Safety and Protective Efficacy of Intravenous Immunization With Cryopreserved Plasmodium Falciparum Sporozoites Under Chemoprophylaxis

NCT02115516 | Completed Phase 1 DMC

• 2 other identifiers: TUCHMI-0022013-003900-38
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 1

Brief Summary

TÜCHMI-002 is a single center, randomized, placebo-controlled, double-blinded, PfSPZ Challenge dose finding trial with two chemoprophylactic regimens and subsequent controlled human malaria infection (CHMI).

Conditions

Malaria; Plasmodium Falciparum Malaria

Keywords

Malaria; Plasmodium falciparum malaria; Antimalarial chemoprophylaxis; PfSPZ Challenge; Cryopreserved Plasmodium Falciparum Sporozoites; PfSPZ-CVac

Outcome Measures

Primary Outcomes (2)

• Proportion of volunteers who become parasitemic, detected by thick blood film microscopy, within 21 days following CHMI after immunization using PfSPZ Challenge or placebo under chemoprophylaxis [PfSPZ Challenge Vaccine (PfSPZ-CVac) approach].

  Within 21 days following CHMI

• Occurrence of related Grade 3 adverse events (AEs) and SAEs from time of first administration of an immunizing regimen (chemoprophylactic antimalarial and PfSPZ Challenge) until the end of the study.

  19 months

Secondary Outcomes (2)

• Time to microscopically detectable parasitemia (pre-patent period) in volunteers who become parasitemic within 21 days following CHMI after immunization using PfSPZ Challenge or placebo and an antimalarial.

  Within 21 days following CHMI

• Occurrence of any related AE from time of first administration of an immunizing regimen (chemoprophylactic antimalarial and PfSPZ Challenge) until the end of the study.

  19 months

Other Outcomes (2)

• Proportion of participants who develop low-grade parasitemia, detected by quantitative polymerase chain reaction (qPCR), within 21 days following immunization with PfSPZ Challenge.

  Within 21 days following CHMI

• Occurrence of any (related and unrelated) AE from time of first administration of an antimalarial and PfSPZ Challenge until the end of the study.

  19 months

Study Arms (12)

Stage A: Grp A1 - 3,200 PfSPZ Challenge

EXPERIMENTAL

Group A1 (PfSPZ Challenge) (n=9) receives three injections of 3,200 PfSPZ Challenge intravenous (IV) at 4-week intervals. Immunizations are given under a standard chemoprophylactic regimen with chloroquine. Two days before the first PfSPZ Challenge injection volunteers receive one oral dose of 10 mg/kg CQ base. On Day 5 volunteers will receive 5 mg/kg CQ base. Subsequently, volunteers will receive 5 mg/kg CQ base in weekly intervals for a total of ten doses. Eight weeks after the last immunization, volunteers will undergo homologous CHMI with 3,200 PfSPZ Challenge IV. Early unblinding for this group may be done on Week 19, if required. All groups in Stage A are scheduled to be unblinded on Week 27.

Biological: PfSPZ Challenge

Stage A: Grp A2 - 12,800 PfSPZ Challenge

EXPERIMENTAL

Group A2 (PfSPZ Challenge) (n=9) starts when Group A1 receives the second immunization. Group A2 receives three injections of 12,800 PfSPZ Challenge IV at 4-week intervals. Immunizations are given under a standard chemoprophylactic regimen with chloroquine. Two days before the first PfSPZ Challenge injection volunteers receive one oral dose of 10 mg/kg CQ base. On Day 5 volunteers will receive 5 mg/kg CQ base. Subsequently, volunteers will receive 5 mg/kg CQ base in weekly intervals for a total of ten doses. Eight weeks after the last immunization, volunteers will undergo homologous CHMI with 3,200 PfSPZ Challenge IV. Early unblinding for this group may be done on Week 23, if required. All groups in Stage A are scheduled to be unblinded on Week 27.

