Down in one: Developing a single-dose, drinkable typhoid vaccine
According to World Health Organization estimates, typhoid fever kills over 200 000 people globally per year. The disease, caused by infection with Salmonella typhi, is a major problem in developing countries, where children and young people are disproportionately affected. Typhoid fever also poses a risk to travellers visiting endemic areas.
The disease causes a range of symptoms, including headache, fever, rash and abdominal pain. Infected people (who can be ill themselves or 'healthy' carriers) shed the bacteria in their faeces. The disease is spread when people consume food or drink that has been contaminated by infected faeces, for example when sewage leaks into a drinking-water source. This means that typhoid can be a particular problem in disaster zones.
Untreated, around 10 per cent of people with typhoid fever die. This rate can be reduced to less than 1 per cent with antibiotic therapy, but S. typhi strains that are resistant to commonly used antibiotics are becoming increasingly prevalent in a number of endemic areas.
Several vaccines are currently available to protect against typhoid fever, including - among others - a four-dose drinkable vaccine and a single-dose injectable vaccine. Current vaccines also have limited efficacy in children under six years old - the group at greatest risk of contracting typhoid fever in endemic areas.
In 2005, the Wellcome Trust made a Strategic Translation Award of nearly £2 million to the biopharmaceutical company Emergent BioSolutions Inc. to advance the clinical development of the firm's single-dose, drinkable typhoid vaccine. The vaccine is based on a live attenuated strain of S. typhi, which has had two genes deleted to remove its ability to cause disease.
Initial testing in healthy adults in the UK and the USA suggested that Emergent's single-dose, drinkable vaccine candidate triggered a significant immune response.
A Trust-funded phase II trial in 27 adults in Vietnam built on these findings by showing that the Emergent vaccine caused the same level of immunity as in US participants, and was well tolerated and safe. This study was carried out in conjunction with Professor Jeremy Farrar and colleagues at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, the site of one of the Trust's Major Overseas Programmes.
This team was also involved in a phase II study in Vietnamese children aged from five to 14 years old. In the randomised, placebo-controlled trial, 101 children received the Emergent drinkable vaccine and 50 received a placebo. The results of the study, released in early 2008, showed that the vaccine was safe and effective - it elicited an immune response in 97 per cent of children who received a dose.
In June 2008, Emergent BioSolutions announced plans for a randomised, double-blind, placebo-controlled 'bridge study' in healthy adults in the USA. This is now underway and will test the safety, tolerability and immune effects of a vaccine candidate manufactured at the company's large-scale manufacturing facility. This is a necessary prelude to further clinical trials at population level.
If taken successfully through phase II efficacy trials and approved, this would be the first drinkable, single-dose typhoid vaccine suitable for children and adults. This vaccine would not only protect visitors to endemic areas from the typhoid bacterium, but would also offer a means to prevent typhoid fever in those living in such areas. As the vaccine is given as a single dose, it is simple and convenient. This also means that people need only be seen by health practitioners once to ensure that the course of vaccination is complete.
References
Crump JA et al. The global burden of typhoid fever. Bull World Health Organ 2004;82:346-53.
Kirkpatrick BD et al. Comparison of the antibodies in lymphocyte supernatant and antibody-secreting cell assays for measuring intestinal mucosal immune response to a novel oral typhoid vaccine (M01ZH09). Clin Diagn Lab Immunol 2005;12(9):1127-9.
Kirkpatrick BD et al. Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers. Vaccine 2006;24(2):116-23.
Kirkpatrick BD et al. The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations. J Infect Dis 2005;192(3):360-6.