Malaria, VivaxPhase 2NCT04739917
Efficacy of a Synthetic Vaccine Derived From Plasmodium Vivax Circumsporozoite Protein (PvCS) in naïve and Semi-immune Volunteers
A Phase 2 study testing Vaccine PvCS N+C+R 150 mcg in people with Malaria, Vivax, run by Malaria Vaccine and Drug Development Center at 1 site in Colombia.
Trial summary
This is a randomized, double-blind, controlled, which seeks to compare two groups of volunteers (naive and previously exposed to malaria) vaccinated with three doses of a synthetic derivative of the CS protein of Plasmodium vivax to determine their protective efficacy. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Malaria, Vivax
- What is being tested?
- Vaccine PvCS N+C+R 150 mcg
- Type of treatment
- Vaccines
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 120 participants
- Where
- 1 siteColombia
- Study dates
- 1 Jun 2021to 1 Dec 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Naïve group:
- Non-pregnant, healthy men and women between 18-45 years old.
- Freely and voluntarily sign an IC, accompanied by two witnesses who must also sign.
- Absence history of malaria infection.
- To have negative serology for the PvCS protein by the ELISA test.
- For women, not be pregnant.
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- Use of an adequate contraceptive method from the beginning until the contraceptive restriction is lifted by a study doctor, at the end of the study.
- To accept not to travel to areas considered as endemic for malaria from the infectious challenge period and to the end of its follow-up (1 month).
- Be reachable by phone throughout the study period.
- To be Duffy positive (Fy +).
- Have Hemoglobin (Hb) levels> 11 g / dl.
- Be willing to participate during the period in which the study will take place.
- Not be participating in another clinical study.
- Be affiliated with the general health social security system of Colombia, in any of its regimes (subsidized or contributory)
- Semi-immune group:
- Non-pregnant, healthy men and women between 18-45 years old,
- Freely and voluntarily sign an informed consent, accompanied by two witnesses who will also sign.
- Have a history of malaria infection (s) and positive serological tests (ELISA) for P. vivax.
- For women, not be pregnant or nursing.
- For women, use of adequate contraception from inception until the contraceptive restriction is lifted by a study physician.
- Be a permanent resident of the municipality of Quibdó during the study.
- Be reachable by phone throughout the study period.
- Availability to participate during the period in which the study will take place.
- Be affiliated with the general health social security system of Colombia, in any of its regimes (subsidized or contributory)
Who cannot join
- Naïve group:
- Glucose 6 phosphate dehydrogenase deficiency (G-6-P-D).
- Present any hemoglobinopathy (eg HbS).
- Personal history of allergies to medications or insect bites.
- Have received vaccination against malaria.
- Clinical or laboratory abnormalities determined by the investigator (s).
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- IFAT> 1:20 for P. vivax in screening tests.
- Have lived in a malaria-endemic region during the 12 months before the study.
- Clinical or laboratory evidence of systemic disease, including kidney, liver, cardiovascular, pulmonary, psychiatric, or other diseases that may negatively impact and alter study results.
- Evidence of active hepatitis B or Hepatitis C infection
- Evidence of active HIV infection.
- History of transfusion of any blood product in the 6 (six) months before the study.
- Plan to have surgery from the recruitment period to the end of the post-challenge follow-ups.
- Presence or history of autoimmune disease (lupus, rheumatoid arthritis, thyroiditis, or other).
- Splenectomized volunteers.
- Volunteers in treatment with drugs with activity on the immune system (steroids, immunosuppressive agents, or immunomodulators).
- History of alcoholism or drug abuse defined as a habit that interferes with the normal social functioning of the individual.
- Any condition that may interfere with the ability to provide a free and voluntary IC.
- Not being affiliated with the general health social security system of Colombia, in any of its regimes (subsidized or contributory)
- Semi-immune group:
- IFAT negative (<1:20) for P. vivax in screening tests.
- The other criteria used in the case of naïve volunteers, except the antecedent of having lived in the endemic area.
Trial locations and contacts
1 site in 1 country.