Biological: PfSPZ Challenge

Stage A: Grp A3 - 51,200 PfSPZ Challenge

EXPERIMENTAL

Group A3 (PfSPZ Challenge) (n=9) starts when Group A2 receives the second immunization. Group A3 receives three injections of 51,200 PfSPZ Challenge IV at 4-week intervals. Immunizations are given under a standard chemoprophylactic regimen with chloroquine. Two days before the first PfSPZ Challenge injection volunteers receive one oral dose of 10 mg/kg CQ base. On Day 5 volunteers will receive 5 mg/kg CQ base. Subsequently, volunteers will receive 5 mg/kg CQ base in weekly intervals for a total of ten doses. Eight weeks after the last immunization, volunteers will undergo homologous CHMI with 3,200 PfSPZ Challenge IV. This group is scheduled to be unblinded with all other groups in Stage A Week on 27.

Biological: PfSPZ Challenge

Stage A: Grp A1 - 0.9% Sodium Chloride

PLACEBO COMPARATOR

Group A1 (placebo) (n=5) receives three injections of 0.9% Sodium chloride IV at 4 week intervals. Placebo injections are given under a standard chemoprophylactic regimen with chloroquine. Two days before the first placebo injection volunteers receive one oral dose of 10 mg/kg CQ base. On Day 5 volunteers will receive 5 mg/kg CQ base. Subsequently, volunteers will receive 5 mg/kg CQ base in weekly intervals for a total of ten doses. Eight weeks after the last placebo injection, volunteers will undergo homologous CHMI with 3,200 PfSPZ Challenge IV. Early unblinding for this group may be done on Week 19, if required. All groups in Stage A are scheduled to be unblinded on Week 27.

Biological: 0.9% Sodium Chloride (Placebo)

Stage A: Grp A2 - 0.9% Sodium Chloride

PLACEBO COMPARATOR

Group A2 (placebo) (n=5) starts when Group A1 receives the second immunization. Group A2 receives three injections of 0.9% Sodium chloride IV at 4 week intervals. Placebo injections are given under a standard chemoprophylactic regimen with chloroquine. Two days before the first placebo injection volunteers receive one oral dose of 10 mg/kg CQ base. On Day 5 volunteers will receive 5 mg/kg CQ base. Subsequently, volunteers will receive 5 mg/kg CQ base in weekly intervals for a total of ten doses. Eight weeks after the last placebo injection, volunteers will undergo homologous CHMI with 3,200 PfSPZ Challenge IV. Early unblinding for this group may be done on Week 23, if required. All groups in Stage A are scheduled to be unblinded on Week 27.

Biological: 0.9% Sodium Chloride (Placebo)

Stage A: Grp A3 - 0.9% Sodium Chloride

PLACEBO COMPARATOR

Group A3 (placebo) (n=5) starts when Group A2 receives the second immunization. Group A3 receives three injections of 0.9% Sodium chloride IV at 4 week intervals. Placebo injections are given under a standard chemoprophylactic regimen with chloroquine. Two days before the first placebo injection volunteers receive one oral dose of 10 mg/kg CQ base. On Day 5 volunteers will receive 5 mg/kg CQ base. Subsequently, volunteers will receive 5 mg/kg CQ base in weekly intervals for a total of ten doses. Eight weeks after the last placebo injection, volunteers will undergo homologous CHMI with 3,200 PfSPZ Challenge IV. This group is scheduled to be unblinded with all other groups in Stage A on Week 27.

Biological: 0.9% Sodium Chloride (Placebo)

Stage B: Grp B1 - 51,200 PfSPZ Challenge

EXPERIMENTAL

Group B1 (n=5) will receive the optimal PfSPZ Challenge immunizing dose from the dose-escalation phase (Stage A; 51,200 PfSPZ Challenge (NF54)), using the same standard chemoprophylactic regimen with CQ (10 mg/kg CQ base loading dose, followed by weekly dosing with 5 mg/kg CQ base), but for five instead of ten weeks. Group B1 will receive 3 injections of 51,200 PfSPZ Challenge (NF54) on days 0, 14 and 28. All volunteers in Group B1 will undergo homologous CHMI with PfSPZ Challenge 10 weeks after the last immunization.

Biological: PfSPZ Challenge

Stage B: Group B1 - 0.9% Sodium Chloride

PLACEBO COMPARATOR

Group B1 (placebo) (n=2) will receive three injections of 0.9% Sodium Chloride on days 0, 14 and 28. This group will follow the the same standard chemoprophylactic regimen with CQ (10 mg/kg CQ base loading dose, followed by weekly dosing with 5 mg/kg CQ base), but for five instead of ten weeks. All volunteers in Group B1 will undergo homologous CHMI with PfSPZ Challenge 10 weeks after the last immunization.

