Impact case study - Typhoid

The OVG’s work on typhoid has been hugely influential, changing our understanding of the biology and the potential of vaccination to control the disease. Since typhoid occurs only in humans, it cannot be studied in animals, and so the decision to use human challenge studies, built on an ethical and scientific framework, was a game changer, enabling a new understanding of the pathogenic mechanisms driving the disease, and an evidence-based approach to evaluate interventions like vaccines.

We showed that a small oral dose of 10,000 Salmonella Typhi bacteria resulted in clinical typhoid in two thirds of volunteers. We analysed transcriptional, cytokine and antibody responses during acute disease, identifying an unexpected asymptomatic transcriptional and cytokine signature in all individuals within 24 hours of challenge. Further immunological and transcriptional analyses showed that clinical symptoms were associated with a type I/II interferon signatures that correlated with disease progression. The human challenge model also identified a central role for host tryptophan metabolism in the pathogenesis of typhoid fever, as well as providing new data on diagnosis, antibiotic performance, and immune correlates. The typhoid model is now referenced in the WHO guidelines for vaccine manufacturers, an exemplar for its utility for vaccines development against other diseases.

We also led ambitious large-scale studies on the burden of typhoid in Nepal, Bangladesh and Malawi. These trials, involving 300,000 people, resulted in exquisite analysis showing a higher-than-expected burden of the disease in children after adjusting for healthcare seeking behaviour, phlebotomy rates and blood culture sensitivity. This in turn provided key evidence for WHO decision-making on vaccine use.

In these populations we implemented field vaccine safety and efficacy trials involving 100,000 children across the study sites. An interim analysis of 20,000 children in Nepal showed that the typhoid conjugate vaccine provided 82% efficacy. We corroborated these data using a novel technique for estimating efficacy using serological markers from another trial in India. Working with colleagues in Bangladesh, we verified these findings in a landmark paper showing protection with a single dose even in children under two years of age (Qadri et al, Lancet 2021). The safety data from these field trials were referenced in a review by WHOs Global Advisory Committee on Vaccine Safety (Typhoid vaccines (who.int)).

The work proved instrumental in driving the impetus to use the typhoid conjugate vaccine to protect children in endemic areas and control outbreaks of multiple antibiotic resistant S. Typhi. 10 million doses were used at the end of 2019 to contain an outbreak of extraordinarily resistant (XDR) typhoid in Pakistan, and since then there have been introductions in seven countries with 60 million children already protected amid an ongoing roll out.

We have now begun work on the disease caused by the genetically distinct pathogen, Salmonella Paratyphi A, identifying pathways for pathogenesis, antigenic targets and opening up routes for vaccine development using a new controlled human infection model, with a vision for comprehensive control of enteric fever by driving development of a bivalent typhoid-paratyphoid vaccine.