ABSTRACT
Typhoid fever remains a significant public health concern in endemic regions, with increasing antimicrobial resistance heightening the need for preventive strategies such as vaccination. Zyvac-TCV, a typhoid conjugate vaccine developed by Zydus Lifesciences Ltd. is licensed for use across all age groups. This prospective, multicenter, single-arm post-marketing surveillance study evaluated the safety and immunogenicity of Zyvac TCV in 3037 healthy participants aged 6 months to 45 years, enrolled across multiple Indian centers. Each participant received a single 0.5 mL intramuscular dose. Safety was assessed through monitoring of adverse events (AEs) over a 6-month period, while immunogenicity was evaluated in a subset of 300 participants by measuring serum anti-Vi IgG antibody titers at baseline and Day 28 post-vaccination. Overall, 16.7% of participants reported AEs, predominantly mild or moderate in nature, with no serious adverse events. Immunogenicity results demonstrated a seroconversion rate of 94.7% and a significant increase in geometric mean titers from 4.5 U/mL at baseline to 1787.8 U/mL at Day 28. A post-hoc batch analysis showed consistent immunogenicity across three commercial vaccine batches. Zyvac TCV was well tolerated and elicited a strong immune response in all age groups, supporting its integration into national immunization programs in typhoid-endemic regions.
KEYWORDS: Typhoid conjugate vaccine (TCV), anti-Vi IgG seroconversion, geometric mean titers (GMTs), immunogenicity, post-marketing surveillance
Introduction
Typhoid fever remains a significant global public health challenge, particularly in low- and middle-income countries (LMICs) with inadequate sanitation and limited access to clean drinking water.1 The disease is caused by Salmonella enterica serovar Typhi and is characterized by prolonged fever, gastrointestinal symptoms, and systemic complications. If left untreated, severe cases can lead to intestinal perforation, septicemia, and death.2 In India, the burden of typhoid fever is particularly high, with around 10 million cases reported in 2021 and an incidence rate of 282.4 per 100,000 population in 2022.3
The increasing prevalence of antimicrobial resistance (AMR) in Salmonella enterica serovar Typhi presents a major challenge to typhoid management. The meta-analysis of 13,000 S. Typhi genomes confirms that high-level ciprofloxacin resistance (≥3 resistance determinants) has reached 20% prevalence, significantly limiting treatment options.4 Systematic surveillance reveals a high prevalence of fluoroquinolone resistance in S. Typhi across India, with over 95% of isolates exhibiting non-susceptibility to ciprofloxacin.5 Additionally, extensively drug-resistant (XDR) S. Typhi, resistant to fluoroquinolones, third-generation cephalosporins, and first-line antibiotics such as ampicillin and chloramphenicol, has emerged as a critical concern.6 The rise of AMR has made preventive strategies essential, as antibiotic efficacy continues to decline. While improvements in water sanitation and hygiene (WASH) are critical, there was still an estimated 10.9 million illnesses and 116,800 deaths worldwide in 2017.7 Vaccination remains the most effective long-term approach, offering up to 87% protection against S. Typhi and significantly reducing antibiotic dependence. Recognizing the importance of vaccination, the World Health Organization (WHO) has prioritized typhoid vaccination in high-burden countries like India.
The evolution of typhoid vaccines has improved efficacy, immunogenicity, and safety over time. First-generation vaccines, introduced in the late 19th century, consisted of heat- and phenol-inactivated whole-cell formulations, offering 51–88% efficacy but with high reactogenicity, leading to their withdrawal.8 Second-generation vaccines, including the live attenuated Ty21a and Vi polysaccharide (ViPS) vaccines, provided moderate protection (~65–67%)9 However, Ty21a has several limitations, such as acid-labile and ineffective in young children, while ViPS vaccines, licensed in 1994, are T-cell-independent, resulting in poor immune memory and requiring revaccination every three years.10,11 To address these challenges, typhoid conjugate vaccines (TCVs) were developed by linking the Vi polysaccharide to a carrier protein, enabling T-cell-dependent immunity.12,13 This advancement enhanced long-term protection, elicited immune memory, and allowed effective immunization in infants. Unlike ViPS vaccines, which stimulate only B cells, TCVs activate both B and T cells, providing stronger and longer-lasting immunity.14 Additionally, TCVs do not cause hypo-responsiveness and have demonstrated sustained immunogenicity over extended periods.15 Recognizing these advantages, the WHO prequalified Typbar-TCV in 2018, promoting its inclusion in routine immunization programs.16
Several TCVs have been developed and licensed for use, each offering varying degrees of immunogenicity and protection. PedaTyph (Vi-TT), the first TCV licensed in India in 2008, requires a booster dose at 2.5–3 years to maintain protection.17 Vi-CRM197, developed by GSK Vaccines Institute for Global Health (GVGH), utilizes a diphtheria toxin mutant (CRM197) as a carrier protein. The use of TCVs has demonstrated superior immunogenicity, enhanced immune memory, and long-term protection compared to ViPS vaccines and multiple clinical trials have evaluated the efficacy and safety of TCVs.17–19
Zyvac-TCV, developed by Zydus Lifesciences Ltd, is a Typhoid Vi Conjugate Vaccine (TCV) licensed for administration as a single 25 µg dose in children older than six months and adults. It is a sterile, clear, and colorless liquid formulation, containing 25 µg of purified Vi capsular polysaccharide of Salmonella Typhi conjugated to tetanus toxoid as the carrier protein, along with 2.5 mg of 2-phenoxyethanol as a preservative. A trial conducted with 240 participants across multiple age groups demonstrated immune non-inferiority of Zyvac TCV to already marketed TCV, leading to its approval in India.20 The present post-marketing surveillance (PMS) study aims to evaluate the safety and immunogenicity of Zyvac TCV in a large, multicenter cohort, contributing critical data to support routine immunization policies in endemic regions. The vaccine was prequalified by WHO in October 2024 for active immunization against typhoid fever.
