Study of Co-administered Na-APR-1 (M74) and Na-GST-1 in Gabonese Children

Randomized, Controlled, Phase 1 Study to Assess Safety and Immunogenicity of Co-administered Hookworm Vaccine Candidates Na-APR-1 (M74)/Alhydrogel® and Na-GST-1/ Alhydrogel® in Gabonese Children

Double blind, randomized, controlled, dose-escalation Phase 1 clinical trial in hookworm-exposed children aged 6 to 10 years living in the area of Lambaréné, Gabon. Children will receive three doses of the Na-GST-1/Alhydrogel hookworm vaccine co-administered with the Na-APR-1 (M74)/Alhydrogel hookworm vaccine or the hepatitis B vaccine co-administered with sterile saline. All injections will be delivered intramuscularly (deltoid) on approximately Days 0, 56, and 112 or 180.

Double blind, randomized, controlled, dose-escalation Phase 1 clinical trial in hookworm-exposed children aged 6 to 10 years living in the area of Lambaréné, Gabon. Children will receive three doses of the assigned vaccine(s) delivered intramuscularly (deltoid) on approximately Days 0, 56, and 112 or 180.

Safety will be measured from the time of each study vaccination (Day 0) through 14 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 the first study vaccination through approximately 1 month after each study vaccination. New-onset chronic medical conditions and Serious Adverse Events (SAEs) will be collected from the time of the first study vaccination through approximately 9 months after the third study vaccination (final visit). Clinical laboratory evaluations for safety will be performed on venous blood collected approximately 14 days after each vaccination.

Immunogenicity testing will include IgG antibody responses to each vaccine antigen, by a qualified indirect enzyme-linked immunosorbent assay (ELISA), on serum or plasma obtained prior to each study vaccination and at time points after each vaccination (see Appendix A); the functional activity of vaccine-induced antibodies will be assessed by in vitro enzyme neutralization assays; the induction of B cell memory will be measured by antigen-specific memory B cell responses.

Recruitment and enrollment into the study will occur on an ongoing basis, with each group being recruited and vaccinated in sequence.

60 subjects will be enrolled into 3 groups of 20. The first 20 subjects will be assembled and enrolled into Group 1:

1. Group 1 double-blind IP allocation (n=20):

   • 16 subjects will receive 10 µg Na-APR-1 (M74) plus 5 µg GLA-AF delivered by IM injection in the deltoid muscle, with 10 µg Na-GST-1 administered IM in the alternate arm.

     • 8 will be vaccinated according to a 0,2,4-month schedule
     • 8 will be vaccinated according to a 0,2,6-month schedule

   • 4 subjects will receive hepatitis B vaccine comparator:

     • 2 will be vaccinated according to a 0,2,4-month schedule
     • 2 will be vaccinated according to a 0,2,6-month schedule

2. Group 2 double-blind IP allocation (n=20):

   • 16 subjects will receive 30 µg Na-APR-1 (M74) plus 5 µg GLA-AF delivered by IM injection in the deltoid muscle, with 30µg Na-GST-1 administered IM in the alternate arm.

     • 8 will be vaccinated according to a 0,2,4-month schedule
     • 8 will be vaccinated according to a 0,2,6-month schedule

   • 4 subjects will receive hepatitis B vaccine comparator:

     • 2 will be vaccinated according to a 0,2,4-month schedule
     • 2 will be vaccinated according to a 0,2,6-month schedule

3. Group 3 double-blind IP allocation (n=20):

   • 16 subjects will receive 100 µg Na-APR-1 (M74) plus 5 µg GLA-AF delivered by IM injection in the deltoid muscle, with 100 µg Na-GST-1 administered IM in the alternate arm.

     • 8 will be vaccinated according to a 0,2,4-month schedule
     • 8 will be vaccinated according to a 0,2,6-month schedule

   • 4 subjects will receive hepatitis B vaccine comparator:

     • 2 will be vaccinated according to a 0,2,4-month schedule
     • 2 will be vaccinated according to a 0,2,6-month schedule

Inclusion Criteria:

1. Males or females between 6 and 10 years, inclusive, who are long-term residents of the study area.
2. Good general health as determined by means of the screening procedure.
3. Assumed availability for the duration of the trial (up to 15 months).
4. Willingness of parent or legal guardian for child to participate in the study as evidenced by signing the informed consent document in combination with the child assent form.
5. Negative for hookworm during screening, or if found to be infected with hookworm, has completed a course of three doses of albendazole.

Exclusion Criteria:

1. Inability of parent/legal guardian to correctly answer all questions on the informed consent comprehension questionnaire.
2. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, diabetes, or renal disease by history, physical examination, and/or laboratory studies.
3. Known or suspected immunodeficiency.
4. Laboratory evidence of liver disease (alanine aminotransferase [ALT] greater than 1.25-times the upper reference limit).
5. Laboratory evidence of renal disease (serum creatinine greater than 1.25-times the upper reference limit, or more than 1+ protein, or more than trace blood on urine dipstick testing with the exception of greater than trace blood detected in females during menses).
6. Laboratory evidence of hematologic disease (absolute leukocyte count <4500/mm3; absolute leukocyte count >13.0 x 103/mm3; hemoglobin <9.5 g/dl; or, platelet count <140,000/mm3).
7. Other condition that in the opinion of the investigator could jeopardize the safety or rights of a child participating in the trial or would render the child unable to comply with the protocol.
8. Participation in another investigational vaccine or drug trial within 30 days of starting this study or for the duration of the study.
9. History of a severe allergic reaction or anaphylaxis.
10. Severe asthma as defined by the need for daily use of inhalers or emergency room/clinic visit or hospitalization within 6 months of the child's planned first vaccination in the study.
11. Positive for HCV.
12. Positive for HBsAg.
13. Positive for HIV infection.
14. Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within 30 days of starting this study or expect to use for the duration of the study.
15. Receipt of a live vaccine within past 4 weeks or a killed vaccine within past 2 weeks prior to entry into the study.
16. History of a surgical splenectomy.
17. Receipt of blood products within the 6 months prior to entry into the study.
18. Previous receipt of a primary series (three doses according to a 0, 1, and 6 -12 month schedule) of the hepatitis B vaccine.