Colombia1 site
Malaria Vaccine and Drug Development Center
Cali, Valle del Cauca Department
Sócrates Herrera, MD, sherrera@inmuno.org
About this study
Official title: Safety and Protective Efficacy of a Synthetic Vaccine Derived From the CS Protein of Plasmodium Vivax: a Double-blind, Placebo-controlled, Randomized Clinical Trial in naïve and Pre-immune Colombian Volunteers
This is a randomized, double-blind, controlled, which seeks to compare two groups of volunteers (naive and previously exposed to malaria) vaccinated with three doses of a synthetic derivative of the CS protein of Plasmodium vivax to determine their protective efficacy.
Then volunteers will be subject to an infectious challenge (Controlled Human Malaria Infection) to assess the infectivity of gametocytes in the blood early stage of P. vivax in Anopheles albimanus mosquitoes.
Read the detailed description
This study is a prospective controlled, blinded clinical trial, designed to establish the protective efficacy induced by the vaccine PvCSP between human volunteers with and without history of malaria. Volunteers will be recruited in Cali, Colombia and Quibdó, Colombia.
Study subjects: This study will require the involvement of two types of volunteers, parasite donors and volunteers for immunization
Parasite donors: 5-15 P. vivax-infected patients who will serve as parasites donors for experimental infection of mosquitoes, who will be enrolled in the endemic area.
Volunteers for immunization: Two other groups of volunteers will be immunized with the PvCSP vaccine. A group of 60 people without previous exposure to malaria (naïve) and another 60 people with a history of previous malaria infection (pre-immune).
Methodology Recruitment of infected patients: Parasite donors will be recruited among P. vivax infected patients attending a diagnostic center in the endemic area.
Infection of mosquito's blood from donors will be used to feed three-day-old mosquitoes by artificial membrane feeding technique. At day 7, a sample of mosquitoes will be examined to determine the level of infection by dissection of the mosquito's gut. On day 14, a small number of mosquitoes with a good degree of infectivity will be used to infect challenged volunteers.
Recruitment of pre-immune and naive volunteers: Volunteers for the immunization stage will be recruited both in the city of Cali (Colombia), non-endemic region, and in Quibdó (Colombia), a malaria endemic region, through various activities such as conferences, meetings and other strategies previously approved by the IRB, like posters, radio advertising flyers and social media.
Immunization: Volunteers will be immunized with the vaccine (n=60) or placebo (n=60).
Follow-up of volunteers will be performed under medical vigilance during the first hour following the immunization to detect any adverse reaction. After the first hour period a medical exam will be made. Eight hours after immunization, each volunteer will be contacted via telephone to assess physical condition. Any adverse event (AE) will be registered.
Subsequent follow up will be made on the day next to immunization and 1 or 2 weeks before the next immunization by a new clinical evaluation and AE report. Volunteers will be instructed to contact the research staff at any moment.
Infection of volunteers immunized volunteers will be challenged on day ~150 of the study, 1 month after the third immunization by the bite of 2-4 infected mosquito. A "feeding cage" will be placed on the forearm of a volunteer for 10 minutes, allowing that the feeding window, which will be covered by a mesh surface be placed against the volunteer's skin.
Volunteers will be instructed about the signs and symptoms of malaria and they will have a daily telephone contact during the first 6 days.
Between days 7 and 23 the volunteers will be asked to go to the Clinical Trials Unit daily to establish the presence or absence of disease through thick blood smear and samples will be collected for retrospective real time PCR P. vivax.
From day 23 until day 31, volunteers will receive physical and laboratory evaluation every other day and will have daily telephone contact.
Once the patients present signs and symptoms of the disease curative treatment will be immediately provided, and 15 ml of blood will be drawn, which will be used for immune response assessment.
If the volunteers do not develop the disease during the follow-up period, on day 31 they will be given antimalarial treatment.
Treatment Volunteers will be treated with antimalarial drugs approved by the Colombian Ministry of Social Health: chloroquine (three (3) doses: 600 mg initially, followed by 450 mg at 24, and 48 hours), associated with primaquine (30mg/day) for 14 days. All the volunteers will be asked to return two weeks after starting treatment for a thick blood smear test to ensure cure of malaria.
