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

Stimulation of mucosal immunity by pulmonary delivery of live vaccines.

A safe and effective strategy against TB

Nacho Aguilo ([email protected])

Les Diablerets, 3rd February 2016

TB infection Live TB Vaccine

MIMIC NATURAL ROUTE OF INFECTION

INDUCE STRONG SPECIFIC MUCOSAL RESPONSE IN THE SITE OF INFECTION

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

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

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

Lagranderie et al. 1993. Tubercle and Lung Disease

aerosol

subcutaneous

LogCFUs

Guinea Pigs

EFFICACY DATA IN ANIMAL MODELS

Lihao Chen et al. 2004 Infection and Immunity

Balb/c mice

EFFICACY DATA IN ANIMAL MODELS

***

***

***

***

***

***

***

***

***

0.71 log 1.3 log 1.8 log

Aguilo et al. 2012. Clinical Vaccine Immunology

C57BL/6 mice

EFFICACY DATA IN ANIMAL MODELS

Aguilo et al. 2012. Clinical Vaccine Immunology

ns

*** ***

*** ***

**

*

* ***

C57BL/6 mice Dose response profile in BCG pulmonary

vaccination

EFFICACY DATA IN ANIMAL MODELS

*

Unpublished results

BCG IN boosts BCG SC vaccination

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

Does pulmonary BCG work where parenteral immunization fails?

***

subcutaneous

LogCFUs

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

TB susceptible and resistant mouse strains

Medina et al. 1998 Immunology

DBA/2 MOUSE STRAIN

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

BCG subcutaneous poorly protects DBA/2 mice against TB challenge

DBA/2 MOUSE STRAIN

***

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)

ns

Aguilo et al. Journal of Infectious Diseases. IN PRESS

***

***

**

**

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

***

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

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

8 weeks

PPD-specific immune response

*** ** *** ***

Lung Spleen

** *** *** ***

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

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

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

*** ** ***

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

MUCOSAL IMMUNOGLOBULINS (IgA)

Johansen et al. 2011. Mucosal Immunology

Johansen et al. 1999. Journal of Experimental Medicine

WT pIgR -/-

pIgR FUNCTION

Achkar et al. 2013

ROLE OF IgA IN PROTECTIVE EFFICACY

** ** **

** *** ***

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

Unpublished results

**

PROTECTION AND IgA INDUCTION BY HEAT-KILLED MTB

BAL SAMPLES

*** ***

• 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

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