In 2018, the World Health Organization (WHO) estimated approximately 21 million cases of typhoid fever and 160,000 deaths worldwide annually (Summary of the WHO Position Paper on Typhoid vaccines: WHO position paper, 2018). Although the WHO has not released more recent global estimates (after 2018), other studies offer insights. A 2019 'Global Burden of Disease' modeling study projected 9.2 million incidences of typhoid fever with approximately 110,000 deaths annually (Garrett et al., 2022). This study also identified Southeast Asia as the region with the highest disease burden, followed by the Eastern Mediterranean and African regions. Furthermore, a 2023 surveillance study in urban India highlights the disproportionate impact of typhoid fever on children compared to adults. The study estimates 12–1622 new cases per 100,000 children (aged 6 months to 14 years) annually, compared to 109–970 new cases per 100,000 adults (15 years and older) (John et al., 2023).

Given high incidence of the infection and significant burden of the disease in specific regions around the world and due to growing cases of infection from antimicrobial-resistant strains of S. typhi, the WHO has strongly recommended the use of immunization against the disease, particularly in areas of high endemicity. In fact, since 2008, the WHO has advised the use of Ty21, a live attenuated vaccine, in settings with high pathogen prevalence and in populations at risk of an epidemic. In this regard, aiming for optimal immunization strategies in the future, the SAGE committee of the WHO have set research priorities to gauge vaccine efficacy, effectiveness, and immunogenicity in several regions around the globe. One of the primary research objectives of the committee included the establishment of correlates of protection to credibly measure vaccine-induced protection (Prepared by the SAGE Working Group on Typhoid Vaccines & the WHO Secretariat, 2017; Summary of the WHO Position Paper on Typhoid vaccines: WHO position paper, 2018). In the past 30 years, several clinical trials have been conducted, in which vaccines have shown a highly variable range of efficacy and effectiveness. Moreover, a meta-analysis of clinical trials that included a population size of 2 35 239 subjects showed suboptimal efficacy of approximately 50% (Milligan et al., 2018) (Supplementary Table 1).

The reasons for such discrepancies and suboptimal vaccine efficacy remain unknown and require further investigation. Given this scenario, the effect of the baseline immunological profiles of the host on vaccine (Ty21a)-induced immune responses cannot and should not be ignored. This is particularly true because pre-vaccination immunological profiles have shown direct effects on vaccine-induced immune responses to several vaccines, including hepatitis (Fourati et al., 2022), malaria (Tsang et al., 2020), and influenza vaccines (Nakaya et al., 2015, Tan et al., 2014). Moreover, because of this observation, experts have even proposed a pre-vaccination intervention strategy that would enable a population to attain higher vaccine-induced protection than the current numbers for the mentioned vaccines (Tsang et al., 2020). Hence, understanding the baseline determinants of vaccine responses, especially for oral enteric vaccines, can greatly benefit the design of novel immunization interventions that are in tune with and specific to a certain population. Along with aiding the design and development of interventions for prevention and treatment, such insights would also be beneficial in deducing the susceptibility of a population to infections/diseases and guiding public health strategies.

Hence, to investigate the possible role of the baseline immunological profile on the immunogenicity induced by the Ty21 vaccine, we analyzed pre- and post-vaccination gene expression datasets derived from a study conducted by the Oxford Vaccine Centre using the GEO database (GSE100665) (Blohmke et al., 2017) (Darton et al., 2016).The study originally involved three arms: subjects immunized with the Ty21 vaccine, subjects immunized with the M01ZH09 vaccine, and subjects administered the placebo. Subjects from the M01ZH09 arm were eliminated from the study to focus on Ty21 and live attenuated typhoid vaccine-induced immune responses, and subjects from the placebo arm served as controls. These two arms retrospectively had two sub-arms based on the onset of typhoid-associated symptoms post-challenge with the S. typhi Quailes strain. For the current study, subjects who did not show clinical symptoms of typhoid after challenge were considered as “vaccine responders,” and those who did show symptoms were considered “vaccine non-responders.” Figure S1. provides a detailed explanation of the inclusion and exclusion criteria used for sample selection.