Randomised controlled trials among children in Asia and Africa have revealed a high short-term efficacy of typhoid conjugate vaccines, however, few studies have analysed the persistence of protection beyond two years.
Now, a Lancet study documents the results of randomised controlled trials with more than four years of follow-up in Malawian children, noting the high effectiveness of a single dose of Vi-TT across all age groups, and demonstrating this therapeutic's cost-effective and efficient benefits for managing high disease burden in endemic regions.
In sub-Saharan Africa, Asia and Oceania, typhoid fever inflicts a massive burden of disease and poses a significant threat to public health systems. Estimating the burden of Salmonella enterica serotype Typhi (S Typhi) is difficult due to the lack of surveillance platforms and diagnostic tools within these regions. In 26% of cases, which are severe and complicated diseases, substantial morbidity is often observed.
The global rise of antibiotic resistance has reduced the efficacy of existing treatments, in addition to facilitating the emergence of drug-resistant typhoid strains in Asia. This motivates the urgent need to introduce typhoid vaccination in endemic regions.
The oral Ty21a and Vi polysaccharide (Vi-PS) vaccines are not currently approved for use in children and require several doses. As a result, these vaccines are primarily used for outbreak control and by travellers from high-income countries, rather than in routine immunisation programmes.
A typhoid conjugate vaccine (TCV), which consists of a Vi-PS conjugated to tetanus toxoid, has the potential to manage the high burden of typhoid fever in endemic areas, as TCV can generate more persistent immunity and can be administered to children under two years old. To date, the cost-effectiveness of vaccination strategies using the TCV has been studied in high-incidence countries.
About the study
The current double-blinded, phase 3, randomised controlled trial was conducted in Blantyre, Malawi. Healthy children aged between nine months and 12 years were recruited and randomly administered a single dose of meningococcal capsular group A conjugate (MenA) vaccine or Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT).
The children were recruited from health centres and government schools and only included if they lived in the study areas and were not previously vaccinated against typhoid. Participants, the study team, and the parents or guardians of participants were masked to vaccine allocation, however, the nurses administering the doses were not blinded.
Surveillance was conducted from vaccination until the completion of follow-up to detect febrile illness. The first incidence of typhoid fever, which was confirmed by blood culture, was the primary outcome. Additional intention-to-treat analyses were conducted for all study participants.
Key findings
A single dose of Vi-TT was found to offer at least four years of protection against typhoid fever, with cumulative vaccine efficacy estimated to be 78.3%. Across all age groups, vaccine efficacy loss was only 1.3% yearly over more than four years, reflecting the vaccine's durability and longer follow-up period that can prevent many cases.
More specifically, current estimates indicate that 163 children need to be vaccinated to prevent one case of typhoid, which is significantly lower than the estimate of 278 vaccinated children for the 18-24-month analysis.
Protection was noted across age groups, including children under two.
Given the importance of durability in children, the World Health Organisation (WHO) recommended the administration of a single-dose TCV in the first or second year of life. Vaccine efficacy was estimated to be 70.6% for children younger than two.
A key limitation of the analysis is the pause of surveillance during the 2019 pandemic for at least five months. If most typhoid cases occurred during this pause, then the results presented here should be considered underestimated.
Another study limitation was the decrease in the number of children who presented for blood culture and passive surveillance during the first two years. Although this could have led to an underestimation of the true incidence, it is not expected to bias the vaccine-efficacy results.
The high effectiveness of a single dose of Vi-TT was noted across all age groups, thus demonstrating this therapeutic's cost-effective and efficient benefits, and additional advantage is the possibility of integrating TCV with other vaccines used to prevent measles-rubella and polio.
Study details
Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children
Priyanka Patel, Yuanyuan Liang, James Meiring, Nedson Chasweka, Pratiksha Patel, Theresa Misiri, et al.
Published in The Lancet on 25 January 2024
Summary
Background
Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond two years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group.
Methods
In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked.
We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses.
Findings
Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2–4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3–86·1), and 163 (129–222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4–93·0) for children aged 9 months to 2 years; 79·6% (45·8–93·9) for children aged 2–4 years; and 79·3% (63·5–89·0) for children aged 5–12 years.
Interpretation
A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life.
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