Immunization Via Mosquito Bite With Radiation-attenuated Sporozoites

NCT01994525 | Completed Phase 1

• 1 other identifier: S-12-22
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

This study is to assess the safety, tolerability, and biomarkers of protection in healthy malaria-naïve adults, who will receive bites from Anopheles stephensi mosquitoes either infected with Plasmodium falciparum Sporozoites (PfRAS) (true-immunization) or noninfected (mock-immunization).

Conditions

Malaria

Outcome Measures

Primary Outcomes (6)

• Solicited adverse events

  Occurrence of solicited adverse events (AE) from administration of study immunization (PfRAS)

  7 days

• Unsolicited adverse events

  Occurrence of unsolicited adverse events (AEs) from administration of immunization (PfRAS)

  14 days

• Laboratory adverse events

  Occurrence of laboratory AEs from administration of study immunization (PfRAS)

  7 days

• Serious adverse events

  Occurrence of serious adverse events (SAEs) from administration of immunization (PfRAS)

  52 weeks

• Signs and symptoms related to malaria infection

  Occurrence of signs and symptoms related to malaria infection starting 7 days post-Controlled Human Malaria Infection (CHMI) (these will not be recorded as adverse events because they are expected as a result of malaria infection)

  7 days

• Parasitemia

  Development of parasitemia and time to parasitemia after malaria challenge

  52 weeks

Secondary Outcomes (3)

• Identify and validate immunological PBMC biomarkers

  52 weeks

• Identify and validate immunological serum biomarkers

  52 weeks

• Identify and validate whole blood immunological biomarkers

  52 weeks

Study Arms (7)

Cohort 1: PfRAS-infected

EXPERIMENTAL

5 doses (immunizations) of approximately 200 infectious bites (200-400 bites total) from PfRAS-infected mosquitoes (true-immunization). The target dose is 960 infectious bites. Challenge occurs 3 weeks after final immunization.

Biological: PfRAS; Other: Challenge

Cohort 1: Noninfected

PLACEBO COMPARATOR

Placebo immunization. 5 doses of approximately 200 noninfected bites (200-400 bites total) from irradiated uninfected mosquitoes (mock-immunization). The target dose is 960 noninfected bites. Challenge occurs 3 weeks after final immunization.

Biological: Placebo; Other: Challenge

Cohort 1: Nonimmunized

OTHER

No protective intervention given. Challenge occurs directly after screening.

Other: Challenge

Cohort 2: PfRAS-infected

EXPERIMENTAL

3 to 7 doses (immunizations) of approximately 200 infectious bites (200-400 bites total) from PfRAS-infected mosquitoes (true-immunization). The target dose is dependent on protection results in cohort 1. Challenge occurs 3 weeks after final immunization.

Biological: PfRAS; Other: Challenge

Cohort 2: Noninfected

PLACEBO COMPARATOR

Placebo. 3 to 7 doses of approximately 200 noninfected bites (200-400 bites total) from irradiated, uninfected mosquitoes (true-immunization). The target dose is dependent on protection results in cohort 1. Challenge occurs 3 weeks after final immunization.

Biological: Placebo; Other: Challenge

Cohort 2: Nonimmunized

OTHER

No protective intervention given. Challenge occurs directly after screening.

Other: Challenge

Hyperimmunity PfRAS-infected

EXPERIMENTAL

Cohort 1 sub-cohort 3 doses (immunizations) of approximately 200 infectious bites (200-400 bites total) from PfRAS-infected mosquitoes. This arm will receive the first 3 immunizations of Cohort 2. Challenge occurs at the same time as Cohort 2 (3-20 weeks after the final immunization)

Biological: PfRAS; Other: Challenge

Interventions

PfRAS BIOLOGICAL

Radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) administered by the bite of infected Anopheles stephensi mosquitoes

Also known as: True-immunization, PfRAS infected Anopheles stephensi mosquitoes

Cohort 1: PfRAS-infected; Cohort 2: PfRAS-infected; Hyperimmunity PfRAS-infected

Placebo BIOLOGICAL

Administered by the bite of noninfected Anopheles stephensi mosquitoes

Also known as: Mock-immunization, Noninfected Anopheles stephensi mosquites

Cohort 1: Noninfected; Cohort 2: Noninfected

Challenge OTHER

5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.

Cohort 1: Nonimmunized; Cohort 1: Noninfected; Cohort 1: PfRAS-infected; Cohort 2: Nonimmunized; Cohort 2: Noninfected; Cohort 2: PfRAS-infected; Hyperimmunity PfRAS-infected

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults (male or non-pregnant, non-breastfeeding female) 18-50 years of age (inclusive).
• Available and willing to participate for duration of study.
• Able and willing to provide written informed consent.
• Able to complete an Assessment of Understanding with a score of at least 70% correct.
• In good general health with no clinically significant health problems as established by medical history, physical exam and laboratory screening.
• Females of childbearing potential must have a negative pregnancy test at screening and agree to not become pregnant or breastfeed for the duration of the study. She must be willing to use a reliable form of contraception during the study. Reliable forms of birth control include use of condoms, diaphragm or cervical cap, birth control pills, IUD or sperm killing products.
• Agree to refrain from blood donation (except as required in this study) for 3 years following P falciparum challenge.
• Agree not to travel to a malaria-endemic region during the study.
• Good peripheral venous access.

