Clinical Trial to Evaluate the Safety and Immunogenicity of the Vivaxin Vaccine for Malaria Caused by Plasmodium Vivax."

Vivaxin is being developed for use as a prophylactic vaccine against malaria caused by Plasmodium vivax, the dominant species in Brazil.

The study will consist of the assessment of the safety, reactogenicity, and immunogenicity of the vaccine following intramuscular administration of three doses of 0.3 mL/dose, with a 28-day interval between each dose, in healthy participants of both sexes, aged 18 to 59 years, with no prior exposure to malaria.

This will be a Phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the investigational product, Vivaxin vaccine.

A total of 16 participants will be included in each of the 3 study arms, based on Vivaxin dose levels: 25 µg, 50 µg, and 100 µg. In each arm, 12 participants will receive the Vivaxin vaccine, and 4 participants will receive a placebo. Additionally, a sentinel cohort will be included within each arm:

Arm 1 - 25 µg of Vivaxin (N=12) or placebo (N=4):

Twelve participants will receive three doses of 25 µg of Vivaxin, with 28-day intervals between doses, and four participants will receive three doses of placebo, also at 28-day intervals. The first four individuals enrolled will comprise the sentinel group. Three of these will receive Vivaxin and one will receive placebo, randomized in a blinded manner. They will be observed for at least 7 days prior to proceeding with vaccination of the remaining participants in this arm. Vaccination of the remaining participants will proceed only after confirming that no study-halting criteria have been met.

Arm 2 - 50 µg of Vivaxin (N=12) or placebo (N=4):

Twelve participants will receive three doses of 50 µg of Vivaxin, with 28-day intervals, and four participants will receive placebo under the same schedule. The first four individuals enrolled will comprise the sentinel group (three receiving Vivaxin, one receiving placebo). They will be observed for at least 7 days before vaccination continues in this arm. Continuation is contingent upon confirmation that no halting criteria have been met.

Arm 3 - 100 µg of Vivaxin (N=12) or placebo (N=4):

Twelve participants will receive three doses of 100 µg of Vivaxin, spaced 28 days apart, and four participants will receive placebo at the same intervals. As with the other arms, the first four individuals enrolled will form the sentinel group and will be observed for at least 7 days before vaccination of the remaining participants in the arm is permitted, conditional on the absence of any study-halting criteria.

All participants in the sentinel cohorts will be observed at the research center for 60 minutes post-vaccination (vaccine or placebo). All other participants will be observed for a minimum of 30 minutes. All participants will be followed for 360 days with regular clinical assessments, including:

Telephone follow-ups on Days 1 and 3 (post-first dose), Days 29 and 31 (1 and 3 days post-second dose), Days 57 and 59 (1 and 3 days post-third dose), and monthly thereafter until study completion;

In-person visits on Days 7 and 14 (1 and 2 weeks post-first dose), Day 28 (second dose), Days 35 and 42 (1 and 2 weeks post-second dose), Day 56 (third dose), Days 63 and 70 (1 and 2 weeks post-third dose), and Days 84, 120, 180, 270, and 360 post-vaccination (end of study).

Participants will be sequentially enrolled and allocated to Arms 1, 2, and 3 of the study, receiving 25 µg, 50 µg, and 100 µg of the investigational product, respectively. In each arm, 12 participants will receive the Vivaxin vaccine and 4 participants will receive placebo, totaling 16 participants per arm.

The first four randomized individuals in each arm will comprise the sentinel group and will be observed for at least 7 days prior to continuation of vaccination in that arm. Adverse events (AEs) from each sentinel cohort will be reviewed by the Protocol and Safety Review Team (PSRT) within 7 days following vaccination. If no halting criteria are met, vaccination of the remaining participants in the arm will proceed.