Methodology
Study design
This prospective, multicenter, single-arm PMS study was conducted to evaluate the safety and immunogenicity of Zyvac TCVfrom November 2021 to July 2022.
Study participants
A total of 3037 healthy individuals between 6 months and 45 years of age were enrolled in the study across multiple centers in India. The eligibility was determined through a detailed medical history review and physical examination conducted by the investigator. Participants were required to have no previous history of typhoid vaccination, either oral or injectable. Written informed consent was obtained from all adult participants or from the parents or legal guardians of pediatric population. Additionally, assent was also obtained from pediatric participants aged 7 to 17 years.
Participants were excluded if they had a history of hypersensitivity to any component of the vaccine or a confirmed or suspected history of typhoid fever in the preceding three years. Any individual with a history of household contact with a confirmed Salmonella typhi case, a febrile illness at the time of screening, or any infectious disorder lasting three or more days within the past month was excluded from participation. Participants who had any clinically significant systemic disorder, including cardiovascular, respiratory, neurologic, gastrointestinal, hepatic, renal, endocrine, hematological, or immunological conditions; participants with known immunodeficiency, those receiving immunosuppressive therapy, individuals with coagulation disorders, or those on anticoagulation therapy; women who were pregnant, lactating, or not using reliable contraception, as well as individuals who had received blood products or immunoglobulins in the past three months were also excluded. Participation in any other clinical study within the past three months or an intention to enroll in another study within three months following vaccination was not permitted. Participants with a history of alcohol or drug abuse in the previous year were excluded from the study.
The study population was stratified into four predefined age cohorts. A total of 1537 participants were enrolled in the 6 months to <2 years age group, 499 participants in 2 to <5 years group, 502 participants in 5 to <18 years group, and 499 participants in 18 to 45 years group. Within each cohort, around 10% of the enrolled participants (300 participants in total) were included in the immunogenicity assessment (Table 1).
Table 1.
Distribution of enrolled participants in immunogenicity subset.
| Age cohort | No. of subjects in immunogenicity subset |
|---|---|
| 6 months to <2 years | 150 |
| 2 to <5 years | 49 |
| 5 to <18 years | 51 |
| 18 to 45 years | 50 |
| Total | 300 |
Vaccine administration
Participants enrolled in the study received a single 0.5 mL intramuscular dose of Zyvac TCV. The vaccine was administered under aseptic conditions, with the anterolateral thigh as the preferred injection site for children younger than two years of age, while older children and adults received the vaccine in the deltoid muscle. Participants were closely monitored for at least 30 minutes post-vaccination to assess for any immediate hypersensitivity reactions or other acute adverse events (AEs). Any AEs observed during this period were documented, and medical intervention was provided if necessary. Following vaccination, adult participants or parents of pediatric participants were provided with a diary card to record any local (injection-site) or systemic. The diary cards were collected and reviewed during follow-up visits to assess adverse events reported in the days following vaccination and across all visits up to Day 180.
Follow-up assessments
Participants were monitored for six months with follow-up visits on Day 7 ± 3 days (visit 2), Day 28 ± 3 days (visit 3), Day 90 ± 7 days (visit 4), and Day 180 ± 14 days (visit 5) to assess safety and document adverse events. At visit 2, a clinical examination, including vital signs assessment, was conducted, and diary cards were reviewed for adverse events, ongoing conditions, and medications. At visit 3, a similar evaluation was performed, with blood samples collected from the immunogenicity subset to assess serum anti-Vi IgG antibody titers and completed diary cards were collected to assess AEs recorded over the 28-day period. Visit 4 and visit 5 focused on long-term safety monitoring, recording any newly reported AEs. After Day 28, only serious adverse events (SAEs) and medically attended adverse events (MAAEs) were documented, with follow-up until resolution.
