Understanding typhoid disease after vaccination; version 1.

• Research type

  Research Study

• Full title

  Understanding typhoid disease after vaccination: a single centre, randomised, double-blind, placebo-controlled study to evaluate M01ZH09 in a healthy adult challenge model, using Ty21a vaccine as a positive control.

• IRAS ID

  58996

• Contact name

  Claire Waddington

• Sponsor organisation

  Buckinghamshire NHS Trust

• Eudract number

  2011-000381-35

• Clinicaltrials.gov Identifier

  N/A

• Research summary

  Research Summary

  Typhoid is a serious infection killing up to 600,000 people every year; it is a frequent cause of fever and hospital admission in disease endemic regions. Infection with Salmonella Typhi, the causative agent of typhoid fever, only occurs in humans. This presents the possibility that with suitable control measures such as vaccination, typhoid fever could be eradicated. However, currently available vaccines lack the necessary efficacy to achieve this. We propose to use a recently established human typhoid challenge model in order to evaluate a novel oral vaccine candidate and to develop new methods for diagnosing typhoid.Although there are currently available vaccines to protect against typhoid fever, they cannot be used in young children in whom disease predominates.,The effectiveness of novel vaccines against typhoid cannot be predicted, as correlates of protection against typhoid are unknown. As a result, implementation of vaccine programmes in disease endemic regions currently requires large and expensive trials in each new population, significantly delaying programmatic implementation.We will use a typhoid challenge model to achieve our goal of accelerating the introduction of more effective vaccines into populations with a high burden of disease. Healthy adults will be vaccinated with either a novel oral typhoid vaccine or vaccine-placebo prior to being infected with the bacteria causing typhoid. This will allow us to measure the effectiveness of the vaccine and to identify components of the immune response important in producing protection against infection.Current methods for confirming typhoid infection are slow and lack sensitivity and specificity, particularly in endemic regions where the cost of laboratory equipment is prohibitive. In this project, we will explore ways to diagnose typhoid, with the aim of developing tests that are quick, reliable and cost-effective in resource-poor settings. This would improve both individual patient management, and allow accurate measurement of disease burden, which is vital to improve the efforts of vaccine programmes.

  Summary of Results

  Our study aimed to evaluate a new typhoid vaccine (M01ZH09) for the prevention of typhoid infection, which we assessed in a typhoid challenge model. The new single dose vaccine M01ZH09 did not provide any significant protection to those participants who received it, compared with placebo. While this is a negative result for the new vaccine, the study has actually given rise to many additional interesting insights regarding the mechanism of typhoid infection. We did demonstrate, for example, that 3 doses of the licensed Ty21a vaccine were more effective in preventing infection, although the level of protection seen in these vaccine recipients also was not great, it was similar to the protection reported for Ty21A in field trials. Of note, a single dose of the new vaccine (M01ZH09) did cause a significant delay in the onset of infection, and also considerably (and significantly) reduced the bacterial burden of infection in vaccine recipients.
  What does this mean for the development of a new vaccine? We were able to show that the challenge model we have set up in Oxford is very useful for assessing new vaccine candidates, and we now have a useful benchmark to compare future vaccines and related infections (such as paratyphoid) against. We have gone on to perform several additional studies to explore the mechanism of the delay in the onset of infection and also why some individuals seem to be susceptible despite mounting a good immune response after vaccination. Of key importance, the presence of certain pre-existing antibodies appears to convey a degree of protection against challenge in our model. In nature, the dose of typhoid causing infection may well be lower than that used in the challenge model, and therefore the protection provided by these antibodies may be even greater. Further work is currently being undertaken to explore the levels of these specific antibodies in different populations in order to determine the level of susceptibility to typhoid in different age groups and settings.

• REC name

  South Central - Oxford A Research Ethics Committee

• REC reference

  11/SC/0302

• Date of REC Opinion

  18 Aug 2011

• REC opinion

  Further Information Favourable Opinion