Phage Therapy - Sciensano

Phage therapy, a “new” approach in the combat against

bacterial infections

Dr. Daniel De Vos, Laboratory for Molecular and Cellular Technology

Queen Astrid Military Hospital (QAMH), Brussels, Belgium

(Daniel.devos2@mil.be)

WIV/ISP, Brussels, 27 November 2014

2

The worldwide antibiotic (AB) resistance crisis

A bad understanding of AB’s and a lack of fundamental knowledge and integration of ‘evolutionary biology’ in medicine

(mechanistic medicine >< evolutionary medicine)

Overuse and misuse of AB’s (static molecules >< living system)

Resistance!

(Bacterio)phages • Bacteriospecific virus (also active

against «superbugs»!!!)

• Natural controllers/predators of bacteria

• Co-evolve with their bacterial host cell

• A self amplifying and evolving antibacterial (darwinian medicine)

• Sustainable treatment approach

Phage therapy: The mechanism

• Estimated phage number on our planet:

1031 (= at least 10x the number of bacteria)

• Present in seas, rivers (up to billion phages/ml surface water), soil, food (cheese, yogurt, salami…), plants, animals (incl. human beings!), wherever there are bacteria

• However, no infection by phages has been reported and no DNA sequence of phage origin could be detected in the human genome (<-> 10% retrovirus!)

We live in an ocean of phages

Natural bacterial controllers (Ex.: Self-limiting nature of seasonal cholera epidemics)

Faruque et al. PNAS 2005

Lytic phages constitute a symbiotic immune system against invasive bacteria

(Ex.: our gut mucus layer)

Barr et al., PNAS 2013

Phage therapy : potentially sustainable

The phage/bacterium interaction is dynamic (co-evolution): a typical ‘arms race’ consists in the repetitive emergence and fixation of new virulent parasite and countering bacterial defence characteristics.

Phages vs. Antibiotics (ABs)

PHAGES

• Very specific (species or even strain specific and does not disturb the commensal flora)

• Infecting bacteria need to be known (cocktails could solve this; use of rapid diagnostics)

• Development of new phage preparations: quick and cheap

• No side effects known so far

ANTIBIOTICS

• Not specific (disturbs the commensal flora/collateral dammage)

• Infecting bacteria don’t need to be known (large spectrum ABs)

• Development of new AB: time consuming and costly

• Multiple side effects

Complementary and synergic!

George Eliava and Felix d’Herelle in Tbilisi

Phage Therapy Renaissance

Pirnay et al., Future Virology 2012

Allows quick reaction

Thousands of patients 54 died, hundreds with sequellae

In three days: several lytic phages identified

Antibiotics were of no use!

Authorities didn’t consider phage therapy

as a potential treatment

« In fact, Nestlé Research Center offered a lytic phage to the German public health

sector during the epidemic »

H. Brüssow, Virology 2012

Hurdles! • False perception of viruses as ‘enemies of life’ (L. P. Villarreal, 2005)

• Not compatible with current pharmaco-economic model • Need for an adapted regulatory framework (phages are no

conventional drugs) • Patent issues (phages are biological natural entities)

Pirnay et al., Future Virology 2012

Phage therapy in the QAMH

•Development of phage cocktails against o Pseudomonas aeruginosa and Staphylococcus aureus o Acinetobacter baumannii (incl. “IraqiBacter”) o Enterobacteriaceae (Ex.: EHEC et Klebsiella pneumoniae)

•Development of an adapted regulatory framework for phage therapy (EP, EC, DG SANCO, EMA, DG JRC,..)

•Co-evolutionary studies phage/bacterium (Buckling, Exeter, UK; Hall, ETH, Swiss)

•Some patients treated under the umbrella of the « Declaration of Helsinki »

•EU funded Project FP7 “PhagoBurn”

A phage cocktail (BFC-1) with QA/QC

• Lack of well defined and quality controled products

• Bacterial-Phage interaction often not optimized(empiric)

Endotoxin presence (purity)

• A “GMP-like” production product

BFC 1

• A modest and humble protocol did not allow to show clear evidence • BFC-1 application did not provoke any nefast side-effect • Medical and nursing staff got used to the phage therapeutic concept and are

convinced of its intrinsic safety and potential usefullness, especially against MultiDrugResistant (MDR) bacteria

• We are convinced that this small pilot study was a great step into the re-introduction of phage therapy in modern Western medicine

Verbeken et al., Future Medicine, 2, 485-491, 2007.

Merabishvili et al., PLoS ONE. 2009; 4(3): e4944.

Kutter et al, Current Pharmaceutical Biotechnology,11, 69-86, 2010.

Therapeutic application in burns

A first safety study at the MHQA

A phage application at the Queen Astrid Military Hospital under the umbrella of the Helsinki declaration and patients informed

consent

Phage application on shotwound at the Mil. Hosp. in Gori, Georgia

HMRA, Bruxelles

Eliava Institute, Tbilis

PhagoBurn: providing evidence! • Multicentric (France, Belgium, Switzerland)

clinical trial (P. aeruginosa and E. coli burn wound infection)

• EU funding: 3.8 milj. EUR

• Start: 1 June 2013

P.H.A.G.E.org

A collaborative effort • QAMH

• Belgium (UGent, VUB, KUL, ULB, UCL, ULg)

• Canada • Georgia • Russia • France • Switzerland • UK • Poland • Portugal • US

Thank you! Daniel.devos2@mil.be