Safety assessments
The safety of Zyvac TCV was evaluated through systematic monitoring of AEs throughout the study duration. Participants were closely observed for any immediate reactions following vaccine administration, and all adverse events occurring during the follow-up period were carefully documented. All adverse events were categorized based on severity, duration, outcome, and relationship to vaccination. Events were classified as mild, moderate, or severe, and the investigator assessed whether each event was related or unrelated to Zyvac TCV. Serious adverse events (SAEs) were defined as events that resulted in death, life-threatening conditions, hospitalization, prolonged hospitalization, persistent disability, or any significant medical condition requiring intervention. MAAEs, which required consultation with healthcare professionals, were also documented.
Immunogenicity assessments
The immunogenicity of Zyvac TCV was assessed in a subset of 300 participants. To evaluate the immune response induced by the vaccine, blood samples were collected at baseline before vaccination (Day 0, visit 1) and again 28 days after vaccination. The assessment focused on measuring anti-Vi IgG antibody titers, with a particular emphasis on determining the proportion of participants who exhibited a four-fold or greater increase in antibody levels following vaccination. For the purpose of seroconversion and GMT calculations, samples with titers below the lower limit of quantification (LLOQ) of 7.4 U/mL were assigned a value of 3.7 U/mL (i.e., half of the LLOQ). The four-fold rise criterion was applied consistently to all participants, including those whose baseline titers were below the LLOQ.
Additionally, the geometric mean titers of antibodies were analyzed before and after vaccination to evaluate the magnitude and consistency of the immune response across different age groups. The immunogenicity analysis was performed using commercial VaccZyme™ ELISA kits of ‘The Binding Site Group Ltd., UK’ and using the WHO International Standard for anti-Vi IgG (NIBSC code − 16/138) at the central laboratory. To evaluate immunogenicity across different vaccine batches, a post-hoc analysis was conducted using data from participants in the immunogenicity subset who received one of three different commercial batches of Zyvac-TCV. Seroconversion rates and post-vaccination GMTs were compared across batches to assess uniformity in immunogenic performance.
Statistical analysis
The sample size for the safety cohort (N = 3037) was determined based on WHO’s Technical Report Series No. 1030, 2021 (Annex 2), which recommends a safety database of at least 3000 participants for post-marketing surveillance of typhoid conjugate vaccines (TCVs). This sample size provides 95% probability of detecting at least one adverse event that occurs with a frequency of 1 in 1000 individuals. Accordingly, this PMS study was designed to evaluate the safety of Zyvac TCV in a large, real-world population in line with WHO guidance.21
All study data, including safety and immunogenicity assessments, were recorded in case report forms (CRFs). Safety data were analyzed descriptively, with adverse events summarized by frequency, severity, and relationship to vaccination. Immunogenicity was assessed by analyzing anti-Vi IgG antibody titers at baseline and Day 28 post-vaccination, with seroconversion rates (defined as four-fold or greater increase in antibody titer) and geometric mean titers (GMTs) calculated. Age-wise analysis of post-vaccination GMTs was performed using one-way ANOVA to evaluate differences in antibody responses across the four age cohorts. A post-hoc analysis was conducted to assess the comparability of immune responses across different Zyvac TCV batches. Participants in the immunogenicity subset were stratified based on the vaccine batch they received, and seroconversion rates were compared using Fisher’s exact test. Additionally, GMTs at Day 28 post-vaccination were analyzed to evaluate potential variations in immunogenicity response generated among vaccine batches. Statistical significance was set at p < .05.
Ethical considerations
The study was conducted in compliance with the Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki, and applicable regulatory requirements, including WHO Technical Report Series No. 1030, 2021 (Annex 2). The study protocol received approval from the Drug Controller General of India (DCGI) and was registered on the Clinical Trials Registry – India (CTRI/2021/11/037996) before participants enrollment. The approvals from Ethics Committee of all the participating sites were also obtained prior to initiation of enrollment at respective sites.
Results
Patient disposition and baseline demographics
A total of 3037 participants were enrolled in the study, including 300 participants in the immunogenicity subset. Of the overall population, four participants discontinued after Visit 4, and one participant from the immunogenicity subset was lost to follow-up after Visit 4 (Day 90) (Figure 1). All remaining participants completed the study and were included in the respective safety and immunogenicity analyses. The study population had a mean age of 7.8 ± 11.7 years, with 1652 males (54.4%) and an overall mean weight of 22.2 ± 19.9 kg (Table 2).
Figure 1.
Patient disposition during the study.
Table 2.
