Safety and Preliminary Protective Efficacy of Genetically Attenuated GA2 Parasites.

NCT04577066 | Completed Phase 1 DMC

• 1 other identifier: GA2
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

This study will consist of two phases and be aimed at assessing the safety and tolerability of the new genetically attenuated GA2 malaria parasite (Phase 1) and its preliminary protective efficacy against controlled human malaria infection (Phase 2) in healthy Dutch volunteers.

Conditions

Plasmodium Falciparum Malaria

Keywords

Malaria; Plasmodium falciparum; Genetically attenuated parasites

Outcome Measures

Primary Outcomes (3)

• Number of volunteers with blood-stage parasitemia.

  The number of volunteers developing a breakthrough blood-stage infection after exposure to the GA2 parasite will be calculated as absolute numbers. Frequencies will be calculated by dividing the number of qPCR positive volunteers by the total number of volunteers in each group and multiplying the result by 100.

  From time of exposure to 28 days later.

• Number of volunteers protected against controlled human malaria infection immunisation with the GA2 parasite.

  The number of volunteers protected against CHMI in each group will be calculated as absolute numbers. Frequencies will be calculated by dividing the number of qPCR positive volunteers by the total number of volunteers in each group and multiplying the result by 100. The difference between the intervention group (receiving bites of GA2-infected mosquitoes) and control group (receiving bites of uninfected mosquitoes) will be calculated by means of the Chi square test.

  From first immunisation to 104 days later.

• Number and magnitude of adverse events in Phase 1 and Phase 2.

  The number of graded adverse events occurring in each group will be calculated as absolute numbers. Frequencies will be calculated by dividing the number of graded adverse events occurring in each group by the total number of volunteers in each group.

  From exposure to maximum 264 days later.

Secondary Outcomes (2)

• Humoral immune responses of volunteers exposed to the GA2 and GA1 parasite.

  From time of exposure to maximum 264 days later.

• Cellular immune response of volunteers exposed to the GA2 and GA1 parasite.

  From time of exposure to maximum 264 days later.

Study Arms (3)

Group 1 (GA2)

EXPERIMENTAL

Volunteers will be exposed to GA2-infected mosquito bites.

Other: GA2

Group 2 (GA1)

ACTIVE COMPARATOR

Volunteers will be exposed to the GA1-infected mosquito bites.

Other: GA1

Group 3 (Placebo)

PLACEBO COMPARATOR

Volunteers will be exposed to uninfected mosquito bites.

Other: Placebo

Interventions

GA2 OTHER

15 volunteers will receive 50 GA2-infected mosquito bites. The GA2 parasite is a new genetically attenuated Plasmodium falciparum parasite, which arrests development in the liver and should not be able to cause malaria in humans.

Group 1 (GA2)

GA1 OTHER

10 volunteers will receive 50 GA1-infected mosquito bites. The GA1 parasite is a genetically attenuated Plasmodium falciparum parasite, which arrests development in the liver and is not able to cause malaria in humans.

Group 2 (GA1)

Placebo OTHER

5 volunteers will receive 50 uninfected mosquito bites.

Group 3 (Placebo)

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject is aged ≥ 18 and ≤ 35 years and in good health.
• Subject has adequate understanding of the procedures of the study and agrees to abide strictly thereby.
• Subject is able to communicate well with the investigator, is available to attend all study visits.
• Furthermore, the subject will remain within the Netherlands from day -1 till day +28 after each parasite exposure. After CHMI, subjects have to be reachable by phone (24/7) from day -1 until day 35.
• Subject agrees to inform his/her general practitioner (GP) about participation in the study.
• Subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period and for a defined period thereafter according to Sanquin guidelines.
• Non-pregnant, non-lactating females of reproductive potential (i.e., have a uterus and are neither surgically sterilized nor post-menopausal) agree to use adequate contraception and to not breastfeed for the duration of study.
• Subject agrees to refrain from intensive physical exercise (disproportionate to the subjects' usual daily activity or exercise routine) for twenty-one days following each immunization and during the malaria challenge period.