- Conditions
- Malaria, Vivax
- Being tested
- Vaccine PvCS N+C+R 150 mcg, Placebo SSN Montanide ISA-51 1 mL
- Keywords
- Malaria, Vaccine, Vivax
- Medical subject headings
- Malaria, Vivax, Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vaccine PvCS N+C+R 150 mcgBiological
Vaccine PvCS N+C+R 150 mcg (Montanide ISA-51), freeze dried powder.
Placebo SSN Montanide ISA-51 1 mLOther
SSN Montanide ISA-51 1 mL
| Study group | Role | What they receive |
|---|---|---|
| Arm N Vaccine | Experimental | 30 malaria-naïve subjects from non-endemic areas of Cali, Colombia. Receives: Biological: Vaccine PvCS N+C+R 150 mcg |
| Arm N Placebo | Placebo comparator | 30 malaria-naïve subjects from non-endemic areas of Cali, Colombia. Receives: Other: Placebo SSN Montanide ISA-51 1 mL |
| Arm S Vaccine | Experimental | 30 semi-immune subjects from malaria endemic areas of Chocó, Colombia. Receives: Biological: Vaccine PvCS N+C+R 150 mcg |
| Arm S Placebo | Placebo comparator | 30 semi-immune subjects from malaria endemic areas of Chocó, Colombia. Receives: Other: Placebo SSN Montanide ISA-51 1 mL |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of first case of P. vivax malaria after CHMI and meeting the primary case definition.
The first case of malaria meeting the primary case definition will be defined as the first or only episodes with the presence of Plasmodium vivax parasitemia ≥ 0.1% by thick blood smear and malaria qPCR.
Measured: Assessed over average of 16-18 days post CHMI (range 7 to 60 days)
Secondary outcomes (28)
Concentration of specific anti-PvCS IgG antibodies IgG (isotypes) against the different functional fragments of the Pv-CS protein.
Concentration of specific anti-PvCS IgG antibodies IgG (isotypes) against the different functional fragments of the Pv-CS protein (Amino, Central Repeat and Carboxilo terminal). Expressed both as antibody titers and Reactive Indices (RI) measured by in enzyme-linked immunosorbent assay (ELISA) and Immunofluorescence Test (IFAT). Antibody titers by IFAT are determine as the reciprocal of the end-points dilution showing a positive fluorescence.
Concentrations will be presented as geometric mean concentrations (GMCs).
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Specific cytokine induction
Specific cytokine induction will be measured by IFN- γ, TNF-α, IL-2; IL- 4, IL-6, IL-10
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - Flow cytometry
In vitro proliferation of CD3+ T-cells (CD4+ and CD8+) and intracellular production of cytokines IFN-gamma, TNF-a, IL-12 by flow cytometry. Result will be expressed as percentages.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - ELIspot
Production of IFN-gamma and IL-10 in total PBMC stimulated with the different antigens and / or synthetic peptides by ELIspot assay. Results expressed as the mean number of IFN-γ spot-forming cells (sfc) per 106 Peripheral Blood Mononuclear Cells.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - Bioplex
Multiplex cytokines profile (Th1/Th2/Treg) in sera by bioplex. Cytokine concentrations were calculated from the standard curve using seven-parameter curve fitting software and the results were expressed in pg/mL. The limit of detection for the assay was 10 pg/mL for all cytokines. Results will be expressed as percentages.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Characterization of T lymphocytes
Phenotyping and profiles of memory T lymphocytes will be done in PBMCs using specific panels of markers by flow cytometry. The frequency of cells as a biomarker post CHMI infection will be performed. Cells will be stained by using different antibody cocktails targeting specific cell populations. Cells acquisition will be done on a 4-laser BD flow cytometer and gating analysis with FlowJo software version 10.4.2. Results will be expressed as percentages.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Characterization of B lymphocytes.
Phenotyping and profiles of B lymphocytes will be done in PBMCs using specific panels of markers by flow cytometry. The frequency of cells as a biomarker post CHMI infection will be performed. Cells will be stained by using different antibody cocktails targeting specific cell populations. Cells acquisition will be done on a 4-laser BD flow cytometer and gating analysis with FlowJo software version 10.4.2. Results will be expressed as percentages.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240
Characterization of monocytes
Phenotyping and profiles of monocytes will be done in PBMCs using specific panels of markers by flow cytometry. The frequency of cells as a biomarker post CHMI infection will be performed. Cells will be stained by using different antibody cocktails targeting specific cell populations. Cells acquisition will be done on a 4-laser BD flow cytometer and gating analysis with FlowJo software version 10.4.2. Results will be expressed as percentages.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Antibody functionality in vitro through inhibition of sporozoite invasion (ISI) to Hep-G2 cells.
