A Phase 1/2, randomized, dose-finding/dose-confirmation study to evaluate the reactogenicity, safety and immunogenicity of mRNA-based multivalent seasonal influenza vaccine candidates administered in healthy younger and older adults
- Trial ID
- 2022-502308-66-00
- Protocol
- 217884
- Sponsor
- GlaxoSmithKline Biologicals
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **reactogenicity** profile of the investigational mRNA-based multivalent seasonal influenza vaccine candidates. This is clinically relevant as it ensures the vaccine's tolerability and identifies any adverse reactions in both healthy younger and older adults, which is crucial for its potential widespread use. Additionally, the study aims to assess the humoral **immune response** induced by the investigational vaccine, which is essential for determining its efficacy in preventing influenza infection.
The secondary objective is to further evaluate the humoral immune response induced by the investigational study intervention. This objective is important for understanding the vaccine's ability to elicit a protective immune response, which is a key factor in its effectiveness against influenza.
Participants
The clinical trial involves a total of **834 participants** who are **healthy volunteers** for the prevention of influenza infection. The study population includes both male and female subjects, with an age range of 18 to 50 years in Phase 1 and 18 to 85 years in Phase 2. Participants are required to be either healthy or medically stable, as determined by medical history, clinical examination, and safety laboratory assessments. Individuals with chronic medical conditions, such as metabolic, cardiac, pulmonary, renal, hepatic, neurologic, and hematologic diseases, are eligible if their condition is stable, defined as not requiring significant changes in therapy or hospitalization for worsening disease within three months prior to enrollment. The trial includes individuals with a **body mass index (BMI)** between 18 kg/m² and 35 kg/m². Participants are expected to comply with the protocol requirements, including completing an eDiary and attending follow-up visits. The selection process ensures that both genders are represented, and the trial includes vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified, but participants must provide written informed consent and, if female, adhere to specific contraception guidelines if of childbearing potential.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, reactogenicity, and immunogenicity of mRNA-based multivalent seasonal influenza vaccine candidates. This study is structured as a Phase 1/2, randomized, double-blind, controlled trial. The trial will involve healthy younger and older adults, with the primary objective of assessing the safety and immune response induced by the investigational vaccine. The trial is expected to last until July 2024, with recruitment having commenced in May 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and body mass index. The inclusion criteria specify that participants must be between 18 and 85 years of age, with medically stable conditions if applicable. Following the screening, eligible participants will receive the study intervention and will be monitored through follow-up visits to evaluate the occurrence of any adverse events and the immune response to the vaccine. The primary endpoints include the percentage of participants reporting solicited and unsolicited adverse events, as well as the geometric mean titer of antibody responses at specified time points.
The expected length of participant involvement is approximately 183 days, during which participants will be required to attend multiple follow-up visits. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or the inability to comply with study requirements. The trial will conclude with an end-of-study visit to assess the final safety and immunogenicity outcomes. Throughout the trial, participants will be administered the vaccine via the intramuscular route, and data will be collected to determine the optimal dose and confirm the safety profile of the vaccine candidates.
Treatment
The clinical trial involves the administration of several investigational and comparator treatments. The primary investigational treatment is a **multivalent seasonal influenza vaccine** candidate developed by GlaxoSmithKline Biologicals S.A. This vaccine is formulated as a **dispersion for injection** and is administered via the **intramuscular** route. The active substances in this investigational vaccine include a combination of nucleic acids and structurally diverse substances, specifically identified as GSKVX000000034794, GSKVX000000034795, GSKVX000000034797, GSKVX000000034798, GSKVX000000039711, GSKVX000000040033, GSKVX000000048110, and GSKVX000000048111. The dosing schedule and frequency of administration are determined based on the study protocol, and participant compliance is monitored throughout the trial.
In addition to the investigational vaccine, the trial includes the use of comparator treatments. One such comparator is the **Alpharix-Tetra** vaccine, which is a **suspension for injection** provided in a pre-filled syringe. This vaccine, also developed by GlaxoSmithKline Biologicals S.A., contains active substances such as B/Phuket/3073/2013-like virus, A/Victoria/2570/2019 (H1N1)pdm09-like strain, Influenza virus B/Austria/1359417/2021-like strain, and A/Darwin/9/2021 (H3N2)-like strain. The Alpharix-Tetra vaccine is also administered intramuscularly, and its administration follows the standard dosing schedule for influenza vaccines.