Baseline demographic characteristics.
| Parameter | Overall Population (N=3037) |
Age Cohort |
||||
|---|---|---|---|---|---|---|
| 6 mo to <2 yr (n=1537) |
2 to <5 yr (n=499) |
5 to <18 yr (n=502) |
18 to 45 yr (n=499) |
|||
| Age (years)^ | 1.0 (1.0, 9.0) |
1.0 (0.8, 1.0) |
3.0 (2.0, 3.0) |
10.0 (7.0, 12.0) |
33.0 (26.0, 38.0) |
|
| Gender# | Male | 1652 (54.4%) | 853 (28.1%) | 278 (9.2%) | 236 (7.8%) | 285 (9.4%) |
| Female | 1385 (45.6%) | 684 (22.5%) | 221 (7.3%) | 266 (8.8%) | 214 (7.0%) | |
| Height (cm)* | 101.7 ± 35.3 | 75.4 ± 7.2 | 92.4 ± 10.0 | 130.4 ± 19.6 | 163.5 ± 8.1 | |
| Weight (kg)* | 22.2 ± 19.9 | 9.4 ± 1.8 | 14.0 ± 2.8 | 31.2 ± 12.0 | 60.5 ± 11.2 | |
| Body Mass Index (kg/m2) * | 17.8 ± 4.2 | 16.7 ± 3.4 | 16.6 ± 3.4 | 17.8 ± 4.1 | 22.6 ± 3.7 | |
| Temperature (°C) * | 36.7 ± 0.3 | 36.7 ± 0.3 | 36.7 ± 0.4 | 36.7 ± 0.3 | 36.8 ± 0.4 | |
| Pulse Rate (/min) * | 96.6 ± 18.4 | 108.1 ± 15.4 | 94.7 ± 14.1 | 82.7 ± 9.9 | 77.1 ± 6.3 | |
| Respiratory Rate (/min) * | 25.9 ± 7.3 | 31.3 ± 5.6 | 24.2 ± 3.4 | 19.5 ± 2.8 | 17.5 ± 1.5 | |
mo - months; yr - years.
^Data presented as median (interquartile range).
#Data presented as n (%); % calculated from overall population.
*Data presented as mean ± SD.
Safety outcomes
A total of 507 participants (16.7%) experienced AE, with total number of AE reported was 679, indicating that some participants experienced more than one adverse event and no SAEs were reported. All reported adverse events were of mild to moderate severity. Most of the adverse events were considered related to vaccination. Among the 679 reported adverse events, 96.6% were solicited reactions, documented by participants or caregivers in the diary card and reviewed during follow-up visits. The duration of adverse events varied, with 97.8% of all reported adverse events resolving within three days (Figure 2). A total of 15 medically attended adverse events (MAAEs) were reported during the study, including cases of fever (6), vomiting (3), cough (2), diarrhea (2), headache (1), and upper respiratory tract infection (1). All MAAEs were unsolicited, non-serious, and assessed as not related to the study vaccine.
Figure 2.
Distribution of adverse events by severity, reporting method, association with vaccination, and duration.
The most frequently reported local AEs was pain at injection site (11.7%), followed by redness (1.9%), swelling (1.2%), and induration (0.3%). Among systemic AEs, fever (5.1%) was the most commonly reported reaction, while other systemic events were observed at lower frequencies (Figure 3). AEs were distributed across all age groups, with the highest proportion observed in the 5 to < 18 years age group (22.9%), and lowest incidence was noted in the 18 to 45 years of age-group (9.2%) (Table 3).
Figure 3.
Distribution of local and systemic adverse events reported during the study.
Table 3.
Distribution of local and systemic adverse events in different age cohorts.
| Overall (N = 3037) |
Age Cohort |
||||
|---|---|---|---|---|---|
| 6 mo to <2 yr (n=1537) |
2 to <5 yr (n=499) |
5 to <18 yr (n=502) |
18 to 45 yr (n=499) |
||
| Participants with AEs n (%) | 507 (16.7%) | 252 (16.4%) | 94 (18.8%) | 115 (22.9%) | 46 (9.2%) |
| No. of AEs reported* | 679 | 344 | 125 | 159 | 51 |
| Local AEs* | 461 | 216 | 91 | 112 | 42 |
| Pain | 355 (11.7%) | 156 (10.1%) | 73 (14.6%) | 90 (17.9%) | 36 (7.2%) |
| Redness | 59 (1.9%) | 33 (2.1%) | 10 (2.0%) | 13 (2.6%) | 3 (0.6%) |
| Swelling | 37 (1.2%) | 21 (1.4%) | 7 (1.4%) | 6 (1.2%) | 3 (0.6%) |
| Induration | 10 (0.3%) | 6 (0.4%) | 1 (0.2%) | 3 (0.6%) | 0 (0.0%) |
| Systemic AEs* | 218 | 128 | 34 | 47 | 9 |
| Fever | 155 (5.1%) | 87 (5.7%) | 27 (5.4%) | 34 (6.8%) | 7 (1.4%) |
| Abnormal crying | 16 (0.5%) | 16 (1.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Drowsiness | 11 (0.4%) | 9 (0.6%) | 0 (0.0%) | 2 (0.4%) | 0 (0.0%) |
| Headache | 8 (0.3%) | 0 (0.0%) | 3 (0.6%) | 3 (0.6%) | 2 (0.4%) |
| Irritability | 5 (0.2%) | 5 (0.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Malaise | 5 (0.2%) | 0 (0.0%) | 1 (0.2%) | 4 (0.8%) | 0 (0.0%) |
| Myalgia | 5 (0.2%) | 0 (0.0%) | 2 (0.4%) | 3 (0.6%) | 0 (0.0%) |
| URTI | 4 (0.1%) | 4 (0.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Vomiting | 4 (0.1%) | 4 (0.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Cough | 2 (0.1%) | 1 (0.1%) | 1 (0.2%) | 0 (0.0%) | 0 (0.0%) |
| Diarrhoea | 2 (0.1%) | 1 (0.1%) | 0 (0.0%) | 1 (0.2%) | 0 (0.0%) |
| Loss of appetite | 1 (0.0%) | 1 (0.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
mo – months, yr – years, URTI – upper respiratory tract infection.