Antibody functionality will be tested in vitro through essays of inhibition of sporozoite invasion (ISI) to Hep-G2 cells.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Vaccine-induced protection for P. vivax
Vaccine-induced protection for P. vivax will be assessed by pre-patent period onset after infected mosquito bites exposure
Measured: Thirty days after mosquito bite challenge (Controlled Human Malaria Infection)
Multiomics testing (i.e., transcriptomics, genomics)
Tthe present study also seeks to evaluate host-related variables, especially those affected by the immune status prior to vaccination (naïve vs pre-immune participants).
To accomplish this, transcriptomics and genomics tests will be undertaken on days 0, 30, 195 and, 225.
Measured: Days 0, 30, 90, 195 and 225.
Safety - Number of Subjects With Any and Grade 3 Solicited Local Symptoms
Assessed solicited local symptoms will be pain and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 swelling = swelling spreading beyond 20 millimeters (mm) of injection site.
Measured: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Safety - Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms
Assessed solicited general symptoms will be drowsiness, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], irritability and loss of appetite.
Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity.
Grade 3 fever = fever higher than (>) 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.
Measured: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Safety - Number of Subjects With Any Unsolicited Adverse Events (AEs)
An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
Any will be defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.
Measured: Within the 30-day (Days 0-29) post-vaccination follow-up period
Safety - Number of Subjects With Serious Adverse Events (SAEs)
Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
Measured: Throughout the study period (Day 0 - Month 14)
Safety - Number of Subjects With Hemoglobin Values Outside Normal Ranges With Toxicity Grades
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With White Blood Cell (WBC) Values Outside Normal Ranges With Toxicity Grades
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Platelet Values Outside Normal Ranges With Toxicity Grades
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Alanine Aminotransferase (ALT) Values Outside Normal Ranges With Toxicity Grades
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Creatinine Values Outside Normal Ranges With Toxicity Grades
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Bilirubin Values Outside Normal Ranges With Toxicity Grades
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Alkaline phosphatase Values Outside Normal Ranges With Toxicity
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Blood urea nitrogen (BUN) Values Outside Normal Ranges With Toxicity
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Aspartate aminotransferase (AST) Values Outside Normal Ranges With Toxicity
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Prothrombin time (PT)) Values Outside Normal Ranges With Toxicity
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Partial thromboplastin time (PTT) Values Outside Normal Ranges With Toxicity
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of participants with confirmed pregnancy
Number of participants with confirmed pregnancy during the study duration.
Measured: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency test will be done during baseline evaluation.
Measured: Day 0.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2021
- Study start1 Jun 2021 (estimated)
- Primary completion1 Jun 2022 (estimated)
- Study completion1 Dec 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Malaria, VivaxStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Malaria Vaccine and Drug Development Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Sócrates Herrera, MD, Principal investigator, Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04739917
- Sponsor's protocol ID
- MVDC-2021-001
- Status last verified
- Feb 2021
- First submitted
- 25 Jan 2021
- Last updated
- 1 Mar 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Ademolue TW, Awandare GA. Evaluating antidisease immunity to malaria and implications for vaccine design. Immunology. 2018 Apr;153(4):423-434. doi: 10.1111/imm.12877. Epub 2017 Dec 26.
PubMed 29211303RTS,S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 2014 Jul 29;11(7):e1001685. doi: 10.1371/journal.pmed.1001685. eCollection 2014 Jul.
PubMed 25072396Aliprandini E, Tavares J, Panatieri RH, Thiberge S, Yamamoto MM, Silvie O, Ishino T, Yuda M, Dartevelle S, Traincard F, Boscardin SB, Amino R. Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin. Nat Microbiol. 2018 Nov;3(11):1224-1233. doi: 10.1038/s41564-018-0254-z. Epub 2018 Oct 22.
PubMed 30349082Arevalo-Herrera M, Herrera S. Plasmodium vivax malaria vaccine development. Mol Immunol. 2001 Dec;38(6):443-55. doi: 10.1016/s0161-5890(01)00080-3.
