The goal of this clinical trial is to evaluate the safety and immune responses of three different dose levels a self-amplifying RNA pandemic influenza vaccine (ARCT-2304) in adults. The key objectives of the study are: * To evaluate safety and reactogenicity of different dose levels of the ARCT-2304 vaccine * To describe the Immune responses of different dose levels of the ARCT-2304 vaccine as measured by hemagglutination inhibition (HAI) and neuraminidase enzyme-linked lectin (ELLA) antibody responses Researchers will compare the results with licensed influenza vaccines to select the most optimal dose level and schedule for vaccine administration in terms of safety and immunogenicity for further development of the vaccine. Participants will receive 2 doses of the ARCT-2304 vaccine or 1 dose of licensed influenza vaccine and 1 dose of placebo. They will be asked: * to complete a daily diary for 7 days after each vaccination, answering questions how they have been feeling on that day. * to provide blood samples at each visit in the clinic * to comply with all study visits and procedures (e.g., be available for planned telephone contacts and unscheduled clinic visits, if required)
Phase 1, first-in-human, randomized, controlled, observer blind, dose level and schedule-finding study, to evaluate the safety, reactogenicity, and immunogenicity of a self-amplifying mRNA pandemic influenza (H5N1) vaccine (ARCT-2304) when administered as a 2-dose vaccination series to healthy adults in comparison with an inactivated influenza vaccine. Study drug (ARCT-2304 or control) will be administered as a 2-dose vaccination series as an intramuscular (IM) injection. The study comprises two parts. In Part 1, 120 participants (young adults) will be randomized to one of the three dose levels of the ARCT-2304 vaccine or control vaccine. Participants will be further randomized to one of the two different vaccination schedules. In Part 2, 80 participants (older adults) will be randomized to one of the three dose levels of the ARCT-2304 vaccine or control vaccine. Participants will be further randomized to one of the two different vaccination schedules. Investigational Vaccine: ARCT-2304 Control Vaccines: licensed influenza vaccines
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
212
Each participant will receive 2-dose regimen intramuscular (IM) dose into the deltoid muscle.
Each participant will receive one intramuscular (IM) dose into the deltoid muscle.
Each participant will receive one intramuscular (IM) dose into the deltoid muscle.
Each participant will receive one intramuscular (IM) dose into the deltoid muscle.
Velocity Clinical Research
La Mesa, California, United States
Velocity Clinical Research
San Bernardino, California, United States
Tekton Research
Longmont, Colorado, United States
CTI Clinical Research Center
Cincinnati, Ohio, United States
Number of Participants With Solicited Adverse Events (AEs) Within 7 Days After Each Vaccination
The following solicited local and systemic AEs were recorded from Day 1 to 7 days after each vaccination (dose): Injection site pain, Erythema, Swelling, Fatigue, Headache, Myalgia, Arthralgia, Dizziness, Nausea, Chills, Fever (≥100.4 °Fahrenheit \[F\] /≥38.0 °Celsius \[C\]). A summary of all Serious Adverse Events and Other Adverse Events (non-serious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: 7 days post each dose
Number of Participants With Unsolicited AEs Within 28 Days After Each Vaccination
An AE was any untoward medical occurrence in a participant or participant administered a medicinal product, whether or not considered related to the trial vaccine. An unsolicited AE was defined as any AE not included in the list of solicited AEs (i.e., any event other than injection site pain, erythema, swelling, fatigue, headache, myalgia, arthralgia, dizziness, nausea, chills, or fever (≥100.4 °F / ≥38.0 °C). Solicited AEs that lasted for more than 7 days were considered as unsolicited AEs. Unsolicited AEs were recorded from Day 1 up to 28 days after each vaccination (dose). A summary of all Serious Adverse Events and Other Adverse Events (non-serious) regardless of causality is located in the 'Reported Adverse Events' Section'.