Data presented as n (%) unless specified; % calculated from No. of participants analyzed for safety.
* Data presented as n.
Immunogenicity outcomes
The immunogenicity subset included 300 participants, with serological assessments conducted before and 28 days after vaccination. Seroconversion was observed in 94.7% of participants at Day 28 post-vaccination (Figure 4). The seroconversion rate was consistent across all age groups, with the highest values of 98% in the 2 to <5 years cohort.
Figure 4.
Seroconversion rates of anti-Vi IgG antibodies at day 28 post-vaccination.
The GMTs of anti-Vi IgG antibodies increased significantly from 4.5 U/mL at baseline to 1787.8 U/mL at Day 28 (p < .0001) in overall population, demonstrating a strong immune response to Zyvac TCV (Figure 5). The post-vaccination GMTs were 1745.7 U/mL in the 6 months to <2 years group, 1997.4 U/mL in the 2 to <5 years group, 1766.7 U/mL in the 5 to <18 years group, and 1743.5 U/mL in the 18 to 45 years group.
Figure 5.
Geometric mean titers (GMTs) of anti-Vi IgG antibodies at baseline and day 28 post-vaccination.
Post-hoc immunogenicity analysis
A post-hoc analysis was conducted to evaluate the comparability of the immune response across different Zyvac TCV batches. The immunogenicity subset included 300 participants, with 102 participants receiving Batch 06, 100 participants receiving Batch 07, and 98 participants receiving Batch 08 (Table 4).
Table 4.
Distribution of participants administered respective batch of Zyvac TCV.
| Age cohort | Batch No. of Zyvac TCV administered |
||
|---|---|---|---|
| Batch 06 | Batch 07 | Batch 08 | |
| 6 months to <2 years | 53 | 53 | 44 |
| 2 to <5 years | 16 | 14 | 19 |
| 5 to <18 years | 16 | 16 | 19 |
| 18 to 45 years | 17 | 17 | 16 |
| Total | 102 | 100 | 98 |
Batch 06 = 06EP006; Batch 07 = 06EP007; Batch 08 = 06EP008.
Data presented as n.
The seroconversion rates across the three Zyvac TCV batches were comparable, with no statistically significant differences observed in pairwise comparisons (p > .75 for all comparisons), indicating consistent immunogenicity performance across production lots (Table 5).
Table 5.
Comparison of seroconversion rates of 3 batches of Zyvac TCV.
|
Batch 06 (N=102) |
Batch 07 (N=100) |
Diff (Batch 06 – Batch 07) * | P value# |
| 97 (95.1%) | 95 (95.0%) | 0.1% (−7.3%, 7.6%) | 1.0 |
|
Batch 06 (N=102) |
Batch 08 (N=98) |
Diff (Batch 06 – Batch 08) * | P value# |
| 97 (95.1%) | 92 (93.9%) | 1.2% (−6.4%, 9.1%) | .76 |
|
Batch 07 (N=100) |
Batch 08 (N=98) |
Diff (Batch 07 – Batch 08) * | P value# |
| 95 (95.0%) | 92 (93.9%) | 1.1% (−6.6%, 9.0%) | .77 |
Batch 06 = 06EP006; Batch 07 = 06EP007; Batch 08 = 06EP008.
Data presented as n (%).
*Data presented % (95% CI).
#Fisher’s exact test.
The GMTs also demonstrated a robust immune response across all three batches. At Day 28 post-vaccination, GMTs were 1682.0 U/mL for Batch 06, 1955.4 U/mL for Batch 07, and 1738.4 U/mL for Batch 08. The observed differences in GMTs were not statistically significant (p > .05), confirming comparability of post-vaccination GMTs across batches (Figure 6).
Figure 6.
Comparison of GMTs with 3 batches of Zyvac TCV.