PubMed 11741694Arevalo-Herrera M, Roggero MA, Gonzalez JM, Vergara J, Corradin G, Lopez JA, Herrera S. Mapping and comparison of the B-cell epitopes recognized on the Plasmodium vivax circumsporozoite protein by immune Colombians and immunized Aotus monkeys. Ann Trop Med Parasitol. 1998 Jul;92(5):539-51.
PubMed 9797827Arevalo-Herrera M, Soto L, Perlaza BL, Cespedes N, Vera O, Lenis AM, Bonelo A, Corradin G, Herrera S. Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein. Am J Trop Med Hyg. 2011 Feb;84(2 Suppl):35-42. doi: 10.4269/ajtmh.2011.09-0507.
PubMed 21292876Arevalo-Herrera M, Chitnis C, Herrera S. Current status of Plasmodium vivax vaccine. Hum Vaccin. 2010 Jan;6(1):124-32. doi: 10.4161/hv.6.1.9931. Epub 2010 Jan 26.
PubMed 20009526Arnot DE, Stewart MJ, Barnwell JW. Antigenic diversity in Thai Plasmodium vivax circumsporozoite proteins. Mol Biochem Parasitol. 1990 Nov;43(1):147-9. doi: 10.1016/0166-6851(90)90140-h. No abstract available.
PubMed 2290443Arnot DE, Barnwell JW, Tam JP, Nussenzweig V, Nussenzweig RS, Enea V. Circumsporozoite protein of Plasmodium vivax: gene cloning and characterization of the immunodominant epitope. Science. 1985 Nov 15;230(4727):815-8. doi: 10.1126/science.2414847.
PubMed 2414847Barnwell JW, Galinski MR. Plasmodium vivax: a glimpse into the unique and shared biology of the merozoite. Ann Trop Med Parasitol. 1995 Apr;89(2):113-20. doi: 10.1080/00034983.1995.11812941.
PubMed 7605120Barnwell JW, Galinski MR, DeSimone SG, Perler F, Ingravallo P. Plasmodium vivax, P. cynomolgi, and P. knowlesi: identification of homologue proteins associated with the surface of merozoites. Exp Parasitol. 1999 Mar;91(3):238-49. doi: 10.1006/expr.1998.4372.
PubMed 10072326Bermudez M, Moreno-Perez DA, Arevalo-Pinzon G, Curtidor H, Patarroyo MA. Plasmodium vivax in vitro continuous culture: the spoke in the wheel. Malar J. 2018 Aug 20;17(1):301. doi: 10.1186/s12936-018-2456-5.
PubMed 30126427Burkot TR, Wirtz RA, Paru R, Garner P, Alpers MP. The population dynamics in mosquitoes and humans of two Plasmodium vivax polymorphs distinguished by different circumsporozoite protein repeat regions. Am J Trop Med Hyg. 1992 Dec;47(6):778-86. doi: 10.4269/ajtmh.1992.47.778.
PubMed 1471735Cattani JA, Tulloch JL, Vrbova H, Jolley D, Gibson FD, Moir JS, Heywood PF, Alpers MP, Stevenson A, Clancy R. The epidemiology of malaria in a population surrounding Madang, Papua New Guinea. Am J Trop Med Hyg. 1986 Jan;35(1):3-15. doi: 10.4269/ajtmh.1986.35.3.
PubMed 3511748Cerami C, Frevert U, Sinnis P, Takacs B, Clavijo P, Santos MJ, Nussenzweig V. The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of Plasmodium falciparum sporozoites. Cell. 1992 Sep 18;70(6):1021-33. doi: 10.1016/0092-8674(92)90251-7.
