Phase IIa/b Trial of PvCS/Montanide ISA-51 Malaria Vaccine in Adults in Chocó, Colombia

Determination of the Protective Efficacy of the PvCS/Montanide ISA-51 Vaccine Formulation Against Controlled Infection With Plasmodium Vivax Sporozoites

This clinical study will evaluate an investigational malaria vaccine called PvCS/Montanide ISA-51 to determine whether it is safe and whether it can protect adults from infection with Plasmodium vivax, one of the main parasites that causes malaria. P. vivax malaria is common in tropical regions, including Colombia, and can lead to recurrent fever, anemia, and prolonged illness. Currently, no licensed vaccine effectively prevents P. vivax infection.

The investigational vaccine (PvCS) contains synthetic peptides derived from the circumsporozoite (CS) protein located on the surface of P. vivax sporozoites. The vaccine is formulated with the adjuvant Montanide ISA-51 to enhance the immune response. This study aims to assess the safety of the PvCS/Montanide ISA-51 formulation and to determine whether it can prevent malaria after controlled exposure to the parasite.

This is a Phase IIa/b, randomized, double-blind, placebo-controlled clinical trial conducted by the Malaria Vaccine and Drug Development Center (MVDC/CIV) in collaboration with ASOCLINIC IPS and the Pacific Health Institute (INSALPA) in Quibdó, Chocó, Colombia. A total of 72 healthy adults aged 18-50 years from malaria-endemic areas will participate.

Participants will be randomly assigned in a 2:1 ratio to receive either the PvCS/Montanide ISA-51 vaccine or a placebo. The study product will be administered by intramuscular injection at months 0, 2, and 4. After each vaccination, participants will be monitored for side effects and provide blood samples to measure immune responses, including antibody levels and T-cell activity.

Approximately one month after the third vaccination, participants will undergo a controlled human malaria infection (CHMI), during which they will be exposed to P. vivax through the bite of infected mosquitoes under strict medical supervision. Following exposure, participants will be monitored daily using blood tests to detect malaria at the earliest stage.

If malaria parasites are detected-or if 21 days pass without infection-participants will receive prompt, effective antimalarial treatment based on Colombian national guidelines. All participants will continue to be followed for up to 12 months after the challenge to ensure safety and assess long-term outcomes.

Primary goals of the study include:

Determining whether the PvCS/Montanide ISA-51 vaccine prevents P. vivax infection after CHMI.

Measuring the time between exposure and first detection of parasites (pre-patent period).

Evaluating the safety and tolerability of the vaccine.

Secondary goals include:

Measuring immune responses generated by the vaccine. Exploring relationships between immune responses and protection from infection. The total duration of the study is expected to be approximately 30 months, including recruitment, immunizations, challenge procedures, and follow-up. Results will help determine whether this vaccine can safely protect adults against P. vivax malaria and guide planning for future larger-scale vaccine trials in endemic populations.

This Phase IIa/b randomized, double-blind, placebo-controlled clinical trial is designed to evaluate the protective efficacy, safety, and immunogenicity of the PvCS/Montanide ISA-51 vaccine when followed by a controlled human malaria infection (CHMI) with Plasmodium vivax. The investigational product consists of synthetic peptides representing the central repeat and flanking regions of the P. vivax circumsporozoite (CS) protein formulated with the Montanide ISA-51 adjuvant. This vaccine formulation was selected based on earlier phase studies demonstrating acceptable safety and immune reactivity in adults.

The study will enroll 72 healthy adults aged 18-50 years residing in a malaria-endemic region of Chocó, Colombia. Participants will be randomized in a 2:1 ratio to receive either the PvCS/Montanide ISA-51 vaccine or placebo. Vaccinations will be administered intramuscularly at months 0, 2, and 4. Safety assessments will include clinical evaluations, laboratory monitoring, and systematic documentation of all adverse events throughout the vaccination and follow-up periods.

Immunogenicity will be characterized using standardized assays to quantify antibody responses (ELISA and indirect immunofluorescence) and cellular responses (ELISpot), including measurements of IFN-γ-secreting T cells. Samples will be collected at predefined time points to evaluate the magnitude, kinetics, and durability of immune responses.

Approximately one month after the third vaccination, participants will undergo CHMI via exposure to Anopheles albimanus mosquitoes infected with P. vivax sporozoites. The challenge will be conducted in a controlled setting with continuous clinical oversight. After CHMI, participants will undergo daily parasitological monitoring by thick smear, supplemented by PCR assays, until the detection of parasitemia or for up to 21 days post-challenge.

Participants who develop parasitemia will receive immediate antimalarial treatment according to national guidelines. Extended follow-up will include evaluations of treatment response, late-onset adverse events, and persistence of vaccine-induced immune responses for up to 12 months after CHMI.

The primary objectives are to determine whether vaccination with PvCS/Montanide ISA-51 reduces the risk of developing P. vivax parasitemia after CHMI and whether it prolongs the pre-patent period compared with placebo. Safety outcomes include the frequency and severity of local, systemic, and laboratory adverse events. Secondary objectives include detailed characterization of humoral and cellular responses and exploratory analyses assessing associations between immunogenicity and protection.

The study is expected to last approximately 30 months, including recruitment, immunization, challenge procedures, and follow-up. Results will provide critical data to guide future development of P. vivax CS-based vaccines and inform decisions regarding advancement to larger efficacy trials in endemic settings.

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Inclusion Criteria Age 18-50 years, male or female. Healthy adults, as determined by medical history, physical examination, and screening laboratory tests.

Able and willing to provide written informed consent prior to any study procedure.

Available for the full duration of the study, including follow-up through 12 months post-challenge.

Group-specific criteria:

Malaria-naïve cohort: No prior malaria infection or residence in malaria-endemic areas; negative malaria serology at screening.

Semi-immune cohort: Residence ≥ 5 years in a P. vivax-endemic area and documented or self-reported prior malaria exposure.

Screening negative for HIV, hepatitis B surface antigen (HBsAg), and hepatitis C virus antibodies.

For women of childbearing potential:

Negative pregnancy test at screening and prior to each vaccination and/or CHMI. Commitment to use effective contraception (hormonal, IUD, barrier methods, or abstinence) from screening through the end of follow-up.

Willingness to comply with all study procedures, including repeated blood sampling, controlled human malaria infection (CHMI), and inpatient or outpatient monitoring as required.

Exclusion Criteria Previous participation in any malaria vaccine clinical trial or any controlled human malaria infection (CHMI) study.

History of severe allergic reactions, including anaphylaxis, to vaccines or vaccine components such as Montanide ISA-51 VG, adjuvants, or synthetic peptides.

Clinically significant acute or chronic medical conditions that may increase risk or interfere with study participation, including but not limited to:

Cardiovascular disease Hepatic or renal impairment Neurological or psychiatric disorders Autoimmune diseases Hematologic abnormalities Immunodeficiency or immunosuppressive conditions Use of immunosuppressive therapies, systemic corticosteroids, antimalarial medications, or other agents that may interfere with vaccine immune responses within 30 days prior to enrollment.

Receipt of immunoglobulins or blood products within 3 months prior to screening.

Pregnancy or breastfeeding at screening or planned pregnancy during the study period.

Participation in another clinical trial of an investigational product or device within 30 days prior to enrollment or planned participation during the study.

Any clinically significant abnormality on screening laboratories, ECG, or physical examination that, in the investigator's judgment, could:

Pose a safety risk, Confound study results, or Impair adherence to study procedures. Any condition or circumstance that, in the investigator's opinion, could compromise volunteer safety or the integrity of the trial.