Time frame: D1,29 Cohorts: up to Day 29 and up to Day 57 (28 days post each dose), D1,57 Cohorts: up to Day 29 and up to Day 85 (28 days post each dose)
Number of Participants With Serious Adverse Events (SAEs), Medically Attended AEs (MAAEs), AEs of Special Interest (AESIs), and AEs Leading To Early Termination From Day 1 to 28 Days After Second Vaccination
An SAE was defined as any AE that resulted in death, was life-threatening, resulted in persistent disability/incapacity, or required inpatient hospitalization or prolongation of existing hospitalization. AEs potentially associated with messenger ribonucleic acid (mRNA) vaccines and influenza vaccines were reported as AESIs. MAAEs were defined as AEs with medically attended visits including hospital, emergency room, urgent care clinic, or other visits (including phone/telehealth visits) to or from medical personnel for any reason but did not fulfil seriousness criteria. A summary of all Serious Adverse Events and Other Adverse Events (non-serious) regardless of causality is located in the 'Reported Adverse Events' Section'.
Time frame: D1,29 Cohorts: up to Day 57, D1,57 Cohorts: up to Day 85
Geometric Mean Titer of Antibody Response to Hemagglutinin (HA) Glycoprotein Measured By Hemagglutinin Inhibition (HAI) Assay
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Antibody titers were expressed as Geometric Mean Titers.
Time frame: D1,29 Cohorts: Day 1, Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 1, Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Geometric Mean Titer of Antibody Response to Neuraminidase (NA) Glycoprotein Measured By Enzyme-linked Lectin Assay (ELLA)
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Antibody titers were expressed as Geometric Mean Titers.
Time frame: D1,29 Cohorts: Day 1, Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 1, Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Geometric Mean Fold Rise of Antibody Response to HA Glycoprotein Measured By HAI Assay
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Geometric Mean Fold Rise was reported as a ratio to Day 1.
Time frame: D1,29 Cohorts: Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Geometric Mean Fold Rise of Antibody Response to NA Glycoprotein Measured By ELLA
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Geometric Mean Fold Rise was reported as a ratio to Day 1.
Time frame: D1,29 Cohorts: Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Percentage of Participants With Seroconversion of Antibody Response to HA Glycoprotein Measured By HAI Assay
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Seroconversion was recorded if participant had pre-vaccination antibody titer \< Lower Limit Of Quantitation (LLOQ) and a post-vaccination antibody titer ≥ 4 x LLOQ, or a pre-vaccination antibody titer ≥LLOQ and a ≥4-fold increase in post-vaccination antibody titer.
Time frame: D1,29 Cohorts: Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Percentage of Participants With Seroconversion of Antibody Response to NA Glycoprotein Measured By ELLA
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Seroconversion was recorded if participant had pre-vaccination antibody titer \< LLOQ and a post-vaccination antibody titer ≥ 4 x LLOQ, or a pre-vaccination antibody titer ≥LLOQ and a ≥4-fold increase in post-vaccination antibody titer.
Time frame: D1,29 Cohorts: Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Percentage of Participants With HAI Titers Above or Equal to Prespecified Thresholds
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. The prespecified antibody threshold levels were as follows: ≥1:10, ≥1:20, ≥1:40, ≥1:80, ≥1:160, and ≥1:320.
Time frame: D1,29 Cohorts: Day 57 (28 days post dose 2), D1,57 Cohorts: Day 85 (28 days post dose 2)
Percentage of Participants With ELLA Titers Above or Equal to Prespecified Thresholds
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. The prespecified antibody threshold levels were as follows: ≥1:10, ≥1:20, ≥1:40, ≥1:80, ≥1:160, and ≥1:320.
Time frame: D1,29 Cohorts: Day 57 (28 days post dose 2), D1,57 Cohorts: Day 85 (28 days post dose 2)
Number of Participants With SAEs, MAAEs, AESIs, and AEs Leading To Early Termination From Day 1 to Day 240
A SAE was defined as any AE that resulted in death, was life-threatening, resulted in persistent disability/incapacity, or required inpatient hospitalization or prolongation of existing hospitalization. AEs potentially associated with mRNA vaccines and influenza vaccines were reported as AESIs. MAAEs were defined as AEs with medically attended visits including hospital, emergency room, urgent care clinic, or other visits (including phone/telehealth visits) to or from medical personnel for any reason, but did not fulfil seriousness criteria. A summary of all Serious Adverse Events and Other Adverse Events (non-serious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Day 1 to Day 240
Geometric Mean Titer of Antibody Response To HA Glycoprotein Measured By HAI Assay at Day 240
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Antibody titers were expressed as Geometric Mean Titers.