PubMed 1326407
Study at a glance
From the registry record, last updated by the sponsor on 1 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety and Protective Efficacy of a Synthetic Vaccine Derived From the CS Protein of Plasmodium Vivax: a Double-blind, Placebo-controlled, Randomized Clinical Trial in naïve and Pre-immune Colombian Volunteers
- ClinicalTrials.gov ID
- NCT04739917
- Acronym / sponsor ID
- MVDC-2021-001
- Conditions
- Malaria, Vivax
- Keywords
- Malaria, Vaccine, Vivax
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 120 participants (estimated)
- Lead sponsor
- Malaria Vaccine and Drug Development CenterUniversity, hospital or other
- Study start
- 1 Jun 2021 (estimated)
- Primary completion
- 1 Jun 2022 (estimated)
- Study completion
- 1 Dec 2022 (estimated)
- First posted
- 5 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a randomized, double-blind, controlled, which seeks to compare two groups of volunteers (naive and previously exposed to malaria) vaccinated with three doses of a synthetic derivative of the CS protein of Plasmodium vivax to determine their protective efficacy.
Then volunteers will be subject to an infectious challenge (Controlled Human Malaria Infection) to assess the infectivity of gametocytes in the blood early stage of P. vivax in Anopheles albimanus mosquitoes.
Detailed description
This study is a prospective controlled, blinded clinical trial, designed to establish the protective efficacy induced by the vaccine PvCSP between human volunteers with and without history of malaria. Volunteers will be recruited in Cali, Colombia and Quibdó, Colombia.
Study subjects: This study will require the involvement of two types of volunteers, parasite donors and volunteers for immunization
Parasite donors: 5-15 P. vivax-infected patients who will serve as parasites donors for experimental infection of mosquitoes, who will be enrolled in the endemic area.
Volunteers for immunization: Two other groups of volunteers will be immunized with the PvCSP vaccine. A group of 60 people without previous exposure to malaria (naïve) and another 60 people with a history of previous malaria infection (pre-immune).
Methodology Recruitment of infected patients: Parasite donors will be recruited among P. vivax infected patients attending a diagnostic center in the endemic area.
Infection of mosquito's blood from donors will be used to feed three-day-old mosquitoes by artificial membrane feeding technique. At day 7, a sample of mosquitoes will be examined to determine the level of infection by dissection of the mosquito's gut. On day 14, a small number of mosquitoes with a good degree of infectivity will be used to infect challenged volunteers.
Recruitment of pre-immune and naive volunteers: Volunteers for the immunization stage will be recruited both in the city of Cali (Colombia), non-endemic region, and in Quibdó (Colombia), a malaria endemic region, through various activities such as conferences, meetings and other strategies previously approved by the IRB, like posters, radio advertising flyers and social media.
Immunization: Volunteers will be immunized with the vaccine (n=60) or placebo (n=60).
Follow-up of volunteers will be performed under medical vigilance during the first hour following the immunization to detect any adverse reaction. After the first hour period a medical exam will be made. Eight hours after immunization, each volunteer will be contacted via telephone to assess physical condition. Any adverse event (AE) will be registered.
Subsequent follow up will be made on the day next to immunization and 1 or 2 weeks before the next immunization by a new clinical evaluation and AE report. Volunteers will be instructed to contact the research staff at any moment.
Infection of volunteers immunized volunteers will be challenged on day ~150 of the study, 1 month after the third immunization by the bite of 2-4 infected mosquito. A "feeding cage" will be placed on the forearm of a volunteer for 10 minutes, allowing that the feeding window, which will be covered by a mesh surface be placed against the volunteer's skin.
Volunteers will be instructed about the signs and symptoms of malaria and they will have a daily telephone contact during the first 6 days.
Between days 7 and 23 the volunteers will be asked to go to the Clinical Trials Unit daily to establish the presence or absence of disease through thick blood smear and samples will be collected for retrospective real time PCR P. vivax.
From day 23 until day 31, volunteers will receive physical and laboratory evaluation every other day and will have daily telephone contact.
Once the patients present signs and symptoms of the disease curative treatment will be immediately provided, and 15 ml of blood will be drawn, which will be used for immune response assessment.
If the volunteers do not develop the disease during the follow-up period, on day 31 they will be given antimalarial treatment.