Biological: 0.9% Sodium Chloride (Placebo)

Stage B: Grp B2 - 51,200 PfSPZ Challenge

EXPERIMENTAL

Group B2 (n=5) will receive 3 injections of 51,200 PfSPZ Challenge on days 0, 14 and 28, using same std chemoprophylactic regimen with CQ (10 mg/kg CQ base loading dose, followed by weekly dosing with 5 mg/kg CQ base), for 5 instead of 10 wks. But Group B2 will receive extended-release azithromycin (ER-AZ, 2g) on the day of 1st PfSPZ Challenge and monitored for parasitemia by quantitative real time polymerase reaction (qPCR). In case that all CQ+ER-AZ treated volunteers are parasite-free until Day 11 following first PfSPZ Challenge injection, it will indicate that ER-AZ effectively killed the parasites in the liver prior to development of parasitemia. With demonstration of the effectiveness of ER-AZ, the 2nd and 3rd immunizations will be done under ER-AZ alone, otherwise CQ prophylaxis will continue and ER-AZ will not be administered for the 2nd and 3rd injections. Group B2 will undergo homologous CHMI with PfSPZ Challenge, 10 weeks after the last immunization.

Biological: PfSPZ Challenge

Stage B: Group B2 - 0.9% Sodium Chloride

PLACEBO COMPARATOR

Group B2 (placebo) (n=2) will receive three injections of 0.9% Sodium Chloride on days 0, 14 and 28, using the same standard chemoprophylactic regimen with CQ (10 mg/kg CQ base loading dose, followed by weekly dosing with 5 mg/kg CQ base), for 5 instead of 10 wks. But Group B2 will receive ER-AZ, 2g on the day of 1st placebo injection and monitored for parasitemia by qPCR. In case that all CQ+ER-AZ treated volunteers are parasite-free until Day 11 following 1st injection, it will indicate that ER-AZ effectively killed the parasites in the liver prior to the development of parasitemia. With demonstration of the effectiveness of ER-AZ, the 2nd and 3rd immunizations will be done under ER-AZ alone, otherwise CQ prophylaxis will be continued and ER-AZ will not be administered for 2nd and 3rd injections. Group B2 will undergo homologous CHMI with PfSPZ Challenge 10 weeks after last immunization.

Biological: 0.9% Sodium Chloride (Placebo)

Stage B: Grp B3 - 51,200 PfSPZ Challenge

EXPERIMENTAL

Group B3 (n=9) volunteers will receive CQ and PfSPZ Challenge simultaneously every five days with one additional dose of CQ five days after the third PfSPZ Challenge injection. A 10 mg/kg CQ base loading dose is given at the time of first PfSPZ Challenge inoculation, followed by 5 mg/kg CQ base on the day of second and third inoculation and five days after the last PfSPZ Challenge inoculation. Group B3 will undergo homologous CHMI with PfSPZ Challenge 10 weeks after the last immunization.

Biological: PfSPZ Challenge

Stage B: Group B3 - 0.9% Sodium Chloride

PLACEBO COMPARATOR

Group B3 (placebo) (n=2) volunteers will receive CQ and 0.9% Sodium Chloride simultaneously every five days with one additional dose of CQ five days after the third placebo injection. A 10 mg/kg CQ base loading dose is given at the time of first placebo injection, followed by 5 mg/kg CQ base on the day of second and third injections and five days after the last placebo injection. Group B3 will undergo homologous CHMI with PfSPZ Challenge 10 weeks after the last immunization.

Biological: 0.9% Sodium Chloride (Placebo)

Interventions

PfSPZ Challenge BIOLOGICAL

Aseptic, purified, vialed, cryopreserved, infectious P. falciparum sporozoites, strain NF54

Stage A: Grp A1 - 3,200 PfSPZ Challenge; Stage A: Grp A2 - 12,800 PfSPZ Challenge; Stage A: Grp A3 - 51,200 PfSPZ Challenge; Stage B: Grp B1 - 51,200 PfSPZ Challenge; Stage B: Grp B2 - 51,200 PfSPZ Challenge; Stage B: Grp B3 - 51,200 PfSPZ Challenge

