A safe and effective strategy against TB Nacho Aguilo - - PowerPoint PPT Presentation

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May 22, 2023 19 likes •312 views

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

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

Nacho Aguilo (naguilo@unizar.es)

Les Diablerets, 3rd February 2016

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

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Lagranderie et al. 1993 Kaushal et al. 2015 Chen et al. 2004 Giri et al. 2006 Aguilo et al. 2015 Goonetilleke et al. 2003 Tree et al. 2004

ANIMAL MODELS TESTED WITH PULMONARY LIVE VACCINES

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Pulmonary vaccination with live vaccines is safe in preclinical models

Tree et al. 2004

SAFETY DATA OF BCG PULMONARY VACCINATION IN PRECLINICAL MODELS

Lagranderie et al. 1993

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Weekly BCG doses of 3x107 by the aerosol route
No hepatic or pulmonary toxicity was doccumented during the study

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Lagranderie et al. 1993. Tubercle and Lung Disease

aerosol subcutaneous

LogCFUs

Guinea Pigs EFFICACY DATA IN ANIMAL MODELS

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Lihao Chen et al. 2004 Infection and Immunity

Balb/c mice EFFICACY DATA IN ANIMAL MODELS

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*** *** *** *** *** *** *** *** ***

0.71 log 1.3 log 1.8 log

Aguilo et al. 2012. Clinical Vaccine Immunology

C57BL/6 mice EFFICACY DATA IN ANIMAL MODELS

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Aguilo et al. 2012. Clinical Vaccine Immunology

ns *** *** *** *** ** * * ***

C57BL/6 mice Dose response profile in BCG pulmonary vaccination EFFICACY DATA IN ANIMAL MODELS

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Unpublished results

BCG IN boosts BCG SC vaccination RE-VACCINATION OF BCG SC-IMMUNIZED MICE WITH BCG IN

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Does pulmonary BCG work where parenteral immunization fails?

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***

subcutaneous

LogCFUs

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

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TB susceptible and resistant mouse strains

Medina et al. 1998 Immunology

DBA/2 MOUSE STRAIN

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Medina et al. 1999 Immunology Gruppo et al. 2002 Microbiology

BCG subcutaneous poorly protects DBA/2 mice against TB challenge DBA/2 MOUSE STRAIN

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s.c. BCG Danish 106 CFUS i.n. Challenge H37Rv ≈ 150 CFUS Sacrifice

8 weeks 4 weeks

BCG s.c does not confer protection to DBA/2 mice PROTECTIVE EFFICACY (CFU in lungs)

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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s.c. or i.n BCG Danish 106 CFUS Sacrifice

8 weeks 4 weeks

i.n. Challenge H37Rv ≈ 150 CFUS

BCG i.n confers protection to DBA/2 mice in lungs and spleen PROTECTIVE EFFICACY (CFU in lungs and spleen)

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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***

s.c. or i.n BCG Danish 106 CFUS

8 weeks Survival

i.n. Challenge H37Rv ≈1000 CFUS

PROTECTIVE EFFICACY (Survival)

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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s.c. or i.n BCG Danish 106 CFUS

8 weeks

PPD-specific immune response

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Lung Spleen

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IFNg IL17A BCG intranasal induces both local and systemic higher Th1 and Th17 IMMUNOGENECITY PRE-CHALLENGE

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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s.c. or i.n BCG Danish 106 CFUS Sacrifice: CFUs and PPD-specific immune response

8 weeks 4 weeks

i.n. Challenge H37Rv ≈ 150 CFUS

CFUs PPD-specific immunity IMMUNOGENECITY POST-CHALLENGE

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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challenge p=0.02

* *

challenge

Th17 lung response post- challenge correlates with better protection IMMUNOGENECITY POST-CHALLENGE

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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*** ** ***

s.c. or i.n BCG Danish 106 CFUS Sacrifice

8 weeks 4 weeks

i.n. Challenge H37Rv ≈ 150 CFUS
PPD-specific immune response

aIL17A treatment (clone 17F3)

IL17A contributes to protection mediated by BCG intranasal ROLE OF IL17A IN PROTECTIVE EFFICACY

Aguilo et al. 2016. Journal of Infectious Diseases. IN PRESS

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MUCOSAL IMMUNOGLOBULINS (IgA)

Johansen et al. 2011. Mucosal Immunology

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Johansen et al. 1999. Journal of Experimental Medicine

WT pIgR -/-

pIgR FUNCTION

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Achkar et al. 2013

ROLE OF IgA IN PROTECTIVE EFFICACY

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** ** **

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pIgR

100 kDa 120 kDa

Induction of MTB-specific IgA by BCG intranasal in an IL17-dependent fashion IgA INDUCTION BY BCG IN BAL

Aguilo et al. Journal of Infectious Diseases. IN PRESS

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Unpublished results

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

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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

SUMMARY

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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 Grupo de Genética de Micobacterias http://genmico.unizar.es 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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