Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal

Abstract

BACKGROUND: Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS: In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS: A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P<0.001). A total of 132 serious adverse events (61 in the TCV group and 71 in the MenA vaccine group) occurred in the first 6 months, and 1 event (pyrexia) was identified as being vaccine-related; the participant remained unaware of the trial-group assignment. Similar rates of adverse events were noted in the two trial groups; fever developed in 5.0% of participants in the TCV group and 5.4% in the MenA vaccine group in the first week after vaccination. In the immunogenicity subgroup, seroconversion (a Vi IgG level that at least quadrupled 28 days after vaccination) was 99% in the TCV group (677 of 683 participants) and 2% in the MenA vaccine group (8 of 380 participants). CONCLUSIONS: Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161.).

Shown for reading. Its publisher allows quoting it, not republishing it.

References 29

1. 1.
   The burden of typhoid fever in low- and middle-income countries: A meta-regression approach · 2017

   No notice
2. 2.
   The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017 · 2019

   No notice
3. 3.
   Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010. · 2012

   No notice
4. 4.

   Mogasale Vittal, Maskery Brian Burden of typhoid fever in low-inocme and middle-income cuntries: a systematic, literature-based update with risk-factor adjustment. Lancet Glob Heal 2014;2:570–80.

   Not in our library10.1016/s2214-109x(14)70301-8

5. 5.

   World Health Organisation Typhoid vaccines: WHO position paper, March 2018 – Recommendations. Vaccine 2019;37(2):214–6.

   Not in our library10.1016/j.vaccine.2018.04.022

6. 6.

   Karkey A, Aryjal A, Basnyat B, Baker S Mini-Review Article Kathmandu, Nepal: Still an enteric fever capital of the world. J Infect Dev Ctries 2005;4–8.

   Not in our library10.3855/jidc.162

7. 7.

   Karkey A, Arjyal A, Anders KL, Boni MF, Dongol S The Burden and Characteristics of Enteric Fever at a Healthcare Facility in a Densely Populated Area of Kathmandu. PLoS One 2010;5(11):e13988.

   Not in our library10.1371/journal.pone.0013988

8. 8.

   Pradhan R, Shrestha U, Gautam SC, et al. Bloodstream Infection among Children Presenting to a General Hospital Outpatient Clinic in Urban Nepal. PLoS One 2012;7(10):e47531.

   Not in our library10.1371/journal.pone.0047531

9. 9.

   Zellweger RM, Basnyat B, Shrestha P, et al. A 23-year retrospective investigation of Salmonella Typhi and Salmonella Paratyphi isolated in a tertiary Kathmandu hospital. PLoS Negl Trop Dis 2017;11(11):1–16.

   Not in our library10.1371/journal.pntd.0006051

10. 10.

    Kelly DF, Thorson S, Maskey M, et al. The burden of vaccine-preventable invasive bacterial infections and pneumonia in children admitted to hospital in urban Nepal. Int J Infect Dis 2011;15(1):e17–23.

    Not in our library10.1016/j.ijid.2010.05.021

11. 11.

    Andrews JR, Qamar FN, Charles RC, Ryan ET Extensively Drug-Resistant Typhoid — Are Conjugate Vaccines Arriving Just in Time? New Engl J Med 2018;379(16):1493–5.

    Not in our library10.1056/nejmp1803926

12. 12.
    Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins · 2018

    No notice
13. 13.

    SAGE Working Group on Typhoid Vaccines and the WHO Secretariat Background paper to SAGE on typhoid vaccine policy recommendations. Strateg Advis Gr Expert Immun - 17-19 Oct 2017, WHO HQ, Geneva Switz 2017;(9 ):105–204.

    Not in our library

14. 14.

    Mohan 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(3):393–402.

    Not in our library10.1093/cid/civ295

15. 15.
    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 · 2017

    No notice
16. 16.

    Meiring JE, Gibani M, Basnyat B, et al. The Typhoid Vaccine Acceleration Consortium (TyVAC): Vaccine effectiveness study designs: Accelerating the introduction of typhoid conjugate vaccines and reducing the global burden of enteric fever. Report from a meeting held on 26–27 October 2016, Oxford. J Vaccine 2017;35(38):5081–8.