You may not qualify if:

• Positive HIV, HBsAg, or HCV serology.
• Positive sickle cell screening test, including evidence of sickle trait.
• Reactivity by CSP or AMA1 ELISpot assay or ELISA as determined by IMRAS Study Specific Procedure #204.
• Anemia (below normal reference laboratory value of hemoglobin) on screening.
• Weight less than 110 pounds (this does not apply to infectivity controls as it is a weight cut-off for subjects undergoing leukapheresis procedure)
• Any history of malaria infection or travel to a malaria endemic region within 6 months prior to first immunization.
• History of long-term residence (\> 5 years) in area known to have significant transmission of Pf \[cumulative lifetime exposure\].
• Use of systemic immunosuppressant pharmacotherapy for greater than 10 days within 60 days of scheduled first immunization (inhaled and topical steroids are allowed; short duration or tapered corticosteroid regimens of 10 days or less that have been discontinued prior to first immunization are allowed).
• Current significant medical condition (cardiovascular, hepatic, renal, pulmonary, or hematological) or evidence of any other serious underlying medical condition identified by medical history, physical examination, or laboratory examination (includes bleeding disorders).
• Plan for surgery between enrollment and day 28 post-challenge (minor procedures, elective corrective vision surgery, and dental procedures are allowed).
• Receipt of immunoglobulin and/or any blood products within 90 days of scheduled leukapheresis or immunization. Version 13.0 (08May2015) 70 US Government Proprietary Deleted: 8 Deleted: 08JULY2014
• Has evidence of increased cardiovascular disease risk (defined as \> 5%-10%, 5-year risk) as determined by the method of Gaziano (2008). Risk factors include sex, age (years), systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg/m2), reported diabetes status, and blood pressure.
• An abnormal electrocardiogram (ECG), defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block.
• History of a splenectomy.
• History of any other illness or condition that, in the investigator's judgment, may substantially increase the risk associated with the subject's participation in the protocol or compromise the scientific objectives. This may include psychiatric disorders (such as personality disorders, anxiety disorders, or schizophrenia) or behavioral tendencies (including active alcohol or drug abuse) discovered during the screening process that in the opinion of the investigator would make compliance with the protocol difficult.

Sponsors & Collaborators

• U.S. Army Medical Research and Development Command: lead
• Seattle Children's Hospital: collaborator
• Bill and Melinda Gates Foundation: collaborator

Study Sites (1)

Naval Medical Research Center Clinical Trials Center (CTC)

Bethesda, Maryland, 20889, United States

Location

Related Publications (4)

• Oyong DA, Duffy FJ, Neal ML, Du Y, Carnes J, Schwedhelm KV, Hertoghs N, Jun SH, Miller H, Aitchison JD, De Rosa SC, Newell EW, McElrath MJ, McDermott SM, Stuart KD. Distinct immune responses associated with vaccination status and protection outcomes after malaria challenge. PLoS Pathog. 2023 May 17;19(5):e1011051. doi: 10.1371/journal.ppat.1011051. eCollection 2023 May.

  PMID: 37195999 DERIVED

• Du Y, Hertoghs N, Duffy FJ, Carnes J, McDermott SM, Neal ML, Schwedhelm KV, McElrath MJ, De Rosa SC, Aitchison JD, Stuart KD. Systems analysis of immune responses to attenuated P. falciparum malaria sporozoite vaccination reveals excessive inflammatory signatures correlating with impaired immunity. PLoS Pathog. 2022 Feb 2;18(2):e1010282. doi: 10.1371/journal.ppat.1010282. eCollection 2022 Feb.

  PMID: 35108339 DERIVED

• Sedegah M, Hollingdale MR, Ganeshan H, Belmonte M, Huang J, Belmonte A, Inoue S, Velasco R, Hickey B, Teneza-Mora N, Lumsden J, Reyes S, Banania JG, Reyes A, Guzman I, Richie TL, Epstein JE, Villasante E. IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. PLoS One. 2021 Aug 20;16(8):e0256396. doi: 10.1371/journal.pone.0256396. eCollection 2021.

  PMID: 34415964 DERIVED

• Hickey B, Teneza-Mora N, Lumsden J, Reyes S, Sedegah M, Garver L, Hollingdale MR, Banania JG, Ganeshan H, Dowler M, Reyes A, Tamminga C, Singer A, Simmons A, Belmonte M, Belmonte A, Huang J, Inoue S, Velasco R, Abot S, Vasquez CS, Guzman I, Wong M, Twomey P, Wojnarski M, Moon J, Alcorta Y, Maiolatesi S, Spring M, Davidson S, Chaudhury S, Villasante E, Richie TL, Epstein JE. IMRAS-A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents. PLoS One. 2020 Jun 17;15(6):e0233840. doi: 10.1371/journal.pone.0233840. eCollection 2020.

  PMID: 32555601 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Human Challenge Trials as Topic

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Clinical Trials as Topic; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Nimfa Teneza-Mora, MD

  Naval Medical Research Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2013
• First Posted: November 25, 2013
• Study Start: January 24, 2014
• Primary Completion: December 20, 2016
• Study Completion: February 1, 2017
• Last Updated: September 17, 2019

Record last verified: 2019-03

Locations

US (1)