerosol Vaccination for Measles and Rubella 1
Acute Adverse Events (% incidence)
N
Reactions
(307)
SC
(225)
AEROSOL
P
Fever
Rhinitis
Cough
joint pain
Diarrhea
6
...
3
17
...
9
1
...
6
0
...
4
0
0
0
...
02
0
...
0001
0
...
7
55
...
5
98
...
9
159
...
04
0
...
4
PV seropositivity
Seroconversion
92
...
4
99
...
8
0
...
001
Measles
Rubella
1Data
from Sepulveda-Amor, J
...
, 2002
Micro- and Nano-particle Vaccine Delivery Systems
Monolithic micro- and
nano-particles that are ideal
for encapsulation of
subunit or inactivated
vaccine
Reservoir or ‘balloon’
microcapsules designed
for live vaccine or active
protein