Vi-TT—a typhoid conjugate vaccine for infants and young children
Authors: Thomas F Wierzba, Avinash K Shetty
Journal: The Lancet Global Health (2021)

Salmonella enterica serovar Typhi (S Typhi) is the causative agent of typhoid fever. Globally, typhoid fever affected 9·24 million people and caused 110 000 deaths in 2019, primarily in areas lacking potable water and with poor sanitation.1Institute for Health Metrics and Evaluationhttp://www.healthdata.org/results/gbd_summaries/2019/typhoid-fever-level-4-causeDate accessed: September 23, 2021Google Scholar Infants and young children, especially those living in urban impoverished settings are at high risk. Multidrug-resistant strains are common. Over many decades, investigators have deployed several vaccines against typhoid fever. As early as 1896, a heat-inactivated whole-cell parenteral vaccine was available.2Plotkin S History of vaccination.Proc Natl Acad Sci USA. 2014; 111: 12283-12287Crossref PubMed Scopus (254) Google Scholar The vaccine, widely used during World War 1 was efficacious in US troops,3Shanks GD How World War 1 changed global attitudes to war and infectious diseases.Lancet. 2014; 384: 1699-1707Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar but caused severe local and systemic adverse events. An oral live attenuated typhoid vaccine, Ty21a (67% efficacy) was licensed in Europe in 1983 and the USA in 1989.4Levine MM Ferreccio C Black RE Germanier R Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation.Lancet. 1987; 1: 1049-1052Summary PubMed Scopus (268) Google Scholar A parenteral unconjugated Vi-polysaccharide vaccine (61% efficacy) was licensed in the USA in 1994. The Ty21a and Vi-polysaccharide were licensed for adults and children older than 2 years. In 2008, WHO recommended Ty21a and Vi-polysaccharide vaccines for use in endemic and epidemic settings. However, the need for multiple doses, intolerance of oral formulation, poor efficacy in young children, and short length of protection precluded their use in routine childhood immunisation programmes. In 2001, a double-blind, randomised trial showed that a prototype two-dose typhoid conjugate vaccine (TCV), Vi-rEPA, a formulation linking capsular polysaccharide Vi to carrier Pseudomonas aeruginosa exotoxin A, was safe and effective (>90% efficacy) in Vietnamese children aged 2–5 years.5Lin FY Ho VA Khiem HB et al.The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children.N Engl J Med. 2001; 344: 1263-1269Crossref PubMed Scopus (352) Google Scholar The protein carrier, which allows T-cell help to B cells, induces pronounced immune responses to polysaccharides in infants and young children. Immunogenicity data suggest that T-cell dependent conjugate vaccines confer longer-term protection compared with Vi-polysaccharide vaccines. Despite the early promise of Vi-rEPA, there was a considerable delay before a commercially available new generation TCV was developed. In 2015, data from a phase 3 trial in India showed that a single dose, Vi polysaccharide-tetanus toxoid (Vi-TT) conjugate vaccine, Typbar-TCV (Bharat Biotech International, India), was safe and immunogenic in infants, children, and adults up to age 45 years.6Mohan VK Varanasi V Singh A et al.Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.Clin Infect Dis. 2015; 61: 393-402Crossref PubMed Scopus (112) Google Scholar A human challenge trial showed the vaccine to be efficacious.7Jin C Gibani MM Moore M et al.Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.Lancet. 2017; 390: 2472-2480Summary Full Text Full Text PDF PubMed Scopus (170) Google Scholar The Drug Controller of India has licensed the vaccine and the WHO prequalified it in 2017. Mila Shakya and colleagues present the results of a phase 3 trial of Typbar-TCV done among more than 20 000 children aged 9 months to younger than 16 years in Nepal.8Shakya M Voysey M Theiss-Nyland K et al.Efficacy of typhoid conjugate vaccine in Nepal; final results of a phase 3, randomised controlled trial.Lancet Glob Health. 2021; 9: e1561-e1568Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar The trial was comparator vaccine controlled (meningococcal capsular group A conjugate vaccine), randomised, and double blind, and investigators followed children for 24 months. The vaccine was immunogenic. Although decreasing over time, still at 18 months, IgA fold increase from baseline was 28 and IgG fold increase from baseline was 67 compared with less than 1·3 and 1·5 in the comparison groups, respectively. By trial end, nearly eight in every ten vaccinated children were protected from infection. Investigators did not observe a difference in vaccine efficacy by age or by length of follow-up. As reported in an interim analysis,9Shakya M Colin-Jones R Theiss-Nyland K et al.Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal.N Engl J Med. 2019; 381: 2209-2218Crossref PubMed Scopus (84) Google Scholar reactogenicity during the week after vaccination and serious adverse events in the 6 months following vaccination were similar between the typhoid and comparator vaccine. WHO has recommended the use of single-dose TCV in infants and children older than 6 months in endemic settings. The TCV is preferred over other available typhoid vaccines because of its improved immunological properties, use in infants and younger children, and expected longer duration of protection. The results of this trial add to the growing support for widespread use of the Typbar-TCV. However, some knowledge gaps remain. A longer trial follow-up period would help to elucidate the longevity of protection (beyond the 2-year protective efficacy noted in Shakya's study) and to establish the need for a booster dose. Post-licensure effectiveness studies are needed in other endemic areas to evaluate vaccine effectiveness and impact in geographically diverse, high-risk populations and to consider the effects of herd protection. Studies should also monitor vaccine effect on control of drug-resistant typhoid fever. After 130 years from the development of the cellular typhoid vaccine, these study results suggest that incorporating an effective and well-tolerated TCV into routine immunisation programmes in endemic regions is likely to result in substantial health benefits. Endemic countries should consider introducing and scaling up TCV. Population-based, multiyear surveillance projects have been developed in Africa and south Asia to accurately estimate the incidence, severity, and costs of typhoid fever illness.10Carter AS Luby SP Garrett DO Introducing typhoid conjugate vaccine in South Asia: Lessons from the surveillance for enteric fever in Asia project.Clin Infect Dis. 2020; 71: S191-S195Crossref PubMed Scopus (3) Google Scholar Data from surveillance and prospective TCV studies sponsored by the Typhoid Vaccine Acceleration Consortium will enable policymakers to make decisions regarding inclusion of TCV in routine immunisation programmes. As countries begin to introduce TCV, effective collaboration between health-care providers, public health officials, and governments is crucial to promote TCV, educate the public via effective communication strategies and address the global threat of vaccine hesitancy. In addition to TCV rollout, sustainable investments in water and sanitation systems are crucial for control of typhoid fever. We declare no competing interests. Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trialThe final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever. Full-Text PDF Open Access