Treatment Volunteers will be treated with antimalarial drugs approved by the Colombian Ministry of Social Health: chloroquine (three (3) doses: 600 mg initially, followed by 450 mg at 24, and 48 hours), associated with primaquine (30mg/day) for 14 days. All the volunteers will be asked to return two weeks after starting treatment for a thick blood smear test to ensure cure of malaria.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm N Vaccine | Experimental | Biological: Vaccine PvCS N+C+R 150 mcg30 malaria-naïve subjects from non-endemic areas of Cali, Colombia. |
| Arm N Placebo | Placebo comparator | Other: Placebo SSN Montanide ISA-51 1 mL30 malaria-naïve subjects from non-endemic areas of Cali, Colombia. |
| Arm S Vaccine | Experimental | Biological: Vaccine PvCS N+C+R 150 mcg30 semi-immune subjects from malaria endemic areas of Chocó, Colombia. |
| Arm S Placebo | Placebo comparator | Other: Placebo SSN Montanide ISA-51 1 mL30 semi-immune subjects from malaria endemic areas of Chocó, Colombia. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (24 listed)
- Non-pregnant, healthy men and women between 18-45 years old.
- Freely and voluntarily sign an IC, accompanied by two witnesses who must also sign.
- Absence history of malaria infection.
- To have negative serology for the PvCS protein by the ELISA test.
- For women, not be pregnant.
Key exclusion criteria (22 listed)
- Glucose 6 phosphate dehydrogenase deficiency (G-6-P-D).
- Present any hemoglobinopathy (eg HbS).
- Personal history of allergies to medications or insect bites.
- Have received vaccination against malaria.
- Clinical or laboratory abnormalities determined by the investigator (s).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vaccine PvCS N+C+R 150 mcgVaccine PvCS N+C+R 150 mcg (Montanide ISA-51), freeze dried powder. | Biological | Arm N Vaccine, Arm S Vaccine |
| Placebo SSN Montanide ISA-51 1 mLSSN Montanide ISA-51 1 mL | Other | Arm N Placebo, Arm S Placebo |
Primary outcome
Frequency of first case of P. vivax malaria after CHMI and meeting the primary case definition.
Time frame: Assessed over average of 16-18 days post CHMI (range 7 to 60 days)
The first case of malaria meeting the primary case definition will be defined as the first or only episodes with the presence of Plasmodium vivax parasitemia ≥ 0.1% by thick blood smear and malaria qPCR.
28 secondary outcomes
Concentration of specific anti-PvCS IgG antibodies IgG (isotypes) against the different functional fragments of the Pv-CS protein.
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Specific cytokine induction
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - Flow cytometry
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - ELIspot
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - Bioplex
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Characterization of T lymphocytes
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Characterization of B lymphocytes.
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240
Characterization of monocytes
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Antibody functionality in vitro through inhibition of sporozoite invasion (ISI) to Hep-G2 cells.
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Vaccine-induced protection for P. vivax
Time frame: Thirty days after mosquito bite challenge (Controlled Human Malaria Infection)
Multiomics testing (i.e., transcriptomics, genomics)
Time frame: Days 0, 30, 90, 195 and 225.
Safety - Number of Subjects With Any and Grade 3 Solicited Local Symptoms
Time frame: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Safety - Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms
Time frame: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Safety - Number of Subjects With Any Unsolicited Adverse Events (AEs)
Time frame: Within the 30-day (Days 0-29) post-vaccination follow-up period
Safety - Number of Subjects With Serious Adverse Events (SAEs)
Time frame: Throughout the study period (Day 0 - Month 14)
Safety - Number of Subjects With Hemoglobin Values Outside Normal Ranges With Toxicity Grades
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With White Blood Cell (WBC) Values Outside Normal Ranges With Toxicity Grades
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Platelet Values Outside Normal Ranges With Toxicity Grades
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Alanine Aminotransferase (ALT) Values Outside Normal Ranges With Toxicity Grades
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Creatinine Values Outside Normal Ranges With Toxicity Grades
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Bilirubin Values Outside Normal Ranges With Toxicity Grades
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Alkaline phosphatase Values Outside Normal Ranges With Toxicity
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Blood urea nitrogen (BUN) Values Outside Normal Ranges With Toxicity
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Aspartate aminotransferase (AST) Values Outside Normal Ranges With Toxicity
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Prothrombin time (PT)) Values Outside Normal Ranges With Toxicity
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Partial thromboplastin time (PTT) Values Outside Normal Ranges With Toxicity
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of participants with confirmed pregnancy
Time frame: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Glucose-6-phosphate dehydrogenase deficiency
Time frame: Day 0.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Mar 2021.
