Typhoid fever arises due to an intestinal infection instigated by the Gram-negative pathogen Salmonella enterica serovar Typhi, commonly referred to as S. typhi. The primary route of human infection by this bacterium is through ingesting food and water that have been contaminated (Brooks et al., 2005). The progression of an infection caused by S. typhi typically follows a sequential pattern. Initially, patients experience a fever in the first week, which intensifies during the second week. The manifestation of symptoms such as abdominal discomfort, constipation, and the emergence of maculopapular rashes also characterizes this period. As the infection advances into the third week, patients may experience more severe complications, including hepatosplenomegaly, ileocecal perforation, peritonitis, and septic shock. In the absence of appropriate medical intervention, typhoid fever has the potential to lead to mortality (Saha et al., 2019).

S. typhi predominantly impacts areas where clean water and sanitation facilities are scarce, posing a substantial public health challenge in numerous regions across the globe, particularly in less developed countries (Brooks et al., 2005; Saha et al., 2019). The World Health Organization (WHO) estimated in 2019, every year, approximately 9 million people are affected by typhoid fever causing around 110,000 deaths (Typhoid, 2023). The latest estimates reveal an increase in this condition; Roughly 12 million cases of typhoid occur each year, leading to more than 128,000 deaths annually. The highest incidence of S. typhi is in Asia and Africa, where rates exceed 100 per 100,000 person-years, and children are the most affected (Crump et al., 2004; Ochiai et al., 2008; Jamka et al., 2019).

While typhoid fever can be effectively treated with antibiotics, the increasing issue of antimicrobial drug resistance and the associated high expenses present significant challenges, particularly in regions with lower and moderate-income levels (LMICs) where the disease is prevalent (Jeon et al., 2018; Syed et al., 2020). Prevention of S. typhi focuses on better antibiotic management, public sanitation, clean water access, safe food handling, and hygiene education. According to the WHO, Vaccination is the mainstay and one of the most cost-effective measures (World Health Organization, 2019).

Several vaccines have been developed to prevent S. typhi infection. They are divided into three categories: live attenuated whole-cell Ty21a vaccine, purified unconjugated Vi polysaccharide vaccine (ViPS), and Vi conjugated vaccines (TCVs). The FDA has approved two vaccine categories, Ty21a and ViPS, for use in the USA (Hohmann et al., 1996; Crump and Mintz, 2010).

The Ty21a vaccine is an orally administered live attenuated vaccine that requires four doses. It is recognized for its ability to trigger a localized immune response in the intestinal tract by stimulating the production of lipopolysaccharides (Mazzone et al., 1994; Amicizia et al., 2017). TCVs have been proven useful in giving long-term immunity. A study of children in Nepal found that a single TCV treatment provided long-term protection. Specifically, 2 years after immunization, the vaccine’s efficacy in preventing blood culture-positive typhoid fever was similar with previous interim efficacy data, with an efficacy of 81.6% (Shakya et al., 2021). Furthermore, the study observed no significant difference in vaccine efficacy between the first 12 months and the subsequent period (Shakya et al., 2021).

Despite being effective, there are certain limitations to the use of these vaccines in countries where typhoid is endemic and in children under the age of two. The Vi-PS and Ty21a vaccines provide similar levels of protection within 2 years of vaccination. However, neither is authorized for use in infants particularly vulnerable to typhoid. Their protection is not sustained for over a few years (Syed et al., 2020). Additionally, Ty21a is exclusively accessible in capsule form and is not suitable for children under the age of five. It necessitates multiple doses for efficacy and, being a live organism, is not advisable for individuals with compromised immune systems or during pregnancy. Moreover, it demands strict cold chain maintenance, a significant constraint in resource-limited areas (World Health Organization, 2019).

Conjugating a carrier protein to the polysaccharide has effectively developed vaccines against Pneumococcal, Meningococcal, and Haemophilus influenzae infections as well as the Typhoid ViPS vaccine (Medise et al., 2019). The polysaccharide’s antigenic characteristics transform into a T cell-dependent antigen by attaching to a carrier protein. This alteration leads to an improved memory response and the development of protective immunity in both children and adults (World Health Organization, 2019).