Discussion
Typhoid fever remains a major public health concern in endemic regions, and TCVs offer long-lasting protection over polysaccharide vaccines, making them the preferred choice for immunization. The present study evaluated the safety and immunogenicity of Zyvac-TCV, across different age groups (6 months to 45 years). The findings demonstrated that the vaccine was well-tolerated, with a low incidence of adverse events (16.7%), all of which were mild to moderate in nature. Importantly, there were no serious adverse events reported during the study. The vaccine also elicited a strong immune response, with a seroconversion rate of 94.7% and a significant rise in anti-Vi IgG GMTs from 4.5 U/mL at baseline to 1787.8 U/mL at Day 28 post-vaccination. Notably, the seroconversion rate among adults appeared slightly lower than in younger cohorts. One possible explanation for this observation could be the relatively higher baseline anti-Vi IgG titers in adults, which may have influenced the calculated fold-rise required to meet the seroconversion threshold.
In a Phase II/III randomized, controlled, non-inferiority trial, Zyvac TCV was directly compared to Typbar-TCV in 240 healthy Indian subjects aged 6 months to 45 years.20 The study demonstrated that Zyvac TCV achieved overall seroconversion rate of 94.8%, which was statistically non-inferior to comparator TCV (91.6%) when assessed using a predefined non-inferiority margin of −10%. Age-stratified analyses also confirmed comparable performance across both pediatric and adult cohorts, with no significant differences in geometric mean titers at 6 weeks post-vaccination (Zyvac-TCV: 1121 EU/mL; comparator TCV: 1104 EU/mL; P > .05). These results establish Zyvac TCV as immunologically non-inferior to comparator TCV. This evidence was further supported by an age extension study involving adults up to 65 years of age, which showed consistent immunogenicity and safety outcomes in this older cohort. The demonstration of comparable immune response in the extended age group highlights the broader applicability of Zyvac TCV across the full age range recommended for typhoid vaccination and reinforces its utility in diverse epidemiological contexts.
The safety and immunogenicity profile of Zyvac-TCV, including the absence of SAEs and a seroconversion rate exceeding 94%, compares favorably with the outcomes reported by Verma et al. (2025) for Typhibev.22 In that study, Typhibev achieved seroconversion rates of over 91%, and the most frequently reported adverse events were injection-site pain in 5.5% of participants and fever in 2.5%. In comparison, the present study of Zyvac TCV reported injection-site pain in 11.7% and fever in 5.1% of participants, with the majority of events resolving within three days. Despite differences in study design, both vaccines demonstrated high immunogenicity and favorable tolerability profiles in similar age groups.
Study conducted by Reddy et al., evaluated safety outcomes of Typbar-TCV across more than 10 million administered doses in India.23 In that study, adverse events were reported in 22.1% of participants during active surveillance, with fever documented in 10.7%, pain at the injection site in 7.8%, and swelling in 2.54%. In comparison, Zyvac TCV demonstrated an overall adverse event rate of 16.7%, with injection-site pain in 11.7%, fever in 5.1%, and swelling in 1.2%. No SAEs were reported for either vaccine. While these findings offer a useful reference for safety profile of Zyvac-TCV, it is important to emphasize that comparisons between single-arm post-marketing surveillance studies must be interpreted with caution. Differences in surveillance periods, study populations, reporting mechanisms, and sample sizes preclude formal statistical comparison. As such, cross-study comparisons are descriptive in nature and are intended to provide contextual understanding rather than infer equivalence or superiority.
Compared to older typhoid vaccines, such as the Vi polysaccharide vaccine and the Ty21a oral vaccine, Zyvac TCV offers higher and consistent immunogenicity, particularly in younger children, where unconjugated Vi polysaccharide vaccines show limited efficacy due to T-cell independent immune responses.24 In contrast, conjugation of Vi to tetanus toxoid in Zyvac TCV enhances immunogenicity by inducing a robust, T-cell dependent response, which not only improves seroconversion rates but also enables use in children under 2 years – a key limitation of Vi-polysaccharide and Ty21a vaccines. While Ty21a offers long-term protection with a good safety profile, it requires multiple doses and is unsuitable for children below 5 years. The conjugated nature of Zyvac TCV did not increase reactogenicity; injection-site pain (11.7%) and fever (5.1%) were within acceptable limits and lower or comparable to rates seen with non-conjugated Vi vaccines. No clinical cases of typhoid fever were reported among study participants during the six-month follow-up period. This observation is consistent with the absence of any serious adverse events and supports the overall safety profile of the vaccine.
Notably, no serious adverse events were reported during the study period. The study was conducted amid heightened public health awareness due to the COVID-19 pandemic, which likely contributed to reduced infection exposure and hospitalizations. Additionally, the predominantly pediatric study population – less affected by severe illnesses – along with rigorous safety monitoring procedures, likely contributed to the absence of SAEs, supporting the favorable safety profile of ZyVac-TCV.