- Background: PubMed 29211303Ademolue TW, Awandare GA. Evaluating antidisease immunity to malaria and implications for vaccine design. Immunology. 2018 Apr;153(4):423-434. doi: 10.1111/imm.12877. Epub 2017 Dec 26.
- Background: PubMed 25072396RTS,S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 2014 Jul 29;11(7):e1001685. doi: 10.1371/journal.pmed.1001685. eCollection 2014 Jul.
- Background: PubMed 30349082Aliprandini E, Tavares J, Panatieri RH, Thiberge S, Yamamoto MM, Silvie O, Ishino T, Yuda M, Dartevelle S, Traincard F, Boscardin SB, Amino R. Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin. Nat Microbiol. 2018 Nov;3(11):1224-1233. doi: 10.1038/s41564-018-0254-z. Epub 2018 Oct 22.
- Background: PubMed 11741694Arevalo-Herrera M, Herrera S. Plasmodium vivax malaria vaccine development. Mol Immunol. 2001 Dec;38(6):443-55. doi: 10.1016/s0161-5890(01)00080-3.
- Background: PubMed 9797827Arevalo-Herrera M, Roggero MA, Gonzalez JM, Vergara J, Corradin G, Lopez JA, Herrera S. Mapping and comparison of the B-cell epitopes recognized on the Plasmodium vivax circumsporozoite protein by immune Colombians and immunized Aotus monkeys. Ann Trop Med Parasitol. 1998 Jul;92(5):539-51.
- Background: PubMed 21292876Arevalo-Herrera M, Soto L, Perlaza BL, Cespedes N, Vera O, Lenis AM, Bonelo A, Corradin G, Herrera S. Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein. Am J Trop Med Hyg. 2011 Feb;84(2 Suppl):35-42. doi: 10.4269/ajtmh.2011.09-0507.
- Background: PubMed 20009526Arevalo-Herrera M, Chitnis C, Herrera S. Current status of Plasmodium vivax vaccine. Hum Vaccin. 2010 Jan;6(1):124-32. doi: 10.4161/hv.6.1.9931. Epub 2010 Jan 26.
- Background: PubMed 2290443Arnot DE, Stewart MJ, Barnwell JW. Antigenic diversity in Thai Plasmodium vivax circumsporozoite proteins. Mol Biochem Parasitol. 1990 Nov;43(1):147-9. doi: 10.1016/0166-6851(90)90140-h. No abstract available.
- Background: PubMed 2414847Arnot DE, Barnwell JW, Tam JP, Nussenzweig V, Nussenzweig RS, Enea V. Circumsporozoite protein of Plasmodium vivax: gene cloning and characterization of the immunodominant epitope. Science. 1985 Nov 15;230(4727):815-8. doi: 10.1126/science.2414847.
- Background: PubMed 7605120Barnwell JW, Galinski MR. Plasmodium vivax: a glimpse into the unique and shared biology of the merozoite. Ann Trop Med Parasitol. 1995 Apr;89(2):113-20. doi: 10.1080/00034983.1995.11812941.
- Background: PubMed 10072326Barnwell JW, Galinski MR, DeSimone SG, Perler F, Ingravallo P. Plasmodium vivax, P. cynomolgi, and P. knowlesi: identification of homologue proteins associated with the surface of merozoites. Exp Parasitol. 1999 Mar;91(3):238-49. doi: 10.1006/expr.1998.4372.
- Background: PubMed 30126427Bermudez M, Moreno-Perez DA, Arevalo-Pinzon G, Curtidor H, Patarroyo MA. Plasmodium vivax in vitro continuous culture: the spoke in the wheel. Malar J. 2018 Aug 20;17(1):301. doi: 10.1186/s12936-018-2456-5.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sócrates Herrera, MD principal investigator
Director
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Vaccine PvCS N+C+R 150 mcg in people with Malaria, Vivax, run by Malaria Vaccine and Drug Development Center at 1 site in Colombia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 1 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Colombia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Sócrates Herrera, MD (575216231, sherrera@inmuno.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency of first case of P. vivax malaria after CHMI and meeting the primary case definition. (time frame: Assessed over average of 16-18 days post CHMI (range 7 to 60 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04739917, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Mar 2021.