Discussion
non-typhoid fever, typhoid conjugate vaccine, typhoid fever, typhoid
TYPHOID, VIRUS, TYPHOID FEVER, INFLUENZA
In a paediatric population in Malawi, estimates of Vi-TT effectiveness against blood culture-confirmed typhoid fever derived by the simulated test-negative design were almost identical to the gold standard randomised controlled trial vaccine efficacy results. Vi-TT had no effect on non-typhoid fever, further validating a core assumption of the test-negative design. In subgroup analyses by age, sex, and study site, the results remained highly consistent with the randomised trial vaccine efficacy estimates, and Vi-TT similarly had no effect on non-typhoid fever. Further evidence of test-negative design accuracy was shown in a simulated 1:3 case-control matched test-negative design analysis, which produced almost identical results to test-negative design analyses that used all controls, and to the original randomised trial. The finding that case-control matching made little difference to efficacy estimates is consistent with work by Dean and colleagues.Although the test-negative design offers strong advantages and is commonly used to measure the effectiveness of influenza, rotavirus, COVID-19, and other vaccines,Outcome misclassification due to imperfect accuracy of the diagnostic test has been identified as a concern for the test-negative design, with low test specificity posing a greater threat to validity than low test sensitivity.Unlike randomised trials, in which vaccination history is known for each participant, misclassification of vaccination status is a concern for any observational study design, especially in settings where vaccine records are not electronic or centralised. In our sensitivity analysis, if the overall misclassification of vaccination status was 10% or higher, the vaccine effectiveness estimate was no longer reliable; this confirms that the accuracy of vaccination status is crucial in a test-negative design and supports efforts to improve the recording and retention of vaccination data at the individual level, in national programmes and campaigns. The greatest bias occurred in the scenario in which the direction of misclassification differed by case or control status. The smallest vaccine effectiveness estimates were observed when unvaccinated cases were misclassified as vaccinated, and vaccinated controls were misclassified as unvaccinated. Conversely, the largest vaccine effectiveness estimates occurred when vaccinated cases were misclassified as unvaccinated and unvaccinated controls were misclassified as vaccinated. An advantage with the test-negative design compared with other observational studies is that vaccination status is ascertained at the same timepoint (when health care is sought) for both cases and controls, ideally before their test status is known. This strategy reduces the potential for differential misclassification compared with a design in which cases and controls are recruited from separate locations with differential access to vaccination records.Randomised controlled trials have previously been used to evaluate the test-negative design for influenza vaccines, rotavirus, and enterovirus-71 vaccines, and for respiratory syncytial virus monoclonal antibody.In conclusion, post-introduction vaccine evaluations are a crucial component of programme monitoring. Such evaluations can affect other countries’ decisions to introduce vaccines and can play a part in maintaining continued support in the countries of introduction. The test-negative design expands the options for post-introduction typhoid conjugate vaccine evaluation and is well-suited for low-income settings due to its efficiency, convenience, and low cost. To our knowledge, this study is the first to rigorously evaluate the utility of the test-negative design to estimate typhoid conjugate vaccine effectiveness using a large randomised trial in Malawian children. Future evaluations of the test-negative design with different typhoid conjugate vaccines, vaccination coverage rates, or follow-up periods in different countries are needed to confirm the study findings in different populations and settings.