PIM

Paratyphoid infection model

Background

In 2000, paratyphoid accounted for about one fifth of the global burden of enteric fever but this share has increased dramatically over the last decade, particularly in South East Asia as a result of a growing pandemic of infection clinically indistinguishable from diseases caused by S. typhi.  Almost 50% of imported enteric fever cases in returning travelers are now due to S. paratyphi A infection.

The typhoid vaccines currently licensed in the European Union (oral Ty21a and parenteral Vi polysaccharide) provide a moderate level of protection against typhoid fever (Klugman et al., 1987; Levine et al., 2007), but do not prevent disease caused bySparatyphi A (Levine et al., 1987; Black et al., 1990).  Therefore, paratyphoid remains a significant and clinically indistinguishable cause of enteric fever.  Paradoxically, control of typhoid can lead to a rise in paratyphoid cases, assuming these pathogens compete for a similar ecological niche.

There are no vaccines currently available to prevent paratyphoid infection, but several manufacturers are pursuing the development of conjugate vaccines based on the O-antigen (LPS) surface component of S. paratyphi A.  However, the absence of defined correlates of protection for paratyphoid infection is particularly problematic for the advancment of prevention of this disease, and the step from early vaccine concepts to expensive field trials needs innovative new approaches.  Furthermore, as S. paratyphiis a human restricted pathogen, there is no animal model that allows evaluation of protective efficacy of vaccines.

The aim of this project is to establish the first controlled human challenge model of paratyphoid infection that will provide a unique opportunity to study the immune response to Sparatyphi A, with a view to later being able to evaluate the efficacy of novel vaccine candidates and identify potential correlates of protection, thus providing early proof of the vaccine concept.

The model will be developed using healthy volunteers to give an attack rate of 60-75%, and will be a critical and important innovation in driving forward the development of paratyphoid vaccines.

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Growth of the S. paratyphi A salmonella challenge agent on trypticase soy agar plate.

Major milestones

  • Release of the Sparatyphi A strain produced under current Good Manufacturing Practice (cGMP) conditions. Q4 2013
  • Establishment of a human model of paratyphoid with a dose of S. paratyphi Awhich induces a reproducible attack rate of 60-75%. Q4 2014

pim

GMP manufactured S. paratyphi A challenge strain

Achievements

  • EVI funds have been instrumental in obtaining complementary co-funding from the Bill and Melinda Gates Foundation which will allow evaluation of the efficacy of a new paratyphoid vaccine candidate.
  • GMP manufacturing and release of the challenge Sparatyphi strain completed in October 2013.
  • Ethical clearance and regulatory approval to develop the human challenge model received in March 2014
  • Start of the human challenge study in May 2014.

References

  1. Buckle, GC et al. Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010,  J Glob Health. 2012 Jun;2(1):010401.
  2. Klugman, K.P. et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 2, 1165-9 (1987).
  3. Levine, M.M., et al. Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Lancet 1, 1049-52 (1987).
  4. Levine, M.M. et al. Ty21a live oral typhoid vaccine and prevention of paratyphoid fever caused by Salmonella enterica Serovar Paratyphi B. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 45 Suppl 1, S24-8 (2007).
  5. Black, R.E. et al. Efficacy of one or two doses of Ty21a Salmonella typhi vaccine in enteric-coated capsules in a controlled field trial. Chilean Typhoid Committee. Vaccine 8, 81-4 (1990).