Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial

Firdausi Qadri, Farhana Khanam, Xinxue Liu, Katherine Theiss-Nyland, Prasanta Kumar Biswas, Amirul Islam Bhuiyan, Faisal Ahmmed, Rachel Colin-Jones, Nicola Smith, Susan Tonks, Merryn Voysey, Yama F Mujadidi, Olga Mazur, Nazmul Hasan Rajib, Md Ismail Hossen, Shams Uddin Ahmed, Arifuzzaman Khan, Nazia Rahman, Golap Babu, Melanie Greenland, Sarah Kelly, Mahzabeen Ireen, Kamrul Islam, Peter O'Reilly, Karin Sofia Scherrer, Virginia E Pitzer, Kathleen M Neuzil, K Zaman, Andrew J Pollard, John D Clemens, Firdausi Qadri, Farhana Khanam, Xinxue Liu, Katherine Theiss-Nyland, Prasanta Kumar Biswas, Amirul Islam Bhuiyan, Faisal Ahmmed, Rachel Colin-Jones, Nicola Smith, Susan Tonks, Merryn Voysey, Yama F Mujadidi, Olga Mazur, Nazmul Hasan Rajib, Md Ismail Hossen, Shams Uddin Ahmed, Arifuzzaman Khan, Nazia Rahman, Golap Babu, Melanie Greenland, Sarah Kelly, Mahzabeen Ireen, Kamrul Islam, Peter O'Reilly, Karin Sofia Scherrer, Virginia E Pitzer, Kathleen M Neuzil, K Zaman, Andrew J Pollard, John D Clemens

Abstract

Background: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings.

Methods: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110.

Findings: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed.

Interpretation: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses.

Funding: The study was funded by the Bill & Melinda Gates Foundation.

Conflict of interest statement

Declaration of interests VEP has received reimbursement from Merck and Pfizer for travel expenses to scientific input engagements unrelated to the topic of this manuscript and is a member of the WHO Immunization and Vaccine-related Implementation Research Advisory Committee. All other authors declare no competing interests.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile SA 14-14-2=Japanese encephalitis vaccine. Vi-TT=Vi-tetanus toxoid conjugate vaccine.
Figure 2
Figure 2
The cumulative incidence of blood culture-confirmed typhoid fever among vaccinees by treatment group SA 14-14-2=Japanese encephalitis vaccine. Vi-TT=Vi-tetanus toxoid conjugate vaccine.

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