In 2017, the World Health Organization (WHO) accorded prequalification status to Bharat Biotech’s Vi-TT, the inaugural Typhoid Conjugate Vaccine (TCV) developed in India. This vaccine received its initial license from the Drugs Controller General of India (DCGI) in 2013, permitting its use in the private market for children 6 months and older (Mohan et al., 2015; Burki, 2018). A second TCV conjugated to a nontoxic mutant of diphtheria toxoid (Vi-CRM₁₉₇) (TYPHIBEV, Biological E, India) has been licensed by the DCGI and prequalified by the WHO in 2020 (VaccinesWork, 2023).

Typhoid fever remains a public health problem in multiple countries, requiring integrative efforts to control the disease. Enteric fever, including typhoid and paratyphoid fevers, remains a significant public health concern in many parts of the world, particularly in areas with poor sanitation and limited access to clean water (Syed et al., 2020). Efforts to prevent and treat enteric fever have included vaccination programs, improvements in sanitation infrastructure, and public health education. However, challenges persist, and the disease burden in certain regions is still high (Syed et al., 2020).

The Vi-diphtheria toxoid typhoid conjugate vaccine (Vi-DT) represents a promising advancement in typhoid prevention, which combines the antigenic ViPS from S. typhi with the immunogenic diphtheria toxoid protein (Masuet-Aumatell and Atouguia, 2021). Various studies have suggested the safety and efficacy of Vi-DT and other typhoid vaccines in individuals aged 2 years and above (Levine et al., 1987; Kossaczka et al., 1999; Medise et al., 2019). Nonetheless, there is limited available data on the safety and effectiveness of Vi-DT in children under the age of two. The objective of this meta-analysis is to offer a thorough evaluation of Vi-DT’s safety and efficacy in this specific age group.

This review is registered at PROSPERO CRD42023471203¹ and reported in compliance with PRISMA criteria (Moher et al., 2009).

Low- and middle-income countries (LMICs) are deeply concerned about preventing S. typhi infections due to the significant annual mortality rates and financial strain. Although vaccination is widely acknowledged as a highly cost-effective preventive strategy, our research is primarily geared toward examining the safety and immunogenicity of the innovative Vi-DT vaccine. This endeavor aims to improve the accessibility of the S. typhi vaccination. Our research targets explicitly children under the age of two, as they are especially vulnerable to the consequences of typhoid fever. Our comprehensive analysis, encompassing data from five Randomized Controlled Trials (RCTs), demonstrated the safety and effectiveness of the Vi-DT vaccine in children below the age of 2 years. The adverse events after Vi-DT were similar to those after control groups, with immediate reactions within 30 min postvaccination and solicited adverse events within 1 and 4 weeks post-vaccination. These were similar in the intervention and control groups. The findings support the use of this Vi-DT to expand typhoid vaccination in endemic regions, in line with WHO’s strategy.

