Generating the Evidence for Typhoid Vaccine Introduction: Considerations for Global Disease Burden Estimates and Vaccine Testing Through Human Challenge

Abstract

Typhoid fever has had a major impact on human populations, with the causative pathogen Salmonella enterica serovar Typhi implicated in many outbreaks through history. The current burden of disease is estimated at 11–18 million infections annually, with the majority of infections located in Africa and South Asia. Data that have been used to estimate burden are limited to a small number of blood-culture surveillance studies, largely from densely populated urban centers. Extrapolating these data to estimate disease burden within and across countries highlights the lack of precision in global figures. A number of approaches have been developed, characterizing different geographical areas by water-based risk factors for typhoid infection or broader measures of health and development to more accurately extrapolate incidence. Recognition of the substantial disease burden is essential for policy-makers considering vaccine introduction. Typhoid vaccines have been in development for >100 years. The Vi polysaccharide (ViPS) and Ty21a vaccines have had a World Health Organization (WHO) recommendation for programmatic use in countries with high burden for 10 years, with 1 ViPS vaccine also having WHO prequalification. Despite this, uptake and introduction of these vaccines has been minimal. The development of a controlled human infection model (CHIM) enabled the accelerated testing of the newly WHO-prequalified ViPS–tetanus toxoid protein conjugate vaccine, providing efficacy estimates for the vaccine, prior to larger field trials. There is an urgency to the global control of enteric fever due to the escalating problem of antimicrobial resistance. With more accurate burden of disease estimates and a vaccine showing efficacy in CHIM, that control is now a possibility.

What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2

“…Microbial challenge studies are useful for providing proof of concept for therapeutic interventions and can substantially reduce the time needed to reach phase 3 studies, as has been shown for malaria and typhoid vaccine development. 74 , 75 , 76 …”

Characterization of a new Leishmania major strain for use in a controlled human infection model

“…Often cited barriers to vaccine development include limited investment, with only $3.7 M of new R&D funding globally in 2018 18 , an excess of candidate antigens and delivery systems 19 , the questionable predictive capacity of pre-clinical animal models 20,21 , lack of good correlates of protection and a defined target product profile 22 , the costs and challenge of large-scale efficacy studies in disease endemic countries coupled with the high prevalence of asymptomatic infections 23,24 and a fragmented pipeline for translational research 25 . As has been found with other diseases [26][27][28][29][30][31][32][33] , the incorporation of a controlled human infection model (CHIM) into the vaccine R&D pipeline can overcome many of these issues.…”

Outbreak of enteric fever: a fact finding mission

“…The current burden of disease is estimated at 11-18 million infections annually, with the majority of infections located in Africa and South Asia. 8 Kim et al reported 180940 cases in 303 identified outbreaks caused by infection with S. typhi and Salmonella enterica serovar paratyphi A or B (S. paratyphi). The size of the outbreaks ranged from 1 to 42564.…”