You may not qualify if:

• Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine, malignant, hematological, infectious, immune-deficient, psychiatric or other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results. These include, but are not limited to, any of the following:
• a. Body weight \<50 kg or Body Mass Index (BMI) \<18.0 or \>30.0 kg/m2 at screening.
• b. A heightened risk of cardiovascular disease, defined as: An estimated ten-year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); i. An estimated ten-year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); ii. History, or evidence at screening, of clinically significant arrhythmia's, prolonged QT-interval or other clinically relevant ECG abnormalities; or iii. A positive family history of cardiac events in first or second degree relatives (according to the system used in medical genetics) \<50 years old.
• c. Functional asplenia, sickle cell trait/disease, thalassemia trait/disease or G6PD deficiency.
• d. History of epilepsy in the period of five years prior to study onset, even if no longer on medication.
• e. Positive HIV, HBV or HCV screening tests. f. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other drugs that might have an influence on the immune system (excluding inhaled and topical corticosteroids and incidental use of oral anti-histamines), within three months prior to study onset or expected use of such during the study period.
• g. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past five years.
• h. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year.
• i. History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset, positive urine toxicology test for cocaine, amphetamines or cannabis at screening.
• For female subjects: breastfeeding, or positive urine pregnancy test at screening or prior to immunization or prior to CHMI.
• Any history of malaria, positive serology for Pf, or previous participation in any malaria (vaccine) study or CHMI.
• Known hypersensitivity to or contra-indications (including co-medication) for use of atovaquone/proguanil or artemether/lumefantrine, or history of severe (allergic) reactions to MB.
• Receipt of any vaccinations in the three months prior to the start of the study or plans to receive any other vaccinations during the study period or up to eight weeks thereafter. Exceptions are made for influenza vaccination and for vaccination against the coronavirus SARS-COV2 or any other vaccination which cannot be reasonably withheld or postponed.
• Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.
• Being an employee or student of the department of Parasitology, Medical Microbiology or Infectious Diseases of the RadboudUMC or the LUMC.

Sponsors & Collaborators

• Leiden University Medical Center: lead

Study Sites (1)

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

Related Publications (4)

• Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Lancet. 2018 Apr 21;391(10130):1608-1621. doi: 10.1016/S0140-6736(18)30324-6. Epub 2018 Apr 6.

  PMID: 29631781 BACKGROUND

• Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, Doolan DL, Sacci J, de la Vega P, Dowler M, Paul C, Gordon DM, Stoute JA, Church LW, Sedegah M, Heppner DG, Ballou WR, Richie TL. Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J Infect Dis. 2002 Apr 15;185(8):1155-64. doi: 10.1086/339409. Epub 2002 Apr 1.

  PMID: 11930326 BACKGROUND

• Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, van de Vegte-Bolmer M, van Schaijk B, Teelen K, Arens T, Spaarman L, de Mast Q, Roeffen W, Snounou G, Renia L, van der Ven A, Hermsen CC, Sauerwein R. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009 Jul 30;361(5):468-77. doi: 10.1056/NEJMoa0805832.

  PMID: 19641203 BACKGROUND

• Lamers OAC, Franke-Fayard BMD, Koopman JPR, Roozen GVT, Janse JJ, Chevalley-Maurel SC, Geurten FJA, de Bes-Roeleveld HM, Iliopoulou E, Colstrup E, Wessels E, van Gemert GJ, van de Vegte-Bolmer M, Graumans W, Stoter TR, Mordmuller BG, Houlder EL, Bousema T, Murugan R, McCall MBB, Janse CJ, Roestenberg M. Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite. N Engl J Med. 2024 Nov 21;391(20):1913-1923. doi: 10.1056/NEJMoa2313892.

  PMID: 39565990 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum; Malaria

Condition Hierarchy (Ancestors)

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

Study Officials

• Meta Roestenberg, MD, PhD, Prof.

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Phase 1 will be an open label trial, Phase 2 will be a double-blind trial.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This trial has both a sequential as well as a parallel interventional study model. The safety and tolerability of the GA2 parasite will be assessed in phase 1 by means of a sequential study model. There will be 2 cohorts, which will be recruited sequentially and exposed to increasing numbers of infected mosquito bites. The preliminary protective efficacy of the GA2 parasite will be assessed in phase 2 by means of a parallel study model. There will be 3 groups of volunteers, who will be exposed to either GA2-infected, GA1-infected or uninfected mosquito bites.

Study Record Dates

• First Submitted: September 22, 2020
• First Posted: October 6, 2020
• Study Start: September 27, 2021
• Primary Completion: May 30, 2022
• Study Completion: December 22, 2022
• Last Updated: January 13, 2023

Record last verified: 2023-01

Locations

NL (1)