Typhoid is caused by an infection with Salmonella enterica serovar Typhi (S. Typhi).
Typhoid fever presents as a non-specific, febrile, systemic illness with a wide variety of general symptoms – such as malaise, headache, abdominal pain, chills, anorexia, diarrhoea, weight loss and constipation – and may result in severe and sometimes fatal complications.
The disease causes considerable illness and death in developing countries. Although the true incidence of typhoid fever is not known, it is estimated that 21 million typhoid fever cases and 161 000 deaths occur annually. The majority of cases occur in Asia and sub-Saharan Africa.
In endemic areas, typhoid affects infants, school-age children and young adults in particular. In developed countries it is a minor public health threat, but people can contract it after visiting endemic areas.
Vaccination prevents typhoid. S. Typhi expresses a capsule made of polysaccharides, which was discovered in 1934 and named Vi – short for virulence. It is still considered the main virulence factor and only recently it has been shown that the Vi polysaccharide capsule protects S. Typhi from attack by the human immune system. Vi is considered a protective antigen.
Licensed typhoid vaccines, the oral live attenuated Ty21a vaccine and the injectable Vi polysaccharide vaccine, are available in the UK. These vaccines are not suitable for children under 5 and 2 years of age, respectively. Novel Vi-protein conjugate vaccines remedy these shortcomings. A prototype typhoid Vi-protein conjugate vaccine (TCV) was proven to be immunogenic and induced a booster response in young children, and safe and efficacious in pre-school age children and infants. Three Vi-tetanus toxoid conjugate vaccines and one Vi-CRM197 conjugate vaccine are licensed in India. One Vi-tetanus toxoid conjugate vaccine was tested in a controlled human infection model and showed good efficacy. This vaccine was subsequently prequalified by the WHO for use by UNICEF and Gavi, and recently was shown to be efficacious in a phase III field trial in Nepal. Currently, three TCVs are progressing through clinical trials, three are approaching licensure, and a further five are at the pre-clinical stage.
To expedite the licensing process for new TCVs, we produced and evaluated 16/138, the first WHO International Standard (IS) for anti-Vi IgG (human), as well as two ISs for the Vi antigen :12/244 and 16/126.
In addition, the NIBSC holds two ISs for the 1960s whole cell typhoid vaccine: TYVK and TYVL, representative of acetone inactivated- and heat-phenol inactivated whole cell vaccines respectively. Two ISs for Salmonella spp. that cause disease in poultry are also available: SPDS-S2 and SPDS-V.NIBSC staff drafted WHO guidelines on the quality, safety and efficacy of typhoid conjugate vaccines: part A guidelines on manufacture and control.
The enteric vaccine group at the NIBSC is responsible for batch testing of new TCVs, often at the request of WHO. This involves various laboratory tests for potency to determine the quantity and quality of the Vi component, as well as safety tests.
The International Standards for TCV were developed and evaluated with support from WHO and the Bill and Melinda Gates Foundation. We carry out a range of tasks to support this programme.
Another important aspect of our work is to improve the standardisation of physicochemical- and immunoassays, which are used to analyse the Vi component of TCVs or the anti-Vi polysaccharide antibody response in clinical trial volunteers.
TYVK: Typhoid Vaccine (acetone-inactivated) TYVL: Typhoid Vaccine (heat-phenol-inactivated) SPDS-S2: Anti-Salmonella Pullorum Serum (Std. Form S) SPDS-V: Anti-Salmonella Pullorum Serum (Variant Form V)16/138: Anti-Typhoid capsular Vi polysaccharide Ig (Human)12/244: Vi polysaccharide of C freundii16/126: Native Vi polysaccharide (S. Typhi)