A Phase I/II Study of the Safety, Immunogenicity, and Efficacy of Sm-TSP-2/Alhydrogel® With or Without AP 10-701 for Intestinal Schistosomiasis in Healthy Ugandan Adults

Brief Summary

Detailed Description

The study will recruit up to 290 healthy adult males and non-pregnant females into a two-part clinical trial of a vaccine to protect against schistosomiasis caused by infection with S. mansoni. Two formulations of the Sm-TSP-2 vaccine will be tested: one using Alhydrogel® only, and one using Alhydrogel® plus AP 10-701, each at 3 different doses of antigen: 10mcg, 30mcg, and 100mcg. The first part of the study will be a Phase I dose-escalation safety and immunogenicity study followed by a Phase IIb trial in which a larger number of adults will be enrolled to assess the impact of the vaccine on infection with S. mansoni. The impact of the vaccine on infection with S. haematobium will also be assessed although this will be exploratory given that potential cross-protection against this species is only hypothetical at this point. Part A: double blind (within cohort), randomized, controlled, dose-escalation Phase 1b clinical trial in S. mansoni exposed adults living in the area of Kampala, Uganda. In each of 3 cohorts, subjects will be randomly assigned to 1 of 3 groups: Sm-TSP-2/Alhydrogel®, Sm-TSP-2/Alhydrogel®/AP 10-701, or the licensed Hepatitis B vaccine (up to 12 subjects per study vaccine group and 6 subjects in the Hepatitis B vaccine group). Subjects will receive three doses of the assigned vaccine delivered intramuscularly at approximately Days 0, 56, and 112. Safety will be measured from the time of each study vaccination (Days 0, 56, 112 \[Visits 2, 7, 12\]) through 7 days after each study vaccination by the occurrence of solicited injection site and systemic reactogenicity events. Unsolicited non-serious adverse events (AEs) will be collected from the time of each study vaccination through approximately 28 days after each study vaccination. New-onset chronic medical conditions (including adverse events of special interest \[AESI\]) and serious adverse events (SAEs) will be collected from the time of the first study vaccination (Day 0 \[Visit 2\]) through approximately 9 months after the third study vaccination (Day 380 \[Visit 19\]). Clinical laboratory evaluations for safety will be performed on venous blood collected approximately 7 days after each study vaccination. Immunogenicity testing will include IgG antibody responses to Sm-TSP-2 by a qualified indirect ELISA on serum obtained prior to each study vaccination (Days 0, 56, 112) and at time points after each vaccination. Ninety subjects will be enrolled into 3 groups of 30. Recruitment and enrollment into the study will occur on an ongoing basis, with each group being recruited and vaccinated in sequence. Part A of the study is a dose escalation trial in which escalation to the next dose cohort will be determined based on evaluation of pre-defined escalation criteria, which will be evaluated 7 days after all subjects in the currently active cohort have received their first dose of vaccine. Within each cohort, the assignment to Alhydrogel®, Alhydrogel®/AP 10-701, or Hepatitis B vaccine will be randomized and double-blinded (i.e., neither the subject nor the investigator will be aware of the formulation assigned). The study will proceed as follows: 1. Cohort 1, N=30 \[10mcg Sm-TSP-2/Alhydrogel® (n=12) or 10mcg Sm-TSP-2/Alhydrogel®/ AP 10-701 (n=12) or Hepatitis B vaccine (n=6)\] 1. Enroll, randomize, and administer first dose of study vaccine or Hepatitis B vaccine to initial 6 subjects 2. After initial 6 subjects have completed Visit 3, administer the first dose of study vaccine or Hepatitis B vaccine to the remaining 24 subjects 3. Assess 7 day post dose 1 safety data for all subjects 4. Make escalation decision 2. Cohort 2, N=30 \[30mcg Sm-TSP-2/Alhydrogel® (n=12) or 30mcg Sm-TSP-2/Alhydrogel®/AP 10-701 (n=12) or Hepatitis B vaccine (n=6)\] 1. Enroll, randomize, and administer first dose of study vaccine or Hepatitis B vaccine to initial 6 subjects 2. After initial 6 subjects have completed Visit 3, administer the first dose of study vaccine or Hepatitis B vaccine to the remaining 24 subjects 3. Assess 7 day post dose 1 safety data for all subjects 4. Make escalation decision 3. Cohort 3, N=30 \[100mcg Sm-TSP-2/Alhydrogel® (n=12) or 100mcg Sm-TSP-2/Alhydrogel®/AP 10-701 (n=12) or Hepatitis