Download Successful Respiratory Immunization with a Dry Powder Live

Successful Respiratory Immunization with
a Dry Powder Live-attenuated Measles
Virus Vaccine
AAPS Fall Symposium
September 9, 2011
Diane E. Griffin
Johns Hopkins Bloomberg School of Public Health
One of the 10 most
important causes of
death due to infection
in children <5 years
of age
Measles virus
Brindley and Plemper. 2011 Pathogenesis of
measles!
Virus
replication
skin
liver
thymus
lung
lymphatic tissue
spleen
blood
local lymph nodes
respiratory epithelium
Clinical
symptoms
?
rash
Clinical symptoms appear!
at the time of the onset of!
the immune response!
fever
Immune
responses
Koplik's
spots
conjunctivitis
cough
CD8 T cells
IgG
CD4 T cells
IgM
immune suppression
5
10
15
20
Days after infection
Diagram of the pathogenesis of measles virus
infection in humans
Europe has had an
ongoing outbreak of
measles
2006 2007 Muscat et al, Lancet 373:383, 2009 Problems with measles control •  Need for high very high coverage rates to
interrupt transmission (>95%)
–  requires 2 doses
•  Problems with delivery in developing
countries
•  Problems with acceptance in developed
countries
•  (Effects of HIV infection on response to
immunization and on transmission in Africa)
•  Inability to immunize young infants R0 for some important human viruses
Virus
Measles""
Mumps "
Polio " "
Rubella "
Smallpox
Influenza
R0
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"12-18
"10-12
"10-15
" 7-8
" 5-7
" 2-3
This results in a herd immunity threshold of >95%
Current measles vaccine
•  Live attenuated virus derived from the Edmonston
(or related) strain of MV
•  Licensed in 1963
•  Safe and efficacious
•  Often combined with mumps and rubella (MMR)
•  Given at 9-15 months of age
•  Efficacy:
–  85% at 9 months
–  95% at 12 months
Measles vaccine coverage- 2004
Moss and Griffin, Nat Rev Microbiol 4:900, 2006 Swiss measles cases are primarily in unvaccinated persons
Richard et al, Euro Surveill 14:19443, 2009 Population Immunity – 1 Dose % Coverage
% Immune
80
%Vaccine
Efficacy
95
90
95
86
95
95
90
95
90
86
95
80
81
76
Therefore, to interrupt endemic transmission a 2nd dose of vaccine is required
to immunize those that were missed or didn’t respond to the 1st dose
Approaches to delivery of a 2nd dose
•  Through routine vaccination programs –
e.g. required before school entry
•  Through mass vaccination campaigns
–  pioneered by PAHO for S. America
–  immunize all children in a short period of
time
–  repeat campaigns regularly
Measles mortality reduction through
use of campaigns in Africa
2008
Niger 851 cases Ethiopia 3100 cases Tanzania 512 cases Nigeria 9415 cases Malawi 19 cases Zambia 111 cases South Africa 36 cases Zimbabwe 2 cases 16,286 confirmed measles cases reported from 40 countries in surveillance network Moss & Griffin, Lancet, 2011 Niger 797 cases Mali 2929 cases Burkina Faso 823 cases* Senegal 978 cases Benin 914 cases Nigeria 1498 cases Cameroon 870 cases Angola 2442 cases Namibia 1815 cases South Africa 1584 cases 2009
Chad 632 cases Ethiopia 2642 cases Tanzania 654 cases Malawi 50 cases Zambia 26 cases Zimbabwe 706 cases 20,745 confirmed measles cases reported Moss & Griffin, Lancet, 2011 Through October 2010
Mali 792 cases 2 deaths Ethiopia 3742 cases 35 deaths Nigeria 5903 cases 110 deaths Zambia 11995 cases 155 deaths Angola 1299 cases 62 deaths Malawi 72570 cases 152 deaths Namibia 576 cases 10 deaths Mozambique 630 cases 10 deaths Botswana 822 cases Zimbabwe 7784 cases 161 deaths South Africa 12678 cases 0 deaths Lesotho 2497 cases 19 deaths 124,931 confirmed measles cases reported Moss & Griffin, Lancet, 2011 Measles mortality reduction
Approaches to measles vaccination that would
improve routine delivery of 2 doses •  A vaccine that would allow the first dose
before 6 months of age, along with other
EPI vaccines
•  Delivery of the current vaccine in a
heat-stable formulation that could be
given without needles and syringes
Approaches to measles vaccination that would
improve routine delivery of 2 doses •  A vaccine that would allow the first dose
before 6 months of age, along with other
EPI vaccines
•  Delivery of the current vaccine in a
heat-stable formulation that could be
given without needles and syringes
Current delivery of LAV
•  Lyophilized vaccine in 5-10 dose vials
–  cold chain for transport to distribution center
and clinic
•  Reconstituted
–  kept on ice: viability decreases 30-50% in 1
hour at 37o
–  unused vaccine discarded
•  Delivered by needle and syringe
–  trained personnel required
•  Disposal of used needles and syringes
New approaches to delivery •  Aerosol
– 
– 
– 
– 
Would eliminate need for needles and syringes
More “natural”
Works well to boost responses in older children
Requires relicensing of vaccine for this route
•  Studies ongoing in India for liquid aerosol
•  Potential problems
–  Dosing not reliable in young infants
–  Primary immune responses to liquid aerosol not as
good as after subcutaneous delivery Aerosolized live attenuated measles vaccine
BenneK et al, Bull WHO 80:806, 2002 Comparison of the responses of school children
to aerosol and SC measles vaccine
Dilraj et al, Lancet 355:798, 2000 Durability of responses to aerosol and SC measles vaccination
Dilraj et al, Vaccine 25:4170, 2007 However, primary responses of 9 month-old infants
are not as good
Wong-­‐Chew et al, Vaccine 24:683, 2006 Advantages of a dry powder vaccine
•  Cold chain not required
•  Reconstitution not required
•  Single dose packaging and delivery
–  less space during transport and storage
–  decreased waste
•  Trained personnel not required for delivery
Preparation of a small particle dry
powder measles virus vaccine
•  Edmonston-Zagreb strain of measles
vaccine from Serum Institute of India
•  Liquid processed with CO2-assisted
nebulization with a bubble dryer (CANBD) technology – Aktiv Dry, Boulder, CO
–  moisture: 0.7%
–  size: FPF <5.8 µm = 46%; <3.3 µm = 20%
•  Packaged into individual capsules or
blisters
Aerosol delivery of dry powder measles vaccine (MVDP)
PuffHaler
Solovent
Lin et al, PNAS 108:2987, 2011 Rhesus macaque model for measles
8000
Lymphocytes/µl
7000
6000
lymphocyte count
5000
viremia
4000
3000
2000
rash
1000
0
3
7 10 14 16 21 28 35 42
Days after infection
Auwaerter et al, J Infect Dis 180:950, 1999 IT inoculation of wild type
measles virus Bilthoven
Sites of dry powder measles vaccine delivery
Lin et al, PNAS 108:2987, 2011 Current understanding of measles
protective immunity
•  Epidemiologic studies (e.g. Chen et al. JID 162:1036, 1990)
show that vaccine-induced protection correlates with
the level of neutralizing antibody:
–  >120 mIU/ml: Protection from disease (rash)
–  >1052 mIU/ml: Protection from infection (Ab rise)
•  However:
–  Neutralization of lymphoid cell infection by wild type
strains of virus requires high avidity antibody (Polack et al.
Nat Med 9:1209, 2003)
–  Neutralizing antibody alone protects from rash, but not
viremia (Pan et al. PNAS 102:11581, 2005)
–  T cell responses alone do not protect from rash or
viremia, but speed virus clearance (Lin et al. unpubl)
Antibody responses to MVDP
Neutralizing Ab
MeV-specific IgG
Lin et al, PNAS 108:2897, 2011 Quality of antibody induced by MVDP
Avidity
Bone Marrow ASCs
MeV-specific IFN-γ T cell responses to
mask-delivered MVDP are biphasic
Lin et al, PNAS 108:2987,2011 Biphasic responses are to multiple measles virus proteins
MeV-specific IL-4 T cell responses are
also induced after mask MVDP
Lin et al., PNAS 108:2987, 2011 Both CD4+ and CD8+ T cell TNF responses are induced
Lin et al., PNAS 108:2987, 2011 MVDP induces multifunctional CD4+ T cells
Lin et al., PNAS 108:2987, 2011 Memory CD4+ T cells are multifunctional
Lin et al., PNAS 108:2987, 2011 Dry powder measles vaccine protects monkeys
from challenge 1 year later - viremia
Infectious virus
Viral RNA
Lin et al, PNAS 108:2987, 2011 T cell responses to challenge
Lin et al., PNAS 108:2987, 2011 Evidence of an anamnestic T cell and antibody
response to challenge
T cells at 7 days
Neutralizing antibody
Lin et al., PNAS 108:2987, 2011 Conclusions
•  A single dose of MVDP delivered to the
lower respiratory tract induces long term
protective immunity to measles
•  Immune responses are comparable to or
better than those elicited by subcutaneous
inoculation and include:
–  high avidity neutralizing antibody
–  multifunctional T cells
–  Antibody-secreting cells in bone marrow
•  MVDP offers the opportunity to improve
measles vaccine coverage
Acknowledgments
Johns Hopkins
•  Wen-Hsuan (Wendy)
Lin
•  Robert Adams
Becton Dickinson
•  Ken Powell
•  Charles Shermer
Aktiv Dry
•  Robert Sievers •  Steve Cape •  ScoR Winston CDC
•  Paul Rota •  Mark Papania AVANZA
•  Steve Godlin Funding from the NIAID and The Bill and Melinda Gates Foundation