Related Experiment Video
Updated: Mar 16, 2026
Author Spotlight: Optimizing CFU Determination for Efficient Assessment of TB Vaccine Efficacy and Antigen Presentation Analysis
Published on: July 28, 2023
Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the
Thomas C Darton1, Claire Jones1, Christoph J Blohmke1
1Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Insights
A new oral typhoid vaccine candidate, M01ZH09, did not show significant protection in a human challenge study. Pre-existing anti-Vi antibodies, however, were found to reduce typhoid susceptibility.
Area of Science:
- Vaccinology
- Infectious Diseases
- Clinical Trials
Background:
- Typhoid fever remains a significant global health burden, with existing vaccines exhibiting moderate efficacy and limitations for young children.
- Developing new typhoid vaccines is challenging due to the host-specific nature of Salmonella enterica serovar Typhi (S. Typhi) and unclear protection correlates.
- This study investigated the efficacy of a novel oral vaccine candidate, M01ZH09, against typhoid.
Purpose of the Study:
- To evaluate the protective efficacy of a single dose of the oral typhoid vaccine candidate M01ZH09.
- To compare the efficacy of M01ZH09 against placebo and an existing oral vaccine (Ty21a) in a controlled human infection model.
- To explore the role of pre-existing antibodies in typhoid vaccine response.
Main Methods:
- A randomized, double-blind, placebo-controlled trial was conducted with healthy adult volunteers.
- Participants received one dose of M01ZH09, placebo, or three doses of open-label Ty21a.
- Following vaccination, participants were deliberately infected with S. Typhi and monitored for typhoid diagnosis over 14 days.
Main Results:
- A single dose of M01ZH09 showed a vaccine efficacy of 13% (95% CI -29 to 41) compared to placebo.
- Three doses of Ty21a demonstrated a vaccine efficacy of 35% (95% CI -5 to 60).
- Pre-existing anti-Vi IgG antibodies significantly correlated with reduced susceptibility to typhoid infection post-challenge.
Conclusions:
- A single dose of the M01ZH09 oral vaccine did not provide significant protection against typhoid in this human challenge model.
- The study successfully utilized a human challenge model to assess vaccine efficacy.
- Pre-vaccination anti-Vi antibody levels were identified as a key factor influencing protection against typhoid infection.
Background:
Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge.
Methods And Findings:
We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model.
Conclusions:
Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge.
Trial Registration:
ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).
