The Vi-conjugate typhoid vaccine, the only typhoid vaccine that can be used in infants, represents a new tool to help control typhoid
A new typhoid vaccine has proven safe, highly immunogenic and could prevent more than half of typhoid infections according to a new study published in The Lancet. The study is a phase 2b trial of 112 adults and provides the first efficacy data for the leading candidate vaccine being considered for widespread use in children under 2 years, who are disproportionately affected by typhoid.
The trial uses a controlled human infection model, in which healthy volunteers are vaccinated and then deliberately exposed to the pathogen. These types of studies have been used to support the development of various vaccines (including the licenced cholera vaccine) as they can be rapidly deployed to assess vaccine efficacy.
The Vi-conjugate vaccine studied in this trial is only licensed for use in children under 2 years in India, and there are no typhoid vaccines licensed worldwide for use in children under 2 years old.
The study provides evidence to support the development of Vi-conjugate vaccines as a control measure to reduce the burden of typhoid fever, and the authors say that phase 3/4 and cost-effectiveness studies are now needed. The WHO’s Strategic Advisory Group of Experts is due to consider the use of Vi-conjugate vaccines for the control of typhoid fever in October 2017, with subsequent decisions on financing being made by the Global Alliance for Vaccines and Immunisation.
Typhoid affects between 12.5 and 20.6 million people worldwide in regions with inadequate water quality and poor sanitation, particularly in south Asia and sub-Saharan Africa. 1 in 100 cases are deadly and approximately 3% of cases become chronic carriers.
Typhoid is caused by Salmonella enterica serovar Typhi (S. Typhi bacteria) and is usually treated with antibiotics, but antibiotic resistance is increasing. Children are particularly susceptible to typhoid, but no vaccine is licenced for worldwide use in children under 2 years, contributing to poor adoption of typhoid immunisation programmes.
In the study led by the University of Oxford (UK), 112 volunteers in the UK were randomly assigned to receive a single dose of the Vi-tetanus toxoid conjugate vaccine (Typbar-TCV; Vi-TT), the pre-existing Vi-polysaccharide vaccine (TYPHIM Vi; Vi-PS), which cannot be given to young children, or a control meningococcal conjugate vaccine (MENVEO).
One month post-vaccination, participants were given an oral dose of the bacteria (wild type Quailes strain of S. Typhi). Participants were monitored daily for a two-week period and were given a course of antibiotics if they were diagnosed with typhoid. At the end of the two weeks, all participants, including those not diagnosed, were given a course of antibiotics.
Typhoid was diagnosed if the participant had a positive blood culture confirming infection or a persistent fever of 38˚C for 12h or longer. In the control group, 24/31 (77%) of participants were diagnosed with typhoid, compared with 13/37 (35%) Vi-TT recipients and 13/35 (35%) Vi-PS recipients, equivalent to a vaccine efficacy of 54.6% for Vi-TT and 52.0% for Vi-PS.
Symptoms of typhoid disease were less severe in the Vi-TT group, with lower bacterial load found in blood samples from diagnosed participants. Using alternative diagnostic criteria (fever of 38˚C followed by a positive blood sample) resulted in differences in vaccine efficacy at 87.1% for Vi-TT and 52.3% for Vi-PS, which may more accurately represent the efficacy of typhoid vaccines in endemic settings.
“Since the 1960s, controlled human infection models have been used to evaluate the efficacy of typhoid vaccine candidates, successfully supporting the development of one of the currently licenced typhoid vaccines Ty21a. 60 years on, we have used the same type of study to show that a Vi-conjugate vaccine is safe, immunogenic and halves the total number of typhoid infection cases, with the protective effect of the vaccine in endemic settings likely to be much higher. Our study provides further evidence to support the development of Vi-conjugate vaccines as a control measure to reduce the burden of typhoid fever, and individuals living in endemic regions should not be made to wait another 60 years to receive the vaccine,” says author Professor Andrew Pollard, Oxford Vaccine Group, University of Oxford.
The authors note that because of the design of the study, the participants were not representative of the populations where typhoid is endemic and where Vi-TT might eventually be deployed. Nevertheless, other studies of the vaccine have found that participants as young as 2 months old have a high immune response and that antibody responses can last up to 8 years post-vaccination even in typhoid endemic countries.
Writing in a linked Comment, Nicholas A Feasey, Liverpool School of Tropical Medicine (UK) and Myron M Levine, University of Maryland (US) say: “Results of this volunteer challenge have been awaited with much anticipation by the public health community interested in control of typhoid fever in endemic areas of south Asia and sub-Saharan Africa where S Typhi is increasingly antibiotic resistant and few treatment options remain. Vi-conjugate vaccines that have been in development represent a new instrument to help to control typhoid.” They note that the most advanced conjugate vaccine, (Typbar-TCV) is licensed in India where it has been shown to elicit robust serum Vi-antibody responses in Indian infants as young as 6 months of age, and an application for pre-qualification has been submitted to WHO. They add: “If approved, this would allow the vaccine to be procured by UN agencies. However, despite evidence of safety and immunogenicity in Indian children and adults, heretofore, there has been no evidence of actual efficacy of the vaccine in diminishing the attack rate of typhoid fever upon exposure to virulent S Typhi compared with the control participants. Importantly, the authors provide the first data documenting that Typbar-TCV is protective.”
The study was funded by the Bill & Melinda Gates Foundation and the European Commission.