B vaccine (n=6)\] 1. Enroll, randomize, and administer first dose of study vaccine or Hepatitis B vaccine to initial 6 subjects 2. After initial 6 subjects have completed Visit 3, administer the first dose of study vaccine or Hepatitis B vaccine to remaining 24 subjects 3. Assess 7 day post dose 1 safety data for all subjects 4. Complete follow-up for all subjects 5. Close the study Part B: double blind, randomized, controlled, dose-escalation Phase IIb clinical trial in adults living in the area of Kampala, Uganda, who reside in S. mansoni endemic areas with greater than or equal to 25% prevalence in children aged 5-15 years of age. In this part of the study, up to 200 eligible Schistosoma-positive (by Kato Katz fecal thick smear or CAA) adult volunteers will be progressively enrolled and randomized to receive either Sm-TSP-2/Alhydrogel® (with or without AP 10-701) or the Hepatitis B comparator vaccine, in a 1:1 fashion. The dose and formulation (i.e., with or without the point-of-injection addition of AP 10-701) of Sm-TSP-2/Alhydrogel® that will be tested in this part of the study will be chosen based on the interim results of Part A of the trial after all participants have received their third dose of vaccine. All participants in Part B will be treated with praziquantel prior to receipt of the first vaccination. Interim safety and anti-Sm-TSP-2 IgG antibody results up to and including Day 126 of Part A of the trial will be evaluated to determine the dose that will be tested in Part B. Two hundred subjects will be enrolled in Part B. The 12 subjects in Part A who received the same dose/formulation of Sm-TSP-2/Alhydrogel® that is chosen for Part B will be offered the opportunity to transition to Part B for the remainder of their participation in the study. Recruitment and enrollment into the study will occur on an ongoing basis, with participants being recruited, randomized and vaccinated in sequence. Within Part B, the assignment to Sm-TSP-2/Alhydrogel® or Hepatitis B vaccine will be randomized and double-blinded (i.e., neither the subject nor the investigator will be aware of the formulation assigned). Part B of the study will proceed as follows: 1\. Cohort 4, N=200 \[Sm-TSP-2/Alhydrogel® \[dose and formulation TBD\] (n=100) or Hepatitis B vaccine (n=100)\] Subjects will receive three doses of the assigned vaccine delivered intramuscularly at approximately Days 0, 56, and 112. Safety will be measured from the time of each study vaccination (Days 0, 56, 112 \[Visits 2, 7, 12\]) through 7 days after each study vaccination by the occurrence of solicited injection site and systemic reactogenicity events. Unsolicited non-serious adverse events (AEs) will be collected from the time of each study vaccination through approximately 28 days after each study vaccination. New-onset chronic medical conditions (including adverse events of special interest \[AESI\]) and serious adverse events (SAEs) will be collected from the time of the first study vaccination (Day 0 \[Visit 2\]) through approximately 23 months after the third study vaccination (Day 800 \[Visit 21\]). Clinical laboratory evaluations for safety will be performed on venous blood collected approximately 7 days after each study vaccination. Immunogenicity testing will include IgG antibody responses to Sm-TSP-2 by a qualified indirect ELISA on serum obtained prior to each study vaccination (Days 0, 56, 112) and at time points after each vaccination. Efficacy will be evaluated by measuring the impact of vaccination with Sm-TSP-2/Alhydrogel® on fecal and urine Schistosoma egg counts and CAA positivity. After final vaccination, fecal and urine samples will be collected at 12 and 23 months following the final vaccination to determine rates and intensities of re-infection. The primary endpoint to determine the impact of vaccination on infection with S. mansoni will be incidence of infection as determined by a positive CAA test or Kato-Katz fecal thick smear. The impact of vaccination on infection with S. haematobium will be assessed as an exploratory endpoint, by means of urine microscopy for schistosome eggs.

Primary Outcomes

Secondary Outcomes

• Immunogenicity: peak anti-Sm-TSP-2 IgG level(Day 126)
• Immunogenicity: anti-Sm-TSP-2 IgG levels over time(Approximately 14 days after doses one and two and at Days 200, 290, 380 (Parts A and B) after final dose, and at Days 548, and 800 (Part B) after final dose.)