Title: A Phase 3 Multicenter, Observer Blind, Randomized, Controlled Study to Evaluate Safety (Ages 6 Months to 45 Years) and Non-inferiority (Ages 9-12 Months) of Multi-dose and Single-dose Vial Formulations of EuTCV (Vi-CRM197 Typhoid Conjugate Vaccine) against Typbar TCV® and Lot-to-Lot Consistency of the Immune Response (Ages 9-12 Months) to Multi-dose Vial Formulation EuTCV in Healthy African Participants.

Lay Title: Phase 3 study of safety and non-inferiority of single and multi-vial formulations of Eu Typhoid Conjugate Vaccine against WHO prequalified Typbar Typhoid Conjugate Vacccine.

What is the problem/background?

Typhoid fever, an invasive bacterial infection caused by Salmonella enterica serovar typhi (S. typhi), remains an important public health problem, especially in low- and middle-income countries (LMIC). The infection is spread via contact with feces-contaminated food and beverages and/or on occasion by direct contact with other infected humans. There are an estimated 11–21 million cases of typhoid fever and approximately 128,000–161,000 deaths annually1. The alarming increase in multiple antibiotic resistance among typhoid strains has led to the WHO and CDC designating S. typhi as an Antimicrobial Resistance (AMR) threat and to urge accelerated vaccine development and introduction.

What questions are we trying to answer?

The manufacturer of the study vaccine known as EU Biologics is conducting a study aimed at obtaining WHO prequalification for the study vaccine.. The study seeking WHO prequalification of the study vaccine is a phase 1/2 study that is assessing  non-inferiority in the full range of age 6 months-45 years. . After obtaining  prequalification, WHO guidelines  require Eubiologics to submit safety data for 3000 participants. The manufacturers are therefore planning, to conduct this Phase 3 safety study for 3,255 participants in Kenya and Senegal to meet the post-PQ EuTCV commitment of additional safety data. In addition to safety, non-inferiority of single-dose and multi-dose vial formulations of EuTCV against a WHO PQ’ed comparator, co-administration of measles-rubella and yellow fever vaccines at 9 months of age, and anti-Vi IgG persistence will be assessed.

Where is the study taking place, how many people does it involve and how are they selected?

The study will take place in 2 sites one site in Senegal and Kericho site. The study will enroll 3255 participants. A total of 1700 participants are expected to be will be enrolled in Kericho. The potential participants will be enrolled from the community. There is a vibrant community team at the site who engage the stakeholders and identify potential participants and book them for briefing and consenting at the Kericho site.

What does the study involve for those who are in it?

All Participants will receive one dose of the study vaccine and will be monitored for safety. A group of participants will be in the immunogenicity subset . Those in the immunogenicity subset will receive yellow fever and MR concurrently with the study vaccine and will be monitored for immunogenicity.

What are the benefits and risks/costs of the study for those involved?

Participants who receive a locally licensed product will potentially benefit from receiving a recommended vaccine that is not routinely available and which they have not received (per eligibility criteria). Study participants will also benefit by receiving treatment for other illnesses through the ancillary care that is available at the research site. It is possible that study participants may receive no direct benefit from participating in this study. Participation in this study will hopefully contribute to more widespread availability of a vaccine to address a global public health concern. The most common reaction of the experimental vaccine is tenderness at the injection site. The vaccine may contain traces of formaldehyde which is used during the manufacturing process. Caution should be exercised when the vaccine is administered to participants with hypersensitivity to formaldehyde.

Hypersensitivity reactions may occur following the administration of any vaccine, including licensed vaccines, which in rare circumstances may be life-threatening.

How will the study benefit society?

Participation in this study will hopefully contribute to more widespread availability of a vaccine to address a global public health concern.

When does the study start and finish?

The study is expected start in the first quarter of 2022 and take approximately 5 years to end in the year 2027.

Typhoid fever, an invasive bacterial infection caused by Salmonella enterica serovar typhi (S. typhi), remains an important public health problem, especially in low- and middle-income countries (LMIC). Morbidity and mortality from typhoid fever primarily occurs in lower-income countries, with children under 5 years of age experiencing a significant portion of the burden.

Estimating typhoid fever incidence is challenging in the low- and middle-income countries due to the non-specific clinical presentation of the disease, which imitates many other common clinical syndromes (e.g., malaria), and poor access to reliable laboratory-based diagnostics. Although improved sanitation is the most effective solution to preventing widespread typhoid, there are significant costs and difficulties in implementing these measures quickly in resource-poor settings. Since the causative organism is human-restricted, global eradication is possible and an effective vaccine can support elimination efforts. Since S. typhi is an obligate human pathogen, an effective vaccination program could lead to substantial herd protection. In 2018, the WHO reiterated the global health importance of typhoid vaccination and strongly recommended utilization of parenterally administered Vi-conjugate vaccines.

Typhoid Vi-CRM197 Conjugate Vaccine (EuTCV) was developed by EuBiologics and was generally safe, well-tolerated and immunogenic compared to Typbar TCV® (Bharat Biotech Intl Ltd) and Typhim Vi® (Sanofi Pasteur) typhoid vaccines in healthy adults in a Phase 1 trial in the Philippines. EuBiologics conducted a single-dose Phase 2/3 study in the Philippines.

EuBiologics is planning World Health Organization (WHO) prequalification (PQ) dossier submission in Sep 2021, after obtaining a South Korea Ministry of Food and Drug Safety export license. Non-inferiority in the full range of age 6 months-45 years will be assessed in the current Phase 2/3 study which is sufficient for PQ by WHO.

This Phase 3 study will be an observer-blinded, multi-center, randomized trial to assess safety and the non-inferiority of single-dose and multi-dose vial formulations of EuTCV (Vi-CRM197 Typhoid Conjugate Vaccine) against Typbar TCV® in healthy participants between ages 6 months to 45 years in an age de-escalation design.  a total of 3255 participants will be enrolled in the study of whom of 1050 participants will be in the immunogenicity subset. Participants in the immunogenicity subset will receive yellow fever vaccine and MR concurrently with the typhoid vaccine and will have blood drawn for immunogenicity. Participants will be followed up for a period of 7 months and will have a total of 5 study visits.

.Kericho site will enroll up to 1700 participants. Screening to enrollment ratio is 1.5 :1 thus Kericho site anticipates to screen 2550 participants to enroll 1700.