Non-Inferiority Study of BIMERVAX as a Heterologous Booster for SARS-CoV-2 in Adolescents Aged 12-17 Years

Trial ID: 2023-504639-42-00
Protocol: HIPRA-HH-3
Sponsor: Hipra Scientific S.L.

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COVID-19

Objectives

The primary objective of this study is to determine and compare the changes in **immunogenicity** measured by Pseudovirus Based Neutralisation Assay (PBNA) against the Omicron BA.1 variant at Baseline and Day 14, following vaccination of adolescents with a heterologous booster dose of BIMERVAX® versus post heterologous booster dose in young adults (aged 18 to 25 years) from the adult booster study. Additionally, the study aims to assess the safety and tolerability of BIMERVAX® as a heterologous booster dose in adolescents who have been primarily vaccinated against COVID-19 with two doses of the Comirnaty vaccine. These objectives are clinically relevant as they provide insights into the efficacy and safety of BIMERVAX® as a booster in a younger population, which is crucial for informed public health decisions regarding vaccination strategies.

Secondary objectives include: - Determining changes in immunogenicity measured by PBNA against Variants of Concern (VOCs) such as Beta and Delta at various time points post-vaccination. - Analyzing the Geometric Mean Fold Rise (GMFR) against Omicron BA.1 and VOCs at Baseline and Day 14. - Assessing immunogenicity against the Omicron BA.1 variant at later time points. - Measuring total antibody against the RBD of the Spike protein of SARS-CoV-2 using electrochemiluminescence immunoassay (ECLIA). - Evaluating T-cell mediated responses and CD4+ and CD8+ T-cell responses against the SARS-CoV-2 S glycoprotein at Baseline and Day 14 in a subset of adolescents.

Participants

The clinical trial involves **adolescents** aged from 12 to less than 18 years, who have previously received two doses of the Comirnaty vaccine, with the last dose administered at least six months prior to screening. The study population includes both male and female participants, and individuals with a body mass index at or above the third percentile according to local Child Growth Standards. Participants are required to be healthy or have pre-existing, chronic, and stable diseases that are well-controlled. A negative Rapid Antigen Test (RAT) is mandatory at Day 0 before the administration of the BIMERVAX® vaccine. The trial does not include a vulnerable population. Participants who are biologically able to have children must have a negative urine pregnancy test at screening and agree to use adequate contraception or abstain from activities that could result in pregnancy for a specified period. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed as an **open-label**, multi-centre, non-inferiority study to evaluate the safety and immunogenicity of the BIMERVAX emulsion for injection COVID-19 Vaccine (recombinant, adjuvanted) as a heterologous booster for the prevention of **SARS-CoV-2 infection** in adolescents aged 12 to less than 18 years. The trial will compare the changes in immunogenicity measured by Pseudovirus Based Neutralisation Assay (PBNA) against the Omicron BA.1 variant at baseline and Day 14, following the administration of the booster dose. The study will also assess the safety and tolerability of the vaccine in adolescents who have previously received two doses of the Comirnaty vaccine.

The trial is expected to commence recruitment on May 31, 2023, and is estimated to conclude by October 15, 2024. Participants will be involved in the study for a period that includes a screening visit, a baseline visit on Day 0, and follow-up visits on Day 14 and Day 28, with an end-of-study visit scheduled at the conclusion of the trial. The inclusion criteria require participants to be healthy or have stable, well-controlled chronic conditions, a body mass index at or above the third percentile, and a body weight greater than 50 kg. Participants must also have a negative Rapid Antigen Test (RAT) at Day 0 before receiving the BIMERVAX vaccine.

Primary endpoints include the measurement of neutralisation titre against the Omicron BA.1 variant, solicited local and systemic reactions through Day 7, and unsolicited adverse events through Day 28. The study will monitor related adverse events and all serious adverse events through the end of the study. Participants may be terminated early from the study if they experience significant adverse events or fail to comply with study procedures. The trial is conducted in accordance with ethical standards and requires informed consent from participants' parents or legal guardians, along with written assent from the participants themselves.

