Research in context
typhoid conjugate vaccine, typhoid Vi, febrile, typhoid
INFLUENZA, TYPHOID

As typhoid conjugate vaccines are introduced into national immunisation programmes, post-introduction monitoring of vaccine performance is important to understand how vaccines work under real-world conditions. The test-negative design has previously been efficiently used to evaluate post-introduction vaccine effectiveness for other vaccines. We aimed to validate the usefulness of the test-negative design for typhoid conjugate vaccines using a gold-standard randomised controlled trial database. We searched PubMed on Oct 17, 2022, with no date or language restrictions, using the terms (typhoid conjugate vaccine) AND (randomised controlled trial). Our search identified 47 papers, including four randomised controlled trials investigating typhoid conjugate vaccines, and no studies reporting the use of the randomised trials for test-negative design validation in relation to typhoid conjugate vaccines. We did a second search of PubMed on Oct 17, 2022, with no date or language restrictions, using the terms (typhoid conjugate vaccine) AND (case control study or test negative design). This second search identified 20 papers, and did not find any studies reporting the use of the randomised trials for test-negative design validation in relation to typhoid conjugate vaccines.
To our knowledge, this is the first study to rigorously evaluate the use of a test-negative design to estimate vaccine effectiveness. This study validated the test-negative design core assumption that typhoid conjugate vaccine has no effect on febrile illnesses that are not caused by typhoid. Furthermore, this study showed the accuracy and precision of vaccine effectiveness estimates derived using the test-negative design compared with gold-standard randomised controlled trial vaccine efficacy results in a Malawian paediatric population. Importantly, the effect of blood culture sensitivity was minimal for vaccine effectiveness estimation accuracy, especially when typhoid-positive cultures comprised fewer than 10% of all blood cultures.
The effectiveness of new vaccines should be evaluated after their introduction by use of the most rigorous approach possible. In the absence of randomised trials, epidemiological designs can be used to estimate vaccine effectiveness. Our study provides evidence to support the use of the test-negative design to measure post-introduction vaccine effectiveness of typhoid conjugate vaccines in Malawi and other similar settings. This efficient method to evaluate the performance of newly introduced typhoid conjugate vaccines could be a potential tool to generate crucial evidence for the continued support of existing vaccination programmes and to support decisions on whether to introduce typhoid conjugate vaccines in other countries. As in all observational study designs, the test-negative design remains susceptible to selection bias, confounding, and misclassification of vaccine and outcome status. The test-negative design should be considered only when a case-control study design is appropriate.The test-negative design has been extensively used to measure pneumococcal, influenza, rotavirus, and COVID-19 vaccine effectiveness.In this study, we evaluate the test-negative design to estimate typhoid conjugate vaccine effectiveness using a previously published randomised trial of typhoid conjugate vaccine (typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine [Vi-TT]) in Malawi as the gold standard comparator.