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Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing McMaster Immunology Research Centre, Department of Pathology & Molecular Medicine McMaster University, Canada
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Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

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Page 1: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Lung mucosal immunity & mucosal TB vaccination for human application

Zhou XingMcMaster Immunology Research Centre,

Department of Pathology & Molecular MedicineMcMaster University, Canada

Page 2: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Global deaths

HIV/AIDS 1,100,000

Tuberculosis 1,800,000

Malaria 429,000

Infectious diseases for which there are noeffective vaccines

WHO 2016

Page 3: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

French scientists Albert Calmette and Alphonse Guerin, introduced BCG, used first in France as TB vaccine (1921)

American scientist Selman Waksman discovered Streptomycin, the first anti-TB drug (1943); Nobelprize laureate (1952)

Page 4: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

5-10% develop the disease upon exposure1/3 world population latently infected5-10% develop the disease 10.4 million new cases/year1.8 million deaths/year

Lengthy chemotherapy Increasing multi-drug resistant M.tbCollision with HIV/AIDSBCG vaccination will continue

TB FACTS TODAY

WHO Report 2016

Page 5: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Need for developing effective boosting vaccination strategies to enhance protective immunity in the lung following parenteral BCG priming

Page 6: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

[1]

Understanding why the “natural immunity” is ineffective in control of primary pulmonary M.tb infection

Page 7: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Lai et al, Eur J Immunol, 2014; Jeyanathan et al, Mucosal Immunol 2014

Anti-TB “natural immunity”Suppressed innate immune activation in the lung (naïve animals)

TNF-α pg/mL Lung

Days Post-challengeNaive Day 5 Day 10 Day 14 Day 21

0

20

40

60

80

100

0

200

400

600

800

1000

1200

1400

Naïve Day 7 Day 14 Day 21

Days Post-challenge

IL-10 pg/mL Lung

Page 8: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Lai et al, Eur J Immunol, 2014 & submitted 2017; Jeyanathan et al, Mucosal Immunol 2014

D a y s P o s t-c h a lle n g e

D a y 5 D a y 1 0 D a y 1 4 D a y 2 10

5 0

1 0 0

1 5 0

2 0 0

M e d ia

S tim u la ted

T o ta l C D 4 + IF N γ + T c e ll /L u n g (x 1 0 3 )

**

*

L o g 1 0 C F U /lu n g

D a y 5 D a y 1 0 D a y 1 4 D a y 2 14

5

6

7

***

***

D a y s P o s t-c h a lle n g e

Anti-TB “natural immunity”Delayed Th1 immunity and protection in the lung (naïve animals)

Page 9: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Shaler et al, Am J Pathol 2011

Purified CD11b+ APCs

Purified T cells

Airway lumen Granuloma

CD11b+CD11C+ antigen-presenting cells (APCs)CD11b+CD11C+

CD4+ IFNγ+

Anti-TB “natural immunity”Granuloma–a symbiotic immune-suppressed environment (naïve animals)

Page 10: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Day 5 Day 10 Day 14

36.310.812.7

Horvath et al, Mucosal Immunol, 2012

CD4+IFN-γ+ T cells3.2

3.4

3.6

3.8

4

Naïve BCG

Log10 CFU/lung Day 14 post-M.tb

Anti-TB “near-natural immunity”Th1 immunity remains markedly delayed in the lung (s.c BCG-vaccinated animals)

Page 11: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

[2]

New vaccination strategies to induce sufficiently “un-natural immunity” in the lung against M.tb

Page 12: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

A human serotype 5 replication-defective adenovirus-based vector expressing M.tb Ag85A

AdHu5Ag85A

ΔE1 E2 ΔE3 E4

AdHu5 backbone

Ag85ACMV Poly A

Page 13: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

5

5.5

6

6.5

PBS AdAS85Ai.m.

AdAg85Ai.n.

BCG s.c.