After the first 14 days of follow-up of all participants in Arm 1, a blinded safety review will be conducted by the PSRT to determine whether dose escalation may proceed. If no halting criteria are observed, the PSRT will recommend study continuation. Should any halting criteria be met or any PSRT member deem it necessary, a meeting with the Independent Data and Safety Monitoring Committee (DSMC) will be convened. The DSMC, upon review of the safety data, may recommend continuation as planned, propose protocol modifications, or advise study suspension. This procedure will be repeated at each dose escalation stage.

If the PSRT recommends proceeding, participants in Arm 2 (50 µg) will be vaccinated, beginning with the sentinel cohort of four individuals who will be observed for 7 days before continued randomization in the arm. Meanwhile, Arm 1 may continue with second and third immunizations, observing the sentinel group of each dose for 7 days prior to proceeding with full-arm administration.

Upon completion of the first 14 days of follow-up in Arm 2, a safety analysis will be conducted by the PSRT to determine whether escalation to Arm 3 may proceed. As with the previous arms, the first four individuals in Arm 3 will form the sentinel group and will be observed for 7 days prior to continued vaccination in that arm.

Inclusion criteria

• Non-pregnant women and men aged between 18 and 59 years;
• Willingness to participate in the study and undergo all study procedures, as demonstrated by signing the informed consent form (ICF);
• In good general health, as determined by medical examination;
• Women of childbearing potential must agree to use an acceptable* contraceptive method for at least 30 days prior to the first vaccination and for at least 6 months following administration of the first dose of the investigational product, ensuring at least 3 months after the final vaccine dose have elapsed;
• Agreement not to donate blood during the course of study participation.

• Acceptable contraceptive methods:

• Barrier methods, including condom or cervical cap;
• Surgically sterile partner/participant (including those who have undergone vasectomy, hysterectomy, bilateral oophorectomy, and/or tubal ligation) who is the sole sexual partner;
• Intrauterine device (with or without hormones);
• Hormonal birth control methods (oral, topical, injectable, or implantable);
• True sexual abstinence that is consistent with the participant's preferred and usual lifestyle.

Note: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) or withdrawal (coitus interruptus) will not be considered acceptable methods.

Exclusion criteria

• Prior history of malaria infection confirmed by serological testing;
• Prior history of malaria vaccination;
• Intention to travel to a malaria-endemic area during the study period;
• Pregnant or breastfeeding women, or those intending to become pregnant or breastfeed within the first 6 months of the study;
• Evidence of clinically active disease, such as but not limited to: neurological, renal, cardiovascular, endocrine, pulmonary, hepatic, hematological, immunological, neoplastic, or infectious diseases;
• Use of concomitant medication for control of an underlying medical condition;
• Positive serological test for HBV, HCV, or HIV;
• Any condition that, in the opinion of the study investigator, could pose a risk to the participant or confound the study results, including clinically stable chronic conditions such as diabetes, hypertension, or neuralgias, among others;
• Psychiatric illness or cognitive impairment that, in the opinion of the investigator, may affect the participant's ability to comply with the clinical study schedule;
• History of alcohol or substance abuse within 12 months prior to enrollment that resulted in family, medical, or occupational problems;
• History of severe allergic reaction or anaphylaxis to any component of the vaccine;
• History of asplenia;
• Participation in any other investigational clinical trial within 12 months prior to inclusion in this study;
• Plans to participate in other clinical trials concurrently with this study;
• Use of any immunosuppressive therapy within 3 months prior to enrollment or plans to use such therapy within 3 months after vaccination, including corticosteroids or other immunosuppressive drugs. An immunosuppressive dose of corticosteroid is defined as the equivalent of 20 mg/day of prednisone for more than one week. Topical or nasal corticosteroids are not considered immunosuppressive;
• Use of blood products (including blood or immunoglobulins) within 3 months prior to enrollment in this study, or plans to use them during the study period;
• Suspected or confirmed fever (axillary temperature ≥ 37.8 °C) within 72 hours prior to study enrollment. Enrollment should be postponed until the participant has been afebrile for at least 72 hours;
• Receipt of any live attenuated or inactivated vaccine within 28 or 14 days, respectively, prior to administration of the investigational product, or plans for immunization within 28 days after enrollment in the study.