Stimulation of mucosal immunity by pulmonary delivery of live vaccines. A safe and effective strategy against TB

Transcription

1 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)

2 Live TB Vaccine TB infection MIMIC NATURAL ROUTE OF INFECTION INDUCE STRONG SPECIFIC MUCOSAL RESPONSE IN THE SITE OF INFECTION

3 ANIMAL MODELS TESTED WITH PULMONARY LIVE VACCINES Goonetilleke et al Tree et al Chen et al Giri et al Aguilo et al Lagranderie et al Kaushal et al. 2015

4 SAFETY DATA OF BCG PULMONARY VACCINATION IN PRECLINICAL MODELS Tree et al Lagranderie et al Pulmonary vaccination with live vaccines is safe in preclinical models

5 Weekly BCG doses of 3x10 7 by the aerosol route No hepatic or pulmonary toxicity was doccumented during the study

6 EFFICACY DATA IN ANIMAL MODELS Guinea Pigs LogCFUs aerosol subcutaneous Lagranderie et al Tubercle and Lung Disease

7 EFFICACY DATA IN ANIMAL MODELS Balb/c mice Lihao Chen et al Infection and Immunity

8 EFFICACY DATA IN ANIMAL MODELS C57BL/6 mice 0.71 log 1.3 log 1.8 log Aguilo et al Clinical Vaccine Immunology

9 EFFICACY DATA IN ANIMAL MODELS C57BL/6 mice Dose response profile in BCG pulmonary vaccination ns * ** * Aguilo et al Clinical Vaccine Immunology

10 RE-VACCINATION OF BCG SC-IMMUNIZED MICE WITH BCG IN BCG IN boosts BCG SC vaccination * Unpublished results

11 Does pulmonary BCG work where parenteral immunization fails?

12 LogCFUs subcutaneous Parenteral BCG immunization confers good protection in preclinical models used to test TB vaccines

13 DBA/2 MOUSE STRAIN TB susceptible and resistant mouse strains Medina et al Immunology

14 DBA/2 MOUSE STRAIN BCG subcutaneous poorly protects DBA/2 mice against TB challenge Medina et al Immunology Gruppo et al Microbiology

15 PROTECTIVE EFFICACY (CFU in lungs) 8 weeks 4 weeks s.c. BCG Danish 10 6 CFUS i.n. Challenge H37Rv 150 CFUS Sacrifice ns BCG s.c does not confer protection to DBA/2 mice Aguilo et al. Journal of Infectious Diseases. IN PRESS

16 PROTECTIVE EFFICACY (CFU in lungs and spleen) 8 weeks 4 weeks s.c. or i.n BCG Danish 10 6 CFUS i.n. Challenge H37Rv 150 CFUS Sacrifice ** ** BCG i.n confers protection to DBA/2 mice in lungs and spleen Aguilo et al. Journal of Infectious Diseases. IN PRESS

17 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

18 IMMUNOGENECITY PRE-CHALLENGE 8 weeks s.c. or i.n BCG Danish 10 6 CFUS PPD-specific immune response Lung Spleen ** IFNg ** BCG intranasal induces both local and systemic higher Th1 and Th17 IL17A Aguilo et al. Journal of Infectious Diseases. IN PRESS

19 IMMUNOGENECITY POST-CHALLENGE 8 weeks 4 weeks s.c. or i.n BCG Danish 10 6 CFUS i.n. Challenge H37Rv 150 CFUS Sacrifice: CFUs and PPD-specific immune response PPD-specific immunity CFUs Aguilo et al. Journal of Infectious Diseases. IN PRESS

20 IMMUNOGENECITY POST-CHALLENGE challenge * * Th17 lung response postchallenge correlates with better protection p=0.02 challenge Aguilo et al. Journal of Infectious Diseases. IN PRESS

21 ROLE OF IL17A IN PROTECTIVE EFFICACY ail17a treatment (clone 17F3) 8 weeks 4 weeks s.c. or i.n BCG Danish 10 6 CFUS - i.n. Challenge H37Rv 150 CFUS - PPD-specific immune response Sacrifice ** IL17A contributes to protection mediated by BCG intranasal ** Aguilo et al Journal of Infectious Diseases. IN PRESS

22 Johansen et al Mucosal Immunology MUCOSAL IMMUNOGLOBULINS (IgA)

23 pigr FUNCTION WT pigr -/- Johansen et al Journal of Experimental Medicine

24 Achkar et al ROLE OF IgA IN PROTECTIVE EFFICACY

25 IgA INDUCTION BY BCG IN BAL Induction of MTB-specific IgA by BCG intranasal in an IL17-dependent fashion ** ** ** 120 kda 100 kda pigr ** Aguilo et al. Journal of Infectious Diseases. IN PRESS

26 PROTECTION AND IgA INDUCTION BY HEAT-KILLED MTB BAL SAMPLES ** Unpublished results

27 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

28 Grupo de Genética de Micobacterias Nacho Aguiló José Antonio Aínsa* Henar Alonso Esther Broset Alberto Cebollada Ana Belén Gómez Jesús Gonzalo Begoña Grácia Mª José Iglesias Gozalo* Carmen Lafoz Elena Mata Raquel Tarancón * IP coordinadores de línea Carlos Lampreave Dessi Marinova Isabel Otal* Ana Pico Sofía Samper * Luis Solans Santiago Uranga Samuel Álvarez Liliana Rodrigues Irene Perez Microbiología Clínica Mª José Revillo Pinilla Asunción Vitoria Dirección General de Salud Pública Grupo de Apoptosis, Inmunidad y Cancer Alberto Anel Julian Pardo Centro de Encefalopatías y Enfermedades Emergentes Marta Monzón Juan J Badiola

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