Wang et al, J Immunol 2004

AdAg85A

Log10 M.tb cfu/lung

Vaccine-induced anti-TB “un-natural immunity”Respiratory mucosal vaccination improves lung protection

Page 14: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Vaccine-induced anti-TB “un-natural immunity”Respiratory mucosal vaccine-induced long-lasting Tissue Resident Memory T cells (Trm) in the lung

Jeyanathan et al, Am J Respir Crit Care Med 2010

d21 d45 d90

Page 15: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Airway lumen

Lung interstitiumnaive

parenteralvaccination

respiratorymucosal

vaccination

Vasculature

Macrophage DC CD8 T cell M.tb

Before M.tb infection Day 14 after M.tb infectionProperty of ImmunityNatural Immunity-Suppressed innate immune responses in the lung/dLN

-Delayed T cell immunityin the lung (18-21 days)

-Mainly CD4 T cells

“Near-natural” Immunity-Suppressed innate immune responses in the lung

-Delayed T cell immunity in the lung (7-14 days)

-CD8 & CD4 T cells

“Un-natural” Immunity-Vaccine-Trained Innate Immunity in the lung

-T cell immunity available in the lung right away

-Tissue resident memory CD8 & CD4 T cells (Trm)

CD4 T cell

Page 16: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

[3]

Validation of the concept of viral-based (AdHu5) respiratory mucosal vaccination in large-size animal models & human studies

Page 17: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

AdHu5Ag85A – preclinical & clinical evaluation

murine studies

guinea pig (TAMU)

goat studies (CReSA)

bovine studies (VLA)

human phase 1

primate studies (W. Univ)

i.m (Canada)

i.m/i.n (Canada)

i.m/i.n (USA)

i.m (Spain)

i.d/e.d (UK)

i.m/i.t/aerosol (China)

Page 18: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

i.m AdAg85A (108 pfu)injection

wk 16wk 1 wk 2 wk 4 wk 8 wk 24 wk 26

-12 BCG-naïve-12 BCG+volunteers

screening baseline

Phase 1 human AdHu5Ag85A Trial Design-intramuscular route-

ConsentBCG historyHIV testQFT testChest x-ray

Anti-AdHu5 AbsWhole blood cultureFresh PBMC ElispotWhole blood ICS

Page 19: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

5:205ra135, 2013

214:1996, 2016

Page 20: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Assembled inhaled aerosol delivery system for clinical TB vaccine studies

vaccineloadingreservoir

Inspiratoryairflow

exhalationfilter

vaccineloadingreservoir

Inspiratoryairflow

exhalationfilter

Health Canada-approved clinical aerosolAdHu5Ag85A vaccine trial

Phase 1 inhaled aerosol AdHu5Ag85A trial to be launched…

Page 21: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

MVA85A aerosol MVA85A i.d

Page 22: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

A novel virus-vectored respiratory mucosal vaccine enhancesanti-tuberculosis immunity in a humanized model system

Yao et al, J Infect Dis 2017 (in press)

Page 23: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

8:1373–1387, 2015

Spray dried human and chimpanzee adenoviral-vectored vaccines are thermally stable and immunogenic in vivoS Afkhami, DA LeClair, S Haddadi, R Lai, S Toniolo, HC. Ertl, ED Cranston, MR Thompson, Z Xing

35:2916–2924, 2017

Page 24: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Conclusion

Respiratory mucosal vaccination withviral-based TB vaccine offers effective lung protection by inducing sufficiently “un-natural” immunity

Page 25: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

www.aeras.org 2016

Page 26: Lung mucosal immunity & mucosal TB vaccination for human application · 2017-06-13 · Lung mucosal immunity & mucosal TB vaccination for human application Zhou Xing. ... 10.4 million

Acknowledgments

-Past and present Xing Lab members-McMaster GMP Vector Core members-McMaster clinical TB Vaccine Trial Team (Dr. Smaill et al)-Natl & Intl partners and collaborators