Highlights
– Single‑dose and multidose EuTCV (Vi‑CRM197) were immunologically non‑inferior to Typbar TCV in infants aged 9–12 months at 28 days post‑vaccination.
– Seroconversion in the infant per‑protocol cohort was effectively universal with single‑dose EuTCV (100%) and nearly universal with multidose EuTCV (99.6%) versus 98.0% for Typbar TCV; differences met the prespecified non‑inferiority margin.
– Safety and reactogenicity profiles across infants, children, and adults were similar between EuTCV formulations and Typbar TCV; adverse events were predominantly mild or moderate and no vaccine‑related serious adverse events were reported.
Background: Typhoid burden and the need for TCVs
Typhoid fever, caused by Salmonella enterica serovar Typhi, remains a major public health problem in many low‑ and middle‑income countries (LMICs). Control measures such as improved water, sanitation, hygiene (WASH), diagnostics, and antibiotics are necessary but insufficient to eliminate disease burden, particularly in children. Typhoid conjugate vaccines (TCVs) — which couple the Vi capsular polysaccharide to a protein carrier to elicit T‑cell dependent immunity — have been recommended by WHO for use in endemic settings, including routine immunization of infants and catch‑up campaigns in older children and adolescents. Expanding access to affordable, effective, and programmatically suitable vaccine formulations (including multidose vials to facilitate mass campaigns) is a priority.
Study design
This multicentre, observer‑blinded, randomized phase 3 non‑inferiority trial was conducted at sites in Kenya and Senegal to evaluate EuTCV Vi‑CRM197 (single‑dose and multidose vial formulations) versus Typbar TCV. Healthy participants aged 6 months to 45 years with no prior typhoid infection or vaccination were enrolled into four age‑defined cohorts: cohort 1 (18–45 years), cohort 2 (2–<18 years), cohort 3 (9–12 months), and cohort 4 (6–12–<24 months). Randomization ratios varied by cohort (most cohorts 10:10:1, cohort 3 used 12:5:5), and multidose recipients were additionally randomized across three lots for lot consistency assessment.
All participants received a single masked 0.5 mL intramuscular dose of vaccine. Infants in cohort 3 (9–12 months) received co‑administration with yellow fever and measles–rubella vaccines where applicable. Masking was maintained for participants and clinical staff except for vaccine administrators and pharmacists. The principal endpoints were safety (all vaccinated participants with available safety data) and immunogenicity measured as seroconversion (≥4‑fold rise in anti‑Vi IgG) at 28 days post‑vaccination. Non‑inferiority in the infant per‑protocol population (cohort 3) was prespecified with a −10% margin for difference in seroconversion versus Typbar TCV. Trial registration: PACTR202112680671189.
Key findings
Enrollment and analysis populations
Between May 3, 2022, and June 21, 2023, 4,149 individuals were screened and 3,219 were randomized to single‑dose EuTCV (n=1,266), multidose EuTCV (n=1,630), or Typbar TCV (n=323). Sixty‑eight participants withdrew or were lost to follow‑up after vaccination, but all vaccinated participants were included in the safety analyses.
Immunogenicity — infant cohort (cohort 3, primary non‑inferiority analysis)
The per‑protocol infant cohort (9–12 months) was the prespecified population for non‑inferiority testing. At 28 days post‑vaccination, seroconversion rates were:
- Single‑dose EuTCV: 197/197 = 100.0%
- Multidose EuTCV: 551/553 = 99.6%
- Typbar TCV: 198/202 = 98.0%
Compared with Typbar TCV, the difference in seroconversion was 1.98% (95% CI 0.06 to 3.90) for single‑dose EuTCV and 1.62% (95% CI −0.37 to 3.60) for multidose EuTCV. Both comparisons met the prespecified non‑inferiority margin of −10%, with single‑dose EuTCV showing a point estimate slightly favoring EuTCV and multidose EuTCV also within an acceptably small margin.
Reactogenicity and safety
Solicited local adverse events within 8 days were recorded as follows: multidose EuTCV 442/1,630 (27.1%; 95% CI 25.0–29.3), single‑dose EuTCV 422/1,266 (33.3%; 95% CI 30.7–36.0), and Typbar TCV 92/323 (28.5%; 95% CI 23.6–33.7). Across age groups, adverse events were predominantly grade 1 (mild) or grade 2 (moderate). Importantly, no serious adverse events (SAEs) were attributed to the investigational product in any age cohort.