Another comparator used in the study is the **EFLUELDA** vaccine, a quadrivalent influenza vaccine provided as a **suspension for injection** in a pre-filled syringe. Manufactured by Sanofi Pasteur, this vaccine includes active substances such as B/Phuket/3073/2013-like virus, Influenza virus B/Michigan/01/2021, Influenza virus A/Darwin/9/2021 IVR-228 (H3N2), and Influenza A/Victoria/4897/2022 IVR-238 (H1N1), inactivated. The EFLUELDA vaccine is administered intramuscularly, and its dosing schedule is consistent with standard influenza vaccination protocols.
Throughout the trial, participant compliance with the dosing schedule is closely monitored to ensure the integrity of the study results. The trial aims to evaluate the safety, reactogenicity, and immunogenicity of the investigational vaccine compared to the standard-of-care influenza vaccines.
Efficacy
The efficacy of the investigational mRNA-based multivalent seasonal influenza vaccine candidates will be assessed through a series of primary and secondary endpoints. Primary endpoints include the evaluation of the humoral immune response, specifically the **geometric mean titer (GMT)** and **geometric mean increase (GMI)** of antigen 1 and antigen 2 antibody titers at Day 29. Additionally, the percentage of participants achieving seroconversion and those with antibody titers above a predefined cut-off value will be measured from Day 1 to Day 29. Secondary endpoints extend these assessments to Day 92 and Day 183, evaluating the GMT and GMI of antibody titers over these extended periods.
Data collection will occur at specified timepoints, including Day 1 (pre-dose), Day 8, Day 29, Day 92, and Day 183. The analysis will involve laboratory tests to determine antibody titers, with results expressed as GMT and GMI. The percentage of participants achieving seroconversion and those with titers above the cut-off will also be calculated. These measures will provide a comprehensive assessment of the vaccine's immunogenicity and its potential efficacy in inducing a protective immune response against influenza.
Inclusion and Exclusion Criteria
Inclusion Criteria
- A male or female between and including 18 and 50 years of age in Phase 1 and between and including 18 and 85 years of age (YA: 18-64; OA: 65-85) in Phase 2 at the time of the study intervention administration.
- Healthy participants or medically stable patients as established by medical history, clinical examination and safety laboratory assessments. Participants with chronic medical conditions with or without specific treatment (e.g., chronic metabolic, cardiac, pulmonary, renal, hepatic, neurologic, and hematologic diseases) are allowed to participate in this study if considered by the investigator as medically stable. A stable medical condition is defined as disease not requiring significant change in therapy or hospitalization for worsening disease during 3 months before enrollment.
- Body mass index (BMI) ≥ 18 kg/m² and ≤ 35kg/m²
- Participants who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of the eDiary, return for follow up visits).
- Written informed consent obtained from the participant prior to performing any study-specific procedure.
- Female participants of non-childbearing potential may be enrolled in the study.
- Female participants of childbearing potential may be enrolled in the study if the participant: 1) has practiced adequate contraception for 28 days prior to study intervention administration, and 2) has a negative pregnancy test on the day of study intervention administration, and 3) has agreed to continue adequate contraception for at least 1 month after study intervention administration.
Exclusion Criteria
- Only in Phase 1: Any clinically significant* hematological, biochemical, urinalysis or HbA1c laboratory abnormality. *The investigator should use his/her clinical judgment to decide which abnormalities are clinically significant.
- Participant tested positive for influenza by local health authority-approved testing methods within 180 days prior to Day 1.
- Current or past malignancy, unless completely resolved without clinically significant sequelae (e.g., scars following surgical resection for treatment of basal cell carcinoma cases are allowed) for >5 years.