The post-hoc analysis assessing immunogenicity of 3 batches of Zyvac TCV demonstrated highly uniform seroconversion rates and GMTs across different production lots, indicating a consistent immune response. The minimal variation observed between batches suggests that Zyvac TCV maintains robust and reproducible immunogenicity, reinforcing its manufacturing reliability. This consistency is crucial for large-scale deployment and regulatory approval, ensuring that the vaccine delivers consistent protection across different production runs. Overall, the findings from the present study indicate that Zyvac TCV is immunogenic across all evaluated age groups. The vaccine’s low reactogenicity, strong immune response, and consistent performance across all age groups make it a promising candidate for routine immunization programs in typhoid-endemic regions. Its prequalification by the WHO affirms its adherence to internationally accepted standards for quality, safety, and immunogenicity and supports its use in global and national immunization efforts. Additionally, the study’s large sample size and rigorous multicenter design enhance the generalizability of the findings. However, a limitation of the study is the short follow-up period for immunogenicity assessment (28 days post-vaccination). Future research can focus on long-term persistence of antibody titers, booster dose requirements, and comparative effectiveness studies with other licensed TCVs to further establish the clinical and public health benefits of Zyvac TCV.
Conclusion
Zyvac TCV demonstrated a favorable safety profile and strong immunogenicity across all age groups, with high seroconversion rates and significant GMT increases after vaccination. The vaccine’s low reactogenicity and comparable immunogenicity across batches highlight its potential for widespread use in typhoid-endemic regions. The study results support Zyvac TCV as a reliable option for typhoid prevention.
Biography
Trayambak Dutta, MBBS, MD is Medical Advisor at Zydus Lifesciences Ltd, based at Ahmedabad. He has clinical & research experience of 12 years along with 21 publications across various leading journals in multiple therapy areas with special interest in Vaccines and Biologics.
Funding Statement
This study was sponsored by Zydus Lifesciences Ltd.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
- 1.Antillón M, Warren JL, Crawford FW, Weinberger DM, Kürüm E, Pak GD, Marks F, Pitzer VE, Carvalho MS.. The burden of typhoid fever in low- and middle-income countries: a meta-regression approach. PLoS Negl Trop Dis. 2017;11(2):e0005376. doi: 10.1371/journal.pntd.0005376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Marchello CS, Birkhold M, Crump JA. Complications and mortality of typhoid fever: a global systematic review and meta-analysis. J Infect. 2020;81(6):902–12. doi: 10.1016/j.jinf.2020.10.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.World Health Organization . 2023. Typhoid reported cases and incidence. https://immunizationdata.who.int/global/wiise-detail-page/typhoid-reported-cases-and-incidence?CODE=IND&YEAR=.
- 4.Carey ME, Dyson ZA, Ingle DJ, Amir A, Aworh MK, Chattaway MA, Chew KL, Crump JA, Feasey NA, Howden BP, et al. Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from a meta-analysis of 13,000 salmonella typhi genomes. Elife. 2023;12:12. doi: 10.7554/eLife.85867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.John J, Bavdekar A, Rongsen-Chandola T, Dutta S, Gupta M, Kanungo S, Sinha B, Srinivasan M, Shrivastava A, Bansal A, et al. Burden of typhoid and paratyphoid fever in India. N Engl J Med. 2023;388(16):1491–1500. doi: 10.1056/NEJMoa2209449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Dyson ZA, Klemm EJ, Palmer S, Dougan G. Antibiotic resistance and typhoid. Clin Infect Dis. 2019;68(Supplement_2):S165–70. doi: 10.1093/cid/ciy1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Stanaway JD, Reiner RC, Blacker BF, Goldberg EM, Khalil IA, Troeger CE, Andrews JR, Bhutta ZA, Crump JA, Im J, et al. The global burden of typhoid and paratyphoid fevers: a systematic analysis for the global burden of disease study 2017. Lancet Infect Dis. 2019;19(4):369–381. doi: 10.1016/S1473-3099(18)30685-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Levine MM, Ferreccio C, Black RE, Tacket CO, Germanier R, Committee CT. Progress in vaccines against typhoid fever. Clin Infect Dis. 1989;11(Supplement_3):S552–67. doi: 10.1093/clinids/11.Supplement_3.S552. [DOI] [PubMed] [Google Scholar]
- 9.van den Biggelaar AHJ, Poolman JT. Live-attenuated and inactivated whole-cell bacterial vaccines. In: Nunnally BK, Turula VE, editors. Vaccine analysis: strategies, principles, and control. Springer; 2014. p. 139–186. https://link.springer.com/chapter/10.1007/978-3-662-45024-6_5. [Google Scholar]
