Les Diablerets, 3rd February 2016 Stimulation of mucosal immunity by pulmonary delivery of live vaccines. A safe and effective strategy against TB Nacho Aguilo (naguilo@unizar.es)
Live TB Vaccine TB infection MIMIC NATURAL ROUTE OF INFECTION INDUCE STRONG SPECIFIC MUCOSAL RESPONSE IN THE SITE OF INFECTION
ANIMAL MODELS TESTED WITH PULMONARY LIVE VACCINES Goonetilleke et al. 2003 Tree et al. 2004 Lagranderie et al. 1993 Kaushal et al. 2015 Chen et al. 2004 Giri et al. 2006 Aguilo et al. 2015
SAFETY DATA OF BCG PULMONARY VACCINATION IN PRECLINICAL MODELS Tree et al. 2004 Lagranderie et al. 1993 Pulmonary vaccination with live vaccines is safe in preclinical models
• Weekly BCG doses of 3x10 7 by the aerosol route • No hepatic or pulmonary toxicity was doccumented during the study
EFFICACY DATA IN ANIMAL MODELS Guinea Pigs LogCFUs aerosol subcutaneous Lagranderie et al . 1993. Tubercle and Lung Disease
EFFICACY DATA IN ANIMAL MODELS Balb/c mice Lihao Chen et al. 2004 Infection and Immunity
EFFICACY DATA IN ANIMAL MODELS C57BL/6 mice *** *** *** *** *** *** *** *** *** 0.71 log 1.3 log 1.8 log Aguilo et al . 2012. Clinical Vaccine Immunology
EFFICACY DATA IN ANIMAL MODELS C57BL/6 mice Dose response profile in BCG pulmonary vaccination *** *** ns *** * *** *** ** * Aguilo et al . 2012. Clinical Vaccine Immunology
RE-VACCINATION OF BCG SC-IMMUNIZED MICE WITH BCG IN BCG IN boosts BCG SC vaccination * Unpublished results
Does pulmonary BCG work where parenteral immunization fails?
*** LogCFUs subcutaneous Parenteral BCG immunization confers good protection in preclinical models used to test TB vaccines
DBA/2 MOUSE STRAIN TB susceptible and resistant mouse strains Medina et al. 1998 Immunology
DBA/2 MOUSE STRAIN BCG subcutaneous poorly protects DBA/2 mice against TB challenge Medina et al. 1999 Immunology Gruppo et al. 2002 Microbiology
PROTECTIVE EFFICACY (CFU in lungs) 8 weeks 4 weeks s.c. BCG Danish 10 6 CFUS Sacrifice i.n. Challenge H37Rv ≈ 150 CFUS ns *** BCG s.c does not confer protection to DBA/2 mice Aguilo et al. Journal of Infectious Diseases. IN PRESS
PROTECTIVE EFFICACY (CFU in lungs and spleen) 8 weeks 4 weeks s.c. or i.n BCG Danish 10 6 CFUS Sacrifice i.n. Challenge H37Rv ≈ 150 CFUS ** *** ** *** BCG i.n confers protection to DBA/2 mice in lungs and spleen Aguilo et al. Journal of Infectious Diseases. IN PRESS
PROTECTIVE EFFICACY (Survival) 8 weeks Survival s.c. or i.n BCG Danish 10 6 CFUS i.n. Challenge H37Rv ≈1000 CFUS *** Aguilo et al. Journal of Infectious Diseases. IN PRESS
IMMUNOGENECITY PRE-CHALLENGE 8 weeks s.c. or i.n BCG Danish 10 6 CFUS PPD-specific immune response Lung Spleen *** *** ** *** IFN g BCG intranasal induces both local and systemic higher Th1 and Th17 *** *** *** ** IL17A Aguilo et al. Journal of Infectious Diseases. IN PRESS
IMMUNOGENECITY POST-CHALLENGE 8 weeks 4 weeks s.c. or i.n BCG Danish 10 6 CFUS Sacrifice: CFUs and i.n. Challenge PPD-specific H37Rv ≈ 150 CFUS immune response PPD-specific immunity CFUs Aguilo et al. Journal of Infectious Diseases. IN PRESS
IMMUNOGENECITY POST-CHALLENGE challenge Th17 lung response post- challenge correlates with better protection * * p=0.02 challenge Aguilo et al. Journal of Infectious Diseases. IN PRESS
ROLE OF IL17A IN PROTECTIVE EFFICACY a IL17A treatment (clone 17F3) 8 weeks 4 weeks s.c. or i.n BCG Danish 10 6 CFUS Sacrifice - i.n. Challenge H37Rv ≈ 150 CFUS - PPD-specific immune response *** *** ** IL17A contributes to protection mediated by BCG intranasal ** Aguilo et al. 2016. Journal of Infectious Diseases. IN PRESS
MUCOSAL IMMUNOGLOBULINS (IgA) Johansen et al. 2011. Mucosal Immunology
pIgR FUNCTION WT pIgR -/- Johansen et al. 1999. Journal of Experimental Medicine
ROLE OF IgA IN PROTECTIVE EFFICACY Achkar et al. 2013
IgA INDUCTION BY BCG IN BAL Induction of MTB-specific IgA by BCG intranasal in an IL17-dependent fashion ** ** 120 kDa ** pIgR 100 kDa *** *** ** Aguilo et al. Journal of Infectious Diseases. IN PRESS
PROTECTION AND IgA INDUCTION BY HEAT-KILLED MTB BAL SAMPLES *** *** ** Unpublished results
SUMMARY • Good safety profile of live pulmonary vaccines in different preclinical models. • Pulmonary route of administration is more effective than parenteral vaccination in animal models. • Pulmonary vaccination can work where parenteral immunization fails. • Possible role of IL17 in BCG pulmonary-induced protection. • Good correlation of specific IgA in BAL with protection
Grupo de Genética de Micobacterias http://genmico.unizar.es Nacho Aguiló Microbiología Clínica Carlos Lampreave José Antonio Aínsa* Mª José Revillo Pinilla Dessi Marinova Henar Alonso Asunción Vitoria Isabel Otal* Esther Broset Ana Pico Alberto Cebollada Dirección General de Salud Pública Sofía Samper * Ana Belén Gómez Luis Solans Jesús Gonzalo Grupo de Apoptosis, Inmunidad y Santiago Uranga Begoña Grácia Cancer Samuel Álvarez Mª José Iglesias Gozalo* Alberto Anel Liliana Rodrigues Carmen Lafoz Julian Pardo Irene Perez Elena Mata Raquel Tarancón Centro de Encefalopatías y Enfermedades Emergentes * IP coordinadores de línea Marta Monzón Juan J Badiola
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