A Phase II study on the Vi-DT vaccine developed by Bio Farma in Indonesia revealed its safety and efficacy in children aged 2–11 years old and adults up to 45 years old in the Philippines (Capeding et al., 2018). They administered two doses of the vaccine separated by 1 month. After the study above, Medise et al. (2020) researched the safety and efficacy of a single-dose vaccination in children aged 6 to under 24 months. Their findings revealed that 98.99% of the participants who received the Vi-DT vaccine exhibited seroconversion, compared to only 3.03% in the control group. Furthermore, 4 weeks following vaccination, anti-Vi IgG geometric mean titer (GMT) was significantly higher in the Vi-DT vaccine recipients compared to the control group. Additionally, the safety and immunogenicity of the Vi-DT vaccine (manufactured by SK Bioscience, Korea) were reported in clinical Phase I and II studies conducted on Filipino adults, followed by studies involving children and infants (Capeding et al., 2018, 2020). In the Philippines, a Phase II trial was conducted on children aged 6–23 months to evaluate the Vi-DT vaccine’s safety, immunogenicity, and reactogenicity compared to a placebo. Safety data was collected at three different time points: 60 min, 7 days, and 4 weeks after vaccination. The findings revealed no statistically significant disparities in the occurrence of adverse events between the cohort administered the trial vaccine and the placebo group. Predominantly, the adverse events documented were mild to moderate in severity. Nevertheless, it is significant to mention that one case of severe adverse event was recorded in the Vi-DT group, wherein a child experienced a febrile convulsion, which was ascribed to a urinary tract infection. The study’s authors have stated that this specific adverse event was not associated with the vaccination (Capeding et al., 2018). The study (Medise et al., 2020) noted that the test vaccine (Vi-DT) and the control vaccine led to pain as the most frequently reported immediate reaction. Interestingly, the incidence of pain was higher in the Vi-DT group. However, it’s essential to acknowledge that the study raised some concerns regarding deviations from the intended intervention. The primary study of the Phase III trial conducted in Nepal confirmed the safety and efficacy of the Vi-DT vaccine [34]. Similarly, in the Philippines, a Phase III trial including participants from 6 months to 45 years of age established the immunogenic equivalence and safety of both the multi-dose and single-dose forms of the Vi-DT vaccine (Franco-Paredes et al., 2016). These earlier findings reinforce our results concerning the safety and efficacy of Vi-DT and provide additional support for its consideration for WHO prequalification.

The idea behind conjugating the polysaccharide with a carrier protein is to address the shortcomings of using polysaccharides alone as immunogens and transform them into T cell-dependent antigens. These antigens are effective in children and infants and induce a booster response upon subsequent immunisations, leading to long-lasting protection. Using Diphtheria Toxoid (DT) as a carrier protein offers several advantages. Firstly, DT and ViPS are licensed and locally produced in many developing countries. Additionally, the anti-DT response generated by Vi-DT carries clinical benefits.

These benefits include an increased immune response and broader protection since the conjugation of Vi polysaccharide to the DT protein turns the vaccine into a T-cell dependent antigen, which is more immunogenic than T-cell independent polysaccharide vaccines (Berger, 1998). This increased immunogenicity is especially useful in children and infants, who usually have a lower response to polysaccharide antigens (Berger, 1998). Furthermore, the anti-DT response can provide extra protection against diphtheria, a deadly bacterial illness, in addition to the target disease protection afforded by the Vi polysaccharide components. Conjugate vaccines can be more cost-effective in the long term because they improve immunogenicity and duration of protection, lowering the need for frequent revaccinations and associated healthcare expenses. Finally, removing the necessity for a new carrier protein simplifies the licensing process for Typhoid Conjugate. Vaccines (TCV). These advantages add to the effectiveness and desirability of utilizing Vi-DT in immunization programs, particularly in resource-limited countries where diphtheria remains a hazard and typhoid fever is common.

This review provides evidence supporting the safety and immunogenicity of the Vi-DT vaccine in children under the age of 2 years. The data indicates that Vi-DT does not elevate the risk of immediate reactions or solicited adverse events within 7 days or 4 weeks following vaccination compared to a control group or Vi-TT. Additionally, Vi-DT exhibits higher seroconversion rates at 4 weeks relative to the control and demonstrates immunogenicity that is not inferior to Vi-TT. These results support the potential use of Vi-DT as an effective typhoid fever vaccine for young children. Further studies are warranted to evaluate its long-term safety and effectiveness.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

AMo: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. KA: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. AMa: Investigation, Methodology, Writing – original draft, Writing – review & editing. ME: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. DN: Formal analysis, Investigation, Writing – original draft, Writing – review & editing. RA: Investigation, Methodology, Writing – original draft, Writing – review & editing. PP: Formal analysis, Investigation, Writing – original draft, Writing – review & editing. DB-A: Funding acquisition, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing. CL: Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. AR-M: Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing.