Typhoid Vaccine Models Reveal Optimal Schedules Depend on Local Disease Burden

Typhoid fever remains a formidable public health challenge across much of the world, and the introduction of typhoid conjugate vaccines has offered countries a powerful new tool against the disease. Yet a critical question has lingered among immunization planners: when exactly should children receive the vaccine, and do they need booster doses to stay protected? A new multi-model comparison, commissioned by the World Health Organization and published in PLOS Medicine, provides the most rigorous answer to date. By harnessing four independent mathematical models of typhoid transmission, the research team evaluated how different vaccination schedules would perform across settings with varying levels of disease burden, and whether the strategies would justify their costs under realistic economic assumptions.

The study comes at a pivotal moment. Emerging evidence has suggested that immunity conferred by typhoid conjugate vaccines, or TCVs, may wane over time, raising concerns that a single dose in infancy might not provide lasting protection. This uncertainty has complicated efforts to craft vaccination policies, because the optimal timing of a first dose and the potential value of boosters depend heavily on how quickly protection fades. To resolve the question, the WHO brought together modeling teams operating different approaches, including two agent-based models that simulate individual people and their interactions, and two compartmental models that track populations moving between susceptible and infected states. Comparing multiple models allows researchers to distinguish findings that are robust from those that are artifacts of any single model’s structure.

The modeling teams calibrated their simulations against harmonized age-specific incidence data drawn from settings classified as medium, high, and very high typhoid incidence. This fitting process ensured that each model reproduced the observed patterns of who gets sick and at what ages, which is essential because the best age for vaccination depends on when disease risk peaks in a population. The researchers then tested an array of TCV schedules under two contrasting scenarios for vaccine waning, one slow and one fast. They evaluated routine vaccination at different ages, the addition of booster doses, and the inclusion of catch-up campaigns that would vaccinate older children beyond the routine target age, all assessed over a ten-year time horizon.

The headline finding concerns a strategy that combined several elements: routine vaccination at nine months of age, a catch-up campaign reaching children up to fifteen years old, and a booster dose administered five years after the primary dose. Across the incidence settings examined, this comprehensive approach was predicted to deliver the greatest reduction in disease, cutting cases by a median of 40 to 68 percent. The wide range reflects variation across the different models and settings, but the consistency of the direction of effect across all four models is notable. Catch-up campaigns appear to be a particularly valuable component, because vaccinating older children who currently carry a substantial share of transmission accelerates the decline in disease and provides indirect protection to unvaccinated individuals through reduced circulation of the bacterium.

Cost-effectiveness analysis added a crucial economic dimension to the findings. The team employed the net-monetary-benefit framework, a standard approach in health economics that converts health gains into monetary terms and compares them against intervention costs. Because real-world estimates of the costs of typhoid illness and the risk of dying from it vary widely, the researchers ran their economic evaluations under two representative scenarios, one with high costs of illness and high case fatality risk and one with low values for both. This sensitivity analysis matters enormously, because the economic case for vaccination is far stronger when typhoid kills more frequently and treatment imposes greater financial burdens on households and health systems.

The economic results revealed clear patterns tied to disease burden. In medium incidence settings, introducing TCV with a catch-up campaign proved cost-effective at willingness-to-pay thresholds above 1,250 dollars per disability-adjusted life-year averted, but only when the costs of illness and case fatality risk were high. In high incidence settings, the same strategy was cost-effective even when costs and fatality risk were low, underscoring how a heavier disease burden strengthens the economic argument for vaccination. Most striking were the very high incidence settings, where introducing TCV at either nine months or two years of age was predicted to be cost-saving outright, meaning the vaccine would pay for itself through averted treatment costs and productivity losses regardless of the scenario tested.

The question of boosters received a nuanced answer that hinges on the pace of immune waning. If vaccine protection fades slowly, the standard schedule of a single dose at nine months with catch-up performs well without needing boosters in most settings. But if waning is fast, the models pointed toward a different strategy: delaying the primary vaccination to two or even five years of age, depending on the age at which disease incidence peaks in the community. The logic is straightforward. If protection will not last, giving it too early wastes the most valuable years of immunity on ages when disease risk is comparatively low. In very high incidence settings, however, adding a booster dose at five years of age was cost-effective at most willingness-to-pay values across all scenarios, suggesting that countries with intense transmission should plan for boosters from the outset.

One of the most reassuring aspects of the analysis is the degree of agreement among the four models despite their structural differences. Agent-based models and compartmental models make different simplifying assumptions about how immunity, mixing patterns, and transmission dynamics operate, so when they converge on similar predictions, confidence in the conclusions rises substantially. The researchers reported that model predictions for both health impact and cost-effectiveness were fairly robust to uncertainty in parameter values and model structure. This robustness is exactly what policymakers need, because it suggests the recommendations are not hostage to the idiosyncrasies of any particular modeling approach.

The authors are careful to acknowledge the limits of their work. The available data on indirect vaccine protection, the herd immunity effects that arise when vaccination reduces transmission, remain limited, and this gap constrains how precisely the models can predict population-level benefits. Other simplifying assumptions, including the representation of waning immunity and the treatment of age-specific contact patterns, also introduce uncertainty. These limitations do not undermine the central conclusions, but they highlight the value of continued surveillance as countries introduce TCVs, since real-world post-introduction data will allow the models to be refined and the waning question to be settled definitively.

For global health decision-makers, the study delivers a practical framework rather than a single universal prescription. The optimal typhoid vaccination strategy depends on three key local factors: the incidence rate of typhoid, the case fatality risk, and the waning rate of vaccine protection. Countries with very high transmission can proceed confidently with early routine vaccination and boosters, knowing the investment will likely save money. Countries with moderate transmission face a more contingent calculus that depends on the severity of disease and treatment costs. As more countries introduce TCVs and longer-term effectiveness data accumulate, the models compared in this analysis will provide an evolving evidence base for the WHO’s updated recommendations, helping ensure that every dose of typhoid vaccine is delivered at the age and in the schedule that delivers the greatest benefit.

Subject of Research: Modeling the impact and cost-effectiveness of typhoid conjugate vaccine schedules across transmission settings

Article Title: Evaluating the impact and cost-effectiveness of typhoid conjugate vaccine schedules across diverse settings: A multi-model comparison

Article References: Wenger, C. G. C., Grantz, K. H., Menkir, T. F., Muellenmeister, A. M., Pithawala, Z., Hutubessy, R., Mogasale, V., Kraay, A. N. M., Scott, N., Abeysuriya, R. G., Andrews, J. R., Gauld, J., Lo, N. C., & Pitzer, V. E. (2026). Evaluating the impact and cost-effectiveness of typhoid conjugate vaccine schedules across diverse settings: A multi-model comparison. PLOS Medicine, 23(10), e1005280. https://doi.org/10.1371/journal.pmed.1005280

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005280

Keywords: typhoid fever, typhoid conjugate vaccine, vaccination schedules, mathematical modeling, cost-effectiveness, WHO, immunity waning, booster doses, catch-up campaigns, public health, PLOS Medicine, disability-adjusted life-years