Treatment

The clinical trial involves the administration of **BIMERVAX**, an emulsion for injection, which is a COVID-19 vaccine (recombinant, adjuvanted). The active substance in this vaccine is the **SARS-CoV-2 virus**, specifically the variants B.1.351-B.1.1.7, spike protein, receptor binding domain fusion heterodimer. This vaccine is designed to be administered intramuscularly. The dosage for this trial is set at a maximum of 40 micrograms per day, with a total maximum dose of 40 micrograms. The treatment period is limited to a single day. The vaccine is not formulated specifically for pediatric use, and it is not classified as an orphan drug. The pharmaceutical form of the vaccine is an emulsion for injection, and it is produced by HIPRA HUMAN HEALTH S.L.

In this study, **BIMERVAX** is used as a heterologous booster dose for adolescents who have previously received two doses of the Comirnaty vaccine. The trial aims to assess the safety and tolerability of this booster dose, as well as to evaluate changes in immunogenicity using a Pseudovirus Based Neutralisation Assay (PBNA) against the Omicron BA.1 variant. The study does not involve any non-experimental treatments such as a placebo or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the changes in **immunogenicity** using the Pseudovirus Based Neutralisation Assay (PBNA) against the Omicron BA.1 variant. The primary endpoint involves measuring the neutralisation titre, specifically the inhibitory concentration 50 (IC50), which will be reported as log10 concentration for each individual sample and as the Geometric Mean Titre (GMT) for group comparisons. These measurements will be taken at Baseline and Day 14 post-vaccination. Additionally, the trial will monitor solicited local and systemic reactions through Day 7, unsolicited adverse events through Day 28, and related adverse events, including serious adverse events, through the end of the study. Adverse events of special interest and related medically attended adverse events will also be tracked until the study concludes. Safety laboratory parameters will be assessed for Grade 2, Grade 3, and Grade 4 changes from Baseline through Day 14 after vaccination. The trial aims to compare these outcomes in adolescents receiving the BIMERVAX heterologous booster with those in young adults from a previous study.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adolescents aged from 12 to less than 18 years at Screening.
Participant’s parent(s)/legal guardian(s) willing and able to sign the informed consent and can comply with all study visits and procedures. A written assent will be required for all participants in the study.
Participant must have received two previous doses of Comirnaty, last dose being at least 6 months before screening.
Participant has a body mass index at or above the third percentile according to local Child Growth Standards at Screening Visit.
Healthy participants and participants with pre-existing, chronic and stable diseases (non-immunocompromised), if these are stable and well-controlled according to the investigator’s judgment, are eligible for inclusion in the study.
Has a negative Rapid Antigen Test (RAT) at Day 0 before BIMERVAX® vaccine administration.
Participants biologically able to have children may be enrolled in the study if the participant fulfils all the following criteria: a. Has a negative urine pregnancy test at Screening (Day 0), only for those participants who are biologically able to become pregnant. b. Has practiced adequate contraception or has abstained from all activities that could result in pregnancy for at least 28 days prior to the booster dose, only for those participants who are biologically able to become pregnant. c. Has agreed to continue adequate contraception or abstinence through 3 months following the booster dose.
Participant must have a body weight >50 kg at Screening visit to be eligible for the cellular immunology assays.

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Exclusion Criteria

Acute illness with fever ≥ 38.0°C at Screening or within 24 hours prior to vaccination. Participant can be rescheduled for Screening when they have completed 24 hours without fever. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator.
Received medications intended to prevent or treat COVID-19 before Screening, except for Comirnaty vaccines.
Previous or current diagnosis of MIS-C.
Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of the study intervention(s).
Immunocompromised individuals defined as those with primary and secondary immune deficiencies and those receiving chemotherapy or immunosuppressant drugs other than steroids and glucocorticoids (maximum 1 mg/kg/day of prednisone or total dose of 20mg/day by any administration route for a maximum of 30 consecutive days), within 90 days prior to vaccination or during the study.
Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
Female who is pregnant or breastfeeding.
Receipt of blood/plasma products, immunoglobulin, monoclonal antibodies, or receipt of any passive antibody therapy, within 90 days prior to vaccination or during the study.
Participation in other studies involving study intervention within 28 days prior to screening and/or during study participation.
Received any non-study vaccine (including seasonal Influenza vaccine) within 14 days before or after screening. For live or attenuated vaccines, 4 weeks before or after screening.
History of illegal substance use or alcohol abuse within the past 2 years.
History of a diagnosis or other conditions that, in the judgment of the investigator, may affect study endpoint assessment or compromise participant safety.
Individuals who are family members of the Investigators.
Individuals with documented medical history of microbiologically confirmed COVID-19 will not be eligible for the immunogenicity group.