- 10.Levine MM, Ferreccio C, Abrego P, Martin OS, Ortiz E, Cryz S. Duration of efficacy of Ty21a, attenuated salmonella typhi live oral vaccine. Vaccine. 1999;17:S22–7. doi: 10.1016/S0264-410X(99)00231-5. [DOI] [PubMed] [Google Scholar]
- 11.Vashishtha VM, Kalra A. The need & the issues related to new-generation typhoid conjugate vaccines in India. Indian J Med Res. 2020;151(1):22–34. doi: 10.4103/ijmr.IJMR_1890_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Sahastrabuddhe S, Saluja T. Overview of the typhoid conjugate vaccine pipeline: current status and future plans. Clin Infect Dis. 2019;68(Supplement_1):S22–6. doi: 10.1093/cid/ciy884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Agarwal N, Gupta N, Dutta T, Mahajan M, Agarwal DN, Gupta DN, Nishant D, HS S. Typhoid conjugate vaccine: a boon for endemic regions. Cureus [Internet]. 2024. [cited 2025 Apr 22]. 16. https://www.cureus.com/articles/211374-typhoid-conjugate-vaccine-a-boon-for-endemic-regions. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Szu SC, Li XR, Schneerson R, Vickers JH, Bryla D, Robbins JB. Comparative immunogenicities of Vi polysaccharide-protein conjugates composed of cholera toxin or its B subunit as a carrier bound to high- or lower-molecular-weight Vi. Infect Immun. 1989;57(12):3823–3827. doi: 10.1128/iai.57.12.3823-3827.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Vashishtha VM, Kumar P. Typhoid conjugate vaccines: is a single dose enough for durable protection? Expert Rev Vaccines. 2025;24(1):194–205. doi: 10.1080/14760584.2025.2476525. [DOI] [PubMed] [Google Scholar]
- 16.WHO . WHO recommends use of first typhoid conjugate vaccine. 2018. https://www.who.int/news/item/03-04-2018-who-recommends-use-of-first-typhoid-conjugate-vaccine.
- 17.Chinnasami B, Mangayarkarasi V, Prema A, Sadasivam K, Davis MJ. Safety and immunogenicity of salmonella typhi Vi conjugate vaccine (PedaTyph) in children upto five years. Int J Sci Res. 2013;3. [Google Scholar]
- 18.Tamrakar D, Poudel P, Thapa P, Singh S, Khadgi A, Thapa S, Tamrakar R, Shrestha A, Madhup S, Rai GK, et al. Safety and immunogenicity of conjugate vaccine for typhoid (Vi-DT): finding from an observer-blind, active-controlled, randomized, non-inferiority, phase III clinical trial among healthy volunteers. Hum Vaccin Immunother. 2024;20(1):20. doi: 10.1080/21645515.2023.2301631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Nampota-Nkomba N, Nyirenda OM, Khonde L, Mapemba V, Mbewe M, Ndaferankhande JM, Msuku H, Masesa C, Misiri T, Mwakiseghile F, et al. Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial. Lancet Glob Health. 2022;10(9):e1326–35. doi: 10.1016/S2214-109X(22)00275-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kundu R, Kandulna AK, Nayak U, Jangid SK, Babu TR, Vukkala R, Sharma S, Goyal VK, Daultani P, Mittal R, et al. Immunogenicity and safety of typhoid conjugate vaccine in healthy Indian subjects: a randomized, active-controlled, comparative clinical trial. Indian Pediatr. 2020;57(7):625–630. doi: 10.1007/s13312-020-1890-y. [DOI] [PubMed] [Google Scholar]
- 21.World Health Organization . Recommendations to assure the quality, safety and efficacy of typhoid conjugate vaccines, Annex 2, WHO Technical Report Series No. 1030. Geneva: World Health Organization; 2020. [cited 2025 Jun 26]. https://www.who.int/publications/m/item/tcv71-recommendations. [Google Scholar]
- 22.Thuluva S, Matur RV, Gunneri SR, Mogulla R, Dhar C, Yerroju V, Balne N, Chakravarthy BS, Narang M, Mahantshetti NS, et al. Safety and immunogenicity of biological E’s typhoid conjugate vaccine TYPHIBEVⓇ concomitantly administered with measles rubella vaccine: a phase IV prospective, multicenter study. IJID Reg [Internet]. 2025. [cited 2025 Apr 23]. 15:100611. https://pubmed.ncbi.nlm.nih.gov/40176856/. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Reddy R, Reddy B, Sarangi V, Reddy S, Ella R, Vadrevu KM. A multi-centre, post-marketing surveillance study of Vi polysaccharide–tetanus toxoid conjugate vaccine (Typbar TCV®) in India. Hum Vaccin Immunother [Internet]. 2022. [cited 2025 Apr 23]. 18(1). doi: 10.1080/21645515.2021.1947761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yang HH, Wu CG, Xie GZ, Gu QW, Wang BR, Wang LY, Wang HF, Ding ZS, Yang Y, Tan WS, et al. Efficacy trial of Vi polysaccharide vaccine against typhoid fever in south-western China. Bull World Health Organ [Internet]. 2001. [cited 2025 June 26]. 79:625. https://pmc.ncbi.nlm.nih.gov/articles/PMC2566475/. [PMC free article] [PubMed] [Google Scholar]