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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 " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " "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