Clinical Trial Phase I/IIa to Evaluate the Safety and Immunogenicity of StreptInCor

This is a Phase I/IIa, randomized, double-blind, placebo-controlled, dose-escalation clinical trial to test the candidate vaccine StreptInCor. The study will include four different doses (25 µg, 50 µg, 100 µg, and 200 µg) of StreptInCor produced under Good Manufacturing Practices (GMP) and formulated with aluminum hydroxide as the vaccine adjuvant. The adjuvant alone will be used as a placebo in this trial.

Five groups, each comprising twelve healthy adult volunteers, will randomly receive two doses of the vaccine or placebo with a 28-day interval, along with a booster dose six months after the initial vaccination.

During the selection process, volunteers aged 18 to 45 years will undergo a general health assessment and serological tests to verify the absence of HIV and autoimmune diseases. Exclusion criteria include second-degree relatives or history of Rheumatic Fever (RF) or Rheumatic Heart Disease (RHD), as well as prior infections or recurrent diseases associated with S. pyogenes. All volunteers must sign an informed consent form before any procedures.

In the first phase of the trial, volunteers assigned to receive the lowest dose (25 µg) and three placebo volunteers will begin the vaccination scheme, maintaining blinding. One month after the second vaccination, all volunteers will be re-evaluated for safety, and the results will be submitted to the Data Safety Monitoring Committee (DSMC) for review. Only with a favorable opinion from the DSMC will the booster dose be administered to this group.

After the DSMC assesses the safety of these three doses, the second phase can commence. In this phase, volunteers assigned to the low-intermediate dose (50 µg) and three placebo volunteers will start vaccination, with safety evaluations occurring one month after the second dose. If the DSMC's opinion remains favorable, a booster at six months will be administered and re-evaluated by the DSMC.

If approved, the third phase will include the high-intermediate dose (100 µg) plus three placebo volunteers, with similar safety assessments and DSMC approval for the booster.

The fourth phase will involve volunteers receiving the high dose (200 µg) plus three placebo volunteers, following the same safety evaluation process.

In total, 60 volunteers will be enrolled - 12 per group and 15 per phase. Safety (toxicity) will be monitored by the DSMC after each booster at all protocol stages. The DSMC's operational procedures are based on the Ministry of Health's Guidelines for Data and Safety Monitoring Committees (2008). Safety parameters include serological markers for autoimmune diseases, with safety follow-up extending up to twelve months post-initial vaccination.

The study can be paused at any point if moderate or severe adverse events possibly related to the vaccine occur; in such cases, the DSMC will assess whether the trial or specific steps can be restarted.

The primary efficacy parameter will be at least a fourfold increase in IgG antibody levels after the last vaccination compared to pre-vaccination levels. All samples from the same volunteer will be assessed simultaneously to prevent processing bias, in a blinded manner. Additional efficacy measures include detection of other antibody classes, functionality of antibodies regarding surface binding and inhibition of bacterial invasion/adherence, induction of phagocytosis, cellular immune responses such as cytokine production, antigen-specific T-cell proliferation, and memory T-cell induction.

The dose showing the highest seroconversion rate and an acceptable rate of adverse effects will be selected for Phase II.

Inclusion criteria

• • Healthy male or female volunteers, aged between 18 and 45 years;

• Availability to undergo all procedures throughout the study period;
• Provide free and informed consent to participate in the study.

Exclusion criteria

• Participation in clinical trials within the last year
• Participation in cohort studies
• Diagnosis of concomitant infections or diseases that may affect immunity, including active HIV infection, hepatitis B, hepatitis C, diabetes mellitus, neoplasms, and autoimmune diseases;
• Current or previous diagnosis or family history of ARF, chorea, obsessive-compulsive disorder, or glomerulonephritis;
• Current or previous diagnosis of heart diseases;
• Severe asthma or chronic obstructive pulmonary disease (COPD);
• Abnormal neurological clinical assessment, especially chorea;
• Use of treatments that may affect immunity in the last four weeks, including immunomodulators, corticosteroids (only systemic use for two weeks or more), or antineoplastic agents;
• Use of treatments that may affect heart valves in the last four weeks or planned during the study period, including fenfluramine and dexfenfluramine;
• Renal insufficiency determined by estimated creatinine clearance below 45 ml/min/1.73m²;
• History of intolerance or allergy to any component of the study product, including antigen or adjuvant;
• Presence of valve abnormalities or alterations in cardiac anatomy as defined by echocardiogram;
• Altered electrocardiogram;
• Evidence or suspicion of recent S. pyogenes infection based on clinical symptoms in the last four weeks;
• Pregnancy, breastfeeding mother, or intention to become pregnant during the study period (only female participants);
• Any other condition that may interfere with the study process as assessed by the researchers, including sample size and statistical power.