Immune Equivalence Between Multi-dose and Single Dose Formulation of Vi-DT and Their Overall Safety (Phase III)

A Phase III, Multicenter, Observer Blind, Randomized, Controlled Study to Evaluate Immune Equivalence of Multi-dose Formulation Against Single-dose Formulation of Vi-DT Typhoid Conjugate Vaccine and Safety in Healthy Filipino......

This is a multicenter, randomized, observer-blinded, controlled, immune equivalence study of a multi-dose (MD) formulation with 2PE preservative of SK bioscience Vi-DT compared to single dose (SD) formulation without preservative of SK bioscience Vi-DT in participant (6 months - 45 years) including safety population.

The study objectives are as follows:

• Primary objective. Demonstrate the immune equivalence as measured by anti-Vi IgG Geometric Mean Titer (GMT) of multi dose formulation against single dose formulation of Vi-DT (18-45 year age stratum), at 4 weeks after a single dose.
• Secondary objective 1. Demonstrate the immune equivalence as measured by seroconversion rates of anti-Vi IgG antibody titres of multi dose formulation against single dose formulation of Vi-DT vaccine (18-45 year age stratum) at 4 weeks after a single dose.
• Secondary objective 2. Describe safety profile in all age strata combined (age 6 months - 45 years old) and in each age stratum, at 4 weeks after a single dose of SD/MD formulation/control (Meningococcal Conjugate Vaccine).

There are total 5 scheduled visits as follows:

• Visit 1(D-7 to 0): Screening
• Visit 2(D0): Enrollment, vaccination, safety follow-up and blood collection for immunogenicity assessment (only for subjects 18 years old and above)
• Visit 3(D7): Safety follow-up
• Visit 4(D28): Safety follow-up and blood collection for immunogenicity assessment (only for subjects 18 years old and above)
• V5(D168): Safety follow-up

Study Overview

• Status: Completed
• Conditions: Typhoid
• Intervention / Treatment: Biological: Vi-DT (Multi-dose formulation); Biological: Vi-DT (Single dose formulation); Biological: Control Vaccine

Detailed Description

The vaccines will be administered to 1,500 healthy participants of 6 months to 45 years of age and followed up for 24 weeks after the injection for safety. Adult participants (N=500) will be followed up for immunogenicity at 4 weeks and all participants till 24 weeks for safety post single dose of either MD & SD formulations. 300 healthy participants will be given control vaccine (locally available licensed Meningococcal conjugate vaccine) to check the background safety events. The primary objective is to demonstrate the equivalence of immunogenicity as measured by anti-Vi IgG GMT titer at 4 weeks after a single dose of MD/SD formulation in adults. The secondary objective is to demonstrate the equivalence of immunogenicity in terms of seroconversion rates as measured by anti-Vi IgG ELISA antibody titers, at 4 weeks after a single dose of MD/SD formulation in adults. A descriptive evaluation of safety at 4 and 24 weeks post single dose of (SD/MD/Meningococcal vaccine), will be performed. The Vi-DT vaccine from both MD & SD formulations will be administered as a single dose of 25 µg/0.5 mL.

Eligible participants enrolled into the study will be randomized into one of the three study groups within each age stratum of 6 months to less than 2 years, 2 to less than 18 years, and 18 to 45 years. Participants will be observed at the study site for 30 minutes after vaccination for safety assessment. Solicited adverse events will be recorded on a diary card during 7 days after vaccination. Unsolicited adverse events will be recorded during the 4 weeks after vaccination. Serious adverse events will be recorded during the entire study period. With the exception of designated study site personnel responsible for vaccine administration, site investigators, study nurse, and those assessing clinical outcomes, and data analysts will be blinded to vaccine allocation until data base lock for the final analysis.