- Any confirmed or suspected immunosuppressive or immunodeficient condition, including HIV infection, based on medical history and physical examination (no laboratory testing required). However, in Phase 2, HIV-infected individuals may be enrolled if they have been stable on antiretroviral therapy for the past 6 consecutive months, i.e., their treatment has not been modified, their CD4 cell count is ≥200/mm³ and their viral load has been undetectable (i.e., HIV-RNA <50 copies/mL) (based on medical records, no laboratory testing required). For country specific instruction please refer to Section 10.6.
- History of myocarditis or pericarditis less than or equal to 10 years prior to vaccine administration, including a history of myocarditis or pericarditis following vaccination with an mRNA COVID-19 vaccine.
- Participants with history of hypersensitivity or severe allergic reaction to any previous vaccine or hypersensitivity likely to be exacerbated by any component of the study intervention (including latex, polyethylene glycol, egg protein and aminoglycoside antibiotics).
- History of, or uncontrolled neurological disorders or seizures, including Guillain-Barré syndrome and Bell’s palsy, with the exception of febrile seizures during childhood.
- Any history of dementia or any medical condition that moderately or severely impairs cognition..
- Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
- Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study. Prior/Concomitant therapy
- Administration of an influenza vaccine (including any of the study investigational vaccines) within 180 days before enrollment or planned administration within 28 days (Day 29) after the study intervention administration.
- Phase 1: Administration of a vaccine not foreseen by the study protocol in the period starting 28 days (Day -28) before the study intervention administration, or planned administration within 28 days (Day 29) after the study intervention administration*. Phase 2: Administration of a vaccine not foreseen by the study protocol in the period starting 15 days (Day -15) before the study intervention administration, or planned administration within 28 days (Day 29) after the study intervention administration*. *In case emergency mass vaccination for an unforeseen public health threat (e.g., a pandemic) is recommended and/or organized by public health authorities outside the routine immunization program, the time period described above can be reduced to 7 days if, necessary for that vaccine, provided it is used according to the local governmental recommendations and that the Sponsor is notified accordingly.
- Use of any investigational or non-registered product (drug, vaccine or invasive medical device) other than the study intervention during the period beginning 30 days before the study intervention administration, or their planned use during the study period.
- Administration of long-acting immune-modifying drugs within 90 days before enrollment or planned use at any time during the study period (e.g., infliximab).
- Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 90 days before the study intervention administration, or planned administration during the study period. Administration of monoclonal antibodies specifically directed against the spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), for treatment of COVID-19 disease is allowed.
- Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the study intervention administration. For corticosteroids, this will mean prednisone equivalent ≥ 20 mg/day. Inhaled, topical and intraarticular steroids are allowed.
- Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational intervention (drug/invasive medical device).
- Pregnant or lactating female.
- Bedridden participants.
- Female planning to become pregnant or planning to discontinue contraceptive precautions within the 1-month post-dosing period.
- Alcoholism or substance use disorder within the past 24 months based on the presence of 2 or more of the following abuse criteria: hazardous use, social/interpersonal problems related to use, neglect of major roles to use, withdrawal, tolerance, use of larger amounts or longer, repeated attempts to quit or control use, much time spent using, physical or psychological problems related to use, activities given up to use, craving.
- Any study personnel or their immediate dependents, family, or household members.
- Participants with extensive tattoos covering deltoid region on both arms that would preclude the assessment of local reactogenicity.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 02 May 2023 | 438 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Alpharix-Tetra, suspensie voor injectie in een voorgevulde spuit
Griepvaccingefragmenteerd, geïnactiveerd virion | Comparator | SUSPENSIE VOOR INJECTIE IN EEN VOORGEVULDE SPUIT | INTRAMUSCULAR | — | — | PRD1714270 |
Alpharix-Tetra, suspension injectable en seringue préremplie Vaccin antigrippalvirion fragmenté, inactivé | Comparator | SUSPENSION INJECTABLE EN SERINGUE PRÉREMPLIE | INTRAMUSCULAR | — | — | PRD1700265 |
EFLUELDA, suspensie voor injectie in een voorgevulde spuit
Quadrivalent griepvaccin (gesplitst virion, geïnactiveerd), 60 microgram HA/stam | Comparator | SUSPENSIE VOOR INJECTIE IN EEN VOORGEVULDE SPUIT | INTRAMUSCULAR | — | — | PRD8021424 |