safety and immunogenicity of the na-apr-1 hookworm vaccine in healthy adults

Conditions: Hookworm Infection; Hookworm Disease

Summary: hookworms digest hemoglobin from erythrocytes for use as an energy source via a proteolytic cascade that begins with the aspartic protease, apr-1. vaccination with recombinant apr-1 has protected animals from infection in challenge studies. this study will evaluate the safety and immunogenicity of two formulations of na-apr-1 (m74) in healthy adult volunteers when co-administered with different concentrations of the immunostimulant gla-af.

open-label, dose-escalation phase 1 clinical trial in healthy, hookworm-naïve adults: * study site: george washington medical faculty associates, washington, dc * number of participants: 40 in 2 cohorts of 20. in cohort 1 five (5) volunteers will receive 30 µg na-apr-1 (m74) /alhydrogel®, five (5) will receive 30 µg na-apr-1 (m74)/alhydrogel® plus 2.5 µg gla-af, and ten (10) will receive 30 µg na-apr-1 (m74) /alhydrogel® plus 5 µg gla-af. in cohort 2 five (5) volunteers will receive 100 µg na-apr-1 (m74)/alhydrogel®, five (5) will receive 100 µg na-apr-1 (m74) /alhydrogel® plus 2.5 µg gla-af, and ten (10) will receive 100 µg na-apr-1 (m74)/alhydrogel® plus 5 µg gla-af. the cohorts will be enrolled in a staggered fashion with safety data assessed prior to the na-apr-1 dose escalation from 30 to 100 µg. in addition, within each cohort, vaccinations will be staggered such that formulations containing 0, 2.5, and 5 µg gla-af will be tested sequentially: for example, those receiving na-apr-1 (m74)/alhydrogel® in combination with 2.5 µg gla-af will be vaccinated no sooner than 3 days after the last volunteer is vaccinated with the formulation containing no gla-af, whereas those vaccinated with na-apr-1 (m74)/alhydrogel® plus 5 µg gla-af will be vaccinated no sooner than 7 days after the last one receives the 2.5 µg gla-af formulation. * immunization schedule: study days 0, 56 and 112. * route: im in the deltoid muscle. * doses of na-apr-1 (m74) to be tested: 30 and 100 µg. * doses of alhydrogel®: 240 and 800 µg for the 30 and 100 µg doses of na-apr-1 (m74), respectively. * doses of gla-af to be tested: 2.5 µg and 5 µg. * study duration: 44 weeks (10 months) per study participant; total duration of the study estimated at approximately 13 months.

Eligibility criteria:
inclusion criteria: * males or females between 18 and 50 years, inclusive. * good general health as determined by means of the screening procedure. * available for the duration of the trial (44 weeks). * willingness to participate in the study as evidenced by signing the informed consent document. exclusion criteria: * pregnancy as determined by a positive urine human choriogonadotropin (hcg) (if female). * participant unwilling to use reliable contraception methods up until one month following the third immunization (if female and not surgically sterile, abstinent or at least 2 years post-menopausal). * currently lactating and breast-feeding (if female). * evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, diabetes, or renal disease by history, physical examination, and/or laboratory studies. * known or suspected immunodeficiency. * laboratory evidence of liver disease (alanine aminotransferase \[alt\] greater than 1.25-times the upper reference limit). * laboratory evidence of renal disease (serum creatinine greater than 1.25-times the upper reference limit, or more than trace protein or blood on urine dipstick testing). * laboratory evidence of hematologic disease (hemoglobin \ 10.7 x 103/mm3; absolute neutrophil count \[anc\] \<1700/ mm3; absolute lymphocyte count \<700/mm3; or platelet count \<140,000/mm3). * laboratory evidence of a coagulopathy (ptt or pt inr greater than 1.1-times the upper reference limit). * serum glucose (random) greater than 1.2-times the upper reference limit. * other condition that in the opinion of the investigator would jeopardize the safety or rights of a volunteer participating in the trial or would render the subject unable to comply with the protocol. * participation in another investigational vaccine or drug trial within 30 days of starting this study. * volunteer has had medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months. * history of a severe allergic reaction or anaphylaxis. * severe asthma as defined by the need for daily use of inhalers or emergency clinic visit or hospitalization within 6 months of the volunteer's expected first vaccination in the study. * positive elisa for hepatitis b surface antigen (hbsag). * positive confirmatory test for hiv infection. * positive confirmatory test for hepatitis c virus (hcv) infection. * use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within 30 days of the volunteer's expected first vaccination in this study. * receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to the volunteer's expected first vaccination in the study. * history of a surgical splenectomy. * receipt of blood products within the past 6 months. * history of previous infection with hookworm or residence for more than 6 months in a hookworm-endemic area.

Keywords: human hookworm necator americanus hookworm hookworm disease iron-deficiency anemia soil-transmitted helminth infection neglected tropical disease na-apr-1