Blood samples will be collected at baseline prior to vaccination and at 4 weeks post vaccination from adults (18-45 years) for immunogenicity assessment

• Study Type: Interventional
• Enrollment (Actual): 1800
• Phase: Phase 3

Contacts and Locations

Study Locations

• Philippines
  • Manila, Philippines, 1000
    • University of the Philippines Manila-National Institutes of Health
  • Laguna
    • Calamba, Laguna, Philippines, 4027
      • Lingga Health Research Center
    • San Pablo City, Laguna, Philippines, 4000
      • Magcase Health Center
  • Metro Manila
    • Muntinlupa, Metro Manila, Philippines, 1772
      • Putatan Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy participants 6 months to 45 years of age at enrollment
2. Participants/Parent(s)/LAR who have voluntarily given informed consent/assent
3. Participants/Parent(s)/LAR willing to follow the study procedures of the study and available for the entire duration of the study

Exclusion Criteria:

1. Child with a congenital abnormality
2. Participant who has already received meningococcal conjugate vaccine
3. Participants concomitantly enrolled or scheduled to be enrolled in another trial
4. Known history of immune function disorders including immunodeficiency diseases (Known HIV infection or other immune function disorders)
5. Chronic use of systemic steroids (>2 mg/kg/day or >20 mg/day prednisone equivalent for periods exceeding 10 days), cytotoxic or other immunosuppressive drugs
6. Receipt of blood or blood-derived products in the past 3 months
7. Participant with a previously ascertained or suspected disease caused by S. Typhi (confirmed either clinically, serologically or microbiologically)
8. Participant who has had household contact with and/or intimate exposure to an individual with laboratory-confirmed S. Typhi
9. Individual who has previously received a typhoid vaccine
10. Participant who has received other vaccines from 1 month prior to test vaccination or planned to receive any vaccine within 1 month (except a measles containing vaccine as per government vaccination campaign)
11. Known history or allergy to vaccines or other medications
12. History of uncontrolled coagulopathy or blood disorders
13. Any abnormality or chronic disease which in the opinion of the investigator might be detrimental for the safety of the participant and interfere with the assessment of the study objectives
14. Any female participant who is lactating, pregnant* or planning for pregnancy during the course of study period
15. Participants/Parent(s)/LAR planning to move from the study area before the end of study period
16. As per Investigator's medical judgement individual could be excluded from the study in spite of meeting all inclusion/exclusion criteria mentioned above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vi-DT Multi-dose; 750 participants (6 mo - 45 yrs); Dose: 0.5mL, Vi polysaccharide typhoid vaccine conjugated with Diphtheria toxoid protein (Vi-DT), manufactured by SK bioscience (Republic of Korea); Dosage form: Liquid, 25µg Vi polysaccharide/0.5mL, presented in Type I glass vial (multi-dose formulation Vi-DT contains preservative 2 PE); Mode of Administration: Intramuscular injection; Frequency of administration: Once	Biological: Vi-DT (Multi-dose formulation); Manufacturer: SK bioscience Co., Ltd.; Dose formulation: 25 µg Vi polysaccharide /0.5 mL, presented in Type I glass vial (multi dose Vi-DT with preservative 2 PE); Mode of Administration: 0.5 mL by intramuscular injection in the left anterolateral thigh or left arm deltoid region in participants below 2 years of age, less dominant arm deltoid region in age group 2 to 45 years; Storage Conditions: +2 to +8°C; Other Names: Vi polysaccharide typhoid vaccine conjugated with Diphtheria toxoid protein
Experimental: Vi-DT Single-dose; 750 participants (6 mo - 45 yrs); Dose: 0.5mL, Vi polysaccharide typhoid vaccine conjugated with Diphtheria toxoid protein (Vi-DT), manufactured by SK bioscience (Republic of Korea); Dosage form: Liquid, 25µg Vi polysaccharide/0.5mL, presented in Type I glass vial (single dose formulation Vi-DT without any preservative); Mode of Administration: Intramuscular injection; Frequency of administration: Once	Biological: Vi-DT (Single dose formulation); Manufacturer: SK bioscience Co., Ltd.; Dose formulation: 25 µg Vi polysaccharide /0.5 mL, presented in Type I glass vial (single dose Vi-DT without any preservative); Mode of Administration: 0.5 mL by intramuscular injection in the left anterolateral thigh or left arm deltoid region in participants below 2 years of age, less dominant arm deltoid region in age group 2-45 years; Storage Conditions: +2 to +8°C; Other Names: Vi polysaccharide typhoid vaccine conjugated with Diphtheria toxoid protein
Active Comparator: Control; 300 participants (6 mo - 45 yrs); Dose: 0.5mL, Locally available Meningococcal conjugate vaccine; Dosage form: Lyophilized white powder; Mode of Administration: Intramuscular injection; Frequency of administration: Once (For participants 6 months to 1 year, one more dose will be provided after the study unblinding)	Biological: Control Vaccine; For participant ≥ 1 year one dose of locally licensed Meningococcal conjugate vaccine will be administered; For participants 6 months to 1 year one dose of locally licensed Meningococcal conjugate vaccine will be administered during the study and the next dose will be provided after the study unblinding at the completion of 6 months follow up of last subject.; Other Names: Locally available Meningococcal conjugate vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Titers (GMT) of anti-Vi IgG	If the 95% confidence interval of the ratio of GMT estimate of Vi-DT(MD) over GMT of Vi-DT(SD) is located within the bounds of 0.67to 1.5, then Vi-DT (MD) is equivalent to Vi-DT (SD) in terms of GMT of anti-Vi IgG with significance level of 0.05.	At 4 weeks (28 days) post vaccination of Vi-DT (MD/SD)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seroconversion rates of anti-Vi IgG ELISA antibody titres	If the 95% confidence interval of the estimate of difference of seroconversion rate between Vi-DT (MD) and Vi-DT (SD) at 4 weeks (Day 28) is located within the bounds -10% to 10%, then Vi-DT (MD) is equivalent to Vi-DT (SD) in terms of sero-conversion rate, which is defined as 4 fold increase of anti Vi IgG from baseline with significance level of 0.05.	At 4 weeks (28 days) from baseline (Day 0; before vaccination of Vi-DT (MD/SD)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety endpoints by each formulation and overall and within each age stratum	Frequency of local and systemic solicited adverse events during the 7 days after each doseSolicited local reactions at the site of injection: pain, tenderness, erythema/redness, swelling/induration and pruritusSolicited systemic reactions (adapted to each age group): fever, lethargy, irritability, nausea/vomiting, arthralgia, diarrhea, drowsiness, loss of appetite, chills, headache, fatigue, myalgia and persistent crying; Frequency of unsolicited adverse events during 4 weeks (28 days) after vaccination; Frequency of Serious Adverse Events during the entire study period	Solicited AEs during the 7 days after vaccination/Unsolicited AEs during 4 weeks (28 days) after vaccination/SAEs during the entire study period