Time frame: Day 240
Geometric Mean Titer of Antibody Response to NA Glycoprotein Measured By ELLA at Day 240
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Antibody titers were expressed as Geometric Mean Titers.
Time frame: Day 240
Geometric Mean Fold Rise of Antibody Response to HA Glycoprotein Measured By HAI Assay at Day 240
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Geometric Mean Fold Rise was reported as a ratio to Day 1.
Time frame: Day 240
Geometric Mean Fold Rise of Antibody Response to NA Glycoprotein Measured By ELLA at Day 240
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Geometric Mean Fold Rise was reported as a ratio to Day 1.
Time frame: Day 240
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Percentage of Participants With Seroconversion of Antibody Response to HA Glycoprotein Measured By HAI Assay At Day 240
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Seroconversion was recorded if participant had pre-vaccination antibody titer \< LLOQ and a post-vaccination antibody titer ≥ 4 x LLOQ, or a pre-vaccination antibody titer ≥LLOQ and a ≥4-fold increase in post-vaccination antibody titer.
Time frame: Day 240
Percentage of Participants With Seroconversion of Antibody Response to NA Glycoprotein Measured By ELLA At Day 240
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. Seroconversion was recorded if participant had pre-vaccination antibody titer \< LLOQ and a post-vaccination antibody titer ≥ 4 x LLOQ, or a pre-vaccination antibody titer ≥LLOQ and a ≥4-fold increase in post-vaccination antibody titer.
Time frame: Day 240
Percentage of Participants With HAI Titers Above Or Equal To Prespecified Thresholds At Day 240
A serum HAI assay was used for measuring HA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. The prespecified antibody threshold levels were as follows: ≥1:10, ≥1:20, ≥1:40, ≥1:80, ≥1:160, and ≥1:320.
Time frame: Day 240
Percentage of Participants With ELLA Titers Above Or Equal to Prespecified Thresholds At Day 240
A serum ELLA assay was used for measuring NA-specific antibodies against the A/H5N1/Indonesia/5/2005 influenza strain. The prespecified antibody threshold levels were as follows: ≥1:10, ≥1:20, ≥1:40, ≥1:80, ≥1:160, and ≥1:320.
Time frame: Day 240
Geometric Mean Titer of Antibody Response Against HA Glycoprotein Measured By Microneutralization (MN) Assay
Neutralizing antibody response to H5 hemagglutinin was measured by MN assay. Antibody titers were expressed as Geometric Mean Titers.
Time frame: D1,29 Cohorts: Day 1, Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 1, Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Geometric Mean Fold Rise of Antibody Response to HA Glycoprotein Measured By MN Assay
Neutralizing antibody response to H5 hemagglutinin was measured by MN assay. Geometric Mean Fold Rise was reported as a ratio to Day 1.
Time frame: D1,29 Cohorts: Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Percentage of Participants With Seroconversion of Antibody Response to HA Glycoprotein Measured By MN Assay
Neutralizing antibody response to H5 hemagglutinin was measured by MN assay. Seroconversion was recorded if participant had pre-vaccination antibody titer \< LLOQ and a post-vaccination antibody titer ≥ 4 x LLOQ, or a pre-vaccination antibody titer ≥LLOQ and a ≥4-fold increase in post-vaccination antibody titer.
Time frame: D1,29 Cohorts: Day 29 (28 days post dose 1), Day 36 (7 days post dose 2), and Day 57 (28 days post dose 2), D1,57 Cohorts: Day 57 (56 days post dose 1), Day 64 (7 days post dose 2), and Day 85 (28 days post dose 2)
Percentage of Participants With MN Titers Above Or Equal To Prespecified Thresholds
Neutralizing antibody response to H5 hemagglutinin was measured by MN assay. The prespecified antibody threshold levels were as follows: ≥1:10, ≥1:20, ≥1:40, ≥1:80, ≥1:160, and ≥1:320.
Time frame: D1,29 Cohorts: Day 57 (28 days post dose 2), D1,57 Cohorts: Day 85 (28 days post dose 2)