640. Assessment of the Novel Oral Typhoid Vaccine Candidate, M01ZH09, Using a Controlled Human Infection Model of Salmonella Typhi Challenge
Session: Oral Abstract Session: Vaccines for all Ages
Friday, October 4, 2013: 9:00 AM
Room: The Moscone Center: 200-212
Background:

Salmonella Typhi infection remains a neglected cause of non-specific fever and mortality. Currently available vaccines have limited indications for use in young children. M01ZH09 is a novel live oral attenuated typhoid vaccine candidate that has previously demonstrated high immunogenicity and tolerability in various populations including younger children, when administered as a single dose.

Here, a recently developed controlled human infection model was used to measure the protective efficacy of M01ZH09 in comparison to placebo with a 3-dose comparator vaccine, Ty21a. 

Methods:

Enrolled participants were randomly allocated to receive double-blinded M01ZH09 or placebo, or open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with S. Typhi (Quailes strain) suspended in sodium bicarbonate solution. Participants were observed for 2 weeks, with regular clinical assessment and sample collection. Participants reaching pre-defined endpoints for typhoid diagnosis (temperature ≥38°C for ≥12hours and/or blood culturing S. Typhi) or Day 14 were initiated on antibiotic treatment. 

Results:

Of 99 participants enrolled, 91 completed vaccination and challenge. M01ZH09 was highly immunogenic generating significant increases in anti-LPS and H antibody-secreting cell responses by day 7 post-vaccine, exceeding those seen in Ty21a vaccinated participants.

Participants were challenged with 1.46 to 2.66x104 CFU S. Typhi. Of participants receiving placebo, M01ZH09 and Ty21a, typhoid was diagnosed in 66.7, 58.1 and 43.3% respectively, representing a protective efficacy of 13% for M01ZH09 (95%CI; -7.4, 28%) and 35% for Ty21a (95%CI; 17, 43%). However, participants receiving M01ZH09 demonstrated delayed onset of infection, milder symptom profile, fewer positive blood cultures overall and fewer positive stool cultures prior to typhoid diagnosis. Bacterial load at typhoid diagnosis was significantly reduced in both active vaccine groups.

Conclusion:

While demonstrating immunogenicity, reduced symptoms and favourable microbiological outcomes, M01ZH09, when administered as a single dose, offers limited protection against typhoid challenge at 104 CFU in this antigen-naïve population.

Tom Darton, MRCP(UK), DTM&H1, Claire Waddington, MRCP(UK), DPhil1, Claire Jones, PhD1, Christoph Blohmke, PhD1, Rebecca Sie, BSc1, Anna Peters1, Gordon Dougan, FMedSci, FRS2, Robert Kingsley, PhD2, Stephen Lockhart, DM3, Marcelo Sztein, M.D.4, Myron Levine, MD, FIDSA4, Jeremy Farrar, MD, PhD5, Derrick Crook, MB BCh6, Brian Angus6 and Andrew Pollard, FRCPCH, PhD1, (1)Oxford Vaccine Group, University of Oxford, OXFORD, United Kingdom, (2)Wellcome Trust Sanger Institute, CAMBRIDGE, United Kingdom, (3)Emergent Biosolutions, Inc., Rockville, MD, (4)University of Maryland School of Medicine, Baltimore, MD, (5)Oxford Univ. Clinical Res. Unit, Ho Chi Minh City, Viet Nam, (6)Nuffield Department of Medicine, University of Oxford, OXFORD, United Kingdom

Disclosures:

T. Darton, None

C. Waddington, None

C. Jones, None

C. Blohmke, None

R. Sie, None

A. Peters, None

G. Dougan, None

R. Kingsley, None

S. Lockhart, None

M. Sztein, None

M. Levine, None

J. Farrar, None

D. Crook, Optimer Pharmaceuticals: Investigator and Scientific Advisor, Consulting fee and Research support

B. Angus, None

A. Pollard, None

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