Collaborators and Investigators

• Sponsor: International Vaccine Institute
• Collaborators: Bill and Melinda Gates Foundation; SK Bioscience Co., Ltd.
• Investigators: Principal Investigator: Josefina C Carlos, MD, University of the East-Ramon Magsaysay Memorial Medical Center Inc.

Publications and helpful links

General Publications

• Carlos JC, Tadesse BT, Borja-Tabora C, Alberto E, Ylade MC, Sil A, Kim DR, Ahn HS, Yang JS, Lee JY, Kim MS, Park J, Kwon SY, Kim H, Yang SY, Ryu JH, Park H, Shin JH, Lee Y, Kim JH, Mojares ZR, Wartel TA, Sahastrabuddhe S. A Phase 3, Multicenter, Randomized, Controlled Trial to Evaluate Immune Equivalence and Safety of Multidose and Single-dose Formulations of Vi-DT Typhoid Conjugate Vaccine in Healthy Filipino Individuals 6 Months to 45 Years of Age. Lancet Reg Health West Pac. 2022 May 30;24:100484. doi: 10.1016/j.lanwpc.2022.100484. eCollection 2022 Jul.

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2020
• Primary Completion (Actual): September 11, 2020
• Study Completion (Actual): January 29, 2021

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 18, 2019

Study Record Updates

• Last Update Posted (Actual): August 27, 2021
• Last Update Submitted That Met QC Criteria: August 26, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Immunogenicity; Typhoid conjugate vaccine; Vi-DT
• Additional Relevant MeSH Terms: Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Salmonella Infections; Typhoid Fever; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: IVI T004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No