Overall safety and reactogenicity profiles were described as similar between EuTCV formulations and Typbar TCV among infants, children, and adults. The paper did not report any unexpected safety signals or clinically meaningful differences in systemic adverse events attributable to EuTCV.
Other relevant findings
Infants who received EuTCV concomitantly with routine vaccines (yellow fever and measles–rubella) did not have reported increases in reactogenicity in the 28‑day window. Lot randomization within the multidose arm indicates an intention to assess manufacturing consistency, although detailed lot‑specific immunogenicity results were not emphasized in the summary provided here.
Expert commentary and interpretation
The multicentre phase 3 data indicate that EuTCV Vi‑CRM197 — in both single‑dose and multidose vial presentations — achieves robust early immunogenicity in infants aged 9–12 months, comparable to an established TCV (Typbar TCV). The near‑universal seroconversion rates observed at 28 days align with expectations for conjugate formulations that use CRM197 as a carrier protein to generate T‑cell dependent responses and overcome infant immaturity of polysaccharide responses.
From a programmatic standpoint, demonstration of equivalent immunogenicity and comparable safety for a multidose vial is important. Multidose presentations can lower per‑dose cost, reduce cold‑chain footprint, and facilitate mass vaccination campaigns and catch‑up activities — all pragmatic advantages in endemic LMIC settings. However, programmatic adoption depends on careful handling guidelines, preservative‑related safety data, and post‑marketing surveillance to monitor real‑world performance and potential vial‑handling risks.
Limitations and considerations
Key limitations include the short immunogenicity follow‑up (28 days), which demonstrates early serologic response but not durability of antibody levels or long‑term clinical protection. The trial did not measure vaccine efficacy against clinical typhoid disease, which requires larger field efficacy or effectiveness studies and longer follow‑up. Geographic generalizability is limited to the two West/East African sites included (Kenya and Senegal); immune responses may vary in different epidemiologic contexts or populations with differing baseline exposure to Salmonella Typhi.
Finally, the trial was funded by EuBiologics and the RIGHT Foundation. While industry funding is common in vaccine development, independent post‑licensure evaluation and public‑access safety data will be important to confirm findings.
Clinical and policy implications
The results support EuTCV as an additional TCV option for infants in endemic settings. If WHO prequalification is granted, EuTCV could expand global supply and potentially lower costs through competition, which may accelerate inclusion of TCVs in national immunization programs and campaigns. Clinicians and program planners should weigh the benefits of increased supply and multidose logistics against the need for continuing surveillance for durability of protection and rare adverse events.
Conclusion
This phase 3 trial demonstrates that single‑dose and multidose EuTCV (Vi‑CRM197) are immunologically non‑inferior to Typbar TCV in infants aged 9–12 months at 28 days, with comparable safety and reactogenicity across age groups studied in Kenya and Senegal. These data strengthen the case for WHO prequalification and provide an evidence base for broader use of EuTCV formulations in typhoid endemic settings. Further work should address durability of protection, field effectiveness, and long‑term safety in diverse populations.
Funding and trial registration
Funding: EuBiologics and the RIGHT Foundation. Trial registration: Pan‑African Clinical Trials Registry PACTR202112680671189 (completed).
References
1. Ndiaye BP, Koech L, Mercer LD, et al. Safety and non‑inferiority of multidose and single‑dose vial formulations of EuTCV Vi‑CRM197 versus Typbar TCV in healthy participants in Kenya and Senegal: a multicentre, observer‑blind, randomised, phase 3 study. Lancet Glob Health. 2025 Dec;13(12):e2122‑e2132. doi:10.1016/S2214‑109X(25)00330‑4. PMID: 41240950.
2. World Health Organization. Typhoid vaccines: WHO position paper. Wkly Epidemiol Rec. 2018;93(13):153–172.
Suggested next steps for researchers and policy makers
– Conduct longer‑term immunogenicity follow‑up and effectiveness studies to define duration of protection and correlate serology with clinical outcomes.
– Implement post‑licensure safety surveillance in diverse settings, including monitoring for rare adverse events and assessment of multidose vial usage practices.
– Model programmatic impact and cost‑effectiveness of adding EuTCV (including multidose options) to routine immunization schedules and mass‑campaign strategies in endemic countries.
Practical takeaways for clinicians
– EuTCV Vi‑CRM197 appears to generate strong early immune responses in infants when administered at 9–12 months, including when co‑administered with routine infant vaccines.
– Short‑term safety is reassuring and comparable to an established TCV; clinicians should counsel caregivers about common mild local and systemic reactions and report any suspected serious events through national pharmacovigilance systems.