0.9% Sodium Chloride (Placebo) BIOLOGICAL

Stage A: Grp A1 - 0.9% Sodium Chloride; Stage A: Grp A2 - 0.9% Sodium Chloride; Stage A: Grp A3 - 0.9% Sodium Chloride; Stage B: Group B1 - 0.9% Sodium Chloride; Stage B: Group B2 - 0.9% Sodium Chloride; Stage B: Group B3 - 0.9% Sodium Chloride

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• The volunteer must satisfy all the following criteria to be eligible for the study:
• Healthy adults aged 18 to 45 years.
• Able and willing (in the Investigator's opinion) to comply with all study requirements.
• Willing to allow the investigators to discuss the volunteer's medical history with their general practitioner ('Hausarzt') if required.
• Residence in Tübingen or surroundings for the period of the trial.
• Women only: Must agree to practice continuous effective contraception for the duration of the study (a method which results in a low failure rate; i.e. less than 1% per year).
• Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local and national blood banking eligibility criteria (currently four years in Germany).
• Written informed consent to receive PfSPZ Challenge for immunization and subsequently for CHMI.
• Reachable (24/7) by mobile phone during the immunization and CHMI period.
• Willingness to take CQ and ER-AZ during immunization and a curative antimalarial regimen following CHMI.
• Agreement to stay overnight for observation during the period of intensive follow-up post-challenge if required.
• Answer all questions on the informed consent quiz correctly.
• A body mass index \<35.
• A hemoglobin concentration ≥12 g/dl for women and ≥13.5 g/dl for men.

You may not qualify if:

• The volunteer may not enter the study if any of the following apply:
• History of Pf malaria.
• Planned travel to malaria endemic areas.
• Use of systemic antibiotics with known antimalarial activity within 30 days of study enrollment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin).
• Receipt of an investigational product in the 30 days preceding enrollment, or planned receipt during the study period.
• Prior receipt of an investigational malaria vaccine.
• Immunization with more than 3 other vaccines within the past month.
• HIV infection.
• Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed).
• Use of immunoglobulins or blood products within 3 months prior to enrolment.
• Presence of sickle cell anemia, sickle cell trait, thalassemia or thalassemia trait, glucose-6-phosphate dehydrogenase deficiency.
• Pregnancy, lactation or intention to become pregnant during the study.
• A history of allergic disease or reactions likely to be exacerbated by malaria.
• Contraindications to the use of the following antimalarial medications: atovaquone/proguanil, artemether-lumefantrine, mefloquine, azithromycin and chloroquine.
• History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ).

Sponsors & Collaborators

• Sanaria Inc.: lead
• Institute of Tropical Medicine, University of Tuebingen: collaborator
• German Federal Ministry of Education and Research: collaborator

Study Sites (1)

Institute of Tropical Medicine, University of Tuebingen, Wilhelmstr. 27

Tübingen, D-72074, Germany

Location

Related Publications (2)

• Mordmuller B, Surat G, Lagler H, Chakravarty S, Ishizuka AS, Lalremruata A, Gmeiner M, Campo JJ, Esen M, Ruben AJ, Held J, Calle CL, Mengue JB, Gebru T, Ibanez J, Sulyok M, James ER, Billingsley PF, Natasha KC, Manoj A, Murshedkar T, Gunasekera A, Eappen AG, Li T, Stafford RE, Li M, Felgner PL, Seder RA, Richie TL, Sim BK, Hoffman SL, Kremsner PG. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature. 2017 Feb 23;542(7642):445-449. doi: 10.1038/nature21060. Epub 2017 Feb 15.

  PMID: 28199305 RESULT

• Requena P, Gomez-Perez GP, McCall MBB, Barrios D, Aguilar R, Fernandez-Morata J, Vidal M, Campo JJ, Sanchez C, Yazdabankhsh M, Sim BKL, Hoffman SL, Kremsner P, Lell B, Mordmuller B, Dobano C, Moncunill G. Effect of controlled human Plasmodium falciparum infection on B cell subsets in individuals with different levels of malaria immunity. Med Microbiol Immunol. 2025 Sep 27;214(1):47. doi: 10.1007/s00430-025-00847-x.

  PMID: 41014333 DERIVED

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Benjamin Mordmüller, MD

  Institute of Tropical Medicine, University of Tuebingen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2014
• First Posted: April 16, 2014
• Study Start: April 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: April 1, 2016
• Last Updated: May 15, 2017

Record last verified: 2016-02

Locations

DE (1)