    Not in our library10.1016/j.vaccine.2017.08.001

17. 17.

    Theiss-Nyland K, Shakya M, Colin-Jones R, et al. Assessing the Impact of a Vi-polysaccharide Conjugate Vaccine in Preventing Typhoid Infections Among Nepalese Children: A Protocol for a Phase III, Randomized Control Trial. Clin Infect Dis 2019;68(Supplement 2):S67–73.

    Not in our library10.1093/cid/ciy1106

18. 18.

    Colin-Jones R, Shakya M, Voysey M, et al. Logistics of Implementing a Large-scale Typhoid Vaccine Trial in Kathmandu, Nepal. Clin Infect Dis 2019;68(Supplement 2):S138–45.

    Not in our library10.1093/cid/ciy1125

19. 19.

    Surveillance standards for vaccine-preventable diseases, second edition Geneva: World Health Organization; 2018 Licence: CC BY-NC-SA 3.0 IGO.;

    Not in our library

20. 20.

    Sur D, Ochiai RL, Bhattacharya SK, et al. A Cluster-Randomized Effectiveness Trial of Vi Typhoid Vaccine in India. N Engl J Med 2009;361(4):335–44.

    Not in our library10.1056/nejmoa0807521

21. 21.

    Khan MI, Soofi SB, Ochiai RL, et al. Effectiveness of Vi capsular polysaccharide typhoid vaccine among children: A cluster randomized trial in Karachi, Pakistan. Vaccine 2012;30(36):5389–95.

    Not in our library10.1016/j.vaccine.2012.06.015

22. 22.

    Simanjuntak CH, Totosudirjo H, Haryanto P, et al. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 1991;338(8774):1055–9.

    Not in our library10.1016/0140-6736(91)91910-m

23. 23.

    Lin FYC, 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(17):1263–9.

    Not in our library10.1056/nejm200104263441701

24. 24.

    Voysey M, Pollard AJ Seroefficacy of Vi Polysaccharide–Tetanus Toxoid Typhoid Conjugate Vaccine (Typbar TCV). Clin Infect Dis 2018;67(1):18–24.

    Not in our library10.1093/cid/cix1145

25. 25.

    Yang HH, Wu CG, Xie GZ, et al. Efficacy trial of Vi polysaccharide vaccine against typhoid fever in south-western China. Bull World Health Organ 2001;79(7):625–31.

    Not in our library

26. 26.

    World Health Organization Weekly epidemiological record - Global Advisory Committee on Vaccine Safety 5 - 6 December 2018. 2019.

    Not in our library

27. 27.

    Bilcke J, Antillón M, Pieters Z, et al. Cost-effectiveness of routine and campaign use of typhoid Vi-conjugate vaccine in Gavi-eligible countries: a modelling study. Lancet Infect Dis 2019;19(7):728–39.

    Not in our library10.1016/s1473-3099(18)30804-1

28. 28.

    Meiring JE, Laurens MB, Patel P, et al. Typhoid Vaccine Acceleration Consortium Malawi: A Phase III, Randomized, Double-blind, Controlled Trial of the Clinical Efficacy of Typhoid Conjugate Vaccine Among Children in Blantyre, Malawi. Clin Infect Dis - Suppl Artic 2019;68(Suppl 2):S51–8.

    Not in our library10.1093/cid/ciy1103

29. 29.

    Theiss-Nyland K, Qadri F, Colin-Jones R, et al. Assessing the Impact of a Vi-polysaccharide Conjugate Vaccine in Preventing Typhoid Infection Among Bangladeshi Children: A Protocol for a Phase IIIb Trial. Clin Infect Dis 2019;68(Supplement 2):S74–82.

    Not in our library10.1093/cid/ciy1107

Cited by papers we hold 3

• One-month evaluation of safety and immunogenicity of a Vi-DT typhoid conjugate vaccine (Bio-TCV®) in Indonesian subjects 6 months to 45 years: A phase III randomized clinical trial · 2025
  Not checked
• Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children · 2021
  No notice
• Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial · 2021
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.